ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ONCOLOGIC DRUGS ADVISORY COMMITTEE**
>
> **ENDPOINTS IN CLINICAL CANCER TRIALS**
>
> **AND**
>
> **ENDPOINTS IN LUNG CANCER CLINICAL TRIALS**
>
> Tuesday, December 16, 2003
>
> 8:05 a.m.
>
> Advisors and Consultants Staff Conference Room
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> PARTICIPANTS
>
> Donna Przepiorka, M.D., Ph.D.
>
> Johanna Clifford, M.S., RN, BSN, Executive Secretary
>
> MEMBERS:
>
> John T. Carpenter, Jr., M.D.
>
> Bruce G. Redman, D.O.
>
> Sarah A. Taylor, M.D.
>
> Otis W. Brawley, M.D.
>
> Stephen L. George, Ph.D.
>
> Bruce D. Cheson, M.D.
>
> Gregory H. Reaman, M.D.
>
> James. H. Doroshow, M.D.
>
> Pamela J. Haylock, RN (Consumer Representative)
>
> Alexandra M. Levine, M.D.
>
> Maria Rodriguez, M.D.
>
> CONSULTANTS (VOTING):
>
> Philip Bonomi, M.D.
>
> David Ettinger, M.D.
>
> Thomas Fleming, M.D.
>
> Bruce Johnson, M.D.
>
> David Johnson, M.D.
>
> Scott Saxman, M.D.
>
> PATIENT REPRESENTATIVES (VOTING):
>
> Michael S. Katz
>
> Sheila Ross
>
> ACTING INDUSTRY REPRESENTATIVE (NON-VOTING):
>
> Antonio Grillo-Lopez, M.D.
>
> GUEST SPEAKERS (NON-VOTING):
>
> Paul Bunn, M.D.
>
> Richard Gralla, M.D.
>
> FDA:
>
> Robert Temple, M.D.
>
> Richard Pazdur, M.D. (by telephone)
>
> Martin Cohen, M.D.
>
> Grant Williams, M.D.
>
> Patricia Keegan, M.D.
>
> Ning Li, Ph.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order and Introduction of the Committee,
>
> Donna Przepiorka, M.D., Ph.D. 4
>
> Conflict of Interest Statement,
>
> Johanna Clifford, M.S., RN, BSN 6
>
> **Endpoints in Clinical Cancer Trials**:
>
> Opening Remarks, Grant Williams, M.D. 9
>
> General Regulatory Background,
>
> Ann Farrell, M.D. 10
>
> Endpoints for Past Approvals,
>
> Ramzi Dagher, M.D. 16
>
> Selected Issues in Oncology Trial Design,
>
> Grant Williams, M.D. 22
>
> Clarification questions to Presenters 46
>
> Introduction of the Questions,
>
> Grant Williams, M.D. 78
>
> Questions for Discussion 80
>
> **Endpoints in Lung Cancer Clinical Trials**:
>
> Non Small Lung Cancer Regulatory Background,
>
> Martin Cohen, M.D. 190
>
> FDA/ASCO Non-Small Cell Lung Cancer Workshop Summary,
>
> Paul Bunn, M.D. 199
>
> Quality of Life and Patient Reported Outcomes
>
> as Endpoints in Clinical Cancer Trials,
>
> Richard Gralla, M.D.
>
> Clarification Questions to Presenters 228
>
> Open Public Hearing:
>
> Mr. Mark Scott 287
>
> Questions for Discussion 292
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. PRZEPIORKA: Good morning to all. I would like to call the meeting
> to order. This is a meeting that is covering no drug evaluations but,
> in fact, methods for drug evaluations. I think it is a good time for
> this talk because there are very new types of drugs coming out for
> which these issues may be very germane.
>
> I would like to start the meeting by an introduction of the committee
> members, if we could start with Dr. Grillo-Lopez and just go around.
> Let us know who you are and where you are from.
>
> DR. GRILLO-LOPEZ: My name is Antonio Grillo-Lopez. This is my first
> time sitting around this table. I am a hematologist/oncologist. I
> spent half of my career in industry and half in academia so I am
> hoping to make some positive contributions here. Thank you.
>
> DR. GEORGE: Stephen George, from Duke University.
>
> DR. CHESON: Bruce Cheson, Georgetown University, Lombardi
> Comprehensive Cancer Center.
>
> DR. DOROSHOW: Jim Doroshow, City of Hope Comprehensive Cancer Center.
>
> DR. RODRIGUEZ: Maria Rodriguez, M.D. Anderson Cancer Center in
> Houston, Texas.
>
> DR. BRAWLEY: Otis Brawley, Emory University, Winship Cancer Institute.
>
> MR. KATZ: Michael Katz. I am a 13-year myeloma survivor.
>
> DR. FLEMING: Thomas Fleming, University of Washington.
>
> DR. LEVINE: Alexandra Levine, University of Southern California,
> Norris Cancer Center.
>
> DR. REAMAN: Gregory Reaman, Children\'s Hospital and George Washington
> University.
>
> DR. PRZEPIORKA: Donna Przepiorka, University of Tennessee Cancer
> Institute.
>
> MS. CLIFFORD: Johanna Clifford, FDA, Executive Secretary to this
> meeting.
>
> MS. HAYLOCK: Pamela Haylock, oncology nurse and doctoral student in
> Galveston, Texas.
>
> DR. CARPENTER: John Carpenter, medical oncologist, University of
> Alabama at Birmingham.
>
> DR. REDMAN: Bruce Redman, University of Michigan Comprehensive Cancer
> Center.
>
> DR. TAYLOR: Sarah Taylor, University of Kansas Medical Center.
>
> DR. LI: Ning Li, FDA Biometrics.
>
> DR. WILLIAMS: Grant Williams, Deputy Director, Oncology Drug Products.
>
> DR. PRZEPIORKA: Thank you to all.
>
> DR. WILLIAMS: And on the phone, of course, is Dr. Pazdur.
>
> DR. PAZDUR: Hi. I hope you don\'t hear the dog barking.
>
> DR. WILLIAMS: I was going to say that this was the first time that Dr.
> Pazdur has ever been speechless\--
>
> DR. PAZDUR: And you love that, Grant!
>
> \[Laughter\]
>
> DR. PRZEPIORKA: Welcome and, Dr. Pazdur, thank you for joining us. We
> would like to move now to the reading of the conflict of interest
> statement.
>
> **Conflict of Interest Statement**
>
> MS. CLIFFORD: The following announcement addresses the issue of
> conflict of interest with respect to this meeting and is made a part
> of the record to preclude even the appearance of such at this meeting.
>
> Based on the agenda, it has been determined that the topics of
> today\'s meeting are issues of broad applicability and there are no
> products being approved at this meeting. Unlike issues before a
> committee in which a particular product is discussed, issues of
> broader applicability involve many industrial sponsors and academic
> institutions.
>
> All special government employees have been screened for their
> financial interests as they may apply to the general topics at hand.
> To determine if any conflict of interest existed, the agency has
> reviewed the agenda and all relevant financial interests reported by
> the meeting participants. The Food and Drug Administration has granted
> general matters waivers to the special government employees
> participating in this meeting who require a waiver under Title XVIII,
> United States Code Section 208. A copy of the waiver statements may be
> obtained by submitting a written request to the agency\'s Freedom of
> Information Office, Room 12A-30 of the Parklawn Building.
>
> Because general topics impact so many entities it is not prudent to
> recite all potential conflicts of interest as they apply to each
> member, consultant and guest speaker. FDA acknowledges that there may
> be potential conflicts of interest but, because of the general nature
> of the discussion before the committee, these potential conflicts are
> mitigated.
>
> With respect to the FDA\'s invited industry representative, we would
> like to disclose that Dr. Antonio Grillo-Lopez is participating in
> this meeting as the acting industry representative, acting on behalf
> of regulated industry. Dr. Grillo-Lopez is employed by Neoplastic and
> Autoimmune Disease Research.
>
> In the event that the discussions involve any other products of firms
> not already on the agenda for which FDA participants have a financial
> interest, those participants\' involvement and their exclusion will be
> noted for the record. With respect to all other participants, we ask
> in the interest of fairness that they address any current or previous
> financial involvement with any firm whose product they may wish to
> comment upon. Thank you.
>
> DR. PRZEPIORKA: Thank you. The first item on the agenda then is the
> opening remarks. Dr. Pazdur, will you be making those opening remarks?
>
> DR. PAZDUR: Why don\'t we have Dr. Williams do that?
>
> DR. PRZEPIORKA: Dr. Williams?
>
> **Opening Remarks**
>
> DR. WILLIAMS: Just a few remarks. First of all, we are just very
> appreciative of all of your presence here today to give us advice. I
> think we are actually pretty excited about the whole process of
> getting endpoints out and discussed. For us it is a very difficult
> problem. We have multiple end of Phase II meetings, multiple different
> clinical settings and trying to be consistent with the endpoints that
> we require for drug approval across these many settings is quite a
> challenge.
>
> This reflects a process that we started about a year ago of looking
> into endpoints, or even before that internally, and our plan in this
> process is to have a series of workshops, a series of ODAC meetings on
> specific clinical settings. We have engaged the National Cancer
> Institute, AACR and ASCO to help us with picking experts in the field
> to do workshops on very specific endpoint settings and we plan to
> follow these with ODAC meetings, and this is the first after these
> workshops. We had a lung cancer workshop in I think March or April and
> then this afternoon we plan to have discussions on lung cancer
> endpoints.
>
> As we thought about moving toward creating a guideline or guidances we
> also considered that we should have some sort of a broad discussion to
> sort of set the foundation, and then also to lay the foundation for a
> background section of the guidance. So, that is what we are trying to
> do here this morning. This afternoon we would like some voting on some
> specific questions. As we go along we will try to determine those that
> seem appropriate for voting.
>
> But this morning it is more of a broad discussion that we are looking
> for. What are those principles that we should be evaluating as we move
> forward to evaluate endpoints? What are those value judgments globally
> so that we can then apply them to specific instances, specific
> clinical settings?
>
> So, we look forward to the discussion today. I think it is going to be
> very interesting and fun. The first talk will be by Dr. Farrell, who
> will talk about regulatory considerations with endpoints in oncology.
>
> **General Regulatory Background**
>
> DR. FARRELL: Good morning, everyone.
>
> \[Slide\]
>
> I am here to discuss regulatory considerations for endpoint used for
> approval. Requirements for marking approval have been codified and
> further defined in response to perceived need. Prior to 1938 there
> were no requirements for marketing approval. As a result of the
> sulfonamide tragedy, Food, Drug and Cosmetic Act required
> manufacturers to provide evidence that their product was safe for
> marketing.
>
> In 1962 Congress, concerned about misleading and unsupported claims
> being made about marketing products, amended the FDAC to require that
> manufacturers provide evidence that the product was effective. This
> was to demonstrate substantial evidence of effectiveness. In the
> practice the agency has understood that adequate and well controlled
> investigations or substantial evidence of effectiveness means that
> efficacy must be demonstrated in at least two adequate and
> well-controlled trials.
>
> In 1997 Congress passed the Food and Drug Modernization Act which
> stated that the requirement for substantial evidence of effectiveness
> could constitute one adequate and well-controlled trial plus
> supportive evidence.
>
> \[Slide\]
>
> There are two basic mechanisms for approval, regular and accelerated
> approval. The requirement for adequate and well-controlled studies is
> the same for both mechanisms. The regular approval mechanism provides
> for approval based on clinical benefit or on an established surrogate
> for clinical benefit.
>
> The clinical benefit endpoint is usually an endpoint thought of as
> reflecting quality or quantity of life. In oncology, examples of these
> endpoints include survival or improvement in a disease-related
> symptom.
>
> Accelerated approval is a mechanism for those products designed to be
> used for the treatment of serious and life-threatening illness. The
> mechanism provides for approval based on a surrogate that is deemed
> reasonably likely to predict clinical benefit. The new therapy must
> provide an advantage over available therapy, and that can be the
> ability to treat patients who are unresponsive to or intolerant of
> available therapy, or it can be a therapy that provides an improvement
> patient response over available therapy.
>
> \[Slide\]
>
> The accelerated approval mechanism, as I said, is based on a surrogate
> endpoint believed to be reasonably likely to predict clinical benefit
> or it can be based on an effect on a clinical endpoint other than
> survival or irreversible morbidity. In any case, post-marketing
> studies are required to determine clinical benefit.
>
> \[Slide\]
>
> The evidence for accelerated approval should be substantial evidence
> from well-controlled clinical trials regarding a surrogate endpoint,
> not borderline evidence regarding a clinical benefit endpoint in a
> poorly conducted trial.
>
> \[Slide\]
>
> As I stated before, ideally the substantial evidence should come from
> more than one adequate and well-controlled investigation. The passage
> of FDAMA allows us to consider the evidence from one adequate and
> well-controlled trial plus other supportive evidence. The
> effectiveness guidance discusses supportive evidence and the
> characteristics of the single trial.
>
> \[Slide\]
>
> This slide outlines examples of situations where extrapolation from
> existing studies combined with a single clinical trial could support a
> new indication or new drug application. In pediatrics, if there is
> bioequivalence in modified-release dosage form, for different doses or
> for different regimens.
>
> \[Slide\]
>
> The effectiveness guidance lists the characteristics of a single trial
> supporting approval. In general these trials should be large,
> multi-center. The primary results should show consistency across study
> subsets. This could be thought of as various age categories. The study
> should be large enough so it could be considered to have multiple
> studies in a single study, and that could be done through a factorial
> design. And, the results from secondary endpoints, if positive, could
> also be supportive for the use of that single trial. The primary
> endpoints should show statistically persuasive results.
>
> \[Slide\]
>
> In oncology we have accepted oncology supplemental applications based
> on a single trial supported by data in a different stage of disease.
> The FDA has approved cancer drug supplements in an NDA in an adjuvant
> setting when there has been a single trial plus supportive evidence in
> a metastatic setting. One example of this would be Irimidex from the
> adjuvant treatment of women who are postmenopausal. We have also
> accepted applications in first-line settings with one trial when there
> has been supportive evidence based on approval in a refractory
> setting. An example of that is Gleevec.
>
> In addition, we have accepted applications for the use of products in
> combination therapy when there has been an approval in a monotherapy
> setting. An example of that would be Zoloda in combination with
> Taxotere when Zoloda had already received approval as monotherapy in
> the treatment of breast cancer.
>
> Theoretically, we could accept an application and approve it based on
> a single trial in a second cancer if there was already an approval in
> a closely related cancer.
>
> \[Slide\]
>
> In summary, the agency has some flexibility in judging what
> constitutes adequate information to meet its requirements of
> substantial evidence from adequate and well-controlled investigations.
> However, all products must demonstrate that they are both safe and
> effective. Because oncology is a serious and life-threatening illness
> we have actually two mechanisms for approval, regular and accelerated
> approval.
>
> Accelerated approval can be based on a surrogate endpoint with planned
> completion of a post-marketing study to verify the clinical benefit.
> Approval can also be based on one trial plus supportive evidence.
> Endpoints differ for different approval mechanisms. Drs. Dagher and
> Williams will discuss this issue in greater detail. Thank you.
>
> DR. PRZEPIORKA: Thank you very much, Dr. Farrell. Next, Dr. Dagher
> will be talking about endpoints for past approvals.
>
> **Endpoints for Past Approvals**
>
> DR. DAGHER: Good morning.
>
> \[Slide\]
>
> In the next few minutes I would like to summarize endpoints used for
> approval of oncology drugs.
>
> \[Slide\]
>
> This slide provides a summary of endpoints commonly used in the
> oncology clinical trial setting. Survival has been considered the gold
> standard in many settings and provides an unambiguous endpoint that is
> easily measured. Time to progression may provide several advantages as
> well as challenges, which Dr. Grant Williams will discuss later this
> morning. Disease-free survival is an endpoint utilized in the adjuvant
> setting. Objective tumor response is an endpoint that measures an
> effect largely related to treatment, independent of the natural
> history of the disease. Tumor-related symptoms and patient-reported
> outcomes are quite relevant from the patient\'s perspective.
>
> \[Slide\]
>
> For the purposes of regular approval we have considered improvements
> in survival or tumor-related symptoms as evidence of clinical benefit.
> In the adjuvant breast cancer setting we have also considered
> disease-free survival as evidence of clinical benefit.
>
> \[Slide\]
>
> In some settings, where tumor shrinkage has been associated with
> symptom benefit or survival, we have considered objective tumor
> response as an endpoint supporting regular approval. In leukemias and
> some solid tumors, such as testicular cancer, durable or complete
> responses have been utilized for this purpose. In the case of hormonal
> therapies for breast cancer partial responses have been considered
> evidence of clinical benefit.
>
> \[Slide\]
>
> A summary of endpoints and approvals from our Division, published in
> [The Journal of Clinical Oncology]{.underline}, reveals that more than
> half of the approvals have been based on endpoints other than
> survival. This applies to all approvals as well as those excluding
> accelerated approval, a setting in which response rates are often
> utilized.
>
> \[Slide\]
>
> The following table, adapted from this publication, illustrates the
> diversity of endpoints used. For approvals between 1990 and the end of
> 2002 in the Division of Oncology Drug Products survival was used in 18
> of 55 approvals. Response rate, either alone or in conjunction with
> improvements in tumor symptoms or time to progression, was utilized in
> 26 approvals. As discussed, improvement in tumor-related symptoms has
> been used as a basis for approval. Disease-free survival or other
> endpoints were used infrequently.
>
> \[Slide\]
>
> The first two bullets of this slide provide examples where improvement
> in tumor-related symptoms was the basis for regular approval. In
> patients with advanced hormone refractory prostate cancer a pain scale
> was utilized to evaluate mitoxantrone plus prednisone versus
> prednisone alone.
>
> Photofrin was evaluated for obstructive esophageal lesions. In this
> case a dysphasia scale was used with supportive evidence for objective
> tumor response.
>
> In the case of several bisphosphonates approval was based on
> evaluation of a number of skeletal related events, including
> pathologic fracture, radiation to bone, surgery to bone or spinal cord
> compression. In the case of prostate cancer, pain requiring change and
> anti-neoplastic therapy was also a component of the evaluation.
>
> \[Slide\]
>
> As Dr. Farrell mentioned, accelerated approval is based on a surrogate
> endpoint reasonably likely to predict clinical benefit. In our
> experience, most of the accelerated approval indications were based on
> an evaluation of objective tumor response in studies without an active
> comparator, that is, single-arm studies or those comparing two dose
> levels of the drug in question. However, randomized trials were
> conducted in some settings with an active or placebo comparator,
> allowing for evaluation of time to event endpoints such as
> disease-free survival or time to progression. Some examples are shown
> here.
>
> \[Slide\]
>
> As was also discussed, accelerated approval requires further
> evaluation of the drug to confirm clinical benefit. Therefore, two
> strategies have emerged for approaching accelerated approval and
> subsequent confirmatory evaluation of clinical benefit.
>
> With the first strategy accelerated approval is based on response rate
> evaluated in single-arm studies of refractory patients and
> confirmatory studies are conducted in related populations such as
> those with less refractory disease. This approach has the potential
> advantage of allowing rapid completion of single-arm studies.
>
> \[Slide\]
>
> However, accelerated approval may influence the ability to enroll
> patients for confirmatory studies. Furthermore, it has become more and
> more challenging to evaluate marginal benefits in more and more
> refractory populations, and findings in refractory populations may not
> be relevant to other populations which may benefit from the drug. In
> fact, evaluation in refractory populations first may lead us to miss
> an active drug. The single-arm component of the strategy is associated
> with its own limitations: First, an inability to evaluate time to
> event endpoints in a non-randomized setting and difficulty in
> completely assessing the toxicity profile.
>
> \[Slide\]
>
> The second strategy for accelerated approval depends on evaluation of
> a surrogate endpoint and an interim analysis of a randomized study,
> with subsequent evaluation of clinical benefit in the same trial using
> a final analysis. This approach allows for evaluation of the same
> population for accelerated approval and regular approval and
> facilitates completion of a confirmatory study. The randomized setting
> allows comparison to available therapy and a thorough evaluation of
> the toxicity profile.
>
> \[Slide\]
>
> However, this approach may require more time and patients than
> single-arm studies and accelerated approval could still influence
> completion of the study.
>
> \[Slide\]
>
> In summary, improvements in survival or tumor-related symptoms have
> been considered evidence of clinical benefit. In some settings
> durable, complete or partial responses have been considered endpoints
> supporting regular approval. Finally, objective tumor responses in
> single-arm trials have been the basis of approval in most cases of
> accelerated approval. Thank you.
>
> DR. PRZEPIORKA: Thank you Dr. Dagher. We are going to hold questions
> until the end of the presentations and Dr. Williams will now talk to
> us about selected issues in oncology trial designs that are pertinent
> to this morning\'s topic.
>
> **Selected Issues in Oncology Trial Design**
>
> DR. WILLIAMS: Well, thank you, Dr. Przepiorka.
>
> \[Slide\]
>
> Members of the committee, ladies and gentlemen, what I would like to
> do is to first review the selected issues in oncology trial design
> before we go to discussing specific problems and your recommendations
> for our further deliberations.
>
> \[Slide\]
>
> Here is the outline of my presentation. I will begin with several
> difficulties we face in oncology that are well-known to all of you,
> and I will briefly discuss the non-inferiority trial design and the
> difficulties we face with this approach. Finally, I will discuss time
> to progression, expanding upon some of the regulatory issues presented
> by Dr. Farrell and Dr. Dagher, especially the issues relating to the
> meaning of clinical benefit and also surrogates for clinical benefit.
> Then I will discuss the pros and the cons of TTP as an approval
> endpoint.
>
> \[Slide\]
>
> During our end of Phase II meetings with sponsors we often ask whether
> trials can be blinded and we are usually told they cannot. These are
> the reasons that we are told, first, that there are toxic side effects
> that are said to unmask both the physician and the patient. Second,
> the investigators adjust doses based on drug-specific toxicities and
> the investigators believe they need to know drug assignment to do this
> safely. These seem to be very difficult problems, although I think
> maybe the first point might bear some further discussion\--has anyone
> actually studied the degree of unmasking by side effects of oncology
> drugs? As we move to new potentially targeted therapies and to oral
> therapies we should consider whether we can blind more trials.
>
> \[Slide\]
>
> Placebos are widely used in many areas of drug development. The use of
> the placebo is seldom feasible in evaluation of advanced cancer. There
> are some cancer settings where placebo use may be possible. Blinded,
> placebo-controlled studies might be performed in some early disease
> settings where no effective treatments exist. In advanced settings the
> so-called add-on design can allow placebo use comparing drug A plus
> placebo to drug A versus drug B. In some settings it may be reasonable
> to continue placebo and drug B even beyond progression. An example of
> this were the bisphosphonate trials which assessed effects on bone
> morbidity even after chemotherapy was changed.
>
> \[Slide\]
>
> So, the unfortunate result of not having blinded, placebo-controlled
> studies is that we must use controls which are active. If we use a
> superiority trial design the new drug must beat the active drug, or we
> can use an add-on design. Not surprisingly, many trials for drug
> approval are based on drug combinations and add-on designs. Certainly,
> this can lead to toxic combinations.
>
> The other possibility is to do non-inferiority studies. As I will
> discuss, these tend to be very large trials and the quality of
> historical data in oncology is frequently insufficient to support this
> approach. Again unfortunately, in this setting where blinded,
> placebo-controlled trials may not be feasible it is very difficult to
> demonstrate the new drugs are less toxic but have similar efficacy to
> an approved drug.
>
> \[Slide\]
>
> The frequent use of drug combinations in oncology also present
> regulatory challenges. Since marketed approval is for a single drug
> rather than a combination of drugs, trials supporting regulatory
> approval need to isolate the effectiveness of the proposed agent.
> Evidence is needed showing not only the effectiveness of the
> combination but also establishing that there is a contribution of the
> new drug to that regimen.
>
> \[Slide\]
>
> Now I would like to turn to the topic of non-inferiority. Obviously, I
> am not a statistician but I will try to share with you what I
> understand about it. The reason we are not having statisticians do
> this discussion is because we don\'t want to be at this a whole day on
> non-inferiority.
>
> \[Laughter\]
>
> \[Slide\]
>
> So, here is the way I see it. First I want to review some
> non-equivalent words. I don\'t know if anybody caught the pun in the
> title here. First of all, we love superiority. We love to hear the
> word superiority; we love superiority trials. Equivalence is a word
> you should never say to a statistician, but I was corrected on this,
> it is all right to say it to a Bayesian.
>
> \[Laughter\]
>
> Equivalence is something that can never be proven. Because we cannot
> show equivalence we rule out inferiority by a prespecified margin. We
> call this demonstration of non-inferiority. A very important
> regulatory concept is that proof of non-inferiority does not
> necessarily prove efficacy, and we will discuss this a bit further. I
> think the use of these words in our oncology journals can create
> serious misconceptions. A common problem is the assumption in oncology
> journals that no statistical difference is the same as equivalence or
> non-inferiority.
>
> \[Slide\]
>
> This slide lists the steps needed to perform a non-inferiority
> analysis. Just the number of steps should suggest the complexity of
> this process and the potential for error. In this example we are
> demonstrating that drug B is effective. In order to do this we refer
> to the effect of drug A observed historically in randomized studies. I
> think I have these steps out of order; I will stick to the third one.
>
> We then prospectively identify a margin that includes an acceptable
> fraction of drug A\'s efficacy. We randomized drug A versus drug B. We
> prove that drug B is no worse than drug A by that margin. Probably the
> step that is most often ignored is that we determine that the
> constancy assumption is valid. Invalid assumptions at any stage of
> this process could lead to a false result and this is why
> non-inferiority studies are not FDA\'s favorite trial design.
>
> \[Slide\]
>
> The important constancy assumption is the historically observed drug
> effect of the active control drug also exists in the current
> non-inferiority trial and in the population. The problem is that
> conditions are never the same in historical trials and a current
> trial. Differences include different populations; differences in
> supportive care; differences in availability of new drugs that can be
> taken after failing, including the possibility of crossover. Finally,
> the designs can be different with different frequency of follow-up.
> So, any of these could change the sensitivity of the trial to detect
> the treatment effect. The serious result of violating that constancy
> assumption could lead to the approval of what has been termed a toxic
> placebo.
>
> \[Slide\]
>
> This is another property of non-inferiority trials that Dr. Temple has
> noted, sloppiness obscures the observations of differences. For
> superiority trial designs sloppiness obscures efficacy but for
> non-inferiority trials sloppiness could lead to a false efficacy
> claim. Again, this is why we like superiority trials. I think that is
> a common theme you will be hearing here perhaps.
>
> \[Slide\]
>
> A critical problem in doing non-inferiority studies in oncology is the
> paucity of studies that are available to determine the historical
> effect of the active control drug. We basically strike out at the
> first step of this process. What we really need is multiple trials
> showing a consistent, large effect and we need to perform a
> meta-analysis of those trials which provides us with a dependable
> effect precisely estimated.
>
> The real situation in oncology, almost without exception, is that we
> have one or two rather small trials with small effects and with
> marginal statistical significance. This leads to small historically
> documented effect sizes; small margins; and very large non-inferiority
> studies. The process becomes even more complicated when we consider
> drug combinations and the contribution of individual drugs to
> historical effect.
>
> The reason I am presenting this is that I think this is such a complex
> topic and people don\'t understand why you don\'t do a non-inferiority
> study. I don\'t think you can say it without trying to go through all
> these steps, but it is basically just not possible in many of our
> settings at least using the primary endpoints.
>
> \[Slide\]
>
> Now I would like to turn to endpoints and surrogates. Dr. Farrell and
> Dr. Dagher provided an overall review of regulations on oncology
> endpoints. So, I want to briefly review the history of regulatory
> standards for efficacy endpoints.
>
> The 1962 amendments to the FD&C Act simply stated that a drug must be
> shown to have the effect claimed in the label. However, subsequent
> judicial decisions established that effectiveness meant that the drug
> must have clinical meaning. In the 1970s marketed applications for
> cancer drugs were approved primarily based on objective response rates
> and on rather minimal activity we would say today.
>
> However, based on advice from ODAC in the late \'70s and early \'80s,
> FDA determined that the response rate should generally not be the sole
> basis for drug approval because the possible benefits associated with
> tumor shrinkage did not necessarily justify treatment with toxic
> anti-cancer drugs. Acceptable endpoints for drug approval were
> improvement in survival or improvement in physical functioning or
> relief of pain.
>
> As Dr. Dagher discussed, in the 1990s FDA struggled with the
> difficulty of measuring patient benefit and in some settings found
> various surrogates to be adequate in specific clinical situations.
>
> \[Slide\]
>
> There are various definitions for a surrogate. In this context we will
> use the definition from Dr. Temple. A surrogate endpoint of a clinical
> trial is a laboratory measurement or a physical sign used as a
> substitute for a clinically meaningful endpoint that measures directly
> how a patient feels, functions or survives. Changes induced by a
> therapy on a surrogate endpoint are expected to reflect changes in the
> clinically meaningful endpoint.
>
> \[Slide\]
>
> In various settings for many years FDA has based regular drug approval
> on surrogate endpoints which were judged by FDA and experts in the
> field to be reliable indicators of clinical benefit. Examples outside
> the field of oncology included blood pressure, blood sugar and blood
> cholesterol.
>
> \[Slide\]
>
> It may be useful to review where we have used the term surrogate in
> oncology. In accelerated approval the surrogate need only be
> reasonably likely to predict benefit. Obviously, this is a lower
> standard than the usual use of the word surrogate.
>
> We have discussions with statisticians\--Dr. Fleming, regarding
> validated surrogates and we expect to prove quantitatively the
> relationship between the surrogate and the established endpoint.
> Unfortunately, in oncology we have very few settings where we
> quantitatively validate the surrogate. It would be easier to validate
> surrogates if we had more effective drugs with large effects to
> compare surrogate and clinical benefit. Finally, we have surrogates
> that have been used to support regular approval of cancer drugs in
> very specific settings, usually based on clinical inference and
> judgment that these surrogates relate to clinical benefit.
>
> \[Slide\]
>
> At the recent colon cancer workshop Dr. Fleming reviewed Prentice\'s
> criteria for strictly validated surrogates. The surrogate endpoint
> must be correlated with the clinical outcome. The surrogate must fully
> capture the net effect of the treatment on that clinical outcome.
>
> \[Slide\]
>
> In the clinical setting this would involve meta-analyses of clinical
> trials and a comprehensive understanding of the disease and the
> intended an unintended effects of drugs. As I stated, where possible
> this is the kind of evidence we would like for a surrogate endpoint.
> The question for us today is what should we do with endpoints we have
> today? What can we use for approval endpoints today and in what
> settings can we use them? And, what can we do to gather more data for
> the future?
>
> \[Slide\]
>
> As we looked at TTP to ask whether it is an acceptable surrogate in
> various settings, I propose that the question we should ask should not
> be whether an improvement in TTP has clinical meaning. I suggest that
> nobody in the field of oncology really doubts that it is good to delay
> the growth of cancer. That is not really the question that we need to
> answer.
>
> \[Slide\]
>
> The real question is whether you can reliably measure TTP and, if you
> can, what does it mean? How much delay in progression is worth how
> much toxicity? With survival we seldom quibble about the size of the
> effect. Given the low statistical power of our studies, a
> statistically convincing survival benefit is generally considered to
> be worth the toxicity of treatment. However, can we say the same for
> the delay in TTP? That is, when progression is determined by only
> images on a scan. So, the real question is how do we trade off a TTP
> benefit compared to drug toxicity?
>
> Another question is the relative value of treatments evaluated by
> different endpoints. When a well-established survival benefit exists
> for an approved drug what is the meaning of the claimed TTP effect for
> an investigational drug? Although two treatments are not required to
> have equal efficacy this is, nonetheless, an important consideration
> for us.
>
> \[Slide\]
>
> FDA\'s approach to endpoints for hormonal treatment of cancer
> illustrates how clinical judgment has played a role in the acceptance
> of surrogates for regular drug approval. For many years these drugs
> have been approved primarily based on comparison of response rates
> with two reasonably large, randomized, controlled studies. TTP and
> survival were assessed as secondary endpoints. Many hormonal drugs
> have been approved with this approach. I think that everybody is
> satisfied that we approved effective drugs through this approach.
>
> So, what allowed this approach? These are what I believe are the
> critical factors. We have a long experience with tamoxifen and,
> despite little data with regard to a survival or TTP benefit,
> tamoxifen was widely observed to provide benefit to patients. The main
> indicator of activity was response rate. Given the non-toxic nature of
> the drugs and similar mechanisms of action, response rates seemed a
> reliable indicator of clinical benefit in this setting.
>
> \[Slide\]
>
> Four years ago at ODAC we discussed TTP as an approval endpoint for
> first-line cytotoxic treatment of breast cancer. The committee was not
> supportive of TTP for regular approval but did suggest its use for
> accelerated approval. Prominent in the ODAC deliberations was whether
> the standard treatment doxorubicin produces a survival effect and, if
> so, what size is that benefit. Committee members noted that current
> treatments only produce small TTP effects and they questioned whether
> there was or was not a correlation between TTP and survival, whether
> it was reliable. As I note in later discussion, I think this question
> needs to be carefully evaluated because of the under-powered nature of
> most of our studies.
>
> Questions were also raised about the reliability of TTP measurement
> and also a claim that in order to measure TTP accurately frequent
> scans would be needed. So, the ODAC criticisms were varied and they
> addressed the data available at the time in the specific cancer
> setting.
>
> \[Slide\]
>
> So, I would like to take a closer look at TTP. First of all, what is
> TTP? The basic definition is time from randomization to documented
> progression. However, there are very many different definitions of TTP
> with a lot of different details, such as how do you handle missing
> data and how to censor. If TTP is to be used as an important endpoint
> there should be careful agreement between FDA and the sponsor on the
> protocol, case report form and the statistical analysis plan.
> Difficult issues include how to follow the patient for new lesions and
> how to define and validate progression of non-measurable disease.
>
> \[Slide\]
>
> I want to mention three TTP-like endpoints that we frequently
> encounter, time to progression, progression-free survival and time to
> treatment failure. For TTP the measured event is progression. TTP may
> be thought of as a measurement of anti-tumor activity. Patients going
> off study for toxicity and non-tumor deaths are not counted as events.
> Note that for non-tumor deaths censoring occurs at the last visit
> where TTP was evaluated. This censoring makes the assumption there is
> no relation between death and progression, an assumption that might be
> questioned.
>
> \[Slide\]
>
> With progression-free survival all deaths are counted as progression
> events. Dr. Fleming suggested at the recent colon cancer workshop if
> TTP is being considered as a clinical benefit surrogate, perhaps the
> deaths should be counted. FDA has often counseled sponsors to keep TTP
> and death separate however, that is, to measure TTP without the deaths
> and to measure deaths in the survival analysis. The main concern with
> including deaths is that patients lost to follow-up will subsequently
> be counted as progression events at the time of death. In such a
> scenario sloppy progression to follow-up leads to longer progression
> times and asymmetric follow-up of such cases could lead to a false
> result. If deaths are included in the analysis, then careful symmetric
> follow-up is needed. Perhaps we need analysis rules to deal with
> patients who have inadequate follow-up.
>
> \[Slide\]
>
> Time to treatment failure is a composite endpoint measuring time from
> randomization to discontinuation of treatment for any reason,
> including progression, treatment toxicity and death. Because it
> combines elements of safety and efficacy, TTF is not an acceptable
> endpoint for documenting efficacy. Time to treatment failure has not
> supported drug approval.
>
> \[Slide\]
>
> Let\'s look more closely at TTP as a potential regulatory endpoint.
> Here as some of the positive qualities of TTP. TTP is measured in all
> patients and might, therefore, be a better measure of overall benefit
> than response. TTP does not require massive tumor shrinkage and might
> be a better measure for metastatic agents.
>
> From a practical standpoint, progression is often the reason
> oncologists change therapy. Therefore, an advantage of TTP is that TTP
> is measured before patients cross over to other therapies. This is of
> growing importance as we develop more effective drugs. Moreover,
> because progression often occurs months to years before death much
> smaller studies may be needed to study TTP than survival and this can
> vary dramatically with the different diseases.
>
> Finally, some would argue that delaying progression has face validity
> as an indicator of benefit. The benefit seems obvious because
> progression is a necessary step between cancer growth, patient
> morbidity and death.
>
> \[Slide\]
>
> But here are some problems with TTP. It has been said that it may not
> correlate with survival. It is an indirect measure of clinical
> benefit, sometimes reflecting minor changes on a radiograph.
> Therefore, small differences in TTP may be of unclear clinical value,
> especially when one is evaluating toxic treatments.
>
> There are obvious concerns relating to ascertainment bias in unblinded
> trials, and there are concerns regarding the reliability of a small
> effect with the kind of trials we have today with monitoring schedules
> which may vary from patient to patient. Finally, careful assessment of
> progression at frequent intervals is labor intensive and expensive.
>
> \[Slide\]
>
> We encounter difficulties in determining the exact relationship
> between TTP and survival. First of all, there are many different
> cancer settings so the database for any one setting may not be large
> and it isn\'t clear when you can combine data across different
> cancers. Secondly, unfortunately, we don\'t have many treatments that
> produce large survival effects.
>
> A fundamental difficulty is that there is always more statistical
> power for the analysis of TTP than survival. On this basis alone even
> if TTP were a perfect surrogate one would expect some studies to show
> a statistically positive TTP benefit without a statistically positive
> survival benefit. Oncology studies are virtually never large enough to
> rule out a meaningful survival effect and, thus, individually cannot
> establish a lack of correlation.
>
> Finally, there is the crossover issue. Even if TTP were a perfect
> surrogate for survival, crossover to other effective therapies could
> prevent detection of a potential benefit.
>
> In summary, with the trials of the size we usually see in oncology or
> therapies of only marginal benefit it would be difficult to determine
> the exact relationship between TTP and survival.
>
> \[Slide\]
>
> In reviewing these slides from the 1999 ODAC, I came upon this one.
> Dr. Johnson I thought did a really good job of summing up a comparison
> of survival and TTP. Survival time is precisely determined regardless
> of follow-up. Survival is a known entity. On the negative side,
> survival takes longer to assess, needs larger trials and its benefit
> can be obscured by secondary therapy.
>
> \[Slide\]
>
> TTP is only a surrogate, not a direct measure of clinical benefit.
> Later today during your deliberations we want to hear your thoughts on
> the important factors FDA should consider when evaluating TTP as a
> surrogate for clinical benefit in specific settings. For instance,
> would TTP be more acceptable in cancer settings where symptoms occur
> at the time of or soon after progression? What TTP benefit increment
> would be persuasive? How important is the toxicity of treatment in
> evaluating a TTP benefit? Finally, to what extent is the benefit of
> other available drugs important? For instance, what if other drugs
> produce a substantial survival benefit?
>
> One approach to the problem of TTP measurement has been to convert TTP
> to a direct measure of clinical benefit by measuring time to worsening
> of cancer symptoms. For years FDA has suggested this endpoint to
> sponsors at the end of Phase II meetings. However, sponsors and
> investigators have cited several problems with this approach. First,
> there is the ever-present problem of lack of blinding and potential
> bias thus the endpoint may not be reliable. Another problem is the
> usual delay between the time of objective progression and the onset of
> cancer symptoms. Often alternative treatments are begun before
> reaching the symptom endpoint. At our colon cancer workshop Dr.
> Langdon Miller presented data suggesting that in colon cancer there is
> a fairly long time lag between progression and onset of symptoms. When
> alternative treatments are begun prior to symptom progression the
> issue of confounding effects arises, just as it does in analysis of
> survival.
>
> \[Slide\]
>
> We must remember a critical difference between analyses of survival
> and tumor progression. The date of death, represented by the star in
> this cartoon, will not change regardless of the evaluation schedule or
> censoring. For progression measurement, however, the date we assign
> for progression is usually the date of a scheduled visit occurring
> some time after the actual progression date. It should not be
> surprising that assessing progression at longer intervals leads to
> longer time to progression and that asymmetry in this process could
> lead to bias.
>
> \[Slide\]
>
> With measurements repeated over many visits assessment of TTP by
> traditional methods is difficult and labor intensive. Many problems
> are encountered by FDA during reviews such as not all lesions being
> followed, or extra scans being performed, or measurements being
> missing. So, how do you assure equal measurement? How do you assess
> the impact of bias? How do you verify progression of evaluable disease
> by unblinded investigators? These are the difficult issues for review
> of TTP data.
>
> \[Slide\]
>
> One approach to making progression assessment practical and reliable
> would be to consider different progression endpoints. An approach that
> seems worthy of research is to assess progression at only a single
> time point. This would considerably decrease the burden in the amount
> of data collected and eliminate the concern of time-related assessment
> bias. Scans would need to be evaluated only at baseline and either to
> document progression for that time or at the prespecified time to
> document stable disease.
>
> \[Slide\]
>
> Progression measured at a single point would be much easier to audit
> and verify, needing only two sets of scans per patient and
> time-related bias, as mentioned, would be minimized if not eliminated.
>
> So, I think research into approaches such as this would be of great
> interest to identify the benefits and problems. In this case you would
> certainly lose some statistical power, requiring larger studies. There
> would be concern that you would miss a transient TTP benefit if you
> hit the wrong point with your single time analysis, and we would lose
> the information we are used to seeing about other parts of the curve,
> such as the early effects or the potential benefit of a plateau.
>
> \[Slide\]
>
> In conclusion, here are some issues you may wish to consider in your
> deliberations. As FDA proceeds with the workshops and meetings on
> endpoints for cancer treatment settings, is TTP ready for active
> consideration as a drug approval endpoint? If so, what are the factors
> that determine the acceptability of TTP as a drug approval endpoint?
> What amount of TTP evidence would be needed to support a TTP claim,
> such as number of trials, value, magnitude and precision of TTP
> benefit?
>
> \[Slide\]
>
> And, can we improve our approach? Do we need research on novel
> progression endpoints such as a single point analysis? Do we need
> research on the association between TTP and survival data to validate
> TTP as a survival surrogate? Should we develop an approach to TTP
> endpoint definition and censoring methods that are standard? Do we
> perhaps need a separate workshop just to concentrate on TTP
> methodology? Can more trials be blinded? Does independent blinder
> radiologic review improve endpoint assessment? And, can symptoms be
> incorporated into the endpoint?
>
> So, this ends my presentation. I think what we will do is take
> questions from our seats and just briefly introduce the questions at
> the beginning of the question discussion rather than to do it now. How
> long do we have for questions?
>
> **Clarification Questions to the Presenters**
>
> DR. PRZEPIORKA: Two hours, just for clarification or the actual
> questions? Until the break\--about 20 minutes. We have the floor open
> now for questions for the presenters for this morning.
>
> I have a question for Dr. Williams. Just for a point of clarification,
> for non-inferiority you are not truly looking for non-inferiority per
> se in terms of the response but it has to be non-inferior in terms of
> its treatment effect as well as less toxic to be a real winner in that
> sort of design.
>
> DR. WILLIAMS: Well, let me start with just non-inferiority in general.
> It just means that you have met your margin. Okay? Non-inferiority for
> the FDA means that you have met your margin and that margin means the
> drug works. It is a separate judgment about whether you are less
> toxic; I mean about the risks and benefits. But there wouldn\'t be a
> direct requirement to be less toxic from our regulations, I don\'t
> think.
>
> DR. PAZDUR: I think a lot of people confuse that issue of toxicity and
> non-inferiority since several applications came in dealing with
> perceived less toxic drugs and comparing them to a standard drug. But,
> as Grant said, the toxicity evaluation is different. Many times what
> we actually see is not really less toxic drugs but a different
> spectrum of toxicity, and that is another thing that people have to
> consider also when they are evaluating toxicity.
>
> DR. WILLIAMS: We have never applied this approach but I know I have
> heard Dr. Fleming talk about it and we have talked about it before,
> you could always have the toxicity affect your margin. That means you
> might be willing to accept less proof of efficacy if you knew it was
> less toxic. But that would be involved in the judgment process.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: The grim reality of non-inferiority studies is that we
> usually set a margin at something like preserving half of what we
> think the effect of the drug is. That is not very gratifying. I mean,
> you would hate to lose half of the valuable effect and, yet, if you
> explore sample sizes it is really not possible to do much better than
> that. So, in return for getting a drug that might have less toxicity,
> or is easier to give, or is a different dosage form and things like
> that, we do the best we can sometimes, as Grant pointed out, there
> often isn\'t. So, it is a tremendous problem to get less toxic or more
> easily taken drugs. The same problem actually arises when you are
> looking for drugs that mitigate the side effect of another drug. If
> you want to show that you preserve the effect of the drug, I can\'t
> imagine what size studies would make a convincing case and, as Grant
> said, there is often very unclear evidence on what the actual
> beneficial effect of the drug is in the first place. This isn\'t
> unique to oncology; it occurs everywhere but it is a major challenge.
>
> DR. PRZEPIORKA: Mr. Katz?
>
> MR. KATZ: Where in this do we account for differences in durability of
> response? For instance, you could have two treatments that have
> equivalent TTP but very different duration of response and that would
> be something that would be very different in terms of patient benefit.
>
> DR. WILLIAMS: Well, I guess it would be a separate judgment. If they
> had the same TTP, that is one thing but duration of response would
> relate also to response rate. I have never had considerations where we
> were looking at TTP as a primary endpoint and we saw differences in
> response rate and we were making a judgment. But I think, obviously,
> if you are looking at response rate, duration of response is always an
> important consideration and a big judgment call when you have such a
> long duration. I think the O\'Shaunnesy paper had some discussions
> about that in the early \'90s about certain settings with big response
> rates and long durations of response that we might consider using it
> as an endpoint for clinical benefit, but it is very much of a judgment
> call.
>
> MR. KATZ: I guess I was raising it strictly because of, you know, the
> difference in quality of life between being treated with something
> constantly over a three-year period between your randomization and
> progression versus being treated with a blast at the front. That is a
> significant difference. You know, it is separate from the response
> rate.
>
> DR. PRZEPIORKA: Dr. Grillo-Lopez?
>
> DR. GRILLO-LOPEZ: I believe that TTP is an excellent endpoint for
> regular approval even and that, in fact, it is much better than
> survival. It may not be obvious but survival is plagued by a number of
> biases that we can discuss during the course of the day. One would
> tend to state that F is the ultimate endpoint when you are talking
> about survival but, again, there are a number of biases when you are
> looking at death as an endpoint.
>
> But to address your question, I think that one way to address the
> issue of TTP and its relationship to response is to do an analysis of
> TTP for responders. When you look at TTP for responders, this is even
> a better endpoint than duration because the problem with duration of
> response is that you are looking at two time points, both of which are
> variable. The duration of response starts from the first day that you
> see a response, and that can vary depending on when the evaluations
> are done, and ends with progression of disease which, again, can be
> somewhat variable. Whereas, TTP at least has a definite calendar date
> for the onset of TTP.
>
> DR. WILLIAMS: WHO does response duration\--or ERTC or somebody\--from
> the time of randomization. That is where they routinely measure
> response duration but, obviously, there is a longer but perhaps more
> precise measure.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: I was just going to comment on duration of response. There
> certainly have been situations where very long response was considered
> sort of self-evidently beneficial in some of the leukemia/lymphoma
> drugs. In testicular cancer, if you are still alive and have not
> progressed at a year everybody assumes that you would have been dead.
> So, there are some of those cases but as an endpoint in clinical
> trials we have never been successful, to my best knowledge, in
> incorporating that particular measurement into the overall evaluation.
> We sort of say if it is too short, that might not be meaningful but I
> don\'t think it has been more precise than that except when you get
> these partial responses that last for a year and everybody is very
> impressed by that as a likely clinical benefit.
>
> DR. WILLIAMS: That was a big role with IL2, wasn\'t it, Pat? Long
> duration response?
>
> DR. KEEGAN: Yes, that was the basis for the approval both in
> metastatic renal cell and metastatic melanoma. Although there were
> relatively few responses\--I think it was less than a 15 percent
> overall response rate for either one. The responses were measured in
> months for partial responders and years for complete responders.
>
> DR. TEMPLE: And the treatments for hairy cell leukemia all sort of had
> those characteristics.
>
> DR. PAZDUR: And that was for Fludara and for valcane too.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: Dr. Farrell, just for my own clarification because I heard
> the words being used in the same sentence, in the regulations clinical
> benefit is not defined as survival?
>
> DR. FARRELL: Right.
>
> DR. REDMAN: It is defined as clinical benefit. What we are trying to
> discuss is what is a clinical benefit and assuming that time to
> progression is a surrogate endpoint to survival may be false just by
> definition.
>
> DR. WILLIAMS: But as I said in my talk, clinical benefit it not in the
> regs, or at least it is not in the Act. Do you want to say more about
> it, Dr. Temple?
>
> DR. TEMPLE: It is definitely not in the Act. An important court of
> appeals case\--whether that really changes the law or not is
> debatable, but Warner Lambert versus Heckler said it is just obvious
> that the Commissioner needs to consider what the effect is. He
> doesn\'t have to approve something silly, like there used to be drugs
> to increase bile flow. You know, that doesn\'t sound like it is very
> useful. But that is what it is and it has never been defined as a
> particular thing. In other words, as Grant said, everybody thinks that
> delayed time to recurrence in adjuvant settings probably is a clinical
> benefit because, you know, you don\'t have tumor yet or you don\'t
> know you have tumor yet or because it is usually symptomatic. That is
> okay. If somebody thinks that very delayed time to progression must
> correlate\--there is a lot of judgment in it. There is no rule;
> nothing is written down.
>
> As Grant said, up until 1985 we used to approve everything based on
> response rate. We didn\'t think that was illegal but we concluded it
> wasn\'t so good.
>
> DR. WILLIAMS: And looking back at the history of oncology, at the very
> time that we made this decision the Supreme Court was evaluating
> Laetrile and the Supreme Court was supporting the FDA that we could
> demand proof of efficacy in terminal cancer patients. The words used
> were symptoms, function and survival. So, I mean, it is a collection
> of sort of legal arguments as sort of the basis I think.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: In considering the concept of clinical benefit, I think
> many of us have, across many disease areas, considered direct measures
> of clinical benefit to be measures that unequivocally reflect measures
> tangible benefit to patients. So, Grant had put forward examples of
> those. Obviously, duration of survival; measures that reflect quality
> of life; disease-related symptoms, those are obvious measures.
>
> Where we struggle is that in any disease area there are targeted
> mechanisms by which we are hoping to achieve those clinical benefits,
> and we may be more or less right about those. In oncology we would
> tend to think those would be most directly measures that reflect
> disease tumor burden. Time to progression, response rate are, in that
> regard, measures that we would give considerable attention to. One
> could argue though that you could shrink a tumor by a certain fraction
> or delay time to progression by a certain fraction and that doesn\'t
> necessarily lead to something that the patient would be tangibly aware
> of unless, as was pointed out\--I think Bob pointed out, if
> progression is associated with symptomatic disease or disease-free
> survival, if the delay in the time to having detection of disease
> provides a psychological benefit. Those are direct tangible factors.
>
> But the complication that arises here is that time to progression may,
> in fact, be the intended mechanism by which we hope to achieve
> clinical benefit but the problem is may you delay progression by two
> weeks or four weeks without that translating into something that the
> patient is tangibly aware of in terms of longer survival or
> improvement in symptoms or quality of life.
>
> DR. REAMAN: For clarification, are we lumping together time to
> progression and time to recurrence and the issue of stable disease as
> an endpoint?
>
> DR. WILLIAMS: I am specifically mentioning time to progression. We
> will talk about disease-free survival during the questions. We have
> taken a stronger stance, as Dr. Dagher has stated, that with
> disease-free survival in some settings is a clinical benefit.
> Disease-free survival in the adjuvant setting I don\'t think we would
> say is the same as time to progression. So, our discussion here so far
> has just been time to progression. If you would like to bring up the
> other now, but we will certainly discuss it later too.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: I think what we are going to find here at the end of the
> day is that the importance of the various endpoints is going to vary
> considerably by disease. Dr. Temple was citing all these examples
> about how drugs got approved, single agents, all hematologic
> malignancies. What has been referred to this morning has been more
> referable to solid tumors. So, this is going to be really complicated.
>
> I would like to get some input from people like Dr. Fleming, all too
> often we see that time to progression does not translate into a
> survival advantage. The cause of that is because the survival
> measurement is under-powered, or is it because once they progress with
> a longer time to regression they don\'t respond to subsequent therapy?
> What is the explanation for this because we see it all too often?
>
> DR. FLEMING: That is a good question and it is one in general that
> arises as we consider markers as potential replacement endpoints. Just
> as a quick, brief response to your question, if we are using time to
> progression and we are using it as a measure of the intended mechanism
> by which we hope to achieve clinical benefit, such as survival, why is
> it that you may see a time to progression effect and not a survival
> effect? Part of it may be that it is not fully captured in the entire
> mechanisms through which these processes are influencing outcome.
>
> A better example I think of that might be if you used objective
> response rate as the surrogate because it may be that you are
> under-estimating the true effect on the clinical endpoints, such as
> survival, because the intervention has a cytostatic component that
> delays progression without necessarily shrinking tumors.
>
> Of course, the other factor is the clinical endpoint can be influenced
> by unintended mechanisms so that you may be having a potentially
> partial beneficial effect mediated through the intended delay in time
> to progression, but that could be offset by other unintended
> mechanisms, toxicities etc. which would yield in the end a lesser
> impressive survival effect.
>
> Typically the marker is more proximal and often the true clinical
> endpoint is more distal. So, it is not surprising that the nature and
> magnitude of the effect on the more proximal measure may be different
> from the more distal.
>
> The critical issue in validating a surrogate, as we will get to later
> on, is that it shouldn\'t be assessed in terms of statistical
> significance, yes/no. It should be assessed in terms of does a
> relative risk reduction in the time to progression translate into some
> definable and predictable relative risk reduction in survival. So, if
> we reduce progression by a rate of 30 percent, is that a pretty
> reliable estimate of a reduction in death rate by 20 percent? In fact,
> if that is true, clearly a study is going to be more adequately
> powered for progression than survival because you can detect a 30
> percent reduction with half the sample size of a 20 percent reduction
> of death.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: I would like to talk a little more about the time to
> progression in symptoms issue. I think we all would tend to agree that
> conceptually, ignoring the methodologic difficulties, a delay in
> progression is a good thing. We have a lot of problems with measuring
> it, and how the design is done and all these things that contribute to
> it. But it seems to me that if we are after a clinical benefit, an
> important clinical benefit is that development of symptoms. So, you
> have some diseases I suppose where you have the distribution of time
> to development of symptoms after progression that would be relatively
> short, in which case you would look to build that probably into the
> definition somehow. In other diseases you might have a very long time,
> and that becomes a lot more problematic I think because that would be
> more variable and longer-term in individuals and then you really have
> to worry about how it translates into individual patient benefit.
>
> I noticed you briefly talked about some related things, like
> progression-free survival, and you just kind of briefly touched on
> them. So, do you have any more comments about this issue?
>
> DR. WILLIAMS: Certainly, we look forward to your deliberations on this
> matter. Of course, right now this is just questions to the speaker.
> That is one of the biggest things we would like to know, can you do
> this or not? If you can\'t do it, then forget it. And, that is
> basically the answer we have got from most investigators, we can\'t do
> this. But if you can, we would love to see it.
>
> DR. PRZEPIORKA: Just to clarify, I don\'t mean to put words into Dr.
> George\'s mouth but, again, it seemed that you were somewhat negative
> on the concept of progression-free survival as opposed to time to
> progression. Would you like to expound on that?
>
> DR. WILLIAMS: Okay, what I should have said was that we have often
> said don\'t do progression-free. It has been our approach because we
> have been disturbed by loss to follow-ups coming in as deaths, you
> know, prolonging survival. It is a very sloppy business and there is
> no rule in there about how you deal with that. As a secondary endpoint
> I think that is quite reasonable but I think, as Dr. Fleming said, if
> you are really going to try to capture more in this endpoint if it is
> relevant, then include deaths. I think that is a good thing for you to
> discuss, is that reasonable to do? But if we do, then we have to do
> something to make sure those deaths don\'t mess up our analysis and
> produce unreasonable results like, you know, three-year
> progression-free survival and then death, things like that.
>
> DR. PRZEPIORKA: Again, your definition of progression-free survival
> does not include death?
>
> DR. WILLIAMS: TTP does not include deaths. Progression-free survival
> includes deaths. That is the terminology I use.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: With TTP you censor the deaths and don\'t count them. With
> progression-free survival your worry is that you gain credit for very
> great delay in progression because nobody observed you for a long time
> until you died. It doesn\'t have an obvious bias, it just gives you a
> wrong number.
>
> DR. WILLIAMS: Well, both of them produce wrong results. I mean, we
> like to censor the visit before the death instead of at the death but
> still, you know, that is being cut off because the patient died. Was
> really that death unrelated? If it was related, then you have
> non-informative censoring. So, it is which kind of bad data do you
> want. So, the real way to do it is to do the trial right and not have
> these kinds of things.
>
> DR. TEMPLE: Can I pursue a previous discussion with anybody? The
> practical difficulties of doing time to death in addition to time to
> progression I don\'t think have been adequately recognized. Just as a
> quick example, which will be statistically incorrect, if you delay
> progression from six to eight months my quick hazard ratio is 0.75. If
> you improve survival from 12 to 14 months, the same difference; you
> can\'t expect to have a bigger effect. So, your hazard ratio is only
> 0.86.
>
> Now, the implications of that for sample size are major and I haven\'t
> even calculated a crossover. So, if you imagine that the crossover to
> study drug now reduces your advantage from two months to one month, we
> are talking about major differences in sample size. I am not sure
> anybody has actually modeled the difficulty but it is clearly going to
> be very, very hard just on practical grounds alone. You don\'t even
> have to postulate that there is a difference in effect on progression
> to survival. I am just assuming it is the same but still I am sure the
> sample size goes up a factor of four with what I just said, but
> someone can correct that. It is a very substantial problem, not really
> addressed.
>
> DR. WILLIAMS: But underlying that, Bob, we have had many of these
> discussions and the issue is do you assume a constant hazard or do you
> assume a constant increment? I don\'t know what we should expect.
>
> DR. TEMPLE: Grant, why would anybody imagine that a two-month increase
> in time to progression would lead to a four-month increase in
> survival?
>
> DR. WILLIAMS: I don\'t know but you heard Tom do it and I think the
> statisticians continually do kind of assume a constant hazard when
> they go from one endpoint to the other.
>
> DR. PRZEPIORKA: However, this again begs the question of whether or
> not one is supposed to be a surrogate for the other, or can you say
> time to progression is a clinical benefit and we don\'t have to worry
> about whether it is a surrogate?
>
> DR. TEMPLE: Right, but one of the tempting reasons to do that is the
> implication for sample size.
>
> DR. WILLIAMS: Maybe we could hear Tom. What is the assumption and
> which is valid?
>
> DR. FLEMING: Well, I think the essence of what Bob is saying is what
> drives interest in looking at replacement endpoints. The example I
> gave was a 30 percent reduction in progression rate compared to a 20
> percent reduction in death rate and that would lead to a doubling in
> sample size.
>
> DR. TEMPLE: It depends how much delayed death is compared to
> progression.
>
> DR. FLEMING: Indeed. The example you gave, Bob\--you are actually not
> too far off, it would be a three- to four-fold difference in numbers
> of events required to detect a 12- versus 14-month difference in
> survival rather than a six- versus eight-month difference in time to
> progression. It is what drives a lot of interest in looking at
> replacement endpoints. It is not just because they occur six months
> sooner that would cut six months off the regulatory process, but the
> relative risk that you would expect to see in the endpoint that is the
> direct mechanism by which you hope to achieve ultimate benefit, and it
> is more proximal, is typically going to be greater.
>
> There are counter examples, Bob? How could it be that there is a
> counter example? Because your surrogate may be noisy and may not, in
> fact, be capturing the essence of the mechanism by which you achieve
> clinical benefit. So you may, in fact, have as impressive a result on
> the more distal clinical endpoint. But in general what you say is
> right, and that is that typically you are going to see a bigger
> relative risk reduction.
>
> So, the challenge is can we achieve that payoff of a quicker
> assessment based on a smaller sample size, using Bob\'s logic, without
> paying the price of having less reliability? When is this quicker
> answer reliably telling us what we need to know longer term?
>
> But while I have the mike let me just quickly go back to one of your
> earlier issues and defend what Grant had indicated I had advocated in
> the past, which is disease-free survival. Disease-free survival and
> time to progression are both important markers. Time to progression is
> censoring the deaths and if one is really trying to get at the
> mechanism by which I am achieving clinical benefit, a targeted
> mechanism such that what I really want to look at is the treatment
> effect on the targeted mechanism of tumor burden and I don\'t want
> that assessment to be clouded or complicated by the noise of unrelated
> deaths, I will censor the deaths and look at time to progression. That
> would make sense if it is a supportive measure of biologic activity.
> But if it is a registrational endpoint you want it to be as close as
> possible to what is really clinically relevant and clinically
> interpretable.
>
> What is really relevant here would be to say I want to delay the time
> that I have progression or death. A good thing is to be alive and free
> of progression. So, those deaths should count. When you censor the
> deaths, and I think it is important for clinicians to know the game
> that statisticians are playing, if Grant and I are going along and I
> die and Grant doesn\'t and we are in the same arm, I am censored in
> time to progression but I am not left out. Some people think I am
> censored and I am taken out. No, I am still in the analysis and we are
> imputing my time to progression by what Grant\'s time to progression
> is.
>
> Now, it is an incredible assumption of informative censoring that
> because I die I am no definition than Grant. I am probably more frail;
> I am different and so my time to progression would have been different
> from his. So, when we look at time to progression I would hope that we
> would also look at that with tremendous caution because we are
> censoring the deaths and we are making a major assumption about
> non-informative censoring that is almost certainly not true.
>
> DR. PRZEPIORKA: Grant, I have a question for you. You talked about
> validated surrogates. Who is responsible for validating surrogates,
> the FDA or the sponsors?
>
> DR. WILLIAMS: Well, I really don\'t think that we use the term as a
> regulatory term. We are looking for something that is a substitute. In
> this case I was using validated to refer to the Prentice criteria for
> strict quantitative analyses. Certainly, our regulations don\'t have
> validated surrogate in them. I don\'t think we really have a
> regulatory answer for what a validated surrogate is, maybe Bob does.
>
> DR. TEMPLE: No, we don\'t. But the accelerated approval rule says you
> know those other surrogates we used to use\--blood pressure, blood
> sugar, the ones we are talking about now are less validated than that.
> That is really all it says. It gives you a direction and that is quite
> explicit in the preamble, but it doesn\'t say the other ones meet the
> Prentice criteria. I don\'t think anything has ever met the Prentice
> criteria because there is too much noise in the system to make a very
> persuasive case for that. But the contrast is with blood pressure,
> blood sugar and cholesterol which a lot of people would argue about
> anyway even though those are widely accepted. But it is a qualitative,
> somewhat seat-of-the-pants judgment about whether this is persuasive
> or not.
>
> DR. PAZDUR: Could I answer Donna\'s question?
>
> DR. PRZEPIORKA: Sure.
>
> DR. PAZDUR: I think the academic and scientific community have the
> obligation to validate these surrogates. We could accept or not accept
> the information that is provided to us but this tends to be a long and
> complicated process and what we are looking for is basically external
> validation that these are real, true scientific findings to them base
> regulatory decisions on.
>
> DR. PRZEPIORKA: In that case I would like to follow-up and I am going
> to assume that there is no guidance document on what would accept as a
> validated surrogate. Is there a guidance document available for how to
> validate a surrogate?
>
> DR. TEMPLE: No, there isn\'t and when you actually get into it, it
> becomes extremely difficult. For example, I bet if you looked at all
> studies over all time, shrinking tumors is probably good; I mean I
> think it is likely if you had a large enough database. What does that
> tell you about an individual study where the difference in tumor
> response is a small percent? In putting a quantitative thing on these
> is extremely difficult. I mean, people could try to do that. It would
> be a massive project but I wonder how much it would help you in each
> individual case as to whether it was plausible or not. But your
> question leads to the answer that there really isn\'t much in the way
> of guidance on this.
>
> DR. PAZDUR: But to follow-up on Bob\'s comment, I think this is one of
> the major problems we have had in oncology, that is, as we try to make
> some correlation here basically our treatment effects have been so
> small that it is hard to really impact the subsequent endpoint.
>
> DR. PRZEPIORKA: Dr. Dagher, a question for you. You had gone through
> the list of all the ways of accelerated approval and obviously they
> need further follow-up for full approval. Can you tell us has there
> been any drug that has been approved on accelerated approval but had
> its post-marketing study turn out to be negative, and what did we
> learn from that and what did we do with it?
>
> DR. DAGHER: Well, we discussed some of these at the March ODAC last
> year and I mentioned that you could have confirmatory benefit either
> in the exact same population or I used the term related population.
> The reason I mention that is that it is intuitive that you would
> expect confirmatory studies to be done in the less refractory
> populations when you are looking for people for second- or third-line
> accelerated approval. But we have had settings where we have had
> evidence of clinical benefit confirmed in related populations.
>
> What do I mean by that? We have some settings where we still had
> somewhat refractory populations but they were related. For example,
> the approval for Taxotere was for failure of prior athracycline. Then
> when we looked at confirmatory benefit, that was a population where
> there were some patients that had failed prior alkylator therapy. So,
> if you look at the label, after we did the conversion we now have a
> slightly expanded population, if you will, to say failure of prior
> chemotherapy which might have included either athracycline or
> alkylators. So, that is one situation where you could argue, okay, the
> population was still somewhat refractory but it is a slightly
> different population.
>
> In the case of irinotecan, the evidence that was helpful in providing
> evidence to confirm clinical benefit came, as you know, from two
> European studies not the studies that were originally intended as the
> studies that were designated originally as those that would provide
> clinical benefit. In those studies, you could say those were fairly
> close populations in terms of the patient populations.
>
> So, basically what we are saying is that you could have confirmation
> of benefit either in the same population or related populations. In
> terms of regulatory guidance, the 1996 document on reinventing the
> regulation of cancer drugs illustrated some concepts. One of the
> concepts was that clearly we recognize that confirmation of clinical
> benefit doesn\'t always necessarily have to occur in the exact same
> population that we use for accelerated approval. Obviously, the reason
> for that is that it could be more informative for us that further
> studies are done in different populations. For example, if you had
> accelerated approval in a third-line setting one could argue that it
> would be much more informative to have further studies done in the
> first-line setting and evaluate benefit in that setting.
>
> DR. PRZEPIORKA: I think my question was probably addressing more a
> specific individual study as opposed to a confirmatory trial where a
> drug received accelerated approval on the bases of a surrogate but in
> long-term follow-up survival was either not different or, in fact,
> worse with the new drug. Has that ever occurred?
>
> DR. PAZDUR: Yes. Donna, a recent example of this is oxaliplatin.
> Although we approved the drug on the basis of an interim analysis of a
> randomized study which showed an improvement in time to progression
> and response rate, the survival did not show any advantage. Hence, you
> know, we knew that this was a high probability because there was a
> built-in crossover for all patients to receive the drug subsequently.
>
> I think an important aspect is that when we take a look at accelerated
> approval\--and this came out in the March talk\--that we really have
> to take a look at the whole context of the drug development. It is not
> just one trial, this drug also had positive trials in a first-line
> study in an adjuvant setting. So, yes, there are examples. I think we
> have to take a picture of how the drug fits into the context of other
> trials going on.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: Well, the oxaliplatin is a very telling example and
> certain studies in breast cancer in my opinion came out roughly the
> same way despite a dramatic effect on disease-free survival. But that
> is because of the reason we gave before. There is crossover and it is
> later so it is much harder to win.
>
> There are some examples, I mean there is a near miss, if you like. In
> the ordinary course of things Iressa probably would have been approved
> for third-line therapy with a requirement that they go study
> first-line therapy. Well, we know what happened there. They would have
> failed utterly. The message I think is, you know, you are not always
> as smart as you think you are. Drugs don\'t always work better\--
>
> DR. BUNN: \[Not at microphone; inaudible\]
>
> DR. TEMPLE: I am just talking about the results of the well publicized
> first-line therapy study that was done, an excellent pair of studies.
> Nobody criticized the design. Yet, if those studies had been the
> requirement on an accelerated approval\--other studies are now the
> requirement for accelerated approval\--you would have had a case where
> you didn\'t get confirmation but, of course, it was a different
> disease. So, it is possible. Can I say accelerated approval
> contemplates that. It contemplates the possibility that we will put a
> drug into the marketplace that ultimately proves not to be effective.
> The risk is considered worth it in bad diseases with no good
> treatment.
>
> DR. PRZEPIORKA: Dr. Fleming, a final question?
>
> DR. FLEMING: I was just following up on what I thought your question
> was, which is are there examples where an accelerated approval is
> granted and then a validation study is done and the results are not
> confirmatory. I think in the March 12 and 13 ODAC committee meeting we
> had we saw several examples. One of those examples was ethiol in
> advanced non-small cell lung cancer that was used for chemoprotection
> against renal toxicity, and where a validation study was done and
> duration of responses were much shorter with ethiol and survival was
> shorter, time to progression was shorter. Survival was almost
> statistically significantly shorter and was, in fact, shorter in the
> subgroup of ECOG performance status.
>
> That was, in fact, an issue that came to light in that advisory
> committee, that not all validation studies are going to be positive
> and it is not as simple as saying, well, with crossovers at
> progression we are going to dilute survival differences. At times
> makers don\'t give a reliable assessment of what the ultimate clinical
> benefit will be. And, one of the complexities here is when those
> validation studies are quite unfavorable what happens?
>
> DR. PRZEPIORKA: Dr. Dagher?
>
> DR. DAGHER: Just to follow up, this is why Dr. Pazdur was emphasizing
> this concept of an overall development plan because we talk about
> confirming clinical benefit in the exact same population or in
> different populations, the fact is that you could have for a variety
> or reasons, as Dr. Fleming mentioned, studies that are \"designated\"
> as those that are going to be supportive for approval and, yet, those
> either aren\'t completed or when they are completed they don\'t show
> the results you expect.
>
> This is why we encourage sponsors to sort of have a broad view of the
> development plan, meaning that we would like to have, you know,
> several trials ongoing or in the process of being developed that could
> ultimately support that full approval. Like in the irinotecan example
> I provided, because there were other large randomized studies being
> conducted, even though they weren\'t designated as those that would be
> reviewed for confirmation of benefit because they were ongoing they
> could provide that evidence. So, when we talk about an overall
> development plan one of the things we are talking about is having
> other trials ongoing even if they are not necessarily \"designated\"
> at the time of the original accelerated approval as the ones we are
> going to necessarily review for confirmation of clinical benefit.
>
> DR. PRZEPIORKA: Thank you. I think we are going to stop here for a
> break and we will come back for the open public hearing and Dr.
> Temple\'s comments starting at 9:45.
>
> \[Brief recess\]
>
> DR. PRZEPIORKA: Is there anyone in the public who wishes to make a
> comment? Now would be the time. Please come forward to the microphone
> in the front of the room. Seeing no takers, we will proceed to the
> discussion of the questions and Dr. Williams I think will give us some
> introductory comments.
>
> **Introduction of the Questions**
>
> DR. WILLIAMS: I don\'t know if Dr. Pazdur is on the phone; I don\'t
> hear a cough. I imagine that is going to be the rest of our Division
> next week.
>
> I just want to introduce you to the questions, sort of the structure.
> Why don\'t you turn to them? This morning there will be just sort of
> general discussion questions that we want to take general principles
> from to guide us as we go to specific areas. In the afternoon we will
> look into the questions on lung cancer and have a few voting questions
> if it seems that that will be helpful.
>
> For this morning\'s session the first question is just on survival. It
> will be a continuation of what we have had here. The second question
> is about time to progression. We have had a lot of trouble trying to
> figure out how to do this. So, what happened is, you know, Dr. Pazdur
> took all of my little questions and was going to throw them away.
> Instead, I stuck them in the appendix.
>
> \[Laughter\]
>
> So, what we need to do is to talk about time to progression but also
> all of the different factors about time to progression, how important
> are the different factors? In the appendix I have sort of taken the
> different factors out to give you a little idea of what we are talking
> about, if you need to refer to that, things like relationships of time
> to death; whether patients are symptomatic; the magnitude and
> precision of the benefit; whether or not there is a benefit out there
> that has a survival effect for instance, whether that matters; how
> much does it matter if the endpoint is highly reliable or if it is
> more fuzzy; toxicity and the design, superiority versus
> non-inferiority.
>
> I mean, you can come up with all kinds of scenarios but these are the
> factors that we are often considering when we say is this acceptable
> or not. So, there is a question here that mentions each of these
> factors and if you need to think more about them there is the
> appendix.
>
> Then, there is the question of disease-free survival. We didn\'t
> really present on it but there is a little discussion here. Basically
> the issue is we have accepted disease-free survival in breast cancer,
> partly because it is hormonal therapy and I think one of the early
> defenses was that these patients were more symptomatic at the
> progression so it is more like delaying symptoms. But others will
> argue that disease-free survival itself is clinical benefit, that you
> don\'t have known cancer and now you do and now you get toxic
> treatment. So, how you weigh in there I think will be important to us
> as we move forward.
>
> Those are really the main two questions for this morning. Certainly,
> if you feel like there are other questions or points that you want to
> discuss, that is fine. So, I will turn it over to Dr. Przepiorka.
>
> **Questions for Discussion**
>
> DR. PRZEPIORKA: Thank you. Dr. Williams, just as a point of planning
> for this discussion and trying to make sure we get everything in,
> especially that last question which may actually have some importance
> regarding hematologic malignancies, and recognizing the complexities
> of the discussion for TTP, would you mind terribly if I took some of
> these out of order?
>
> DR. WILLIAMS: You are welcome to.
>
> DR. PRZEPIORKA: Thank you. Let\'s start with the first question for
> the committee. Discuss the role of survival as an endpoint. Consider
> in your discussion the importance of whether existing therapies
> prolong survival and the potential confounding of survival results by
> patient crossover or where several subsequent therapies may also
> affect survival.
>
> We actually discussed this a little bit about four years ago, if I
> recall. At that time I do recall Dr. Pazdur very pessimistically
> stating there is no drug that really improves survival in cancer so
> crossover shouldn\'t make any difference. But I think in the modern
> era that is no longer true, or am I incorrect about that? Dr. Grillo?
>
> DR. GRILLO-LOPEZ: Perhaps even before we start discussion we need to
> make a distinction between survival as a goal and objective and
> survival as an endpoint. Survival is a goal for all of us here in this
> room because we are all involved either in patient care or in some way
> trying to better the lot of patients. You know, I have taken care of
> cancer patients and survival is very important to me. I am a cancer
> survivor myself. Survival is very important to me. But it is a word
> that is very compelling and that has a lot of emotional baggage behind
> it. Perhaps because of that we are tempted many times to follow it
> with the phrase gold standard and perhaps we shouldn\'t.
>
> Perhaps as you said earlier in our discussions today in considering
> TTP, and we will hear a lot about the pros and cons of TTP, we have to
> divorce that from survival as TTP being a surrogate for survival
> because survival is not a very good endpoint in fact. I love survival
> as a goal, as an objective. I dislike it intensely as an endpoint
> because it is subject to so many biases and a lot of people don\'t
> recognize that. The most important one may be that patients do get
> subsequent therapies and those subsequent therapies may or may not be
> active but there are extremes. There is the patient who chooses to
> have the best possible care, who takes care of himself, who follows
> treatment and who happens to respond to subsequent therapies. He will
> have a longer survival than at the other extreme, the patient who
> chooses to expedite his demise ultimately, perhaps even through
> suicide. If you have done enough clinical trials you will have had
> patients who committed suicide. It can be subtle at times. It can be
> as subtle as stopping your medication and no one knows about it but
> you. But we think it is just jumping under the train; it is not like
> that. So, it is a very biased endpoint. It has more biases, in my
> mind, than TTP does.
>
> DR. PRZEPIORKA: Dr. Brawley?
>
> DR. BRAWLEY: I am sorry, are you talking about survival as measured in
> a randomized clinical trial or are you talking about survival as
> simply increased time from diagnosis to death as measured through
> comparing various trials?
>
> DR. WILLIAMS: Randomized trial as a primary endpoint.
>
> DR. TEMPLE: It is not that you couldn\'t be persuaded by a
> historically controlled trial but it just almost never happens.
>
> DR. BRAWLEY: I have a second question which is more for Dr. Fleming
> and Dr. George. I sort of mentioned it to both of them. Are we
> assuming that increased survival in a randomized clinical trial
> translates in a decrease in either overall mortality or cause specific
> mortality?
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Since I heard my name mentioned\--yes, we talked about
> this at the break. Well, let\'s talk about lung cancer since we are
> going to talk about it this afternoon, I think it is traditional to
> use overall survival as the primary endpoint even though in many
> studies, if you look at attribution of cause of death, there are quite
> a few deaths that are not attributable to the treatment, not
> attributable to the disease but are from other competing causes of
> risk. So, I don\'t think we are assuming that. What we are doing
> though is we are saying that we don\'t really know; we can\'t really
> trust this attribution, first of all, in cause of death. Secondly, we
> wouldn\'t know quite how to interpret, say, a difference in cause
> specific mortality, say in lung cancer in this case, in the two
> treatments if there wasn\'t an overall survival difference because we
> don\'t know what the full mechanism of action of the treatments is.
>
> So, I think it is not true that we are assuming anything about the
> different causes of mortality but what we are doing is saying that the
> overall survival is the important thing in those kinds of settings.
>
> DR. PRZEPIORKA: Mr. Katz?
>
> MR. KATZ: Well, I think we have to be careful to talk both about the
> difficulty and the practicality of each of these measures separately
> from the validity of these measures as true measures of patient
> benefit because they are different issues. It seems apparent that we
> don\'t really have the capacity since we can\'t freeze time and we
> don\'t have computer models to basically run clinical trials in the
> blink of an eye, we can\'t answer the questions adequately.
>
> I think Dr. Cheson said that the punch lines are likely to be
> different for different disease settings. I agree. But I think the
> other thing is that the punch line in terms of whether a certain
> endpoint is really an indicator of patient benefit is likely to be
> different for different patients because different patients may view
> overall survival benefit of eight months as something huge, whereas
> someone else, you know, may value disease-free, progression-free
> survival and maintaining a constant in terms of their current life
> styles as a higher benefit. So, I think we ought to view all of these,
> and is each of them valid to use as a measure and sort of add them as
> arrows and quivers as opposed to saying which is the best one to use
> because we have to use a lot of them I think to get the right result.
>
> DR. PRZEPIORKA: The question not here that I would like to throw out
> came up with our journal club back at home yesterday. We were
> reviewing a paper where difference in median survival ended up being
> 1.2 months but, because there were so many patients, the p value was
> 0.003. Dr. Williams I believe stated earlier that survival, when
> considered the endpoint, was easy to measure because when it is
> significantly different it is acceptable. But here our group looked at
> a paper and said we still wouldn\'t change therapy based on that. Any
> discussion on what is a meaningful increase in survival? Dr. Cheson?
>
> DR. CHESON: Again getting back to what I said before, it is all
> relative. Whether you are talking lung cancer, whether you are talking
> follicular lymphoma or let\'s look at melanoma. We have some
> interesting drugs there. A difference of two months may be very
> meaningful. Yet, if you look at that in follicular lymphoma, as you
> know, we would go \"pah.\"
>
> DR. PRZEPIORKA: I think Dr. Williams asked earlier for discussion of
> principles and I think he is going to want some rather specific
> examples. So, if you would like to discuss what you would consider
> meaningful survival in a lung cancer patient versus a low grade
> lymphoma patient he would probably be happy to hear those numbers.
>
> \[Laughter\]
>
> Just as examples of people who have long lives and short lives.
>
> DR. CHESON: Well, I think also you have to look at whether you are
> talking front-line therapy or relapse therapy and, as he also
> mentioned, the risk of the therapy. For follicular lymphoma in the
> relapse setting I would think four to six months with a new therapy
> might be something important, whereas that would be only of marginal
> interest in up-front where some of the newer agents are, hopefully,
> getting us nine months to a year with additional therapy.
>
> This is a totally moving target, particularly in the hematologic
> malignancies which, as you know, are far ahead of the solid tumors.
>
> DR. PRZEPIORKA: Yes.
>
> DR. CHESON: Every time we get a new drug approved, the bar just gets
> set higher and higher. So, what you say today is not going to be
> relevant in another six months for lung cancer, which I don\'t follow.
> Paul and Bruce can certainly comment much better on what would be a
> meaningful endpoint. I know when I was still in my former job they
> were talking about response rates of interest in lung cancer being in
> the ten percent range. We saw that with Iressa and that would not cut
> it at all in hematologic malignancies, even in the most aggressive of
> those. So, it is a totally moving target.
>
> DR. PRZEPIORKA: Any guiding principle you might come up with though?
> If drug A gives you two years benefit over no therapy and drug B is
> coming along, how much more benefit would you want to see?
>
> DR. CHESON: It is hard to give an absolute number.
>
> DR. WILLIAMS: Dr. Przepiorka, maybe I could focus that a bit?
>
> DR. PRZEPIORKA: Sure.
>
> DR. WILLIAMS: Because we have not, that I know of, not approved a drug
> that had a survival effect that we really believed. I mean, you also
> have to trade off the toxicity. But I think what we would really like
> to know is when you have a drug with a survival effect out there, how
> does that affect your acceptance of another endpoint that isn\'t
> survival? A lot of times these survival effects are not so big\--one
> or two months, as you mentioned, and that is what you have, maybe it
> is a symptom endpoint, maybe it is TTP or another endpoint with
> another drug. How does that, and what magnitude of effect of survival
> would affect the way you looked at this endpoint?
>
> You know, we don\'t have a definite comparative efficacy standard but,
> nonetheless, I do think it is important we do consider these things,
> whether there is a large survival effect or not.
>
> DR. TEMPLE: You have to be specific about the study. I mean, if you
> have a standard therapy out there that you knew something about and
> now along comes another drug and it actually shows improved survival,
> well, you know something about this drug. It is not worse than the
> other drug at least, and even if you are not bowled over by the effect
> it is sort of showing you that it does something other than shrink
> tumors. You might consider that as sort of proof of principle and a
> statement that, well, it is at least as good as what we have and
> actually it is probably better. Even if you think that one month is
> not of particular value, it has told you something about the drug and
> what it can do. Whether that becomes standard therapy or not is a
> different question, but from our point of view maybe it has shown the
> kind of effectiveness you want if it is not over-toxic.
>
> DR. PRZEPIORKA: Dr. Rodriguez?
>
> DR. RODRIGUEZ: You are asking about developing principles and I think
> that coming up with specific numbers doesn\'t address a principle. I
> think a concept of principle would be, as Dr. Cheson has said, that
> there should be different guidelines for each malignancy. We are
> finding today that even within a defined category of malignancies we,
> in fact, have many biological variants of that same disease and we all
> have been bowled over at the recent meetings about how we now have to
> start thinking of proteomics and genomics in the definition of
> treatment for patients.
>
> So, I think that this is, indeed, a moving concept and the principle
> should be that the endpoint should be appropriate for the disease and
> that it should be appropriate for the stage and/or status of the
> disease because patients who are in relapse are different from
> patients who are being treated in the adjuvant setting, or for
> metastatic front-line treatment, and/or for post-transplant, or being
> considered for transplant, etc. I mean, I think we know as clinicians
> that we manage all of these patients very differently so we should not
> have \"standard expectations\" of any one of these categories of
> patients. They should be different.
>
> DR. LEVINE: I would agree. I would add one more point to the
> principle. If, in fact, the survival benefit is a very small one, it
> would seem to me that I would want some confirmatory advantage as well
> as far as symptoms are concerned, or toxicity, or quality of life. So,
> one month in the hospital, you know, on IV morphine, or whatever, is
> not necessarily something that I would be aiming toward. I would want
> that in a small survival difference.
>
> DR. TEMPLE: We don\'t really have authority to refuse a drug because
> its advantage over other therapy isn\'t big enough. We have said
> publicly that in oncology, unlike many situations where we would be
> obliged to approve something even if it was inferior, we would not
> feel obliged to approve an inferior cancer drug because there are
> serious consequences to that. But to insist that it be better is
> really not within our statute. It doesn\'t have to be better.
>
> It is important to make the distinction between showing that you are
> better as a way of showing that you work at all, which is what a
> superiority study does, and showing that you are better because you
> have to show you are better in order to be approved. You really don\'t
> have to show you are better to be approved. The statute and the
> legislative history is very clear that they were not trying to set a
> relative efficacy standard, much as one might want to know that a new
> drug was better. But we can\'t insist on that. What we do is we find
> superiority studies interpretable so that they show that the drug
> works. They also happen to show that it is better but that is in some
> sense incidental.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: It seems to me that a couple of things may be helpful.
> One is that we have diseases, hematologic malignancies or breast
> cancer being examples, where there are a lot of therapies that are at
> least somewhat effective and that probably do impact survival. How one
> stacks up a new therapy at a given stage in that setting and how one
> stacks up a new therapy in, say, disseminated melanoma where I think
> there is probably no generally accepted treatment that dependably
> improves survival are just going to be different scenarios and you
> almost have to have different rules there.
>
> The other thing that has to be factored into this, but there is not a
> very quantifiable scientific way that such a committee always does, is
> to try to balance benefit and toxicity. Richard Gilber\'s analysis in
> breast cancer is one reasonably validated, not very scientific but it
> is an effort to quantify this kind of balance. I am not suggesting
> that we all adopt that but it is that kind of balance that I think is
> going to have to be left as a non-quantifiable but important aspect of
> this.
>
> DR. PRZEPIORKA: Bruce?
>
> DR. REDMAN: I think it is important\--in reading the question, you are
> asking about comparing in a randomized trial against drugs that have
> proven survival benefit. I think that is a kicker because there are
> Phase III trials out there with a survival endpoint and the comparator
> is a drug that has never been proven to show survival. It may be
> approved. Melanoma DTIC, and DTIC has never been shown to improve
> survival but it is used as a comparator. It may actually shorten
> survival; we don\'t know. So, if you are going to accept survival it
> has to be compared against a drug or a therapy that has been proven to
> affect the survival, or one that we think does.
>
> DR. TEMPLE: Right. In a situation that you describe we would never
> accept non-inferiority as meaningful, obviously, but if it was
> superior, and ignoring your concern that the control might actually
> shorten survival\--that is a big problem because you do have to assume
> it is at least neutral, in a study like that you would have to show an
> advantage over the available therapy and the available therapy would
> just be there as your placebo equivalent.
>
> DR. REDMAN: Then the advantage of that has to be predetermined up
> front, what is acceptable. Then we are back to what Dr. Cheson was
> saying. You know, what is acceptable in stage IV untreated the same as
> the advantage in stage IV in someone who has received two prior
> treatments, specific in lung cancer, melanoma, kidney cancer.
>
> DR. TEMPLE: I mean, historically we have taken the position with the
> committee that if there is no available treatment that works for
> people we grant accelerated approval based on a showing of tumor
> response, time to progression, anyone of a number of non-clinical,
> borderline clinical endpoints. We would never worry if somebody
> managed to show improved survival and, as Grant said, even modestly
> improved survival. That has always been the basis for approval if you
> can show it. What you can show is really determined by the sample size
> you choose at the beginning as much as anything. I suppose if you made
> the study big enough you could show improved survival that a lot of
> people wouldn\'t think is very important. Historically, you would
> probably advise us to approve it anyway. That has been the pattern up
> till now.
>
> DR. PRZEPIORKA: That is a very telling comment that you just made
> though since we are supposed to be approving drugs on the basis of
> clinical benefit, but I think I just heard you say, if I can
> paraphrase this correctly, that we always approve drugs on the basis
> of survival even if people don\'t think it is a very meaningful
> survival.
>
> DR. TEMPLE: Yes, in practice studies are hardly ever large enough to
> show a completely trivial effect. So, we are in the 2-month, 2.5-month
> area and the recommendations we have gotten and our actions have
> usually said that is good enough in solid tumors; that is the best you
> can hope for so far.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Could I address the second part\--
>
> DR. PRZEPIORKA: Yes, please, yes.
>
> DR. GEORGE: \--the confounding thing? This always puzzles me somewhat.
> If you have two therapies, let\'s say A and B, and then you have some
> other therapies that would be given after, say, recurrence or at some
> later point and often you don\'t have very good evidence that they
> have any effect, first of all. You might assume they do just to
> explain away the reason you didn\'t get any difference in survival.
> But whether or not they do, let\'s suppose that happens. You had a
> strategy of giving A and B followed by whatever is available at the
> time that they have recurrence, and let\'s suppose that that treatment
> does have some effect and sort of obliterates any potential survival
> effect you would have gotten if you had done an unethical study, say,
> to force people to stay on treatment and not give them anything else
> no matter what happens\--you couldn\'t do that, of course,
> ethically\--so what is the overall conclusion you would come to? To
> me, it is that the treatment strategy you started off doing with A and
> B didn\'t work in terms of the outcome of overall survival in the
> context of that disease and in that setting with other potentially
> available therapies. So, in fact, if treatment A was the comparator
> and treatment B was the new treatment, in terms of overall survival
> you would say it doesn\'t have an effect. That is a simple answer.
>
> Now, in terms of whether it is approvable, that means you had better
> have thought through other endpoints that you might be trying to use
> to get it approved. But in terms of overall survival it didn\'t work
> and it is not worth all the discussion about, well, maybe it was
> because we had all these other therapies or maybe it was this or that.
> The fact is it didn\'t work in this setting at this time.
>
> DR. TEMPLE: The trouble is if the only endpoint that leads to approval
> was survival, then this active drug has just failed.
>
> DR. GEORGE: Exactly.
>
> DR. TEMPLE: Even though if there weren\'t other therapies it would
> have been active in the usual sense. That is the problem.
>
> DR. GEORGE: That just means you had better come up with the right
> endpoints and you had better not be using overall survival.
>
> DR. TEMPLE: That is what we are here for.
>
> DR. GEORGE: Well, I am just pointing out that people spend a lot of
> time discussing why it didn\'t work in terms of overall survival.
>
> DR. TEMPLE: But that is because historically there has been a bias,
> not surprising and not unreasonable, in favor of a survival outcome
> because everybody knows that is tangible, that is a real benefit with
> some expressions of concern even about that. That is hard-wired. It is
> not subject to interpretation too much and everybody likes it. The
> trouble is the very things you are talking about can obliterate the
> ability of a drug that could be valuable to show its effect. That is
> what our trouble is, especially if the crossover is to the very drug
> that is being studied which happens for any marketed drug all the
> time.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: Harking back to something Dr. Rodriguez said, these
> diseases aren\'t failing these drugs. They are different diseases
> looking for the right therapy. We have certainly learned that in the
> hematologic malignancies where we started with, you know, leukemias
> and now we have separated them out into a myriad of different
> diseases. When we approve drugs, as we have seen recently, we are
> going to miss active drugs because the population in which they work
> is obscured by all the patients for whom the drug doesn\'t work, and
> there are some drugs that you all are approving that only work in
> small populations of a certain disease and, yet, they are getting
> generalized to the disease group at large and both of these are
> unfortunate circumstances for a variety of reasons. So, I think we
> need to recognize\--and we certainly will be doing that more and more
> and we certainly do this in leukemias and lymphomas\--that these are a
> bunch of very different diseases and we are going to have to be
> studying them like that. Instead of studying non-small cell lung
> cancer, we are going to have to find out, you know, what are the
> different subsets and how they respond differently to drugs like
> Iressa etc., else we are just going to miss effective drugs and we are
> going to be spending a lot of money on ineffective therapies for
> patients in whom they don\'t work.
>
> DR. PRZEPIORKA: Dr. Grillo?
>
> DR. GRILLO-LOPEZ: I want to go back to what Dr. Rodriguez and Dr.
> Levine said earlier and add to what they said, that another
> consideration in choosing the appropriate endpoint and having an idea
> of what the expected magnitude of the effect should be is whether you
> are evaluating that new agent as monotherapy as opposed to that new
> agent within a combination therapy. If you are evaluating it as
> monotherapy and you are comparing it one-on-one, like the DTIC example
> that was provided by Dr. Redman, then I believe a survival endpoint
> becomes even less desirable because it is seldom that you see a single
> agent be curative in any malignancy. There are some exceptions but
> this is seldom.
>
> The other extreme is when you are evaluating within a combination
> therapy. Now, we do have combination therapies that are curative in at
> least some percentage of patients with certain tumor types. However,
> how long did it take us as a research community to find those optimal
> combinations? It takes years and years and years. Consider in your
> minds the ones that are available and you know how long it took to get
> there. It took many years after approval. Now, are you saying that you
> would deny the oncology community the opportunity to research this via
> an approved drug that can be worked into a combination, or that you
> would deny patients a drug that has shown efficacy in Phase II, that
> has reasonable activity, because you have not determined the optimal
> combination that would be curative and then you can use a survival
> endpoint? I would say no, you can\'t do that. Other endpoints are
> suitable to that outcome because it is very unlikely that during
> development, pre-approval, you are going to have the optimal
> combination identified.
>
> DR. PRZEPIORKA: Dr. Williams?
>
> DR. WILLIAMS: There is an underlying question that I don\'t think has
> really been heard. Let me just give you a situation. You have a
> marginal survival benefit out there. You are accepting TTP now; you
> believe in it as clinical benefit, let\'s say, but you are getting now
> this survival benefit over here so there are a couple of different
> settings. One is something like fairly marginal, two-month median
> survival increase. You have a trial over here that is not even going
> to evaluate that; it is just going to use time to progression alone
> because of its clinical benefit too.
>
> So, what is the tradeoff here? When do you have a survival effect here
> that is so significant that you can\'t do that trial; it is not
> ethical basically to use TTP to approve a drug? You wouldn\'t make the
> tradeoff for TTP because you have something else over here that is so
> good. One setting would be that you compare directly to this drug and
> you beat it in TTP. If you accept TTP, would that lead to approval?
>
> Another would be that you evaluated TTP in another setting and you
> didn\'t beat it; you just showed that you had a TTP benefit. The
> question is when does the survival effect proven in one setting affect
> you so much that you can no longer accept this endpoint in another
> setting?
>
> The way this happens is we have trials coming along. All of a sudden,
> one of these drugs is approved based on some survival benefit. It
> might be a little one; it might be a big one. Then, at what point does
> that become so significant that it affects your ability to consider a
> different endpoint such as TTP?
>
> So, that is the tension that I want to hear some discussion on. For
> instance, in the colon cancer setting, the lung cancer setting where
> you have one- or two-month survival benefit, does that then mean that
> you wouldn\'t even look at TTP as a separate benefit or that you would
> only look at it if you were beating that drug that had the little
> survival benefit? So, when I am talking about the size of survival
> benefit it is not necessarily would you approve it based on survival
> but how does that trade off and affect you looking at other endpoints?
>
> DR. PRZEPIORKA: If I hear your question correctly, when would we
> actually insist on using survival as an endpoint and not use anything
> else?
>
> DR. WILLIAMS: That is assuming that originally you had already
> accepted another kind of endpoint, such as TTP.
>
> DR. TEMPLE: I assume this comes up because of the disconnected nature
> of the approvals. If there was something out there that had a survival
> benefit you would compare the new drug with it because you couldn\'t
> really not.
>
> DR. WILLIAMS: That is a question though. If you have a very small
> survival benefit you either have to say I am going to beat that drug,
> do a non-inferiority study which is impractical, or this is so small
> that it is not of any real meaning.
>
> DR. TEMPLE: But it would be the standard and everybody would use it,
> but what you are saying is now you have just suddenly discovered
> something and you have all these people developing drugs without a
> comparison out there because they didn\'t know about it.
>
> DR. PRZEPIORKA: Dr. Reaman?
>
> DR. REAMAN: These trials are being designed and conducted to
> demonstrate a clinical benefit, not to dictate and define what the
> standard or a new standard is going to be. Correct?
>
> DR. WILLIAMS: Yes, we don\'t do those kind of trials. We don\'t do
> trials to develop standards. So, yes, they are all being developed for
> clinical benefit but it is a different nature of clinical benefit
> here, the survival versus other drugs which might be TTP, let\'s say.
>
> DR. REAMAN: But I think the question you raise really has to be
> considered within the context of the disease and the patient
> population in which the study is being conducted. I just don\'t think
> there are any absolutes that can be given, yes/no, will we always
> demand survival as the ultimate endpoint and can time to progression
> replace it.
>
> DR. TEMPLE: Can I refine the question a little more? I guess if there
> were something that had a major effect in a particular setting, stage
> of disease\--let\'s leave leukemias and cures, but had a major effect,
> most people would think the right way to develop a new drug is to
> compare it with that drug or add it to it or something like that.
> Right?
>
> So, I think Grant is asking if you developed something that had an
> effect like that while other studies were going on that were looking
> at response rate, time to progression, would you be happy approving a
> drug not knowing how its survival effect compared to this thing that
> is now there? That is very important to people who are developing
> drugs without knowledge of what other people are doing at any given
> time. Does that capture your question?
>
> DR. PRZEPIORKA: Do you have a response?
>
> DR. REAMAN: I would say yes. I mean, it may take a very long time to
> know about some of the impacts of drugs being approved and the impact
> that they could have on survival long-term, particularly using
> combinations.
>
> DR. PRZEPIORKA: Dr. Grillo?
>
> DR. GRILLO-LOPEZ: I have to say this is fun. I am practically jumping
> out of my seat here to address what Dr. Temple said. I did that. I
> developed Rituxan and we didn\'t find out until after the year 2000
> that it was adding to the cure rate in intermediate grade lymphoma. We
> presented it to you for low grade lymphoma in a relapse or refractory
> setting, where survival was not an issue because it was not the
> appropriate endpoint, and you approved it. So, this is an example of
> an agent that had the potential of being curative within in a
> combination but got approved earlier on for relapse/refractory
> combination with a single-arm trial where survival was not the
> endpoint, and it was a regular approval.
>
> DR. TEMPLE: Yes, we are well aware that the initial approvals of drugs
> do not define their total use in the community. One of the reasons for
> accelerated approval was a barrage of arguments, often from the
> oncology community, that said, look, if you don\'t have the tools to
> do it, it is just impossible to develop drugs properly. Within limits
> at least, we bought that idea. That is why half of all drugs at least
> are now approved under accelerated approval based on response in
> refractory disease, the thesis being if refractory disease responds it
> is probably useful other places, and people are going to do studies,
> there will be cooperative studies and all that.
>
> So, I think there isn\'t any particular debate about that question.
> There still is a lot of concern about what the standard should be
> given past guidance we have gotten for other kinds of approvals, not
> really most about accelerated approval which is sort of at least
> moderately settled if we know we could get the definitive studies done
> later. It is what should the standard be in first-line therapy given
> sample sizes, given crossover, and maybe that should be different from
> one tumor to the other. That is one of the things you are talking
> about.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: Regarding Dr. Williams\' question, I guess a lot
> depends\--you know, if you are talking about two randomized trials and
> if the comparator in the two trials is different, if the comparator
> arm is different and one shows a survival advantage while the other
> one was powered to show a time to progression advantage, I mean I
> guess you are never dissolve ODAC, you are going to have to ask
> somebody. I don\'t know the answer.
>
> But if the comparator is the same and you said to them at the end of
> Phase II, listen, we will accept this as a valid endpoint as a
> clinical benefit, I think you have to.
>
> DR. WILLIAMS: But it sounds like it is a value judgment and basically
> there is no over-arching rule that we are going to apply across the
> different diseases and it will be a case-by-case kind of discussion.
>
> DR. PRZEPIORKA: I think we have beaten survival to death\--
>
> \[Laughter\]
>
> Just to summarize, I think we started out with excellent philosophical
> points from Dr. Grillo, which is that survival is a goal but not
> necessarily an endpoint, and that survival can be biased, as is
> pointed out in the questions, by subsequent therapy that is not
> standardized. However, under those circumstances we have to ignore the
> confounding factors if the original agreement was that we would look
> at survival; we should have different guidelines for each biological
> subset, meaning the disease, the status or any biological subset
> within a disease or disease status. At this point we can\'t demand
> survival under any specific certain circumstances. Everything has to
> be looked at individually.
>
> Any other comments to add to that? Dr. Fleming?
>
> DR. FLEMING: Well, it may be just a bit of a reinforcement but, to my
> way of thinking, choice of endpoints ought to be based on what it
> would be the patients really care about. In oncology, certainly,
> cancer has a huge effect on duration of survival and, certainly, from
> a patient\'s perspective to prolong survival would be of profound
> importance. That doesn\'t mean though that that is the only benefit
> that patients would look to. I would go back to Mr. Katz\' comments,
> there may well be other measures but I would ask that we distinguish
> whether those other measures unequivocally reflect tangible benefit to
> patients. Others that do, that we have heard a lot about, are
> disease-related symptoms or, as he was talking about, patient\'s
> functional status, being able to carry out normal activities.
>
> Those would all be very tangible benefits. Those need to be put in
> contrast to the mechanisms by which we hope to achieve those benefits.
> In oncology classical measures would be tumor burden type measures
> such as response and time to progression. But I would only caution it
> may well be that we affect those measures which are the treatment
> mechanisms without, in fact, impacting the clinical endpoints of
> interest. I would argue then that our primary endpoints for
> registration should be these measures that unequivocally reflect
> tangible benefit or, as we will talk about a little bit later on,
> measures of biologic activity that have been validated.
>
> I would like to reinforce one more thing that Dr. George pointed out,
> and that is the argument that has been given against survival is that
> it may be impacted by subsequent interventions. I would argue again
> from a patient\'s perspective that the goal here is to formulate
> regimens which, when implemented in the best standard care approach in
> clinical practice, would prolong survival and improve quality of life.
> So, if I randomized to an experimental therapy against a control and
> secondarily supportive interventions allow for equal survival to be
> achieved, that is the truth. That is the truth. Even if the
> experimental therapy would give you an improvement in time to
> progression, if supportive care improves in the control arm such that
> there is no difference, that is the truth.
>
> Now, it may be though that we have the wrong endpoint. In this case
> there may be clinical benefit in other measures. It may be that we are
> reducing the need for other toxic interventions, etc., in which case
> those factors need to be considered as well.
>
> But the one thing that complicates this, and what Dr. Temple referred
> to before, is if best supportive care isn\'t what is being delivered
> to the control regimen but, rather, cross in to the experimental
> therapy so that you are looking at experimental now versus
> experimental later. That is answering the right question if you have
> established that experimental is efficacious and you are just looking
> at what is the optimal timing for delivery.
>
> But it is a circular issue if you are really trying to find out
> whether or not it is truly effective. I realize going down this path
> is going to be a very complicated pathway but I question the ethics
> and the scientific validity of crossing in to an experimental therapy
> that hasn\'t been established to be effective. Is it imperative to do
> so? No, it is not. An example would be the Evastin trials that have
> just been done in advanced colorectal cancer. Is it possible if you do
> that you will still be able to show benefit? The answer was yes, as
> was seen with Herceptin in advanced breast cancer.
>
> But in general, as Dr. George had pointed out, crossing in to a best
> available standard of care is the scientific question of interest.
> That is not a bias. That is not diluting survival. That is the true
> effect on survival and if you are not going to impact survival in that
> way, then a different measure could be the relevant approach but it,
> again, should be a measure that unequivocally reflects tangible
> benefit.
>
> DR. TEMPLE: I just want to make a distinction between the best
> treatment of cancer patients and whether this drug is an effective
> drug because they are not the same thing. Tom, you are saying that if
> order doesn\'t matter, if you are studying drug A versus some
> treatment and now, when you progress everybody gets some other drug,
> if that drug turns out to be effectiveness enough, not necessarily
> more effective than the test drug but equally effective, say, it could
> obliterate or substantially reduce the apparent survival effect.
>
> Now, that may be true information and useful information for the
> community of people treating cancer but it gives you the wrong answer
> on whether drug A works if survival is your endpoint. And, that is our
> worry. Also, if the drug is already available, if you are talking
> about a Phase IV study, you can rail about the undesirability and lack
> of ethics of crossing people over to the test drug but they are all
> going to be crossed over to the test drug anyway despite your view,
> which means that in many cases the confirmatory studies we want are
> perfectly predictably going to be much less powered than you wanted
> them to be in the first place. That is a consequence of insisting on
> survival.
>
> So, I need to press this point because it comes up in conversations
> all the time and it is very important for us to distinguish between is
> this an effective drug and, therefore, should be marketed and what is
> the best way to treat people. It may be that, you know, using the
> other drug first is just as good, or the sequence matters, or any one
> of a bunch of conclusions. That is all fine. But what we want to
> figure out and we want to be able to tell people who come to us for
> advice how to figure out is what do you need to do to show that the
> drug works. And, I am very worried about survival where crossover is
> either predictable or unavoidable for the reason I gave before. I am
> sure somebody could model this. You probably need studies four times
> the current size, five times the current size. l
>
> So, if survival is going to be the endpoint at least in certain
> settings, then everybody has to sit down and say, okay, we are not
> going to allow crossovers or we are going to try as hard as we can to
> prevent them, or we are going to do studies five times the size we are
> doing. You can\'t keep saying survival is the endpoint and not account
> for those things or then you get failure to meet the desired endpoint
> and then you are scuffling for what you really meant in the first
> place.
>
> I am hoping for real straighforwardness in this. If that is really, in
> practical terms, almost impossible to do, then we should hear that and
> not advise people to try to do it because they are not likely to be
> successful if the thing they cross over to is active, or somebody
> should model these things. It wouldn\'t be very hard. We could all do
> it. I couldn\'t but you could. We could model what the consequence of
> crossing over to an active drug is. You could calculate what the
> effect on power would be. But we really need to know the answer
> because otherwise we can\'t give anybody intelligent advice.
>
> DR. PRZEPIORKA: Dr. George, last comment?
>
> DR. GEORGE: Just to follow-up on that a little bit, you certainly
> could model it but it would be based on assumptions. And, one of the
> assumptions that seems to be behind this worry about the crossover is
> that when you cross over that agent that crossed over to, the same
> one, is going to have equal effect. In fact, that might entirely be
> wrong.
>
> DR. TEMPLE: Fifty percent.
>
> DR. GEORGE: Well, even if you assume some percentage, you just don\'t
> know. That is why you are worried about it I guess. But I think there
> are examples that show it is the timing of it that is critically
> important. So, later, at progression, it may not have the same effect
> or maybe a very small effect so you could still get a survival
> benefit. But I think your point is correct that you just have to think
> clearly about those endpoints, and if you think there is a possibility
> that that could occur survival may not be the best thing. You may get
> the right answer in terms of the strategy of using it but the wrong
> answer in terms of whether it is an effective agent.
>
> DR. PRZEPIORKA: Let\'s move on to the questions regarding disease-free
> survival. The FDA has stated that disease-free survival can support
> regular drug approval in cancers where the majority of recurrences are
> symptomatic. Others propose that prolongation of disease-free survival
> should support regular approval in all clinical settings because a
> delay in cancer detection or a delay in the need for toxic cancer
> treatment is of clinical benefit.
>
> So, question number three is discuss whether disease-free survival is
> generally an adequate endpoint for approval of cancer drugs or whether
> additional evidence is needed, such as data demonstrating or
> suggesting that disease-free survival is a survival surrogate. So, I
> guess the question is, is disease-free survival an endpoint or is it
> only a surrogate. Dr. Brawley?
>
> DR. BRAWLEY: I think they are two different things. I think
> disease-free survival without increase in survival could be a patient
> benefit. This is a purely hypothetical example where the patient\'s
> disease is suppressed for a prolonged period of time. The patient is
> without symptoms because of that suppression of disease. When that
> disease comes back and flares up perhaps even more aggressively, than
> if it had not been suppressed by the original drug\--a purely
> hypothetical position, I think there is patient benefit there.
>
> So, again, I am lapsing into what Dr. Cheson and Dr. Rodriguez have
> stressed before, that it is a disease specific entity and perhaps Dr.
> Redman is correct that we are going to prolong the life of ODAC by
> making these arguments but I really do think you can use disease-free
> survival.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: I was just thinking but, no, I do agree with Dr. Brawley.
> I think disease-free survival is important, that the patient has no
> disease. The patient is generally seeing the doctor less commonly, has
> less complications, no treatment, less lab tests. So, even if there
> isn\'t a survival benefit there is generally a quality of life benefit
> and certainly the patients, as was mentioned before, would rather not
> have disease than to have disease around but it is just not
> progressing. But certainly from the quality of life aspect, visits and
> labs, and all that stuff, it is clearly a benefit. Now, whether that
> is important for regulatory approval of drugs is I guess something we
> are talking about.
>
> DR. PRZEPIORKA: I would just like to add that I would also agree that
> disease-free survival is of actual importance, not a surrogate
> specifically in the leukemia patients. Patients we acute leukemia who
> relapse end up having to drop their job; put their lives on hold; get
> back to the hospital and be on therapy for another six months. And,
> being able to delay that by one or two years makes a huge difference
> in their life, especially in young adults who are primary care givers
> in a family. So, I don\'t think disease-free survival as an actual
> endpoint should be limited to the adjuvant setting. There are some
> diseases now with very high response rates where disease-free survival
> could probably be a good endpoint. Dr. Taylor?
>
> DR. TAYLOR: Well, I would agree that disease-free survival is a good
> endpoint but I think, again, you have to go back to it being very
> individual because some of the therapies we use to maintain a
> disease-free survival are very toxic, as with interferon with melanoma
> patients and it is something that you have to really weigh for each
> disease and each drug. I don\'t have any problem with disease-free
> survival but it may not be important if that entire time is spent
> doing high-dose chemotherapy and seeing the doctor anyway. Bruce
> already pointed out if you are going to have less doctor visits and
> less troublesome and better quality of life, that is an important
> aspect of it.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: I just wanted to be clear on this. This is a composite
> endpoint. It obviously can be closely related to survival just by
> definition almost. You know, if you die without a recurrence, I mean,
> that is an event in disease-free survival. So, it is going to be
> important to know in whatever setting we are talking about what is the
> likely percentage of patients that that might occur for. What are the
> sort of competing risks of death in the given disease setting you are
> talking about, and what is sort of known about the expected
> distribution about time from recurrence to death. Those are important
> considerations about whether this is going to be an important
> endpoint. I think in general it is a fairly good endpoint in a variety
> of settings because of those things but it just needs to be
> considered.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: I think this is a critical area. I talked about
> balancing whatever these considerations are with symptoms. To be a
> little bit more specific, disease-free survival without major symptoms
> of disease or major symptoms of treatment is something that I think
> almost all of us would say would be important. The bigger the impact
> of disease symptoms, the bigger the impact of symptoms from treatment,
> I think you would have to down-regulate that same benefit.
>
> DR. TEMPLE: Wouldn\'t you presume that there are no symptoms from the
> disease if you are disease free? I mean, what would we be meaning if
> not that?
>
> DR. CARPENTER: Well, let\'s give an example of allogenic bone marrow
> transplantation. You have no leukemia after your transplant but you
> have graft versus host disease which compromises your quality of life.
>
> DR. TEMPLE: No, I understand about toxicity but not\--
>
> DR. CARPENTER: If it is disease-free, then you are free of disease and
> you have no symptoms from the disease. You are right.
>
> DR. TEMPLE: Yes.
>
> DR. CARPENTER: Absolutely.
>
> DR. WILLIAMS: Dr. George, you mentioned duration from recurrence to
> death. I guess what you are saying is if there is a longer duration
> between recurrence and death it is a less important phenomenon.
> Perhaps for instance, you know, PSA recurrence in prostate cancer
> might be many, many years. Is that what you meant?
>
> DR. GEORGE: This needs to be considered. For example, if you have a
> very short time from recurrence to death you really are talking about
> sort of the same thing, especially if you have a lot of deaths that
> occur without recurrence. But, you know, you need to know that in a
> given setting because when you look at disease-free survival, for
> example in a setting where there is a long time between recurrence and
> death the curve is going to look real short and fast and then you have
> to kind of worry about that translation and relationship to survival.
> But that doesn\'t mean it is not a good thing. I think it is a very
> valid endpoint in many settings and is a good one.
>
> DR. PRZEPIORKA: Mr. Katz?
>
> MR. KATZ: Actually, what I wanted to cover was covered. I would just
> agree that definitely, you know, for a patient\'s standpoint it is a
> benefit to have increase in disease-free survival.
>
> DR. PRZEPIORKA: Dr. Reaman?
>
> DR. REAMAN: I would just argue that I don\'t think disease-free
> survival always connotes the absence of symptoms for every disease.
> Certainly, individuals who have had surgical interventions for
> management of their initial disease may have long-lasting symptoms as
> a result of that. Patients with brain tumors may similarly have
> symptoms which aren\'t going to disappear. I also agree with Dr.
> Przepiorka that disease-free survival should be an endpoint and not
> necessarily be considered as a surrogate for survival.
>
> DR. PRZEPIORKA: Dr. Levine?
>
> DR. LEVINE: I was going to say the same about surrogate. This is not,
> to me, a surrogate; this is a valid endpoint. The only other point
> that I would like to mention is that if this is the only endpoint you
> will exclude some drugs perhaps unnecessarily. In other words, to get
> into that equation you have to be a responder in some sense and there
> may be other benefits of drugs that we are going to talk about later.
> But, to me, this is an extremely valid, real endpoint.
>
> DR. TEMPLE: Well, you almost need either the adjuvant setting or
> something where there are a lot of complete responses or something not
> commonly seen in solid tumors certainly.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: My own sense of whether I would consider a surrogate or
> not a surrogate would depend on the setting. We have heard a number of
> different potential benefits that could arise or could be accrued by
> having a delay in disease-free survival. One is if, in fact, this is a
> disease where at recurrence there is clear and frequent, if not
> standard, occurrence of symptoms, then clearly it is, in fact, a
> direct measure of clinical benefit.
>
> One, of course, might argue that if that were the case then a direct
> symptom outcome measure ought to be able to also show that overall
> benefit. It has also been argued that there are potential
> psychological effects where, if we delay recurrence or detection of
> recurrent disease, there is that overall benefit to the patients. I
> would also accept that although that psychological benefit I would
> consider to be of much less profound importance than an actual delay
> in death.
>
> As has been pointed out, what is the tradeoff in benefit to risk? If
> what we said is we are going to delay by six months or a year the
> knowledge of recurrent disease, how much toxicity would you accept for
> that benefit against saying I am actually going to prevent the
> recurrence of disease; I am curing you of this cancer in 25 percent of
> the patients? I would consider that, as a patient, a far more profound
> piece of information, that I have a 25 percent increased chance of
> being cured than a delay in a year of the time in which I am going to
> have recurrence of disease.
>
> So, it does become important to understand what it is that we can
> reliably conclude from a delay in disease-free survival. It is in
> part, in those cases where it is symptomatic disease, a direct
> clinical efficacy endpoint. In cases where it isn\'t it could also be
> a very relevant measure but now it is in the arena of a surrogate. We
> have to be able to know whether or not a delay in disease-free
> survival is reliably telling us we have a delay in death.
>
> Maybe later in the discussion I will comment that there are specific
> standards that are emerging for what that evidence would have to be,
> but at this point I want to just distinguish that there are two
> different realms in which disease-free survival would be of interest.
> One is a direct clinical endpoint through the symptom aspect and
> another is through its surrogacy for survival.
>
> DR. PRZEPIORKA: Dr. Reaman?
>
> DR. REAMAN: I guess I am still unclear about the symptom issue and why
> it would be a surrogate for survival. I am not aware of any disease
> that is easier to manage once it recurs. So, I don\'t understand why
> disease-free survival couldn\'t be an endpoint for determining
> clinical benefit. It is a clinical benefit if you prevent something
> from recurring.
>
> DR. FLEMING: Yes, I think what I was saying is if, in fact, there was
> something tangible, such as symptom prevention or occurrence of
> symptoms or the psychological benefit, those are, in fact, direct
> clinical benefits. But that is separate from whether this is also
> predicting a prolongation of survival.
>
> DR. REDMAN: But if it prevents the disease from coming back it could
> be predicting a prolongation of survival.
>
> DR. FLEMING: Well, in fact, that is the hope and, yet, there needs to
> be some validation. Of all surrogates, this is one that tends to be
> much more plausibly valid, that if we can delay recurrence of disease
> we are very likely to be prolonging survival.
>
> DR. PRZEPIORKA: Mr. Katz?
>
> MR. KATZ: I think given the fact that we are talking about diseases
> which can\'t be cured, I think we have to view this in terms of
> providing patients with options that they might not otherwise have
> that a rational person could perceive to be a benefit. Something like
> disease-free survival may be absolutely critical to someone based on
> where they are in their life. Someone may be in a position where being
> able to function without the disease for some number of years may be
> critical to putting their family in a financial position so they feel
> they have done the right thing. I mean, there is a lot of theory
> around this but I think it is all about patient options and that
> clearly provides patients with options that they don\'t have.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: I was going to say something similar. Most of the
> situations we are dealing with here have to do with new agents for
> solid tumors and, in fact, curative medical treatment is generally
> unavailable for all these. So, things based on a theoretical increase
> in cure are a little bit far out. Whereas, things that keep your
> disease from coming back for a tangible period of time or that keep
> your disease simply controlled for a tangible period of time seem to
> be a very direct benefit for that person.
>
> DR. PRZEPIORKA: Dr. Brawley?
>
> DR. BRAWLEY: No.
>
> DR. PRZEPIORKA: There are two very interesting questions that are
> lumped into number four which come to the meat of what we do when
> things come here. Consider whether the adequacy of disease-free
> survival varies with the clinical setting in terms of an endpoint. B
> is treatment where the investigational drug shows prolongation of
> survival when randomized against an effective standard therapy where
> the standard therapy has already been shown to impart a survival
> benefit.
>
> Would this august body be inclined to recommend approval based on
> disease-free survival for the investigational drug when compared
> against a drug that has already been shown to have a survival benefit?
> Dr. Carpenter?
>
> DR. CARPENTER: Yes.
>
> \[Laughter\]
>
> DR. CHESON: This gets back to what Dr. Fleming was talking about
> before, that it is a bi-functional endpoint, the surrogate nature and
> the non-surrogate nature. Again, it is going to vary a bit with
> disease but I think in general\--and I would think also when we were
> talking about time to progression before, it is not like you looked at
> survival and you didn\'t look at all the other endpoints along the
> way, like response rates and time to progression and disease-free
> survival. So, you will have some parameters to compare to this drug or
> this regimen that caused prolongation in survival and also had some
> point of disease-free survival and also had some time to progression
> and also had some response rate, looking at it backwards. So, you do
> have something to compare it against, which may give a little more
> support to using it as a surrogate endpoint in that particular
> condition.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: And from a regulatory standpoint you just told us it
> doesn\'t have to be necessarily better to be approvable. It just has
> to be would we consider this evidence of effectiveness, and I think
> probably so.
>
> DR. TEMPLE: Yes, I think B goes to, you know, you have one thing that
> shows that you know has an increase in actual survival. Now comes
> along something that is actually better on disease-free survival which
> you don\'t know the effect on actual total survival. How worried would
> you be not knowing that last?
>
> DR. CARPENTER: Well, if you were to grant accelerated approval, I
> would think that would be the very right setting and you would hold
> that other in abeyance\--
>
> DR. TEMPLE: That is okay, other people would also want to know whether
> they could get regulatory approval on the basis of being superior to a
> drug that is already hot stuff in one measurement that isn\'t ultimate
> survival.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: I sort of agree with the statement that that would be fine
> but I would really like to see the data. What if the disease-free
> survival advantage was compared with the second-line regimen that
> prolonged the survival of the standard therapy that was given after
> those patients relapsed and they lived longer because they had the
> second therapy and now you have brought it up front-line and there is
> no second-line?
>
> DR. WILLIAMS: This is disease-free survival here.
>
> DR. REDMAN: No, no, but something that has shown overall survival
> advantage. It may be that the overall survival advantage is then
> partly due to the regimen that you are now bringing up front.
>
> DR. WILLIAMS: Well, I think what the question is meant to say is that
> you have a treatment that does improve disease-free survival. We know
> that; it is not secondary therapy. You have another treatment that
> comes along. It is either under-powered or the data aren\'t yet mature
> enough and it beats that treatment in disease-free survival but you
> don\'t yet know that it has the survival effect yet it is better in
> this surrogate or also maybe clinical benefit endpoint itself. Is that
> enough or are you going to be nervous about approving it until you see
> a lot more survival data?
>
> DR. REDMAN: I guess I would have to know what the agents are, what the
> disease is. I mean, overall what you are saying is intuitively
> correct. If it beats it in disease-free survival and, you know, the
> other one has gone out longer and shown an overall survival advantage,
> yes. But I couldn\'t in a blanket way say that.
>
> DR. PRZEPIORKA: And I think a number of folks have already indicated
> that under the right circumstances disease-free survival is the
> endpoint. So, we would not be so worried about survival to demonstrate
> efficacy as opposed to let\'s look at the survival information when it
> is available for safety. Dr. Keegan?
>
> DR. KEEGAN: Yes, I would like you to actually revisit the right
> circumstances because the right circumstances seem to be integrally
> involved with the toxicity of the agent. I think this is important if
> we need to meet with sponsors and tell them, well, it depends upon how
> toxic you are and your evaluation of the toxicity of this agent and
> the impact on the quality of life of the patient. Are you suggesting
> that for an agent which has more than minimal toxicity for adjuvant
> treatment or more than extremely short course that we need to be
> measuring some aspect of the quality of life and, if so, what aspects
> do you think are important? Because if, in fact, they lose on that
> they have to have as a backup plan a trial powered to look at
> survival.
>
> DR. PRZEPIORKA: Dr. Grillo?
>
> DR. GRILLO-LOPEZ: Although there are exceptions, usually you are going
> to be evaluating an agent versus a combination therapy which may have
> some prolongation of survival and all of the issues of single agent
> versus combination come up again. It is unlikely that even though you
> are using the experimental agent within a combination that it is the
> optimal combination ever to be found with this agent. So, I would say
> in that situation disease-free survival is still a good endpoint.
>
> If you are doing a single agent study, single agent versus single
> agent, standard single agent and experimental single agent, and you
> have a standard therapy that cures 100 percent of the patients and is
> totally free of adverse events, then disease-free survival is not the
> appropriate endpoint but I can\'t think of an example.
>
> DR. KEEGAN: What about, for instance, areas where there is not a
> curative standard adjuvant therapy accepted so it would be single
> agent against observational control? I mean, obviously, it can\'t be
> less toxic than an observational control so what components of
> toxicity should be evaluated? What are the important factors? One
> thought that was mentioned was that the individual is able to work and
> carry on all their activities of daily living. Is that the important
> component, you know, as opposed to just collection of adverse event
> information, which is hard to put into context of impact of a
> patient\'s physical functioning sometimes.
>
> DR. PRZEPIORKA: Dr. Levine?
>
> DR. LEVINE: A couple of thoughts. I differ a little from the group. In
> this example, B, my thought would be if we do have a curative regimen
> at some level, whatever it is depending on the disease, and now you
> have another drug which shows prolongation of the disease-free
> survival, in that setting I would say that is the surrogate marker.
> This, to me, is what accelerated approval should be all about. It is
> highly likely to convert into a survival benefit in the future. You
> don\'t want to withhold it from the people right now. In that example
> I would say it is a surrogate but I think it is still a good surrogate
> marker.
>
> In answer to the question related to what would be important, I defer
> to Mr. Katz and others but it seems to me that functionality is the
> critical issue. You know, if the patient is on this drug and the
> patient is able to work, or go to school, or care for family, that, to
> me, is critically important and far more objective\--you know, the
> quality of life measures are very difficult to put meaning onto.
> Functionality is easier and more objective, it seems to me, and
> perhaps more valid.
>
> DR. TEMPLE: This is the way you would measure how troublesome the
> toxicity is.
>
> DR. LEVINE: Yes, can you function.
>
> DR. TEMPLE: I have to say that we rarely get data of that kind.
>
> DR. LEVINE: That is probably the most valid, I would think.
>
> DR. CARPENTER: You should though.
>
> DR. TEMPLE: Maybe. We do try. It is extremely hard to do in unblinded
> settings, which most of them are although not all adjuvant settings
> are unblinded. It is just very hard. I mean, in these quality of life
> things you usually don\'t know what to look for in advance. So, you
> are looking at multiple things and it is really hard. Many people have
> brought us patient-reported outcome data and very few of them have
> been even close to persuasive.
>
> I wanted to throw one thing out as part of the discussion. We are
> talking here about controlled trials where there is a control group.
> It is a fact though that for many years we have recognized the
> potential benefit of a very durable complete response, which is sort
> of related to disease-free survival, and we don\'t see that very often
> but where it does occur that has been a persuasive endpoint even on
> sort of historically controlled observations and I think that reflects
> the same thing you are saying here. All the treatments for testicular
> cancer that are approved were approved based on data like that.
>
> DR. PRZEPIORKA: Mr. Katz?
>
> MR. KATZ: Actually I have three points that have been stacking up
> here. One, relative to Dr. Keegan\'s question or comment, you know, I
> think that we have to distinguish between toxicities that are kind of
> quality of life issues and toxicities that are irreversible because,
> clearly, safety issues are a big deal.
>
> You know, relative to Dr. Temple\'s comments, I think that that is one
> of the reasons that we, patients, are really grateful to be at the
> table here because I think the size of the instruments that you guys
> come up with to measure quality of life is indicative of the fact of
> how hard it is to really explain. So, I think having real patient
> input on those things is really the only way to gauge that.
>
> Also, I agree wholeheartedly with Dr. Levine. You know, when we are in
> the situation where we have low cure rates, low effectiveness of cure
> with these treatments I think we would all hope that people sitting
> around this table are basically asking themselves would a reasonable
> clinician gives to a patient and expect a better result even though we
> don\'t know for sure, and we don\'t want to hold back something that
> is potentially valuable. I think that is what I hear in this room and
> I am very encouraged by it.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: I am just wondering about this issue that you asked
> about, functionality and how you measure impact. Functionality, even
> though hard to measure and maybe frequently we are unable to, I think
> most of us would accept is important. The other thing is some way to
> measure the impact of the symptoms on the person\'s function. And, how
> many measures or how many other drugs in an adjuvant setting have to
> be used to take care of the toxicity or the side effects of the
> treatment, however you would want to quantitate that, it seems that
> one way to try to assess impact on quality of life and sometimes it is
> easier to count that or ask a few things. Pain medications are a
> long-standing thing but certainly not the only things used.
> Particularly in an adjuvant setting, you wouldn\'t expect to use many
> of them. But there are other things which may have to be used.
> Neuropathy would be a common thing that could have a big impact and is
> important in certain adjuvant settings\--some way to try to measure
> that or sort that out because what you want is to control all the
> symptoms and not have the disease come back in this setting and some
> kind of way to quantitate how close you have come to do that. It seems
> to me a way to be able to compare and know what the impact of the new
> thing may be.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: Most of what I was going to ask has already been said. But
> it gets a little more complicated because some of these therapies that
> prolong disease-free survival may be something you give immediately at
> the time you are initially treating the patient and some may be things
> you have to chronically administer and that has a different impact on
> patient quality of life, how you are going to follow toxicity, etc.
>
> I certainly agree that we need in any circumstance to continue to
> monitor the AEs because there may be untoward events that are clearly
> unanticipated. Secondary malignancies are the ones that always come to
> my mind. It is nice that people are 100 percent functional but if five
> years down the line the risk of acute leukemia becomes eight or ten
> percent, then we have to reconsider what we are doing.
>
> DR. PRZEPIORKA: Dr. Li?
>
> DR. LI: I would like to hear Dr. Fleming\'s and Dr. George\'s comment
> on the single-point analysis discussed by Dr. Williams. The issue was
> raised for different assessment period imposed for the TTP or
> disease-free survival and that may cause bias and the need for a
> similar analysis at one-year survival or two-year survival as a
> single-point analysis for TTP or disease-free survival that may
> provide a kind of alternative. So, I would like to hear some comment
> from the committee.
>
> DR. GEORGE: It has a certain charm but is, like other things, I think
> a risky thing to do because you have to settle on what that point is.
> In terms of determining the progression you have to assess it at that
> time or enough to it, whatever that means, so it makes sense. If you
> miss it, that is worse than having a sequence of values of which you
> are missing one. So, it has some appeal in a setting where you know
> what that time would be and you are sure you are going to get all
> readings. Otherwise, I doubt that it would be of benefit. You are
> obviously losing some information and the question is whether that
> information is critical. I don\'t know. I would tend to say that is
> not the way to go. That is my feeling. You just need to develop
> procedures and carefully design studies so you kind of minimize the
> problems we talked about, that Grant talked about this morning, but
> not try to fix it with a single point.
>
> DR. PRZEPIORKA: So, in summary, I think we are saying that\--oh, Dr.
> Fleming?
>
> DR. FLEMING: Had you already gotten to part C or are you still
> looking\--
>
> DR. PRZEPIORKA: No, C is open for discussion.
>
> DR. FLEMING: Okay, if it is open discussion I might just add that C
> becomes much more problematic than B. I think we have discussed the
> complexities with B. In C, what we are saying is we haven\'t proven
> superiority; we have just ruled out that disease-free survival is
> meaningfully worse by some margin.
>
> I think C is an extremely complex circumstance and I come back to this
> distinction again, is disease-free survival itself a clinical endpoint
> because it carries with it symptomatic improvement and it carries with
> it the psychological benefit? Or, is the major focus or a different
> focus of disease-free survival that it is, in fact, a surrogate at
> some level of validity for evidence for prolongation of survival?
>
> In that first domain it is entirely possible to say that if, in fact,
> we are using this as a measure of symptom relief efficacy could follow
> if we establish that we are maintaining at least half of the symptom
> relief. On the other hand, if we are using it as a way of providing
> evidence that we are actually going to have a survival improvement,
> which I still maintain, to my way of thinking, is a much more profound
> benefit if the intervention is actually providing a survival
> improvement. It is now very problematic as to whether or not not being
> a certain amount worse in disease-free survival allows me to conclude
> we maintained some of the survival benefit. So, I go back to some of
> the earlier comments and we will talk about this in more depth with
> time to progression later on this afternoon.
>
> If we have established that an agent improves survival, let\'s say,
> and following Grant Williams\' discussions from this morning we are
> saying we want to know that we are maintaining at least half the
> benefit we have to know not only that a benefit on the surrogate is
> telling us we have a benefit on the clinical endpoint, let\'s say
> survival. To do a non-inferiority argument we have to know how much
> improvement we can have or need to have in the surrogate to get a
> certain amount of improvement in survival. For example, it may be
> that, as with 5-FU, levamisole, 5-FU levorin in the adjuvant colon
> setting, we have a 40 percent reduction in the rate of disease-free
> survival and that translates into a 33 percent reduction in death
> rate. If we want to maintain at least half that benefit in survival,
> how much reduction can we see in disease-free survival to maintain
> half? That is wishful thinking, to think we know the answer to that.
> So, essentially what we are doing is what I often refer to as my worst
> nightmare, a non-inferiority trial design in the context of using a
> surrogate endpoint.
>
> \[Laughter\]
>
> So if, in fact, here disease-free survival is of importance to us in a
> substantial manner because of its prediction of survival benefit, C
> becomes incredibly problematic. On the other hand, if all we care
> about in disease-free survival isn\'t because it tells us anything
> about survival but it is just that it tells us something about symptom
> relief, then it is possible to do this, although I would say it is
> pretty weak evidence that we know we are maintaining a small fraction
> of the symptom relief that standard of care would provide.
>
> DR. PRZEPIORKA: So, in summary, I think what we are saying is that
> disease-free survival could be a primary endpoint rather than
> surrogate, most useful in diseases that have high response rates,
> testing drugs that have a very good likelihood of giving a high
> response rate. It is important to keep people off therapy or on
> treatment with little more mostly reversible toxicities; that
> functionality is what is critical when looking at disease-free
> survival, and that we should also keep in mind the other endpoints
> that should be looked at just for confirmation of clinical benefit. In
> the situation for randomized trials where the comparator is already a
> highly effective therapy that has a curative fraction, there is some
> variation in thought regarding whether that disease-free survival
> should be an adequate endpoint or just a surrogate.
>
> Let\'s move back to question number two\--
>
> DR. TEMPLE: Can I just comment on Tom\'s thing? I am sure it won\'t
> placate your nightmares\--
>
> \[Laughter\]
>
> \--but for the adjuvant setting, at least in breast cancer, we have
> asked for 75 percent retention of the effect on disease-free survival.
> Also, for what it is worth, even for tamoxifen I don\'t believe very
> many individual studies have actually shown improved survival. The
> meta-analysis does but that is not the same thing if you are talking
> about an individual trial. So, that is not so easy.
>
> DR. PRZEPIORKA: So, time to tumor progression, it has been proposed as
> an endpoint for regular approval, not a surrogate. Page two at the top
> lists the pros and cons that Dr. Williams has already gone through.
> What we need to do for the next 35 or 40 minutes or so is to discuss
> whether clinical settings exist where time to progression improvement
> should be considered an established surrogate for clinical benefit and
> should support regular drug approval. We need to identify the factors
> that determine when time to progression is an adequate endpoint for
> drug approval.
>
> The factors that we are supposed to consider include reliability in
> measuring the endpoint, the relationship of disease progression to
> death, established benefit of available therapy, drug toxicity, and
> whether progressing patients are symptomatic. Dr. Williams has kindly
> provided us with a host of scenarios to stimulate our discussion.
>
> If we could actually just pick up with Dr. Li\'s question from before
> about whether or not the clinicians on this panel also have any
> comments about the single endpoint with regard to time to progression.
> Dr. Cheson is chomping at the bit.
>
> DR. CHESON: I think using the single endpoint\--again, I am thinking
> from my sphere of diseases, has the potential to be very dangerous. If
> you take some therapies where the initial toxicity, whether it be
> pharmacogenomic or for whatever reason, is exceptionally toxic and if
> you survive that you do well, then you are going to miss that initial
> real drop-off which might be a very undesirable effect. I drew a
> little curve here but, you know, the curve may go straight down and
> then sort of level off for the people who survive the therapy and you
> would miss that because of the same six-month point or whatever point
> you choose. Another therapy might get there but not have this initial
> somewhat disastrous effect on a large proportion of patients. So, I
> would be strongly opposed. I think you would lose too much very
> important information on patients proximal to that point in time.
>
> DR. PRZEPIORKA: Yes, I would tend to agree in that the name of the
> endpoint is time to progression, not progression-free survival at some
> point. So, if we really wanted to say that time to progression is what
> provides clinical benefit, we actually have to look over a course of
> time.
>
> One issue raised earlier today is how do you measure this, knowing
> that patients come in for their staging at various time points and
> that can be somewhat difficult. My response to that was if the sponsor
> chooses to use time to progression as an endpoint, they need to do the
> work and they need to provide the data. If the data is missing, then
> they haven\'t done the study and they shouldn\'t get approval based on
> lack of data.
>
> DR. TEMPLE: Could you talk about that a little more? One possible
> argument is that too infrequent measures decrease the precision of the
> measurement but, unless there is a bias tendency to get people in to
> look, it might not introduce a bias. So, how do you rate those two
> things? I mean, it might be true anyway even though you are only
> seeing them every three or four months. You might still be able to
> detect a difference as long as, say, the visits were similar in the
> two groups and there wasn\'t a bias. So, which is the worst problem or
> which problem are you focusing on?
>
> DR. PRZEPIORKA: I think the problem that I would focus on is missing
> patient data and missing the fact that if somebody doesn\'t show up
> for staging in a year you really can\'t make measurements based on
> every three-month interval. I mean, it is the difference between
> looking at a Kaplan-Meier and a life table analysis. In fact, some
> people put out Kaplan-Meier plots and you can tell how frequently they
> do their restaging because the Kaplan-Meier plots fall every three
> months. That is the kind of analysis that needs to be done as opposed
> to continuous analysis. The statisticians may end up having to come up
> with a new way to do comparisons using that sort of data because it is
> clearly not continuous.
>
> DR. TEMPLE: So, they should make sure, if they are going to use this
> as an endpoint, that they are seeing people at some regular interval,
> every two months or every three months or whatever gives you the
> adequate precision.
>
> DR. PRZEPIORKA: Hand-in-hand with that, you are looking at power
> calculations to determine how much of an interval in improvement you
> have to make, that interval has to be at least one interval between
> staging. You can\'t say you are going to stage people every three
> months and then you are going to power to look for a one-month
> difference in time to progression. That would not make sense.
>
> DR. WILLIAMS: I will follow-up on that because I have heard that and I
> honestly do not believe that is true. It depends on whether you are
> trying to precisely estimate the effect; maybe it is true then. But in
> terms of producing a highly statistically valid detection of effect,
> you can do it at one point just as well. So, the frequency really
> doesn\'t determine your ability to detect a small effect. It might
> determine your ability to precisely estimate the difference
> perhaps\--maybe the statisticians can correct me on that point, but I
> have heard that discussed several times at ODAC and I don\'t believe
> it is true that you have to look at an interval that is smaller than
> the measured median difference that you are after.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Just one thing about these kinds of measurements, of
> course, there is a whole big issue in statistics about how you handle
> this in data in longitudinal kinds of studies. This is a little
> different because here let\'s say you do a reading, then you have a
> long interval and you do a reading again and there has not been
> progression, it is reasonable in this setting I think to assume that
> they never progressed. You are not monitoring a process that
> progressed and then un-progressed and you missed it. The problem comes
> in when you have those long intervals when you discover that they did
> progress and you don\'t know exactly when that occurred between this
> measurement here and here. So, you have to consider in this setting
> the disease I guess. We are back to that. What is the disease setting
> and what is your prior estimate of when these things would be
> occurring. So, you just don\'t want that to be too imprecise. You can
> quantitate that if you know something about the setting you are in.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: I agree with Dr. George. I got kind of thrown off by Dr.
> Przepiorka\'s one-year follow-up on a patient with advanced disease
> without progression. But I think, depending on the disease category,
> with the diseases I deal with you can define and I hate to say mandate
> but, you know, if you are going to say you are going to follow the
> patient every month by CT scans and every month you have to have the
> CT scans, and it has become less of a problem in today\'s technology
> world. We just send them to a third party and they actually have
> copies.
>
> I guess the question I have, and Dr. Fleming and I had a conversation,
> I am a little concerned about, you know, what happens in time to
> progression for the patients who die on therapy while they are
> responding. I got the sense from Dr. Fleming that those patients are
> censored and not evaluated and it has been diluted out. I am a little
> bit concerned about that because that somewhat speaks to the toxicity
> of therapy.
>
> DR. TEMPLE: Certainly people look at toxic deaths as a separate item.
> How that gets factored into the analysis is something of a question.
>
> I wanted to be sure about this, could I ask Tom and Steve, should we
> be advising people who are hoping to detect an advantage of, say, two
> months that if they don\'t see patients every two months they don\'t
> have a prayer; it is not valid? Or, could you, in fact, see them every
> three months and still detect a difference of a couple of months? That
> is the question Grant was raising. Is there a precise relationship or
> requirement? This is very important for how we advise people. If they
> are looking for differences that are small, two or three months, they
> had better make sure they are seeing people at least as often as that
> or perhaps more often.
>
> DR. FLEMING: It depends on the nature of the true distributions of
> time to progression. If we just said, for example, if we had
> exponential distributions for time to progression, i.e., time to
> let\'s say a certain amount of growth in tumor volume and there was a
> two-month difference in the median, you could look less frequently
> than two months and you could still see the difference. But, you know,
> sensitivity to that overall difference is going to be somewhat less.
> So, it is not a black and white, yes, you do; no, you don\'t but your
> sensitivity will be somewhat diminished if you are not following them
> with as great a frequency.
>
> In fact, you said before how could you have a bigger survival effect
> than time to progression effect, this is one of the ways. This is one
> of the contributing ways. You are actually getting a noisy measure of
> what truly is happening by the intervention to tumor burden.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: I support Tom\'s opinion on that but I would also say that
> you need to consider the circumstance you are in. That is, there is no
> hard and fast rule that says if you are trying to pick up a certain
> difference you have to do the measurements like this. But you should
> be considering what you know about the rate, or what you suspect would
> be the rate of progression over time. I guess that is what Bruce was
> saying too. In other words, you would do it differently in different
> settings. So, I think you want to have reasonably careful measurements
> in that period where there is a high risk.
>
> DR. PRZEPIORKA: Dr. Grillo-Lopez?
>
> DR. GRILLO-LOPEZ: No.
>
> DR. PRZEPIORKA: Mr. Katz?
>
> MR. KATZ: I would suggest adding one factor to the list that we put
> here. We said whether progressing patients are symptomatic. I think
> whether stable patients are symptomatic is also germane here because
> you have tumor reduction but no symptom relief.
>
> DR. PRZEPIORKA: Could you speak a little bit more about that with
> regards to who might actually be a good candidate for a time to
> progression patient? If somebody is symptomatic already, is time to
> progression really an endpoint that you would consider clinically
> valid? That is, you are sick and as long as you don\'t get any sicker
> it is okay or, is this something for patients who have minimum disease
> and are not exactly ill?
>
> MR. KATZ: Well, clearly if you start in a situation where you are
> highly symptomatic everything is valid. If you can get a treatment and
> it relieves the symptoms and it delays the time to those symptoms
> getting worse, then there is certainly an argument to say that that
> has a value to a patient. If a patient has profoundly serious symptoms
> that are horrible but you know that they can get worse but they are
> not getting worse because we have done this and it hasn\'t progressed,
> then I think that is also valuable. You know, things get more
> acceptable depending on what you are looking at coming next.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: As Grant said, we have been encouraging people for years
> to look at time to symptomatic progression and I would say we have met
> with total failure. Nobody does that for a lot of reasons. I don\'t
> know why. You probably know better than I do why. Symptomatic
> improvement in a group that is symptomatic has always been accepted as
> a valid endpoint. But as Grant also said, except for a couple of pain
> things with prostate, we have had very little success in attempts to
> do that and you have seen them\--esophageal obstruction, you know,
> that works fine but most of the other things have been very resistant
> to success.
>
> DR. PRZEPIORKA: Dr. Levine?
>
> DR. LEVINE: I was just going to say that in considering time to tumor
> progression as the endpoint, not as a surrogate but as a real
> endpoint, it would seem to me that I would want it in the context of
> some sort of confirmatory clinical benefit other than that itself,
> i.e., symptoms are manageable; symptoms are better or have not
> re-occurred; toxicity of the drug is \"acceptable\"; quality of life.
> So, if it is just time to tumor progression alone without these other
> things, I don\'t know that that would be valid in a clinical sense.
>
> DR. CHESON: Again, that depends on the clinical sense because there
> are some settings where you start with nothing. When you \"ain\'t\"
> got nothing you have nothing to lose. If they start in an adjuvant
> setting or some setting where the patients just have disease, are
> asymptomatic, like early stage follicular lymphoma, and they don\'t
> have anything, then it doesn\'t work there.
>
> DR. LEVINE: Right, you are right. So, in other words, it goes back
> again to disease specific situations.
>
> DR. CHESON: Right.
>
> DR. BRAWLEY: Can I ask for a point of information?
>
> DR. PRZEPIORKA: Yes.
>
> DR. BRAWLEY: Was gemcitabine approved for quality of life or for
> prolongation of disease-free survival?
>
> DR. TEMPLE: Two reasons. Lilly invented a clinical benefit scale that
> had some elements of tumor progression and some elements of other
> stuff and they won on that. That is one thing.
>
> But I think what actually persuaded people most was the one-year
> survival of 18 percent versus 2\--not an official endpoint but it sort
> of looked pretty impressive. So, that is what it is for better or
> worse.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Can we talk a little more about the issue of the deaths
> that occur when you are looking at time to progression and death
> occurs before progression? I think if you are in a setting where there
> is some substantial percentage of patients for which that is true,
> that greatly decreases the value of the time to progression kind of
> analysis, in my view, because you don\'t know what that means.
> Further, even if you don\'t have deaths first it is pretty important
> to know something about that distribution from progression to death in
> different diseases, again to get back to the point I made earlier. If
> it is very short then, of course, it is sort of the same as survival
> really but if it is long, then you are in a setting where you probably
> need to consider this more as a surrogate or a potential surrogate.
> But I am worried about a situation in which you have some substantial
> proportion of deaths without progression and how you handle those then
> becomes critical. In the usual way you just kind of censor them but
> that is clearly subject to a lot of problems.
>
> DR. PRZEPIORKA: Dr. Williams also talked about time to treatment
> failure as being an unacceptable endpoint and, yet, if we talk about
> time to treatment failure defined as disease progression or death
> would that satisfy your concern about how to incorporate death?
>
> DR. GEORGE: Yes, but that is more like progression-free survival. I
> like that.
>
> DR. WILLIAMS: I think we need to bring that up and the question is
> when we are looking at TTP as more like clinical benefit endpoint or
> surrogate, should we use progression-free survival, include the deaths
> and do a very careful evaluation and analysis to deal with the deaths
> or should we use TTP? It sounds like there is at least some consensus
> that progression-free survival is a good endpoint.
>
> DR. PRZEPIORKA: Any disease categories where anyone here thinks that
> progression-free survival or time to progression simply would not fit
> and should never be used, or the converse where this is clearly the
> best endpoint because they will never get a remission and all you
> could hope for is progression-free survival?
>
> DR. TEMPLE: Well, just to be clear, I heard some uncertainty about
> that from Dr. Levine. I mean, if along with that you need to improve
> symptoms or something like that, then it is not just progression-free
> survival; it is symptomatic benefit too. So, I think we need to be
> clear on what people do think. But our initial question is, assuming
> you don\'t have all those clinical benefits, do you think
> progression-free survival or time to progression is a good stand-alone
> endpoint in this current, real world? If that is not clear, we are
> very interested in hearing whether it is or not.
>
> DR. PRZEPIORKA: Dr. Redman?
>
> DR. REDMAN: I think progression-free survival, at least in the tumor
> types I deal with, is fine. I don\'t think this is the implication,
> but if you have a drug that is coming in and you say, okay, we are
> going to pick progression-free survival and it cures 100 percent you
> are not going to miss it. I mean, it is going to be there. You are
> just saying what is the lowest, minimum activity or clinical benefit
> we are willing to accept.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: Just to return to kind of a general response to this
> question of where and when can TTP or progression-free survival be
> used for regular drug approval, I would return to the pros and the
> cons and, just in the interest of shortness of time looking at the
> cons, what we have to overcome are these uncertainties, uncertainties
> that arise because it is an indirect measure. The clinical meaning of
> TTP differences, of small differences is unclear. The reliability of
> unblinding interpretation results are issues. I would add to that
> another one that, in fact, did come up in the oral presentation, and
> that is just the noise and the variability factors add complications
> due to variability in imaging assessments or timing of assessments, as
> we were talking about some ten minutes ago, and missing data. There
> tends to be a bigger missing data problem with the TTP endpoint, less
> so with progression-free survival and, obviously, even less so with
> survival.
>
> Because of this issue of clinical relevance and missingness induced by
> death, I find TTP especially problematic if I am using it as a
> registrational endpoint as opposed to a supportive measure of biologic
> activity. So, among the two, if we were looking at it as a
> registrational endpoint, certainly I would prefer progression-free
> survival.
>
> But I would like to just step back for a minute. Rather than say, yes,
> it is a good endpoint; no, it isn\'t a good endpoint, just talk a
> little bit about the principles that should guide the decision as to
> when it is a good endpoint and what kind of evidence we would like to
> have because there is now a lot of science behind what it takes to
> validate a surrogate.
>
> So, in our November 12 meeting of the FDA ASCO working group,
> basically in that session we talked about a marker such as time to
> progression as being one of four levels. Level one would be the best.
> In level one forget about surrogacy, it is, itself, a clinical
> endpoint. We said examples of that would be when you have the event
> disease-free survival or progression-free survival it is inherently
> linked to symptomatic disease. So, symptomatic events, preventing or
> delaying symptomatic events are inherently of tangible benefit to
> patients. If that is the case, then we have an endpoint that is, in
> fact, in its own right a valid clinical endpoint and surrogacy issues
> don\'t arise.
>
> The second level would be an endpoint that reliably predicts clinical
> benefit. So, when I see an effect on time to progression I can know
> that I will see\--let\'s say if it is a surrogate for survival\--a
> certain level of effect on survival.
>
> The third level is reasonably likely to predict clinical benefit where
> the agency then uses this as a measure for accelerated approval but
> with the understanding that the ultimate answer on clinical endpoints
> will still have to be obtained in a validation trial.
>
> The fourth level I will call none of the above, none of the above
> often being a correlate. There are an awful lot of correlates out
> there that, in fact, aren\'t any of the top three levels.
>
> What does it take to be in level two, versus three, versus four? Well,
> the first thing we will look for is if it is a correlate. Is time to
> progression a correlate of survival or whatever the clinical endpoint
> is on a patient specific basis? Almost certainly it is but, in
> essence, that doesn\'t tell us anything about whether specifically the
> benefit or the outcome on the clinical endpoint is mediated through
> that. For example, you may have CEA correlated with survival but it is
> not through changing CEA if the disease process leads to an outcome in
> survival. So, changing CEA may not change survival. That could be a
> level four.
>
> So, we have to go beyond that. The evidence that we typically look at
> to go beyond that is guided by the Prentice criteria. So, what we are
> typically looking for is not just having a correlate. That is a
> necessary condition. It is not a sufficient condition for validity of
> a surrogate. We want to find out whether or not the effects on that
> marker are, in essence, capturing the net effect on the intervention
> of the clinical endpoint. At a certain level of persuasiveness that
> would get us to level three and I think in many settings people would
> argue time to progression because it is, in fact, directly\--getting
> at tumor burden is very likely to be at that level but obviously it
> needs to be addressed on a case-by-case basis.
>
> The bigger challenge is to say when is it a valid surrogate such that
> I know if I achieve an effect on this measure I don\'t need
> accelerated approval; I have actually established clinical benefit.
> That best evidence is obtained by meta-analyses of studies that have
> looked at an array of trials, an array of studies that establish
> treatment effect on the surrogate\--in this case I will call it time
> to progression and treatment effect on the clinical endpoint I will
> call survival\--specifically saying what is the functional
> relationship between a certain level of reduction in the failure rate
> on time to progression versus a level of reduction in the failure rate
> on survival.
>
> Understanding that is really critical and, in fact, in many settings
> we don\'t have that kind of evidence and, as has been pointed out
> before, partly because we are looking at interventions that at this
> point don\'t establish much of an effect on the clinical endpoint. But
> the essence of validating a surrogate and saying we can use time to
> progression as a surrogate for, for example, survival would be having
> meta-analyses of studies that would show reduction in time to
> progression rates and reliably would tell us we would have reductions
> in whatever the clinical endpoint is, such as death rate\--reduction
> in the rates. So, if we reduce the rate of time to progression we are
> improving time to progression and we want to reduce the rate of death
> to improve the survival time.
>
> DR. PRZEPIORKA: Dr. Williams?
>
> DR. WILLIAMS: Dr. Fleming, I saw your categories at the workshop on
> colon cancer but when I was preparing my talk I was wondering what
> category we would put our practice of breast cancer hormones and
> response rates. I mean, perhaps category four, which is even worse
> than accelerated approval category or what I think it is, it is
> clinical inference about number one. I don\'t know if you have a
> category for that and I don\'t think you do.
>
> DR. FLEMING: Well, my sense is that if you are talking about response
> rate in breast cancer\--I think that is the example you were giving\--
>
> DR. WILLIAMS: Well, it was hormonal breast cancer where there is a
> long history with gemoxifen\--
>
> DR. FLEMING: Right.
>
> DR. WILLIAMS: \--and assume benefit but a long history of using
> tamoxifen and it was felt certainly by experts in the field that it
> was useful and this was used as a surrogate and maybe the blood
> pressure and maybe some of these others. I don\'t see a category here
> that I could put them in. They are basically clinical judgment,
> clinical inferences about the benefit. So, what do you do with those?
>
> DR. FLEMING: Certainly, my sense has been\--and you can clarify what
> your sense is, but my sense has been for some of these interventions
> that provide a duality here, that are providing some direct evidence
> of benefit through, for example, delay in symptoms and a surrogacy
> aspect of them, saying that if you are in fact delaying progression
> that is some suggestion of a prolongation in survival. The duality of
> that in the context of a very safe intervention is giving you
> adequately persuasive evidence of benefit to risk. In the end that is
> what it comes down to. In the end is benefit to risk established to be
> favorable? The stronger the evidence of efficacy, then the more
> resilient you are on safety and, similarly, if you have an incredibly
> safe intervention you might accept or you might be more resilient in
> what you consider adequately strong efficacy. Certainly showing a
> survival benefit I would say in many ways is the most compelling thing
> to do because it is the most compelling benefit and provides more
> resilience to issues of irregularities in trials and issues in safety
> that could arise.
>
> In this case, what I understand you to be doing is really, in essence,
> saying we have partially a level one here because we have some very
> direct tangible benefits that are occurring and it is reinforced by an
> anticipation at some level, valid or invalid, that you are actually
> delaying death as well. With a very safe intervention that is
> favorable benefit to risk.
>
> DR. WILLIAMS: I think that is really basically a lot of what we are
> doing here today with progression-free survival. Are there settings
> where we can accept, or the clinical experience with this endpoint,
> the broad experience it seems clear we don\'t have the strong
> quantitative validation we would like but, you know, what are those
> factors which might allow it to be used in some very specific settings
> at this time?
>
> DR. FLEMING: Just one last response to this, you identified some of
> those in your appendix. So, specifically the ideal settings are C, E,
> P, J and N, C being itself patients are symptomatic so you have at
> least in part a level one endpoint. By delaying time to progression
> you are directly getting evidence of an improvement in symptoms or
> delay in symptoms.
>
> I might challenge whether there would have been another way to do
> that, specifically looking at a symptom endpoint as a way to establish
> that. I also might challenge that that is, in my own view, not as
> compelling as actually having evidence of a survival effect. But C
> does get, in my definition, potentially into level one. So, surrogacy
> issues are not as compelling.
>
> If we don\'t have C, and many times we don\'t have specifically
> symptomatic disease at progression. In November 12 meeting that was
> certainly the agreement, that in first-line colorectal cancer at the
> time of progression we don\'t typically see symptoms. Then, these
> other aspects that come into play are do we have a large and precisely
> defined benefit? The larger the benefit on the measure, obviously the
> more plausible it is going to be that it actually translates into
> clinical benefit. Hence, P, a superiority trial, is far more
> persuasive a setting. A non-inferiority trial and surrogate, as I have
> already said, is my worse nightmare.
>
> Blinded trials are important and we probably can achieve that
> routinely so it does, in fact, diminish our confidence. We can in fact
> though, as you say in K, try to have some kind of an independent
> evaluation committee that is itself blinded.
>
> N, drugs that have minimal toxicity, that is where I see in part the
> example you have given comes into play. The evidence on efficacy is
> somewhat less but if you have an intervention with an established
> record that is extremely safe you may, in fact, have a little more
> resilience on what the strength of evidence on efficacy would be.
>
> DR. PRZEPIORKA: Dr. Grillo?
>
> DR. GRILLO-LOPEZ: Having heard all of that with a bit of impatience\--
>
> \[Laughter\]
>
> \--I have to say that clinical medicine even today is still an art and
> clinical research resists our efforts to quantitate it; it is also an
> art. And, there is no such thing as a perfect endpoint. There is no
> such thing as a perfect endpoint and TTP has its problems but it has a
> lot of pros. You have to also make a distinction between those
> problems that are inherent to TTP and those problems that have to do
> with how TTP is measured, presented, how the data is acquired in the
> clinic, issues like GCP, sloppy data or good quality data, and put
> those aside because your assumption has to be that the data is going
> to be of good quality. That should not be a deciding factor on whether
> or not TTP is a good endpoint. You have to assume it is going to be
> good quality.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: Just one more small comment. Listed under your pros there
> is a theme. TTP is a measure of tumor effect in all patients, rather
> than measure effect in a subset of patients. I would look at that as a
> con rather than a pro. We are talking about all the different subsets
> of patients that may respond totally differently and you have to have
> a very strong impact on the right group to overcome\--going back to
> Iressa for example\--to overcome the negative impact on another
> personal bias but that is how I would look at that.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: I have a comment along the same lines. One of the
> difficulties, and you have described this repeatedly, is that we are
> trying to look for an effect in an overall population when we are only
> probably influencing a small fraction. That is a real burden. In most
> other conditions you don\'t have to do that and you have some hope of
> treating everybody\'s headache even if that is not true. So, that is
> all going to get better when we get all pharmacogenomics\--
>
> \[Laughter\]
>
> \--I think Grant listed that as a pro for the following reason and I
> wonder what people think about it, that to actually shrink tumor
> volume by 50 percent you really have to be quite a good responder.
> There may be people who don\'t get quite that good a response but
> whose tumor growth is slowed, and you might think there are more of
> those than the former. That is why I think he thought that might be a
> more powerful measure.
>
> But I also have a question. Remember, I don\'t treat patients with
> cancer so if you think this is really stupid just tell me. If there is
> no really good follow-on therapy, which is often the case, why do we
> monitor progression other than by symptomatic progression at all if
> there is nothing much we can do about it? If everybody progressed with
> symptoms then there wouldn\'t be any argument about it. So, why do we
> do that? If that is really a stupid question, just tell me.
>
> DR. PRZEPIORKA: Dr. Taylor?
>
> DR. TAYLOR: No, it is not a stupid question. For many of us who have
> patients in whom there won\'t be treatment we don\'t do repeated
> x-rays and you do go by symptoms and you treat them by symptoms
> because that is the most practical thing to do. In essence, that is
> why ASCO recommendations are for follow-up after adjuvant breast
> cancer, to follow symptoms and to do mammograms and physical exams.
> So, that is not a stupid question.
>
> The only time we are compelled I think to look for progression is when
> we are in an investigative setting in which we want to know what is
> going on with this particular drug.
>
> DR. TEMPLE: For what it is worth though, we wouldn\'t mind seeing a
> study that was simplified and that only weighted for symptomatic
> progression. Whether it is ethical to do that is a different question.
> But if it was time to symptomatic progression there would be no debate
> about whether that was clinically meaningful at all.
>
> DR. TAYLOR: Again, I would say that is only specific diseases. There
> are some diseases where you do need to monitor.
>
> DR. BRAWLEY: For example, in certain diseases\--I live in the world of
> prostate cancer, the patients insist upon PSA to look for relapse.
> There are other diseases as well where the patients insist upon some
> type of radiologic imaging to look for relapse. Believe me, it is very
> difficult to explain to the patient that I don\'t really know if this
> is in your best interest.
>
> DR. PRZEPIORKA: The other issue is always medical-legal. If you miss a
> diagnosis the patient always comes back and says, well, maybe I would
> have survived two years longer had you caught my tumor before it
> became symptomatic. So, that is another big issue. Dr. Rodriguez?
>
> DR. RODRIGUEZ: The reality is, at least in the patient subset that I
> follow and I mostly treat patients with lymphomas, is that they can
> have other malignancies, not just lymphomas and that the second or
> third malignancies could be potentially curable if caught early. So,
> that is another overlying concern.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: However, there have been two to three randomized
> trials\--you say you don\'t know whether it is ethical or not to do
> them\--in which patients with lymphoma both Hodgkin\'s lymphoma and
> non-Hodgkin\'s lymphoma, have been randomized to looking at patients
> presenting with symptoms, physical examination and simple things like
> that versus regular CT scans at certain intervals, and the overall
> outcome was identical. The patient was in general the best indicator
> of when the disease was coming back, although we all have patients
> where we do pick up things early and, in the grand scheme of things,
> survival was not adversely effect in any of those three studies.
>
> DR. PRZEPIORKA: Dr. Williams?
>
> DR. WILLIAMS: I wonder if all this discussion mostly refers to
> settings where the disease has gone away and you are not treating
> them. I am thinking that when you are giving cytotoxic therapy I think
> a lot of investigators feel like they need to know whether there is
> progression or not and generally they tend to stop the treatment,
> cytotoxic treatment\--Dr. Temple brought up the question, if it is not
> a toxic treatment do you really need to know or you can just continue
> the drug anyway.
>
> DR. TEMPLE: Of course, we don\'t really know if it is time to stop a
> therapy just because it has progressed. Maybe it is still providing
> benefit. We have had lots of conversations with companies about that
> with these newer non-cytotoxic therapies. But I guess if it is
> cytotoxic everybody wants to get rid of it.
>
> DR. PRZEPIORKA: Other comments? Yes? Could you come up to the
> microphone? If you could just identify yourself for the record,
> please?
>
> DR. SRIDHARA: Yes, I am Raji Sridhara, from FDA Biometrics. I am team
> leader. I have a question going back to the first one that George and
> Fleming commented on. You know, when you have crossover you are saying
> that, okay, it can\'t be helped; it happens and we leave it at that. I
> think we get to a point where actually the design is such that your
> primary endpoint is survival and then you don\'t know how much you
> will cross over and at the end you will have some crossover and you
> are left with all these secondary endpoints which were never powered
> properly, or we don\'t have specific secondary endpoints. Would you
> rather suggest then that we should have specific secondary endpoints
> which we can rely on just in case the primary analysis is not feasible
> because of too many crossovers, loss to follow-up or any of those?
>
> DR. GEORGE: You are bringing up a very good point. I think there was
> an issue some time ago, not in cancer, that came before the FDA in
> which the primary endpoint was not survival. The survival endpoint
> seemed to show a survival advantage and then what do you do? You know,
> it didn\'t show something in the primary endpoint which was not
> survival but did show a survival advantage in a surprising way; you
> didn\'t expect it. Could you get approval? That is not a question for
> me I guess.
>
> DR. TEMPLE: Well, in other settings, other than cancer, the unexpected
> discovery of survival benefits turns out, not surprisingly, to carry a
> lot of weight. We agonize a lot but we tend to say, hm, that is good.
>
> DR. GEORGE: I think so. I mean, I think that is the right kind of
> approach but you can get yourself into conundrums with saying this is
> the primary endpoint; survival is secondary. But to answer your
> question, if you really think all of the crossovers and subsequent
> treatments are going to be a serious issue in the trial you really do
> have to rethink whether survival is the proper primary endpoint, and
> in those settings it may not be.
>
> DR. SRIDHARA: Picking up on what you said about other settings where
> there was a survival advantage or where it was not termed as the
> primary endpoint, then should we be considering in all these settings
> co-primary endpoints survival and time to progression so that it will
> allow us to look at either one of them? Since generally until the
> trial is over we don\'t know really how much crossover is going to
> happen.
>
> DR. GEORGE: What does is a co-primary endpoint mean? Does that mean
> you have to meet both of the objectives?
>
> DR. SRIDHARA: One or the other, or however you want\--it depends I
> guess on the disease setting and what we are doing.
>
> DR. TEMPLE: Sorry, did you ask about co-primary?
>
> DR. GEORGE: Yes, what does that mean?
>
> DR. TEMPLE: Usually people divide the alpha appropriately, whatever
> appropriately turns out to be. There have been cases, but not mostly
> in oncology, where we expect a benefit on more than one endpoint. But,
> as everybody knows, that becomes a formidable challenge and we get
> requests to reduce the alpha or make the alpha less demanding. But
> usually that means people have to make some accommodation to
> multiplicity\--always tricky.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: Just to return to this point, it seems to me that
> therapeutically what we are trying to do is improve the regimens and
> the therapeutic strategies. I think that was the term that Dr. George
> used earlier. We are looking at comparing a therapeutic strategy
> involving the experimental agent versus the standard of care strategy
> and trying to show that this experimental strategy is, in fact, better
> in a tangible way to patients. Obviously, that means that we should be
> delivering care in an optimal fashion and when the first intervention
> to which you are randomized leads to failure at some level you are
> going to follow-up with best supportive care, as you should.
>
> In fact, we would hope that we can improve on strategies that will
> ultimately lead to an improvement in survival relative to what is
> available in the standard of care. So, clearly, in many settings it
> would be an appropriate endpoint. But there are many other settings
> where it may not be anticipated that that would be the most sensitive
> measure to what beneficial influence we provide to patients. If, in
> fact, that is in part because of crossovers diluting the long-term
> survival effect, I would still argue that is the truth. That is what I
> am ultimately doing on survival. There may be need for other measures.
> I would argue that those other measures ideally should be direct
> clinical measures of benefit, measures reflecting improvement in
> functional status; measures that reflect overall improvement in
> symptoms. With bisphosphonates, for example, what we have gone to is
> skeletal related events as an alternative clinical efficacy measure.
> Beneficial effects may be reflected in survival but a more sensitive
> clinically tangible measure may be the measure in reduction in
> fractures and spinal cord compression and radiation and surgery to the
> bone, other rescue therapies. So, if I can improve that measure that
> is clinically tangible benefit. I would rather see that measure being
> the co-primary endpoint rather than a surrogate measure, unless that
> surrogate has been truly validated.
>
> I just want to come back to one of my colleague\'s earlier points that
> was raised in the criticism of time to progression. You are absolutely
> right, we want to do high quality studies. So, we are going to presume
> that people are going to the very best study they possibly can on
> whatever endpoint they are looking at. However, certain endpoints lend
> themselves to more readily being assessed in an unbiased, objective
> way. In an unblinded trial it is much more problematic when you have
> an endpoint that requires judgment, such as a symptom endpoint or a
> time to progression endpoint, as opposed to survival. And, missingness
> has over history been more of a problem when we are looking at these
> markers as opposed to survival as an endpoint. In particular, as we
> have said, with time to progression we are building in missingness
> because automatically time to progression, by censoring deaths, means
> you are missing what happens in time to progression subsequent to
> death in those patients who die. So, there are some inherent problems
> that exist with lack of blinding and with censoring deaths that even
> in the best quality study you are going to have some difficulties
> with.
>
> DR. PRZEPIORKA: If I could just summarize\--
>
> DR. GRILLO-LOPEZ: I disagree with that.
>
> DR. PRZEPIORKA: Feel free.
>
> DR. GRILLO-LOPEZ: I cannot agree that you can measure survival better
> than time to progression. I think that if you have an appropriately
> designed trial with the appropriate interval for CT scans you can
> measure time to progression better than you can measure survival
> because of all the biases in the survival measurement that I mentioned
> earlier. So, it all depends on how you design your protocol; how you
> schedule your evaluations and how good the quality of the data is.
> Again, there are so many biases inherent to the survival kind of
> endpoint that it is not an acceptable endpoint in most situations, in
> my mind at least.
>
> The other thing that I would like to mention is that the issue of
> crossover goes away completely if you are not using survival as an
> endpoint. It is an important issue because if you have a drug, a new
> agent that has gone through Phase II trials you know of its clinical
> activity; you know of its safety and you know what the patients know
> of its clinical activity and safety because they go ASH and they go to
> ASCO and they go to the websites and they know that there is an option
> which in some situations, in the refractory setting, may be the best
> option for them and they are not going to go into a Phase III trial
> and take a 50 percent chance of being randomized to a standard therapy
> that may not be as good in fact as the experimental therapy and never
> have the chance to get the experimental agent unless they know that
> there is some opportunity, not perhaps within the same protocol but
> some time later on, to get the experimental agent.
>
> DR. FLEMING: But your response is presuming that access to that
> intervention on a delayed basis is going to provide the essence of
> what the benefit is when you deliver it up front\--in some settings
> more plausible but in other settings much less plausible. And, your
> response hasn\'t addressed the issue of the inherent risk of bias that
> arises in what is typically done in oncology, which is unblinded
> trials, and it hasn\'t addressed the issue of the informative
> censoring that arises if you choose to censor deaths.
>
> DR. GRILLO-LOPEZ: But that is not my assumption. I am saying that it
> is the patient\'s assumption. It is the patient\'s assumption that
> there is benefit and they want to get that experimental\--
>
> DR. FLEMING: That doesn\'t matter if it doesn\'t, in fact, carry a
> substantial part of the overall benefit up front. It doesn\'t matter
> if that is the patient\'s assumption.
>
> DR. GRILLO-LOPEZ: You miss the point. What I am trying to convey is
> the difficulty of doing a Phase III randomized trial if the patient
> knows that he has only a 50 percent chance of getting an agent which
> the patient perceives as an active agent.
>
> DR. FLEMING: The Evastin trial in colorectal cancer was just
> successfully completed in a manner that you are saying couldn\'t have
> been done.
>
> DR. GRILLO-LOPEZ: It may be an exception.
>
> DR. TEMPLE: Surely a company can control whether it makes an
> experimental drug available to everybody and allows crossover or not.
> It is their drug.
>
> But I thought the earlier point you made, and it is one of the reasons
> we are here, is crossover doesn\'t matter if you are measuring time to
> progression because crossover happens after that.
>
> DR. FLEMING: If, in fact, time to progression is the answer to the
> question that we care about and can be addressed without the problems
> of these other biases that arise so it is not getting us out of the
> woods.
>
> DR. TEMPLE: No, it just solves one problem.
>
> DR. PRZEPIORKA: Dr. Brawley, last comment?
>
> DR. BRAWLEY: Well, it was actually somewhat of a question. It is just
> sort of a gut check. I am just sort of remembering all those trials,
> many of them not in cancer treatment but in other areas where initial
> endpoints and initial surrogates seemed to be very positive and then,
> when we finally got to the randomized clinical trials we found out
> that the intervention actually was not as positive. I am thinking
> specifically right now of premarin in the Women\'s Health Initiative,
> although I have some rumblings of Iressa Phase III clinical trials in
> the back of my mind, Iressa trials using Iressa and chemotherapy as
> well. We have to be very careful as we go down this path.
>
> DR. PRZEPIORKA: A very good point. If I could summarize what I heard,
> there are actually a few parallels to our discussion on disease-free
> survival. Specifically for time to progression, we did not think that
> a single endpoint design would be attractive at all. There is concern
> about death on therapy and perhaps progression-free survival might be
> better than just time to progression.
>
> We agree that there has to be rigorous assessment for scientific
> reasons, not for clinical reasons. So, repeated assessments may be
> done in studies where we would not usually do them in clinical
> medicine but we do want to get the scientifically valid results.
>
> We would not use this therapy for patients who are very symptomatic
> because progression there would not be good for those patients as
> opposed to really trying to get a response. And, toxicity needs to be
> factored in as a risk-benefit for whether or not this is something
> useful.
>
> So, it appears that progression-free survival would be for diseases
> with low CR rates in therapies that would be unlikely to alter
> survival because of the underlying disease to be used as a primary
> endpoint, but in a comparative study when standard therapy is already
> shown to have a benefit it would probably only be as opposed to a real
> endpoint. Any other comments on that summary? Dr. Temple?
>
> DR. TEMPLE: One of the points was that we don\'t expect these drugs to
> alter survival. I guess I am not sure that is the assumption. We think
> it may be difficult to demonstrate that because of crossover and
> because it is going to occur later, but I guess I think one of the
> assumptions is that if you have an effect on time to progression, or
> something like that, it probably does have a favorable effect on
> survival even if you are not able to measure it very well. Am I wrong
> in that?
>
> DR. PRZEPIORKA: I don\'t think I would disagree with that but I think
> time to progression would be an excellent endpoint in a disease such
> as metastatic prostate cancer in the elderly where, no matter what you
> do, they are going to end up dying of non-cancer reasons. Whereas, if
> you can keep them symptom free it would be very valuable.
>
> DR. TEMPLE: Actually, the last point is one we didn\'t talk much
> about, survival is tough if it is an old population that is dying of a
> lot of other things. We didn\'t really discuss that but in prostate
> that is probably a major factor.
>
> DR. PRZEPIORKA: We will close this session with an announcement about
> lunch.
>
> MS. CLIFFORD: The statement I made earlier, unfortunately, is not true
> about your badge. It will not grant you access into the building next
> door. I am sorry. At the front desk there is a list of six restaurants
> that are local, that are within walking distance that you are welcome
> to visit. Thank you.
>
> DR. PRZEPIORKA: We will reconvene promptly at 1:00 p.m. Thank you.
>
> \[Whereupon, at 12:05 p.m., the proceedings were recessed for lunch,
> to reconvene at 1:00 p.m.\]
>
> [A F T E R N O O N P R O C E E D I N G S]{.underline}
>
> DR. PRZEPIORKA: In this afternoon session we will discuss non-small
> cell lung cancer endpoints and we do have a different group with us
> this afternoon so, for the record, I would like to go around the table
> one more time with introductions for everyone who is new this
> afternoon and everyone from this morning. If we can, let\'s start with
> introductions with Dr. Ettinger, if you could let us know who you are
> and where you are from, please.
>
> DR. ETTINGER: David Ettinger, the Sidney Kimmel Comprehensive Cancer
> Center at Johns Hopkins in nearby Baltimore.
>
> DR. SAXMAN: Scott Saxman, in the Cancer Therapy Evaluation Program of
> the National Cancer Institute.
>
> DR. BONOMI: Phil Bonomi, Rush Medical College, Chicago.
>
> DR. JOHNSON: David Johnson, Vanderbilt University in Nashville,
> Tennessee.
>
> DR. JOHNSON: Bruce Johnson, from the Dana Farber Cancer Institute.
>
> DR. GRILLO-LOPEZ: Antonio Grillo-Lopez, acting industry
> representative.
>
> DR. GEORGE: Steve George, Duke University.
>
> DR. CHESON: Bruce Cheson, Georgetown University Lombardi Comprehensive
> Cancer Center.
>
> DR. DOROSHOW: Jim Doroshow, City of Hope Comprehensive Cancer Center.
>
> DR. RODRIGUEZ: Maria Rodriguez, M.D. Anderson Cancer Center.
>
> DR. BRAWLEY: Otis Brawley, Emory University, Winship Cancer Institute.
>
> MS. ROSS: Sheila Ross, Washington representative for Alliance for Lung
> Cancer, and I am a lung cancer statistic.
>
> DR. FLEMING: Thomas Fleming, University of Washington.
>
> DR. LEVINE: Alexandra Levine, University of Southern California Norris
> Cancer Center.
>
> DR. REAMAN: Greg Reaman, George Washington University and the
> Children\'s Hospital in D.C.
>
> DR. PRZEPIORKA: Donna Przepiorka, University of Tennessee Cancer
> Institute.
>
> MS. CLIFFORD: Johanna Clifford, FDA.
>
> MS. HAYLOCK: Pamela Haylock, oncology nurse from Texas.
>
> DR. CARPENTER: John Carpenter, University of Alabama at Birmingham.
>
> DR. REDMAN: Bruce Redman, University of Michigan Comprehensive Cancer
> Center.
>
> DR. TAYLOR: Sarah Taylor, University of Kansas Medical Center.
>
> DR. LI: Ning Li, FDA Biometrics.
>
> DR. KEEGAN: Dr. Keegan, CDER Office of Drug Evaluation VI.
>
> DR. WILLIAMS: Grant Williams, FDA Drugs.
>
> DR. TEMPLE: Bob Temple, Director of ODE I.
>
> DR. PRZEPIORKA: This afternoon\'s session is actually split into two.
> The first will be three talks regarding non-small cell lung cancer and
> clinical trials. We will have a brief break, followed by an open
> public hearing and then address the questions that have been posed to
> us by the FDA. We will start this afternoon\'s session with a talk by
> Dr. Cohen on non-small cell lung cancer, the regulatory background.
>
> **Non-Small Cell Lung Cancer Regulatory Background**
>
> DR. COHEN: I am going to review the approval in lung cancer that the
> agency has made through the years.
>
> \[Slide\]
>
> The data that I am going to present is the data that is in the
> individual labels for each drug. So, the data may be somewhat
> different from published data that you would find for each of these
> trials.
>
> \[Slide\]
>
> For non-small cell lung cancer there have been first-line approvals,
> second-line and third-line. There were five approvals for first-line.
> All of these approvals were regular approvals. For second-line there
> has been one approval, also a regular approval. For third-line
> non-small cell lung cancer there is one recent approval which was an
> accelerated approval. For small-cell lung cancer second-line there has
> been one regular approval and there has been one approval for
> palliation of non-small cell lung cancer.
>
> \[Slide\]
>
> This is a listing of the five approvals for first-line non-small cell
> lung cancer. There was one single agent, vinorelbine and four
> approvals for doublets containing cisplatin, and the doublet partners
> have been vinorelbine, gemcitabine, paclitaxel and most recently
> docetaxel.
>
> \[Slide\]
>
> What I am going to do in the next group of slides is review each of
> these approvals. This is the vinorelbine approval. The approval was
> based primarily on an improvement in one-year survival and also, as
> supporting evidence, there was improvement in response rate. In this
> trial the comparator regimen was 5-FU leucovorin given in the Mayo
> Clinic type regimen.
>
> There were 211 patients entered into the study. There was a 2:1
> randomization in favor of vinorelbine. As you can see, the response
> rates were 12 percent versus 3 percent. Median survivals were 30 weeks
> versus 22 weeks and one-year survival was 24 percent versus 16
> percent. The p value refers to the difference in the survival curves.
>
> \[Slide\]
>
> Vinorelbine/cisplatin was evaluated in two studies. In the first study
> vinorelbine/cisplatin was compared to cisplatin alone and 432 patients
> were entered. Response rates favored the combination therapy. Median
> survivals were 7.8 months versus 6.2 months. One-year survivals were
> 38 percent versus 22 percent, and the p value for the survival
> comparisons were 0.01.
>
> The second study was a three-arm study that included vinorelbine,
> cisplatin compared to vinorelbine alone and the third arm was
> vindesine/cisplatin. You can see that the response rates in this study
> favored the vinorelbine/cisplatin combination. Median survivals were
> 9.2 months versus 7.2 months for vinorelbine alone versus 7.4 months
> for the vindesine/cisplatin combination. One year survivals were as
> listed. The p value for survival comparing vinorelbine/cisplatin to
> vinorelbine alone was 0.05 and the p value for the comparison of
> vinorelbine/cisplatin versus vindesine/cisplatin was 0.09.
>
> \[Slide\]
>
> Gemcitabine/cisplatin was also evaluated in two randomized trials. In
> the first trial the comparator regimen was cisplatin alone. There were
> 522 patients entered. Response rates were 26 percent versus 10 percent
> favoring the combination. Median survivals were 9 months versus 7.6
> months and the p value for that comparison was 0.008.
>
> In the second study, which was somewhat smaller, the comparator
> regimen was etoposide/cisplatin. The response rates were 33 percent
> for the gemcitabine/cisplatin regimen versus 14 percent for the
> VP16/cisplatin. Median survivals were 8.7 months and 7.0 months. As
> you can see, that survival difference was not statistically
> significant.
>
> \[Slide\]
>
> Paclitaxel/cisplatin was evaluated in an ECOG trial that was a
> three-arm trial. The first arm included paclitaxel 135 mg/m^2^. There
> was a 24-hour infusion with cisplatin. The second arm was paclitaxel
> 250 mg/m^2^ with cisplatin. The comparator regimen was
> etoposide/cisplatin.
>
> As you can see, both paclitaxel regimens had an increased response
> rate as compared to etoposide/cisplatin. Median survivals were 9.3
> months for paclitaxel 135, 10 months for paclitaxel 250 with cisplatin
> and 7.4 months for the VP/cisplatin regimen. In terms of survival,
> which is listed on the bottom on the right, the survival comparison of
> paclitaxel 135 mg/m^2^ plus cisplatin compared to etoposide/cisplatin,
> the p value was 0.08 and for the paclitaxel 250 mg/m^2^ the p value
> was 0.12. However, if you look at response rates which is a), and time
> to progression which is b) on the bottom, both of these were
> statistically significant in favor of the paclitaxel regimens, with
> paclitaxel 250 doing somewhat better than paclitaxel 135.
>
> \[Slide\]
>
> Docetaxel/cisplatin was evaluated against vinorelbine/cisplatin and
> also against docetaxel/ carboplatin. A total of approximately 1200
> patients were entered into this study. As you can see, the median
> survivals were relatively similar for all three regimens. This was a
> non-inferiority analysis and doing the non-inferiority analysis
> docetaxel/cisplatin retained greater than 50 percent of the
> therapeutic benefit of vinorelbine/ cisplatin. On the other hand,
> docetaxel/carboplatin did not. So, the docetaxel/cisplatin regimen was
> approved.
>
> \[Slide\]
>
> Docetaxel was also evaluated as a second-line treatment regimen in two
> studies. In the first study docetaxel was compared to best supportive
> care and 104 patients were entered. The response rate to docetaxel in
> this patient population was 5.5 percent. Median survivals favored
> docetaxel, 7.5 months versus 4.6 months, with a p value of 0.01.
>
> The second study involved docetaxel compared to chemotherapy that was
> investigator\'s choice and 248 patients were entered. The response
> rates for docetaxel were again in the 5-6 percent range. The median
> survivals were comparable for docetaxel and investigator\'s choice
> chemotherapy. But one year survival for docetaxel was 30 percent
> versus 20 percent for investigator choice, and that p value was
> significant at less than 0.05.
>
> \[Slide\]
>
> Gefitinib or Iressa was recently evaluated as a third-line treatment
> regimen in patients who had failed a platinum and who had failed
> docetaxel. There were 143 patients who met these eligibility criteria.
> They were randomized to receive Iressa 250 or 500 mg/day. Overall, if
> one combines the two treatment groups and that was done because it was
> relatively comparable for each group, the overall response rate was
> 10.6 percent with a 95 confidence interval, as listed, and it was of
> interest that in exploratory analyses response rates were higher in
> females, in nonsmokers and in patients with adenocarcinoma.
>
> \[Slide\]
>
> The one approval in small cell lung cancer was Hycamtin or topotecan
> and that was compared to CAV,
>
> Cytoxan, adriamycine and vincristine. The eligible population for this
> trial were patients who had responded to first-line treatment and who
> had then progressed greater than or equal to 60 days after stopping
> treatment. There were 107 patients in the Hycamtin arm, 104 patients
> in the CAV arm. The difference in this study was only in response
> rate. The response rate was 24 percent for Hycamtin versus 18 percent
> for CAV and this difference in response rate was felt to be of
> sufficient importance to warrant approval.
>
> \[Slide\]
>
> The one palliative approval in non-small cell lung cancer involved
> photofrin photodynamic therapy, and that was compared to nd:YAG laser
> therapy. The patient population eligible for this study were
> individuals with symptomatic obstructive bronchial lesions. Symptom
> severity scales were used as the evaluation tool. Symptoms rated were
> dyspnea, cough and hemoptysis. Photofrin therapy was of comparable
> efficacy to nd:YAG laser therapy.
>
> \[Slide\]
>
> So to summarize the approval endpoints, in first-line, as I mentioned
> earlier, there were five studies. Three of the approvals were based on
> superior survival. One approval was based on non-inferior survival and
> one approval was based on superior time to progression and response
> rate with a trend toward improved survival.
>
> In the second-line setting there was one study and approval was based
> on superior survival in that study. In the third-line setting, which
> was the one accelerated approval in non-small cell lung cancer, the
> accelerated approval was based on response rate. And, there was one
> approval based on symptom palliation.
>
> \[Slide\]
>
> In second-line small cell lung cancer there was one approval and that
> approval was based on response rate. That concludes my presentation.
>
> DR. PRZEPIORKA: Thank you. We will hold questions until all three
> speakers have had the opportunity to presentation. Next, Dr. Paul Bunn
> will talk about the FDA ASCO non-small cell lung cancer workshop.
>
> **FDA/ASCO Non-Small Cell Lung Cancer**
>
> **Workshop Summary**
>
> DR. BUNN: Members of ODAC, members of the FDA and guests, I would
> first like to say that I am honored to be here. It is a privilege to
> be here and I want to mention that I take this extremely seriously
> because what I do for a living is to take care of lung cancer patients
> and I think what you are deliberating is extremely important.
>
> \[Slide\]
>
> With respect to the history of why we are here, Rick Pazdur, in his
> infinite wisdom, I think agreed with a comment that Bruce Cheson made
> this morning and that is not all cancers are the same and in the
> future it is highly likely that we are going to have to look at these
> endpoints in individual cancers based on data from the individual
> cancers, not based on feelings but based on data from these individual
> cancers. Of course, this morning we heard a lot of theoretical
> discussion. Hopefully, this afternoon we are going to be talking about
> data-driven discussion.
>
> So, to put the data into context, the FDA and the American Society for
> Clinical Oncology had a series of telephone conferences and a single
> open public hearing discussing endpoints for approval of drugs for
> lung cancer. What you are hearing this afternoon is somewhat of a
> rehash of that. You will be asked some questions based on what you
> hear.
>
> The way we have done this is that we have divided the discussion into
> two topics. The first topic is what has been called classical
> endpoints. The classical endpoints that we discussed were objective
> response, time to progression and survival. For whatever reason, we
> called another one non-classical endpoints. The distinction I think is
> incorrect but, anyway, that was largely patient-reported outcomes.
> After I get done talking about the classical endpoints of objective
> response, time to progression and survival, Richard Gralla is going to
> talk about patient-reported outcomes.
>
> I have an apology to make. The slides that you have in front of
> you\--my secretary and I were in a miscommunication mode and they have
> nothing to do with what I am going to say\--
>
> \[Laughter\]
>
> \--so don\'t bother looking at your handout. You will be very
> confused. You will actually have to look at the slides and I apologize
> for that.
>
> Before I actually begin I want to make one correction to what Marty
> said and one other comment. Actually, the Albain study of
> vinorelbine/cisplatin versus cisplatin happened after the approval.
> Actually, the LeChevalier study for the combination was the primary
> study and the Crawford study for single agent was the primary study.
> The Albain study actually came later and confirmed what happened but
> was actually not known at the time of the ODAC presentation. I know
> because I am old and I was there.
>
> I have great respect for the consultants here. I also have great
> respect for Dan Ihde. What I am going to say is something that I think
> in 1985 Dan Ihde and I agreed on and I wish he were here to agree with
> me now that what happened in 1985 was a big setback to lung cancer
> drug approvals.
>
> \[Slide\]
>
> I am going to begin by trying to keep this simple, stupid! Why are we
> here? Drug development takes enormous amount of fiscal resources and
> long periods of time. Currently we know more about novel targets than
> ever before. At the same time, there are fewer new drug applications.
> We could ask why is that. It is undoubtedly for many reasons. It is
> possible that stringent FDA requirements for approval at the moment
> are a deterrent to new drug applications.
>
> I think we could all agree that most knowledge about drug utilization
> and toxicity occurs after the initial approval. We might also agree
> that if we had safe and efficacious drugs, expedited drug development
> might benefit society. Therefore, I think it is appropriate that we
> are looking here at criteria for endpoints for NDAs, or new drug
> applications, for lung cancer.
>
> As you heard this morning, FDA regulations require that drugs be safe
> and efficacious for a defined population by adequate and well-designed
> clinical trials. As you also heard this morning, simple statements are
> sometimes gray, not black and white. As you also heard this morning,
> FDA legislation does not require that a drug be shown to be superior
> to other drugs. It has to be safe and efficacious; it doesn\'t have to
> be better than approved drugs, with a single exception which I believe
> should be discussed openly and frankly in this afternoon\'s
> deliberations. Oncology drug divisions is determined that drugs given
> accelerated approval should offer an advantage over existing agents.
>
> DR. TEMPLE: It is in the reg.
>
> DR. BUNN: It is in the reg? Okay. Well, we are going to discuss this
> during my presentation.
>
> \[Slide\]
>
> The question is, well, why would be here just for lung cancer? What
> are some of the differences between lung cancers and other diseases?
> One of the difference is that almost all the patients, three-quarters,
> present with advanced disease. That is, they are III or IV.
>
> Most studies show that 90 percent of patients or more are symptomatic
> at the time of presentation. So, our discussion this morning about
> whether patients would be symptomatic or not, in lung cancer the basic
> idea is that they are symptomatic. When they get relapse they are
> symptomatic; when they present they are symptomatic. The majority of
> patients have co-morbid cardiopulmonary disease. Dr. George was
> talking about deaths from unrelated causes. This is a huge problem in
> lung cancer. If you look at trials of adjuvant radiation and adjuvant
> alkylating agents the hazard rates are 1.2, so a 20 percent increase
> in the hazard rate of death is not due to the disease but it can
> accelerate the disease. Many of those deaths are not actual toxic
> deaths that you would define as a toxic death but these are sick
> people and when they get tough treatments sometimes they die.
>
> In the current SEER data in the U.S. the median age is 70 years old.
> The majority of these patients are elderly. Recruitment to surgical
> trials is extremely difficult. In this disease at the moment,
> unfortunately, complete responses are rare. So, talking about
> disease-free survival is an oxymoron when you talking about stage IIIB
> and IV lung cancer. We don\'t have to have that discussion that we had
> this morning; it doesn\'t happen.
>
> It used to be that objective responses or 20 percent were very rare.
> Fortunately, we have drugs that work now. We have drugs that make
> people live longer and objective responses oftentimes do occur in more
> than 20 percent of patients.
>
> It used to be that second-line therapy did not influence survival but
> now, as you heard from Dr. Cohen, it does. So, some of the issues we
> heard this morning about second-line therapy influencing survival will
> be an issue.
>
> \[Slide\]
>
> So, classical endpoints\--objective response. Up until 1985 this was a
> major deal. In 1985 Dan Ihde, along with the FDA, looked at a bunch of
> data and there was not a wonderful correlation between response and
> survival. That probably would be true today for melanoma and other
> diseases where responses over 10 percent are rare. We are going to
> re-discuss that now in 2003 to actually look at what the relationship
> is between response rates and survival.
>
> Time to progression has not often been used because it is very
> difficult to assess and, in the past, because second-line therapy
> didn\'t affect survival. The difference between progression and
> survival was very short but we will have a little bit of discussion
> about that. Survival I guess is not only FDA\'s favorite endpoint. As
> you heard this morning, most of us can agree that it is a real and
> important endpoint.
>
> \[Slide\]
>
> So, in the past objective response rates were quite variable, not
> consistently assessed; did not always correlate with survival and most
> agents, such as the alkylating agents and the athrocyclines were toxic
> to smoking patients. Some of these agents produced response in up to
> 20 percent but rarely higher of untreated patients but there was no
> survival improvement. Thus, in 1985 the FDA decided that objective
> response rate was not definitely associated with patient benefit.
>
> \[Slide\]
>
> What happened since that time? I think that this is a very important
> study and one which really needs to be updated. In fact, after this
> morning\'s discussion I am thinking about having one of my fellows go
> back and actually do this. I partially did this but not in a real
> meta-analysis.
>
> But there was a study that looked at the correlation between response
> and survival in 176 Phase II trials with 7000 patients between \'76
> and \'95. Since that time, the drugs that Dr. Cohen mentioned have
> largely been approved and were not part of this. The average response
> rate in these trials was only 11 percent. I think since 1995 we are in
> a different place.
>
> In these 176 trials they found 12 drugs, or 11, that had a response
> rate of more than 20 percent. Those are cisplatin, vinorelbine,
> docetaxel and paclitaxel. As you heard, all those are approved. This
> also included small cell so irinotecan, etoposide, vindesine,
> epirubicin and ifosfamide and edatrexate showed up in that list.
>
> They also did a correlation between response rate and survival time.
> You can see that the correlation coefficient and the p value. Then
> they did a logistic regression coefficient and you can see the p value
> between the relationship between response and survival was 0.0003.
>
> \[Slide\]
>
> So, what has happened since 1995 in terms of what is in the
> literature? These are the drugs that most of us would consider the
> most active cytotoxic drugs. We have the Phase II single agent studies
> of these drugs in untreated advanced non-small cell lung cancer. As
> you can see, these have response rates\--these are limited institution
> studies now, not the big cooperative groups and I will get to those.
> They had response rates varying from 20 percent to 27 percent. They
> had median survival times ranging from 7.6 months to 9.7 months and
> one-year survival rates ranging from 22 percent to 41 percent. I think
> from historical controls, any of us would say, if you are an optimist,
> the median survival would be 5 months and the one-year survival rate
> would be 10 percent. Vinorelbine, as you heard a moment ago, is the
> only one of these drugs approved for non-small cell lung cancer.
>
> \[Slide\]
>
> What about multi-institution Phase III trials with these same
> therapies. You can see here that, again, there are large numbers of
> patients but there are some differences. The response rates before
> varied from 20 percent to 27 percent and now the response rates vary
> from 16 to 18. Why is that? The primary reason for that is that the
> cooperative groups require a post CT scan done four or more weeks
> later and most trials have them done eight weeks later. Many of the
> patients don\'t have the second scan and those are unconfirmed
> responses and the cooperative groups don\'t count those patients as
> having a response. So, it is generally true\--and some of the ECOG or
> other people could comment on this\--that in the multi-institutional
> cooperative group trials response rates are approximately five percent
> lower than in the limited institutions primarily for that reason.
>
> You can also see that the confidence intervals around these response
> rates are actually quite narrow. Largely, that is because people can
> actually use RECIST and actually have objective response rates that
> are fairly reproducible. Median survivals in these trials range from
> 6-7 months and one-year survival from 25-33.
>
> \[Slide\]
>
> I am going to come back to first-line therapy after a minute but
> something new happened, and that is patients are living longer. Now,
> just remember that the minority of patients have benefit. If you have
> a response rate of 20 percent means that most patients aren\'t having
> any benefit. Now, median survival is not likely to change a lot when
> 10 percent or 20 percent of the patients are benefited. Two-year
> survival goes from 1 percent to 20 percent in advanced lung cancer
> with treatment but median survival only goes up by a couple of months.
>
> In the second-line setting the drugs that have been approved and the
> drugs that we think about the most are shown here. Response rates
> range from 9 percent to 16 percent in these trials although the
> confidence intervals and the ranges are much broader in the
> second-line limited institution setting than they are in the
> first-line setting.
>
> \[Slide\]
>
> With respect to multi-institution Phase III single-agent therapy in
> non-small cell lung cancer, the data from the trials that we have had
> are listed here. Response rates vary from 8 percent up to 14 percent.
> Now, as you heard, docetaxel is approved and gefitinib is approved.
> Question number six in your handout could be viewed as a pre-setting
> for a pivotal trial looking at pemetrexed in the second-line setting
> and the response rate, median survival and one-hear survival from that
> trial are shown here.
>
> \[Slide\]
>
> So, a question that I hope you all will address, because I think it is
> extremely important\--in 1985 it was basically determined that
> objective response was not either a likely patient benefit or a
> definite patient benefit, and in my opinion objective response that
> exceeds a certain threshold should be considered as likely evidence
> for patient benefit\--likely, not proven. In Dr. Fleming\'s terms this
> morning, that would be his group C. I think that objective response
> over 20 percent in untreated patients is a likely surrogate for
> patient benefit. It is possible that meta-analysis could change that
> into a definite evidence of patient benefit, as documented by symptom
> relief and/or survival.
>
> Every drug that we know of with a response rate over 20 percent in
> limited institution trials and over 16 percent in multi-institutional
> trials has been shown in randomized trials to affect survival, and
> most of them have been shown to relieve \[sic\] patient benefit. I am
> not going to discuss patient benefit in terms of symptoms because
> Richard Gralla is going to talk about that.
>
> So, if one could consider that objective response is a likely
> indicator of clinical benefit, the question is could accelerated
> approval be given based on objective response rates? Certainly, I
> think that they could. One could say that if the surrogate is definite
> it is full approval. If the surrogate is likely, it is an accelerated
> approval. Well, I believe it is likely. It could be definite but I
> think it is likely so it should be considered for accelerated
> approval.
>
> Another thing is that RECIST criteria I believe are actually good and
> can be reviewed independently by the FDA and independent committees.
> So, I believe that the endpoint we are talking about here is a
> reproducible endpoint.
>
> \[Slide\]
>
> In the first-line setting one could argue that if an agent had an
> objective response rate of more than 20 percent in a limited
> institution study or 15 percent in a multi-institution trial that a
> drug might be given accelerated approval. One could argue in a
> second-line setting active agents have objective response rates of
> more than 10 percent in limited institution studies and more than 8
> percent in multi-institutional studies.
>
> Now, to demonstrate this type of response is actually not trivial.
> These data are I think almost right but not exactly right. I have a
> little bit better data from Dr. Piantidosi. If you want to show that a
> drug has a 25 percent response rate, plus/minus 5 percent, a 95
> percent confidence interval of 5 percent, Dr. Piantidosi informs me
> that would be a 400-patient trial. If that goes to plus/minus 4
> percent the number would be 625 patients.
>
> \[Slide\]
>
> This is not actually just an academic consideration here. Not all the
> drugs work that are developed. Current FDA policy promoting Phase III
> survival trials have led to the institution of multiple Phase III
> trials after the completion of a Phase I trial even when no
> single-agent activity was observed in the Phase I trial. No inactive
> drug has ever been shown to improve survival or improve patient
> symptoms when used alone or in combination with chemotherapy. However,
> going straight from Phase I to Phase III has led to multiple negative
> trials costing not thousands but millions of dollars and thousands,
> not hundreds, of patient live resources.
>
> Examples of randomized trials of agents not showing any activity up
> until the time of a survival Phase III trial are shown here,
> tirapazamine, MMPIs and a Gentasense compound and a whole bunch
> ongoing.
>
> \[Slide\]
>
> This is what we have learned from these trials. These inactive agents
> when combined with active agents do nothing. This particular negative
> trial had 700 patients. No benefit to the patient. Probably
> approximately 100 million dollars wasted. If objective response had
> been available to get accelerated approval, people would throw away
> the inactive drugs. Because they can\'t get accelerated approval for
> active drugs, they go straight from Phase I to Phase III, waste
> millions of dollars, thousands of patients lives. I would submit this
> is not a good state of affairs. Obviously, you may all disagree but it
> is not my favorite thing.
>
> \[Slide\]
>
> Single-agent activity of tirapazamine has never been established.
> Nonetheless, for the same reason multiple Phase III trials were done.
> Interestingly enough, one of these Phase III trials, shown here,
> showed an improvement in response rate of tirapazamine/cisplatin
> versus cisplatin. The response rate was higher, survival was higher
> but when this was done in another trial response rate was not improved
> nor was survival. This does show why we should also discuss in certain
> instances why you might want two trials instead of one. Perhaps we can
> discuss that.
>
> \[Slide\]
>
> Now, some drugs that get developed are not all that far from patent
> exploration. When companies need a Phase III survival advantage trial
> to get a drug approved and it is going to take five years and they are
> four years away from their patent expiring, they may not want to
> develop the drug. So, a drug called oxaliplatin was done as a Phase II
> trial in lung cancer. Interestingly enough, it was done in performance
> status II patients which, as everyone knows, is a very bad group of
> patients. The response rate was 15 percent, median survival was 8
> months and there was not a single grade III or IV hematologic
> toxicity.
>
> If accelerated approval was available for this drug, on the basis of
> this probably one would want to do a big trial to try to get
> accelerated approval. The huge question is whether this drug will ever
> see the light of day for lung cancer patients because of the current
> interpretation of how to get a drug approved.
>
> \[Slide\]
>
> When we get into combinations response rate sometimes gets a little
> trickier. This is a trial that makes us all humble of course and it
> highlights the issue about response and median time to progression,
> and perhaps would be used to say that there should be surrogates for
> likely benefit, not definite benefit.
>
> This was a study from Germany that compared cisplatin to Taxol and
> cisplatin. The Taxol and cisplatin arm had a much higher and
> statistically significant higher response rate. It also had a
> statistically improved median time to progression. On the other hand,
> survival was actually a little worse, not statistically so but a
> little worse in the combined therapy arm.
>
> I don\'t know what to make of this trial. It is certainly an outlier
> and it shows why outliers happen. One could argue that this is why
> objective response and time to progression should be surrogates as
> opposed to definite relationship to patient benefit.
>
> \[Slide\]
>
> Now, if accelerated approval was actually available and people took
> advantages, where would be today? Actually, docetaxel, paclitaxel,
> gemcitabine, irinotecan, pemetrexed and cisplatin would be approved
> for lung cancer and I don\'t think there is a single person in this
> room who thinks that would be bad. Drugs that would not be approved
> and have either been shown not to be useful under Phase III trials at
> the moment are equally as many. And, why do we have to go through
> large, 1000-patient, randomized trials for inactive drugs?
>
> There were drugs approved, vinorelbine and gefitinib, and gefitinib
> was actually approved by accelerated approval based on response. That
> precedent that you all set\--I think what you did was right. I think
> what you did should be common, not uncommon. Not every active agent
> has a response rate over 20 percent. Carboplatin, I think most of us
> would agree, is a useful drug and makes people with lung cancer live
> longer but doesn\'t have a response rate over 20 percent.
>
> \[Slide\]
>
> So, just to reemphasize what you did, if gefitinib had not been
> studied in large numbers of patients and approved based on response
> rate, it would be gone because the company did what all the other
> companies have been doing, going straight from Phase I to Phase III,
> and they did that as well. They went straight into combined studies.
> As you all know, those trials were negative.
>
> Besides the fact that most of us think that lonafarnib and gefitinib
> are drugs that should be approved for lung cancer, we have to learn
> how to use them. Look at the time to progression in these trials.
> After the chemotherapy was stopped the groups that got gefitinib did
> better than the group that got placebo in both trials. I think
> everybody in this room thinks we need to understand why that is. We
> wouldn\'t be able to understand why that is if these drugs were not
> given accelerated approval\--these would be gone.
>
> \[Slide\]
>
> Now I am going to talk a little bit about these EGFR inhibitors\--
>
> \[Slide\]
>
> Before I do I want to say one thing, FDG PET hasn\'t been studied
> nearly as much as CT response. In every trial comparing CT response to
> PET response, PET response is correlated with survival better than CT
> response. There is not a single trial were PET response is not
> correlated with survival. I think, if nothing else, we should be
> encouraging our pharmaceutical colleagues to consider this for
> development as a potential surrogate endpoint that actually could be
> better than actually objective response by CT.
>
> \[Slide\]
>
> So, what about subsets? Lung cancer is not one disease. We heard this
> morning that leukemias are not all the same. Bronchoalveolar carcinoma
> and large cell neuroendocrine carcinoma are not the same disease.
> Small cell carcinoma is not the same as non-small cell carcinoma. What
> are we going to do about subsets? If we require that for a subset
> approval a company has to do a Phase III survival trial, forget
> subsets. Forget it. If companies can get accelerated approval based on
> response rates in subsets, we might be able to make some progress.
>
> \[Slide\]
>
> Everyone sitting at this front of the room can identify as a classic
> patient with bronchoalveolar carcinoma, which is one subset of
> non-small cell carcinoma. Those of us who deal with this disease know
> this is not a very chemosensitive disease. We don\'t have a ton of
> data but what data we have suggests response rates are low in
> bronchoalveolar than in any other histology.
>
> Anecdotally it was found that EGFR inhibitors often make responses in
> patients that have this chemorefratory disease. It is also anecdotally
> noted that these patients have high expression of EGFR and HER-2,
> which was unexpected.
>
> \[Slide\]
>
> Now, we have a problem between the pathologist and the clinicians.
> Pathologists say that bronchoalveolar carcinoma has to be
> non-invasive. So, they are talking about infiltration among the
> alveoli septi where there is basically no invasion. They divide
> bronchoalveolar carcinoma into mucinous and non-mucinous forms. When
> we see these bilateral infiltrates what we usually have is invasive
> adenocarcinoma with bronchoalveolar features. So, that is something
> that we have to work out between the clinicians and the pathologists.
>
> \[Slide\]
>
> But as I mentioned, bronchoalveolar carcinomas have very high
> expression of EGFR and HER-2.
>
> \[Slide\]
>
> This is what we know about bronchoalveolar carcinoma clinically.
> Chemotherapy, as I mentioned, has response rates that generally are
> lower. So, Taxol which has a response rate of 25 percent in other
> Phase II trials had a response rate of 14 percent. There tends to be a
> little more indolence so survival is a little bit better even despite
> the low response rates; median survival at one year 50 percent.
>
> There have been two Phase II trials of erlotinib and gefitinib in
> bronchoalveolar carcinoma. Response rates were 24 percent and 19
> percent. Median survival was 12.5 months versus not reached after 7
> months. One-year survivals were 80 percent and 57 percent. Remember,
> these are pills compared to cytotoxic chemotherapy.
>
> \[Slide\]
>
> This is the Southwest Oncology Group, two consecutive trials, not
> randomized. Overall survival standard Taxol\--this is the data we saw
> before. Response rate was 1 percent; median survival 12 months.
>
> \[Slide\]
>
> This is the data with gefitinib in the Southwest Oncology Group. The
> untreated patients had a median survival of 15 months and a one-year
> survival rate of whatever I said, 57 percent. Even the previously
> treated patients had a median survival of 10 months.
>
> It is likely, when we get to randomized trials, that these
> single-agent pills will be better than our standard two-drug
> chemotherapy. Remember, if accelerated approval had not been granted
> for these drugs\--we only had those randomized Phase III
> trials\--these drugs would not be seeing the light of day. And, in
> that large list of other drugs that went to Phase III trials, how many
> are actually active? We don\'t know because people were afraid to give
> approvals based on objective response.
>
> \[Slide\]
>
> Time to progression, there are a lot of problems that you heard about.
> One of the major of those is the frequency of assessment. We are
> looking at changes. Median time to progression in untreated patients
> is four months. A 25 percent reduction is going to be a difference of
> a month of less. We get CT scans every eight weeks. The frequency of
> assessment for time to progression is a huge issue here. Not only
> that, cycle length can actually affect time to progression. If the
> cycle length varies, therefore, the time you get the CT varies.
>
> Another issue is sick and progressing patients may not be evaluated.
> Most of us who treat lung cancer patients, when they get sick and get
> worse, that is the end of it. If they need a CT scan six weeks later
> and they have already progressed, and all that, a CT scan is not
> obtained. As you heard, oftentimes these patients die without any
> documentation of what actually happened.
>
> \[Slide\]
>
> This is an example of some of the problems with TTP that might argue
> it might be surrogate endpoint. This is the four-arm ECOG trial. The
> PIs of that trial are sitting to my right. It was comparing four
> different two-drug combinations. The response rates you see here. Time
> to progression varied from 3.3 \[sic\] months to 4.5 months. The 4.5
> months with gemcitabine and cisplatin was actually statistically
> significant compared to the 3.5 \[sic\] months in the
> paclitaxel/cisplatin arm. But just remember this is a three-week cycle
> and CT scans are obtained every six weeks. This is a four-week cycle
> and CT scans are obtained every four weeks. As you can see, there is
> no difference in any of the survival outcomes. So, this might be a
> surrogate but it would be hard to say that this is a definite
> endpoint, definitely associated with survival and I think in lung
> cancer time to progression has really a lot of issues.
>
> \[Slide\]
>
> You were talking about disease-free survival or time to progression in
> early stage patients. Certainly, if you progress you are symptomatic
> but the question is what is the timing of the assessments.
>
> Another thing is that relapses are essentially always followed by a
> short survival. So, the advantage you have in some other diseases of
> doing this with much shorter intervals may not happen here.
>
> Another problem is that, again, these patients are highly likely to
> die, not from toxic deaths but related to a toxic therapy. Those
> deaths are scored in very many different ways.
>
> \[Slide\]
>
> Just to show you that in the recent trials, this is a trial of a very
> toxic regimen, MIC. Three drugs, mitomycin, ifosfamide, cisplatin.
> Remember, ifosfamide-based treatments increase the hazard-related
> death. In this particular trial there was an improvement with the MIC
> chemotherapy. The hazard rate was 0.89. It wasn\'t statistically
> significant. It certainly favored the chemotherapy. But look at what
> happened in survival. The people who got the chemotherapy were dying
> earlier. They did cross but the hazard rate for survival was 0.96 and,
> obviously, that wasn\'t statistically significant. So, if this had
> been a little bit better in progression-free survival there might have
> been an approval without an improvement in overall survival.
>
> \[Slide\]
>
> That actually happened. These are all trials, by the way, from ASCO
> this year or last year. This was an intergroup trial looking at chemo
> radiation versus chemo radiation followed by surgery. Time to
> progression favored the triple therapy. You can see this is the time
> to progression in the triple therapy and the p value was 0.02. It was
> better in terms of time to progression. What happened in terms of
> survival? The triple therapy arm had a lot of deaths early on. It was
> worse early on. Perhaps it was a little better later on, a p value of
> 0.51.
>
> Now, some people have interpreted this to say that triple modality
> therapy is better. I have a hard time with that. I think we still all
> agree that survival is a pretty hard and important endpoint. And, I
> think that in some of these trials we might have been misled by the
> time to progression analyses, not always, especially if the treatment
> is not so toxic.
>
> \[Slide\]
>
> This is a two-drug platinum based regimen, a more modern regimen
> looked at in the adjuvant setting. This is disease-free survival,
> statistically significantly in favor of the chemotherapy. Survival
> looked like this. Survival was statistically better as well. In this
> case time to progression or disease-free interval and survival were
> the same but it didn\'t take much extra time to find out that survival
> was also better as well.
>
> \[Slide\]
>
> So, I still think that survival does remain as a major indicator of
> clinical benefit and symptom relief may also be a major indicator of
> patient benefit. Richard Gralla is going to talk about that.
>
> \[Slide\]
>
> So, I believe that survival should remain as a major endpoint for
> clinical benefit and for approval. Richard Gralla is going to talk
> about this, but I believe symptom relief can be considered as an
> indicator of clinical benefit and also granted full approval, but Dr.
> Gralla is going to talk about that. In my belief, objective response
> can be considered as a likely endpoint of clinical benefit and,
> therefore, an acceptable endpoint for accelerated approval.
>
> With the current regulations, since new drugs are likely to offer an
> advantage in toxicity over existing drugs, requirement for a benefit
> over existing therapies is not a major obstacle if response was
> considered as a surrogate. But in the future this could limit drug
> development if this requirement of being better isn\'t gotten rid of.
> I hope that you, as ODAC, might advice the FDA whether they really
> ought to look at that accelerated approval improvement requirement for
> being better than existing therapies. Right now if you granted
> accelerated approval based on objective response, I think since we are
> going to have better toxicity with the new drugs it will be okay but
> in the future when we get a bunch of targeted therapies if you got two
> targeted therapies that are active one is not going to be less toxic
> than the other, and why should one be approved and not another? I
> don\'t understand that. I think drugs should be approved because they
> are safe and efficacious, like the law says, not efficacious and
> better than something else. TTP\--I am not sure if it is a marker for
> accelerated approval at the time or not. Thank you very much.
>
> DR. PRZEPIORKA: Thank you, Dr. Bunn. The final speaker for this
> session will be Dr. Richard Gralla who will talk about quality of life
> and patient-reported outcomes as endpoints in clinical cancer trials.
> Due to technical difficulties, why don\'t we take our break a little
> early. Let\'s be back here at 2:10. Thank you.
>
> \[Brief recess\]
>
> DR. PRZEPIORKA: Would you take your seats, please? Dr. Gralla?
>
> **Quality of Life and Patient-Reported Outcomes as**
>
> **Endpoints in Clinical Cancer Trials**
>
> DR. GRALLA: Thank you very much. We had an unplanned pause but it
> looks like we all benefited from it.
>
> \[Slide\]
>
> It is always a pleasure to share the podium with Dr. Bunn and to be
> here at the FDA to discuss these interesting areas. I am going to add
> to the non-small cell lung cancer a little bit on mesothelioma, given
> that it fits all of Dr. Bunn\'s criteria in terms of being a difficult
> disease with very similar parameters.
>
> I also want to thank the many members of the group that contributed to
> the presentation. Obviously, we are not all going to agree. Where you
> agree with me, those are my ideas. If we disagree, those are the other
> folks on the committee.
>
> \[Laughter\]
>
> \[Slide\]
>
> This new term, patient-reported outcomes, PROs, sort of defines
> clinical benefit or a term that probably could have stayed as
> palliation for this purpose and quality of life.
>
> For quality of life we need a multidimensional concept that includes
> areas less likely to be affected by chemotherapy, the spiritual,
> perhaps less the psychological and social but certainly the physical
> and functional.
>
> For clinical benefit, with talked about the original definition. It
> includes areas more likely to be affected by the treatment choice. Why
> isn\'t it just symptom benefit? Well, performance status is not a
> symptom is probably the reason. So, it includes functional and
> physical aspects as well but areas likely to be affected.
>
> So, this is sort of the overall working of PROs\--symptom palliation,
> quality of life of life as well, but quality of life used in a
> denotative way, not as a connotation of oh, it must affect his quality
> of life.
>
> \[Slide\]
>
> This is probably my slide that I should have entitled much like Dr.
> Bunn\'s, sort of the why are we here? Is there really a need to look
> at PROs? I think the answer is absolutely yes. Every physician knows
> that hardly a day goes by that a patient doesn\'t say to us, you know,
> doctor, I am interested in my quality of life as well, and why isn\'t
> that involved in drug approval? It should be and I think we have heard
> the desire for it to be.
>
> Lung cancer mesothelioma are a highly symptom diseases. Survival
> response reveal only a portion of the experience that our patients and
> families have. Our treatments vary in their side effects and risk
> profiles, some of them really being quite toxic but this applies to
> surgery radiation and chemotherapy. So, we have to be able to balance
> that experience in some way. The response rate simply won\'t do that.
> Actually, if we are honest with ourselves, meaningful survival
> differences are most uncommon. Every trial is designed to look at the
> survival differences but they are extraordinary when the occur.
>
> \[Slide\]
>
> The question came up before do we really know what symptoms to look
> at? You are darned right we do in lung cancer. We absolutely do,
> mesothelioma as well. Look at the frequency on presentation or during
> the time for non-small cell lung cancer and small cell lung cancer for
> these common symptoms that our patients present with and tell us
> about.
>
> In the development of the better instruments, which I will talk about,
> the input of patients is absolutely crucial or we could not have been
> able to assemble such instruments. These were not developed by people
> in \"ivory towers.\"
>
> \[Slide\]
>
> Our patients are highly symptomatic at baseline. This is a large,
> 30-center trial. We looked at using a validated quality of life
> instrument in the beginning. As you can see, 80 percent of patients
> present with three or more of these symptoms, 92 percent with two or
> more. So, another way perhaps of doing it, to get away from some of
> the multiplicity issues, is to look at how patients rate their overall
> symptom distress, what the symptoms really mean to them. It gets back
> to some of the functional issues as well. Unfortunately, people at
> presentation first-line are extremely symptomatic.
>
> \[Slide\]
>
> Looking at survival, and this is just a compilation of large
> randomized trials over the past decade. The red bar represents
> supportive care. We no longer have the issue does chemotherapy improve
> survival over supportive care. Seventeen out of 17 trials with this
> design\--way too many\--showed improvement over supportive care. The
> majority of those trials independently showed an improvement in
> survival. Way too many trials were done there.
>
> The next bar, next to the red, is just platinum alone and Dr. Cohen
> told us about platinum alone. But if we look at the last three bars,
> carboplatin combinations, older cisplatin combinations and newer
> cisplatin combinations, yes, the newer drugs have a little bit of a
> benefit for us; they are easier for us to use in many ways and we
> prefer them. But in terms of survival benefit, it is very, very
> difficult to have a meaningful survival benefit although, God knows,
> we don\'t want to talk about what a meaningful survival benefit might
> mean. We have already sort of addressed that one. But it is pretty
> hard to have survival benefit that gets our attention.
>
> \[Slide\]
>
> Dr. Janet Dancy really put together a lot of this and I think she is
> just right. Here PROs can create an accurate picture of the disease.
> Without this we are missing what are patients tell us about in every
> single patient encounter. We must have this to really understand about
> the disease.
>
> The second paragraph\--unfortunately, many studies have shown us that
> we are not so good as nurses as doctors in predicting how our patients
> feel about these things. It is too bad but, unfortunately, has been
> reproduced even in the JNCI and in the Miles trial was shown once
> again.
>
> Interestingly, why we need this is that response rates under-estimate
> the benefit. It appears we don\'t need a major response to be able to
> have enough change to be able to have benefit.
>
> Finally, how do we have this balance between symptom improvement,
> toxicity, the difficulties of treatment and the benefits? There are
> many examples where more toxic regimens are associated with greater
> patient benefits, including their symptom relief, etc. So, to be able
> to put this together is not easy\--actually, it is easy, we have to
> ask the patients and they can tell us.
>
> \[Slide\]
>
> So, the four questions I have always had with these areas are can we
> define quality of life? We surely can define pain, dyspnea and cough.
>
> Can we measure quality of life? That is what a lot of the conversation
> was about. Can we quantify the more subjective aspects? We quantify
> subjective aspects all the time in many different areas in behavioral
> science.
>
> Can we agree on how to analyze the data? I am not sure we are quite
> there yet but I think we are getting closer. We have a lot of good
> people around the table who can help us with that.
>
> Can we present the data in a way that is clear and useful, not looking
> at 99 different endpoints, etc.? That is nuts!
>
> \[Slide\]
>
> Define it. If we ask each one of us in the room to define quality of
> life in one, two or three sentences we will probably end up with some
> disagreement. If we sat here for a while we would probably come pretty
> close and be able to carve out one paragraph. One thing we can agree
> on is this is probably made of these dimensions, the physical such as
> symptoms and side effects; the functional which we talked about
> earlier, psychological, social and spiritual. Spiritual doesn\'t have
> to mean religious; it can be meaning of life. So, these are the
> denotation areas of quality of life. Now, the other PROs, the
> patient-reported outcomes, deal more with the physical and functional.
>
> \[Slide\]
>
> This is the model part of the content or actually the construct
> validity for quality of life. Dr. Patricia Hollen publishes for the
> LCSS instrument. Well, if we look at the physical dimension and the
> functional, those are what are, for the most part, discovered or
> looked at in the other PRO dimensions, the symptoms, the performance
> status. Yes, we can look at functional dimensions. The FACT-L actually
> does a very nice job of looking at the differences in function and how
> function is meaningful, and we don\'t have to look at these as a lot
> of different endpoints. So, we can focus on the physical and
> functional, which account for about 75 percent of the variance in many
> of the studies, and globally capture quality of life in the others.
>
> \[Slide\]
>
> Instrument development has changed, or instrument use has changed in
> quality of life. We have instruments that are good for all populations
> that are kind of interesting to look at, but I think it is clear that
> there would be a need for instruments that are more cancer specific
> than, say, osteoarthritis. The pace of these diseases can be quite
> different.
>
> We talked a little bit about lymphoma. The B symptoms of Hodgkin\'s
> disease are a great deal different than the symptoms of lung cancer.
> Issues such as fertility are issues that we think about all the time
> in younger patients with lymphoma but it is not really such an issue
> in lung cancer. So, we need disease specific instruments. We might
> even need treatment specific. We talked earlier today about adjuvant
> trials. In adjuvant trials in lung cancer in patients with stage I and
> II, we want to look a year later to see if our interventions in an
> adjuvant trial in somebody who has undergone a right pneumonectomy
> whether we have good quality of life a year later. That may be a
> different instrument that refocuses on the functional endpoints than
> we would use in a clinical trial in stage IV where that patient has an
> expected 7-, 8-, 9-month live altogether and we have such instruments
> as well.
>
> \[Slide\]
>
> Here are the three instruments with acceptable psychometrics. We will
> look at the psychometrics in a second, the LCSS, EORTC QLQ30 and the
> FACT-L. The latter two, the EORTC and the FACT-L are similar. They are
> 30-40 items total, a general module 7-13 for the lung cancer. The LCSS
> was developed specifically for clinical trials and clinical
> management. It is shorter; 8 items in mesothelioma, 9 in lung cancer
> and 6 observer items but the observer scale is optional. They take
> between 3 to 10, 12, 15 minutes. These are not the 99-item instruments
> that are out there, and more. We do not need those.
>
> \[Slide\]
>
> What kind of validation have they been through? They have been through
> very serious validation methods. These validation methods were not set
> up for cancer; they were set up for behavioral science and they are
> very strict and are much more difficult than, say, RECIST or most of
> the other things that we have been talking about. We can see that
> these instruments to be useful must be valid, reliable and feasible,
> able to be used in a real clinical practice in real time studies.
>
> Here are some of the psychometrics that are there. As far as the
> content validity, the content of what we looked at if we didn\'t have
> patient agreement, patient input, it wouldn\'t be worthwhile.
> Fortunately, that is true in all these instruments.
>
> \[Slide\]
>
> If we look at internal consistency, if we look at the reliability,
> stability\--do you get the same results if you give it again to the
> same patient? Do you get it if you give it in different groups of
> patients who have the same characteristics? The answer is yes. Dr.
> Nunnally wrote the textbook in this area, not as far as oncology is
> concerned, and the instruments that I showed you, those three
> instruments stand up very, very well.
>
> \[Slide\]
>
> If we look at two of the lung cancer instruments, for instance, that
> are used the most in U.S. trials which is why I looked at them, if we
> look at their reliability coefficients, the Cronbach\'s alpha for
> their core measures, they come out very, very well, and much better
> than needed for a new measure. For the lung cancer module they come
> out really quite well also. In fact, we have a new publication from
> Dr. Chris Earl and Jane Weeks that looked at quality of life and PRO
> instruments in oncology and the lung cancer instruments, specifically
> the LCSS, are among the very best in all of oncology. So, as far as
> lung cancer is concerned, we are blessed by having some really pretty
> good instruments and most of these instruments now are being put into
> electronic format so that they can be very, very easily done with very
> little extra time for patients or data managers.
>
> \[Slide\]
>
> If we look at other types of validity construct criterion related,
> they are really there. They compare well to gold standards and other
> aspects. So, there is no doubt that the validity process that has been
> used for these types of measures in a variety of different conditions
> are met by these validated instruments, not necessarily by other
> instruments.
>
> \[Slide\]
>
> We talk about this clinical meaningful difference. I am just floored
> why it is that this should be answered for these PRO endpoints and
> quality of life but not for survival. I really am amazed that we can
> even talk about non-inferiority if we can\'t set what the border is
> for survival that would be important. I think that this really becomes
> rather difficult. We know it doesn\'t meet non-inferiority but what
> was the border? Why was that boundary selected? The same thing is true
> here.
>
> I like what Dr. Williams said, we look at whether there is a
> statistically significant difference, whether we can be confident that
> there is a difference. Let\'s apply whatever we are applying to these
> PRO or quality of life endpoints too. Either we have a difference or
> we don\'t. It is for somebody to look at and say that three percent
> difference doesn\'t mean much to me. We heard the five-week difference
> didn\'t mean much. But, of course, Dr. Cohen presented a lot of
> five-week differences here that we have approved drugs on, and there
> is value to normative data being collected as well.
>
> \[Slide\]
>
> Phase II trials, single-arm, non-randomized trials, these trials
> suffer from the same problems that survival studies do. We talked
> about the gefitinib trial before. We were all glad to see that
> patients had a rapidly occurring change. Of course, that was really
> looked at from the subscale FACT-L, not necessarily the whole FACT-L
> and, yes, there was symptom improvement and these are all very nice
> things to see. But the problem with these is, just as with survival
> analysis, that with the lack of a control group we don\'t have a
> context.
>
> \[Slide\]
>
> What makes it particularly difficult in symptom control is that we are
> giving standard palliation. It is not a blinding issue. Of course, we
> are giving pain medicines to people who have pain; cough medicines to
> people who have cough and oxygen to people who are dyspneic. We
> wouldn\'t want to do a trial that was any other way. These are
> confounding problems but they are what we deal with in clinical
> medicine every day. So, without having something for context I have no
> idea whether or not that is a great response rate we see or not. So,
> in Phase II these are helpful in hypothesis generating but difficult
> for us to say that they lead to true improvement.
>
> This can lead to an overestimate of benefit. On the other hand, if we
> just looked at the response rates, since less than a major response
> gives benefit, that has been an underestimate of benefit. So, there
> are problems with Phase II. It is probably really good to analyze
> these data in Phase II studies so it can be more useful in trying to
> guess what difference we need to look at in Phase III.
>
> \[Slide\]
>
> What about Phase III trials? What kind of problems do we run into
> there in comparison trials? Well, these are the complaints that we
> hear the most, cumbersome instruments. Yes, but actually the three
> instruments I showed you are not so cumbersome, the 3-, 5-, 15-minute
> analysis isn\'t so bad. It takes a whole lot less time than the MRI
> that we get all the time or the PET scan or the CT scan. People say
> how can you ask a sick person to complete this questionnaire that
> might take them five minutes, you mean as opposed to getting into an
> MRI machine? It is really very easy. It is tough to get the sick
> patient who may have progressed over to the PET scanner but it is not
> so hard to do these instrument and many of these can be done by phone.
>
> Patient deterioration is a big problem and this can lead to the sloppy
> data that we heard about before or asymmetrical follow-up\--nice term;
> I like that term. If we don\'t follow-up equally in two groups in a
> Phase III, that is not good. So, we need to be looking at patients
> even after they progress. Lack of investigator commitment. How do we
> prevent that? We emphasize it from the very beginning.
>
> \[Slide\]
>
> This looks at those same 673 patients that I showed you before with
> those symptoms. We wanted to see after three cycles how many were
> staying on study, 64 percent. The main reason for coming off and not
> having assessment was disease progression. This is completely
> controllable simply by following with something as simple as an
> instrument that costs pennies, not thousands of dollars, to be able to
> follow this.
>
> Another advantage of following the PROs is we talked about the problem
> of contamination with crossover. This isn\'t crossover. We don\'t have
> to worry about that. It is eliminated from looking at this. So, we
> should be able to improve this follow-up by at least 20 percent to be
> able to get 80-90 percent adherence rather than the 64 which is
> certainly not good.
>
> \[Slide\]
>
> Who drops out? Who is in the attrition group? Well, we looked at age
> which is not a prognostic factor in lung cancer and there was no
> difference between the on-study group and the attrition group by age.
> Indeed, if the symptom burden was worse or if the quality of life was
> lower, those patients were disproportionately seen in the attrition
> group. Think what that does. That takes an arm that is inferior in
> terms of response or survival and it drops out the more symptom or
> lower quality of life patients, artificially making the inferior arm
> look better. So, that is a real problem. Is it surmountable? Easily
> and it has been surmounted.
>
> \[Slide\]
>
> This is from mesothelioma study. I will talk a little bit more about
> it. Nick Vogelzang published this study in the JCO this summer. It is
> pemetrexed-CIS versus CIS in advanced mesothelioma. What did then do?
> They conducted a brief training session so that everybody involved
> understood why quality of life and PROs were being done. They included
> baseline quality of life data as part of the randomization which
> emphasized the importance that we really want this as much as we want
> the CT scans. They continued to have emphasis while monitoring the
> trial and, as a result, more than 90 percent of the planned
> assessments\--this was done weekly which I think is excessive and
> there are reasons to believe it is excessive, but more than 90 percent
> of the planned assessments were done. So, this is probably the
> industrial standard.
>
> \[Slide\]
>
> We talk about survival, quality of life and response as being
> separate. We need to analyze them separately, that is correct but, of
> course, they are more related than different. They are related because
> they are largely determined by the malignancy. If we cannot control
> the cancer we will not be able to improve survival very likely or
> quality of life. Of course, if the treatment is harsh then this could
> have a negative impact on survival or quality of life or both.
>
> But when we look at the approved regimens that Dr. Cohen showed us,
> they are all pretty similar in terms of their toxicities. There are
> not big differences. So, we shouldn\'t expect with modern care that
> that is the problem. So, they are inter-related but they are not
> identical, these endpoints, and quality of life is a very important
> one. But I don\'t think we should ever look at quality of life without
> looking at survival or looking at survival without looking at quality
> of life, but either one of these could be a primary endpoint.
>
> I like what Dr. Bunn had to say about response and accelerated
> approval but when we talk about large trials response is probably not
> of great value if it doesn\'t contribute to quality of life or if it
> doesn\'t contribute to survival, and probably any good treatment will
> contribute to both because it is mediated through the malignancy.
>
> \[Slide\]
>
> This looks at the survival based on quality of life at baseline. If we
> look at that group that scored their quality of life in the lower half
> of the group, they had a much inferior ultimate survival when compared
> with the group that scored their quality of life in the top half of
> the group. That is not too surprising but this was a more important
> prognostic factor in multivariate analysis than any other, including
> stage III versus IV, including gender, including performance status.
> So, ignoring quality of life is missing the boat on a lot of these
> areas. Yes, it is more difficult to measure quality of life than to
> use the instrument that we use for survival, that instrument being a
> calendar, but I should think we are little bit more sophisticated than
> just having the ability to use a calendar.
>
> \[Slide\]
>
> For Phase III we have problems in analysis. The standards for
> statistical approaches remain controversial. I do agree that the less
> modeling we can use, the more data that we can include, the better off
> we are. There are problems with simply averaging scores. Survival
> differences complicate quality of life analysis because the attrition
> is not random. But these are correctable.
>
> As Dr. Fleming has emphasized, results from all patients on trial need
> to be analyzed. Instead for looking for a way to adapt for that, we
> need to follow all the patients. They did that in the mesothelioma
> trial and we can do that too.
>
> \[Slide\]
>
> Well, does it really add to response or to survival, the common
> endpoints? Let\'s just look at these data. This is almost a
> 500-patient study. If we look at this in terms of the PRO outcome of
> pain, which is something Dr. Carpenter brought up as something
> important, it is not too surprising to us that patients rated their
> pain control as better if they had either a CR or PR, but we know
> there are not real CRs\--a major response versus stable disease versus
> progression disease.
>
> But what we didn\'t expect to see is if you just look within response,
> because we think of response as a blunt instrument and you either have
> a response or you don\'t, if we looked at how patients rated their
> pain there was a major difference between the pain control for those
> who got the combination regimen, in this case pemetrexed-CIS versus
> the single agent. You can see the yellow bar versus the blue bar.
> These patients were all followed to the same degree. They all
> responded but there was a change in pain. In fact, in all 8 LCSS
> parameters the same pattern existed within responders and patients on
> the combination rated their patient-reported outcome, including
> quality of life, as being better. So, it is possible that this is a
> more sensitive measure than the blunt instrument of response.
>
> \[Slide\]
>
> What about survival? Well, Dr. Vogelzang reported in the JCO that
> there was a survival difference between the combination regimen and
> cisplatin alone. If you look at 12 weeks there was no sign of this. At
> 18 weeks there was only a slight suggestion that there might be a
> survival difference.
>
> But let\'s look at quality of life and symptom distress\--this covers
> all the PRO aspects. If we look at quality of life we can see that
> there was already some difference at week 12 and a larger difference
> at week 18. When patients rated distress from their symptoms the same
> pattern was seen. At 12 weeks this was not significant. At 18 weeks
> this was highly significant, even if one addresses the issues of
> multiplicity, showing that it was easier to show quality of life
> differences and symptom distress as the patients reported which was
> significant earlier on than was survival. In fact, this is predictive
> validity, predicting what will happen to survival which is considered
> to be a very strong validity point.
>
> \[Slide\]
>
> My conclusions would be, and our group said, yes, this is ready for
> \"prime time.\" There are validated instruments but when we do these
> studies we must select carefully. We need to use a validated
> instrument but, remember, some of these instruments measure different
> aspects, such as a clinical trial versus an adjuvant trial, a little
> bit different and we need to be sure that we have the right languages
> and cultural aspects which many of these instruments address.
>
> As with other study endpoints, before the trial begins we need to
> delineate what are the primary endpoints. We need to address areas of
> multiplicity and of analysis. Too often I see protocols that say,
> well, here is the instrument we are going to use and we are going to
> analyze it and then later comes the analysis. No, that has to be
> thought out ahead of time. If so, we will have something that we can
> present to our colleagues at FDA that I think they can probably get
> their arms around.
>
> We need to follow all patients whether they are progressing or not.
> That is one of our biggest areas of problems so we need to follow all
> patients throughout a predetermined interval. So, if we have an
> interval to follow the patient, how long should that interval be?
> Appropriate to be able to see response and appropriate to be able to
> see the toxicities. If we can see that, we can see that area.
>
> There are other uses for quality of life. In terminal care we can look
> at it in those areas but that is a different issue. But in the
> beginning in a clinical trial, follow for a specified time but follow
> all patients. When patients die, is that a problem? It is not a
> problem. Quality of life is a function of life. If some patients have
> died, that is what occurs; we don\'t follow those. But we don\'t look
> for the patient who is no longer contributing, the patient lost to
> follow-up. That is as bad as with toxicity and response.
>
> \[Slide\]
>
> We need to use an appropriate control group. Sometimes this is
> difficult. And, all these comments refer to quality of life measures
> when we are looking at drugs that are likely to have their benefit by
> means of anti-cancer activity. We are not talking about pain medicines
> here. We are talking about anti-cancer drugs and looking at approval
> for those. Their appropriate control group is important.
>
> We need to emphasize compliance throughout the study and as long as
> the investigators and the patients understand this, then I think we
> are likely to have people included. When it is feasible to blind the
> patients and the doctors, especially the staff, that is great but it
> is not always possible to do that and I am not sure that is the
> biggest objection.
>
> \[Slide\]
>
> So, can we define quality of life adequately? Can we measure quality
> of life? I think we have some decent instruments. They are not perfect
> but they are decent. When they are put in electronic media they take
> almost no time from the staff, almost no time from the patients. Can
> we agree on how to analyze quality of life results? We are getting
> closer. There are thoughtful ways that we can talk about. Can we
> present quality of life findings clearly? Sure, we can. We don\'t have
> to present every last aspect, especially when we have determined at
> the beginning of a trial which are the primary endpoints that we wish
> to look at. Thanks.
>
> **Clarification Questions to the Presenters**
>
> DR. PRZEPIORKA: Thank you. Before we have our introduction to the
> questions I would like to actually ask the three speakers to take the
> podium together and have the committee have the opportunity to ask
> them questions. While the synapses are all firing up here, I will take
> the prerogative to ask the first question.
>
> Dr. Gralla, you went through what validation means or quality of life
> which, in the lab, would qualify as qualification rather than
> validation which would be predictive of an outcome. You did mention
> \"the gold standard\" but did not identify it. What do you use as the
> gold standard? For example, if we had a surrogate as a response rate
> we would hope that would predict for survival. What do the quality of
> life instruments measure for?
>
> DR. GRALLA: For instance, predictive validity from an instrument, and
> this could be true for time to progression or whatever and for quality
> of life, predicts for another validated endpoint. But when you do
> against gold standards, if we looked at instruments such as the
> American Thoracic Society dyspnea scale, if we looked at the
> Melzack-McGill pain scale, etc. we now have huge numbers of questions
> to ask. So, what we look for are correlations between using these
> already validated instruments. So, for pain the Melzack-McGill scale
> is one that one could select, there is a whole variety of different
> scales that are out there for different aspects that are used for use
> as gold standards.
>
> This is why if you read the papers, and each one of these three
> instruments have published psychometrics, they tell you exactly which
> scales they used, the PONS, etc. to look at various aspects. It takes
> years to validate these scales which is why we don\'t want to see
> somebody just ad hoc make up a scale to be used in the next myeloma,
> lymphoma, lung cancer trial. So, there are specific scales that are
> found in each of the publications.
>
> DR. PRZEPIORKA: Dr. Levine?
>
> DR. LEVINE: I have kind of a crazy question but people are all
> different. I saw this on one of your slides but, you know, one person
> may call something pain and that is not pain at all to somebody else.
>
> DR. GRALLA: Right.
>
> DR. LEVINE: So, is it valid to just look at what I say is my quality
> or maybe what you should be looking at is change, you know the delta,
> in each given patient. How do you analyze that?
>
> DR. GRALLA: You brought up a very good point. For many of these
> instruments, that is what the Cronbach\'s alpha, the internal
> consistency, can look at. When you look at certain items that don\'t
> make sense\--for instance, the fatigue question, 15 years ago when we
> looked at that we said we don\'t think people understand what fatigue
> is. So, we will look at tiredness; we will look at weakness. Well,
> they all meant different things to different people. It turned out
> that the right term to use, years later with much more testing, was
> fatigue\--
>
> \[Laughter\]
>
> \--and only by testing could you find that out. So, you must find that
> out. In emesis scales, which is different, nausea means something
> rather different. Don\'t ask my mother-in-law what nausea means to
> her. It is entirely different from what it means to others. And, that
> is a real problem. But for each of these instruments those points are
> there.
>
> Now, do you ask about change over time? You must have a time period.
> For instance, if you ask a patient how did you feel nine weeks ago it
> is really difficult for us to say. So, for many of these instruments
> the time frame is in the past day or in the past week.
>
> DR. LEVINE: I didn\'t mean that. I meant let\'s say the instrument is
> done at baseline and then every week. I guess it is an analysis
> question, couldn\'t you just look at changes between week 1, week 2
> and week 3 and that they have answered in a timely way?
>
> DR. GRALLA: Indeed, that is the way that many analyses are looked at.
>
> DR. PRZEPIORKA: Dr. Bonomi?
>
> DR. BONOMI: Along the same lines to Dr. Levine\'s question, maybe we
> could define a quality of life response just relating to the physical
> elements, not the whole quality of life instrument, and the point that
> you made, a baseline and, say, four weeks and eight weeks. What is the
> statistically significant change? I know in gefitinib they talked
> about a difference of two points. I don\'t know the statistics of it
> but it sounds like an awfully small change to be considered
> significant. It seems like we need to look at that. Could we define
> some type of quality of life response that could be then applied
> across studies?
>
> DR. GRALLA: Phil, I think that Dave Cella meant 2 points out of his 7
> questions, and of 29 total points yielding a 7 percent difference. We
> can either accept that or not as such. It is kind of the same
> discussion that we have had before. Think of the risk-benefit aspect
> there. If you were looking at imatinib versus marrow transplant in
> CML, clearly you would have to have a better benefit in the marrow
> transplant to be able to be worthy to most people than, say, just
> giving Tylenol or just giving imatinib. So, the risk-benefit probably
> comes in there and it is just the discussion that we talked about
> before, in rapidly progressive disease, highly symptomatic.
>
> One of the problems is when the baseline is 70 percent where 100 is
> perfect and 0 is terrible and you improve by just 6 or 7 percent, that
> doesn\'t sound like very much but actually it is 25 percent of the
> amount that you could improve. So, it is the relative difference
> versus the absolute. These are very, very difficult things to answer.
> In a progressive disease like lung cancer is it the number of patients
> who report an improved quality of life, a stable quality of life, or
> is it when treatment A preserves more quality of life over that entire
> group versus treatment B even though there is a deterioration in both
> groups? I favor the latter rather than looking at the quality of life
> response.
>
> DR. PRZEPIORKA: Ms. Ross?
>
> MS. ROSS: Thank you. I guess this would be to Dr. Bunn and Dr. Cohen.
> Dr. Bunn made the statement that only in oncology drugs is accelerated
> approval dependent on showing an advantage over existing drugs. Was
> that your statement, Dr. Bunn?
>
> DR. BUNN: Right.
>
> MS. ROSS: I heard someone say that is not true.
>
> DR. TEMPLE: The accelerated approval rule refers to showing an
> advantage over available therapy. That is why you would accept a
> lesser standard of approval.
>
> MS. ROSS: Is that only on oncology?
>
> DR. TEMPLE: Oh, no, it is for everything, for any accelerated
> approval.
>
> MS. ROSS: Has that ever been changed? Is it a rule?
>
> DR. TEMPLE: It is a rule; it is a regulation.
>
> MS. ROSS: It is a regulation?
>
> DR. TEMPLE: Yes.
>
> MS. ROSS: Or is it law?
>
> DR. TEMPLE: It is actually now in law as well. It is part of the
> fast-track provision of FDAMA as well as the rule.
>
> MS. ROSS: Thank you.
>
> DR. BUNN: As I mentioned, right now that is probably not a huge
> problem for oncology because many of the new drugs have less toxicity
> so they do have an advantage over existing drugs in terms of toxicity.
> I brought that up in terms of thinking about the future. You know,
> laws and rules are made to be changed so perhaps in the future one
> would consider whether that provision for accelerated approval is a
> bit too strict. Certainly for regular approval that provision doesn\'t
> exist, only for accelerated approval. Is that right, Bob?
>
> DR. TEMPLE: Yes. There is one thing that is important. The
> Commissioner has announced this. We were trying to decide among
> ourselves whether this has made it into a rule but you can or will be
> able to have a second accelerated approval, say, for another drug that
> is not cytotoxic as long as it still has an advantage over anything
> that has full approval. I don\'t think that completely\--
>
> DR. BUNN: It is halfway there.
>
> DR. TEMPLE: I don\'t think it goes completely to where you want to go
> but that is important.
>
> DR. WILLIAMS: Dr. Bunn, as I read it, there is no reason to have
> accelerated approval. You know, according to your proposal you could
> use a different endpoint then that would be tantamount to full
> approval and there wouldn\'t be any particularly setting where you
> needed it. It would be in every setting. You would get approval in
> every setting for the surrogate endpoint. Right? That is what you are
> proposing? There is no particular setting\--
>
> DR. BUNN: No, no, if you had a response rate in an untreated
> population of 25 percent and you had the same toxicity profile, then
> you wouldn\'t be able to get accelerated approval. If you had a
> response rate of 25 percent and you had less toxicity, then you could
> get accelerated approval.
>
> DR. TEMPLE: If it was still accelerated approval now and it was based
> on response rate alone and there was no other drug and the second,
> third, fourth still had an advantage over available therapy, they
> could still be approved. I think you really want to say if it is a
> useful drug none of that should matter and you would like to make that
> a standard for all cases, but we haven\'t done that\--
>
> DR. BUNN: Right.
>
> DR. TEMPLE: \--but accelerated approval is not terminated by the
> approval of one drug under the accelerated approval rule.
>
> DR. PRZEPIORKA: Dr. Cheson?
>
> DR. CHESON: Paul, response rate in lung cancers to you is an important
> endpoint. Does it matter how long the responses last?
>
> DR. BUNN: Of course, it does but\--
>
> DR. CHESON: Is there a minimum duration of time which you would accept
> for that?
>
> DR. BUNN: We don\'t know that. That hasn\'t actually been looked at
> and it is something that probably could and should be looked at. But,
> surprisingly, there is very little variation in duration of response.
> They are very similar. I don\'t know why it is. You know, why is 20
> percent, more or less, sort of the magic threshold for what will lead
> to an improved survival. It is hard to say. Almost all those drugs
> have a median duration of response in terms of three months. If you
> had one that had a median duration of response of a year it might make
> a bigger impact on survival. If you had one that only had a median
> duration response of a month would it still affect survival? I don\'t
> know and that is because we don\'t have any examples. So, it is
> something that we should certainly look at but there is not a lot of
> data and there is not much we can say about it at the moment. Do any
> of the experts over here disagree with that? I mean, I think at the
> moment it would be hard to put median duration of response into the
> equation.
>
> DR. PRZEPIORKA: Dr. Fleming?
>
> DR. FLEMING: Actually, I have questions for both Richard and Paul but
> to avoid confusion let me just start with Richard.
>
> DR. GRALLA: I was afraid of that, Tom!
>
> DR. FLEMING: Actually, I was pleased to see that you addressed a
> number of the issues with PROs that we struggle with, issues of how
> imperative it is to ensure you are following everybody so you are
> getting an unbiased assessment. I still struggle a little bit with how
> to handle the deaths in that regard.
>
> With the validity issue, you talked a lot about that. Blinding still
> troubles me as to how we could address that. I think blinding is
> really key to the objectivity of measuring these.
>
> A question that I would like to ask or a comment maybe in response to
> one of your questions, you had pointed out this committee, in a sense,
> dodged the question of how much of a survival effect you need to see
> for it to be relevant and you were saying why should we be asking the
> same thing for PROs. At least for some of us the reason that there is
> a difference there comes down to a multiplicity issue with PROs. There
> usually is a wide array, as you have mentioned, with these various
> scales, 6-plus 9 or 15 measures, 30-40 measures etc. It really is
> important to formalize this into something that is a primary endpoint.
> Sometimes that may be based on a composite. What you get then is you
> compromise interpretability for enhanced sensitivity and here is the
> issue, you might now have exquisite sensitivity to small differences
> in these composite measures and then it is, in fact, much more likely
> that you could achieve statistical significance there and wonder if it
> is clinically significant. It is much less to occur on survival, for
> all the reasons we have heard\--it is difficult to get an even
> adequately powered survival study. So, I would say there is a reason.
> I don\'t know if you wanted to comment specifically on the issue of
> multiplicity on this.
>
> DR. GRALLA: I agree with you entirely, Tom, it is a real issue and
> that is why you need to define it in the beginning. First, it is
> simply something as simple as looking at quality of life which can be
> looked at globally, or looking at symptom distress or looking at pain,
> whatever you feel would be most important in this population. You
> don\'t need to look at all of them. The problem we have had the most
> is with people looking afterwards and then choosing, oh, here is the
> one that came out, or overwhelming us standard data in a 99 instrument
> and 44 looked at this and 33 didn\'t. That is over. That time is over.
> Those aren\'t the issues.
>
> When we use these instruments we can look at families and maybe we do
> give away some sensitivity but, in fact, in looking at some of the
> data that I was pleased to see with some of the trials that I
> mentioned, we in fact don\'t have a multiplicity issue. When we look
> at two or three of these areas, even if we adjust for the fact that we
> are looking at three endpoints, it is still significant.
>
> I know that that gets back to your other point of looking at small
> differences in survival. Again, we are talking lung cancer. Marty
> showed us approvals with five-week, three-week survival. So, I don\'t
> think that we should be rushing to worry about those small
> differences. I can\'t understand why a patient would say to me, well,
> let\'s see, doctor, there was only a 7, 9, 10, 12, you-name-it,
> percent difference, why wouldn\'t I want the one that had that 12
> percent difference? And we look at what patients want and whether we
> are fulfilling those needs.
>
> The blinding, it is great to do when you can and often it can be done
> and should be done but, you know, when you think about it, you have a
> large trial and you are looking at pain control and you give the
> patient the pain visual analog scale. The patient I think is pretty
> honest about telling you what it is and as an investigator in a
> 400-patient trial I have no clue as to how that affects. In other
> words, I am not putting my input in, the patient is. I am not sure the
> patient understands which one is better in that regard.
>
> Where it is also important though is the context. Did it require more
> pain medicine to be able to get that pain control result? So, we do
> need to look at that. Anyway, that is sort of how I would address some
> of those key issues that you bring up, Tom. They are important but
> they need to be thought of, just as survival, ahead of time; just as
> whether we are going to look at disease-free survival, TTP, TTF and
> survival. I think they are similar issues.
>
> DR. FLEMING: I think it is when we use the composite scales that are
> harder to interpret and then we can see very small differences. Yes, I
> would say a small difference is better than no difference if I can get
> it for free but then it is benefit to risk.
>
> Let me get to a question that is probably more for Paul although it
> relates a little bit to what you were talking about as well, Richard.
> Paul, one of the take-home messages I get from what you are saying is
> you are identifying concerns with launching large-scale Phase III
> trials because we have to show survival effects when there really
> isn\'t adequate evidence at hand at baseline to say the plausibility
> of achieving that positive effect on survival is adequately high. Gee,
> if we had responses and we were looking at 15, 20 percent responses,
> then your sense from the data you are looking at is that it is much
> more likely that we will see a survival effect. I guess one take-home
> message I get from what you are saying is then we ought to have fewer
> study settings jumping from Phase I to Phase III. Let\'s do that Phase
> II trial with 100 people and see if we get a 15 or 20 percent response
> rate.
>
> The issue that is troublesome here, and is a little bit related to
> what Bruce\'s comment was before, as I look at response it seems to me
> that response is a component of what we would think of as an integral
> causal pathway through which the oncology disease process is
> influencing outcome like survival. My worry is that when we look at
> percent of patients that achieve a certain level of tumor shrinkage
> would dichotomize the world and that dichotomization may be missing
> part of what the intervention and disease process is really doing
> here. It is not just a matter of did you achieve a response. What was
> the magnitude of that response? What was the durability of that
> response? It is easy to envision that an intervention could readily be
> achieving intended benefit on clinical endpoints like survival and an
> oversimplification of what is really happening to the disease process,
> to the tumor burden may not be adequately captured by percent
> responding.
>
> One of the things that troubles me too, and you and I had a brief
> chance to talk about this, when you look at that meta-analysis of the
> 176 Phase II trials, those studies are looking at the relationship
> between whether somebody responds and what the overall survival is.
>
> So, Richard and Paul, you are vigorous and I am frail at time zero. In
> fact, Richard, you have a better quality of life than I do and, Paul,
> you have a better response than I achieve and both of you survive
> longer. What do we see from those data? That there is an obvious
> correlation between quality of life and survival and response and
> survival. Now, Richard, I don\'t care that that is the case in what
> you are advocating because quality of life is a value to me whether or
> not it is a surrogate for survival. But with response, Paul, I do care
> because I do want to know that this is, in fact, giving me evidence
> that mediated through that response I am causally inducing what I
> really care about.
>
> Here is the rub, we could have a million patients in the data set that
> you have been providing to us. What it does is it tells us about a
> correlation that exists but it could be that the causal mechanism for
> that correlation is not induced responses leading to prolonged
> survival. What I need for that, and this is critical information, is
> properly controlled trials that can compare what is the treatment
> induced influence on response versus the treatment induced influence
> on survival. That relationship across a meta-analysis is telling me
> whether or not I am causally influencing survival mediated through
> response.
>
> DR. BUNN: I don\'t really disagree with what you say. One of the
> issues gets down I suppose to semantics but, you know, it has to do
> with cytotoxic versus cytostatic. If a lot of the drugs that we have
> actually worked by being cytostatic this would be a huge problem.
> Maybe bevicuzimab will be the first but maybe some day we will get
> confounded by cytostatic. But most of the drugs that improve survival
> and, in fact, in my belief all of them at the moment, have actually
> worked because they are killing cancer cells. Even tamoxifen causes
> objective responses in patients and certainly Iressa causes objective
> responses.
>
> So, I think when the mechanism is to kill cancer cells, that objective
> response actually makes sense. Sometimes, you know, examples are
> useful. I think it is not out of school to be actually thinking about
> what is coming along. You heard about a trial that looked at a
> non-inferiority survival advantage in second-line non-small cell as
> the major endpoint. In every efficacy parameter, including symptoms,
> both pemetrexed and docetaxel were identical. It is the biggest trial
> ever done in second-line non-small cell. But the non-inferiority p
> value was 0.051. I don\'t know what the committee will do but I do
> know that the response rate to pemetrexed was 9.1 and to docetaxel it
> was 8.8 and the symptoms were just as often relieved.
>
> So, if the committee can\'t deal with a single trial with a p value of
> 0.05 in terms of non-inferiority, accelerated approval could be given
> on the basis of response for, you know, a drug that I think needs to
> see the light of day in this disease and killing some of these drugs
> may be the end of the light of day. Erlotinib is going to come before
> this committee in a trial where the hazard rate for the study was a
> hazard rate of over 30 percent reduction for a single pill in second-
> or third-line non-small cell that is a big change and that may not
> make it against best supportive care in terms of survival but I will
> eat my hat if in terms of response it is not highly statistically
> significant and if it isn\'t eight percent or higher.
>
> DR. FLEMING: But your example is a bit changing the topic here because
> you gave an example where you were talking about evidence on response
> and time to progression and survival, and you are really asking the
> question, in a non-inferiority setting, what is an adequate amount of
> evidence on the aggregate of those measures, which is different from
> the thrust of your presentation which was let\'s reexamine whether or
> not there is adequate evidence that if you can induce an impressive
> response rate at a certain level that is now adequately reliable
> evidence for benefit.
>
> DR. BUNN: Right, if erlotinib has nine percent and best supportive
> care has two percent I would say accelerated approval should be given.
>
> DR. PRZEPIORKA: Dr Cheson?
>
> DR. CHESON: Paul, coming back to part of your elegant presentation,
> there are some drugs which you had on your list that never should have
> gone on to Phase III because they are inactive as single agents. I
> take issue with that because there are some drugs, particularly one of
> them that you had on your list, which are probably not active as
> single drugs but work better by enhancing the activity of other
> agents. What I am thinking of is Gentasense, for example. So, I would
> be reluctant to throw out some drugs like that have a unique mechanism
> of action. Some of the growth factor receptors may be the same sort of
> thing. The typical cytotoxics, okay, but when you get to the new
> targeted therapies I think a lot of them may work better and should be
> studied going right from Phase I to Phase III if there is [in
> vitro]{.underline} rationale for such combinations.
>
> DR. BUNN: I am sorry I don\'t have my slide to put up but the bottom
> sentence on that was unless there is very good compelling preclinical
> evidence for why that would happen. So, that is not uncommon to the
> situation up until now but I certainly don\'t disagree with your
> sentiments but I think there should be compelling preclinical reasons
> for that. Again, you know, bevicuzimab may be the first one to
> actually prove me wrong but I will be happy to be wrong.
>
> DR. PRZEPIORKA: Dr. George?
>
> DR. GEORGE: Richard, I have a couple of things. One is that you make
> very compelling arguments of why we should be able to these kind of
> studies in quality of life. One of the frustrating things to me,
> sitting on this committee, is we don\'t see these things. We don\'t
> see good, well done studies in this area and I was wondering if you
> have any notions, accepting what you have said, that we are not seeing
> them because they certainly could add a lot to a lot of these kinds of
> applications.
>
> DR. GRALLA: Steve, I agree with you 100 percent. The problem is in the
> past we really haven\'t seen so many good ones. In fact, over the last
> five years what we have seen is sort of leapfrogging. Each trial gets
> a little bit better than the last at doing these. We see more trials
> that start to use validated instruments. We have even heard of some ad
> hoc instruments. I think now with the electronic way of keeping the
> data we are there on some of these. So, I think that we are now poised
> for you to be seeing more of these.
>
> The second line in small cell approximated some of these, approximated
> one of the validated instruments. It wasn\'t really an elegant
> presentation for looking at the topotecan second-line but it was
> getting there. So, I think why we are here is to encourage that and to
> try to set some points along the road to help those who are doing
> these studies to be able to present trials in that way to this group
> so that you are more able to evaluate these results.
>
> We have had some presentations at ASCO this past year that looked in
> that way, and maybe the year before. So, I think that is what we are
> going to be seeing in the future.
>
> DR. GEORGE: This just seems to be an area where theory and practice
> seem to be far apart.
>
> DR. GRALLA: You have a very good point but I think we are getting
> much, much closer now and I think you will see them soon.
>
> DR. GEORGE: One quick question, just a small point, on this blinded
> evaluation, blinded to the interventions, there are other types of
> blinding that can be equally important in this area. I guess we saw
> some of that before. For example, just knowing sort of the clinical
> development of things could presumably influence quality of life. That
> is, you have to know when you are asking these questions if the
> patient was just told that they had, say, a response\--
>
> DR. GRALLA: Right.
>
> DR. GEORGE: \--Mrs. Jones, your tumor is shrinking. Now, would you
> please as this question, how do you feel?
>
> DR. GRALLA: Right. That is why all of these instruments believe your
> point and have taken it for granted. It is not just a response; how
> about your white count? Your white count is 1.9. We are not going to
> treat you today. Oh, my God, I am going to die. So, for almost all of
> these instruments is when you repeat the measure. You do it before the
> patient sees the doctor and before the patient gets any clinical
> results. You are 100 percent correct. That must be done or you could
> have wonderful impact on the study through more subtle means. So,
> those areas have been addressed.
>
> DR. BUNN: I would like to make just one comment. I think, you know, we
> are getting better. The FDA actually has said for a long time that
> symptom benefit could be for a primary approval but sometimes the
> studies have been so bad that that hasn\'t happened. I will just give
> you that same example again where there are going to be three
> endpoints. There is going to be survival, and in my opinion the study
> is a bit under-powered because it is looking for a big survival
> advantage, but there is symptom benefit. This is erlotinib versus best
> supportive care. I believe full approval should be granted if there is
> a tend in survival and there is symptom benefit that is statistically
> significant if you believe it was done well. If you don\'t believe it
> was done well and there is a statistically significant difference in
> response and the response is eight percent of higher, then I believe
> accelerated approval should be given based on response. So, I mean,
> you have three endpoints and you need to decide what to do.
>
> DR. PRZEPIORKA: We are approaching the scheduled time for the open
> public hearing but I don\'t want to squash questions. I see a few more
> hands back there. Dr. Bonomi?
>
> DR. BONOMI: I have a question for Tom. I think there is no question
> that response is at least a treatment-related diagnostic factor but,
> you know, the cause and effect thing\--we have been talking about it
> for 25 years and we used to plot out the curves, the PRs and the
> stable disease and we can\'t do that because maybe the people who were
> better, who were going to live longer also exhibit a biologic
> response. But with all the data we have and all the cooperative group
> studies, is there some type of statistical modeling that could be done
> to try to elucidate this? You know, my gut feeling is response does
> translate into some benefit for the patient but how can we go at this?
>
> DR. FLEMING: Absolutely, there is and you are exactly right to say
> that it has been 25 years since we have recognized this issue that,
> you know, responders live longer than non-responders but that is not
> evidence that I have a treatment-induced effect on survival mediated
> through response because, as you say, people who are intrinsically
> better may be the people who would have survived longer and would be
> more likely to respond and treatment has just labeled those people who
> were better.
>
> It is, however, the first step. If I have a marker that I am going to
> use as a potential replacement endpoint the first thing I need to know
> is, is it correlated. So, it is not a useless step. By the way, if it
> is correlated then, in that sense, it can be useful in other ways. PSA
> can be correlated with prognosis and it could be a very good measure
> to counsel patients or to detect disease but that doesn\'t mean that
> it is a good measure to indicate treatment effect. What we have to
> know for that is that the disease influence on the clinical endpoint
> is predominantly captured by this marker, that this marker is in that
> pathway mediated through which these benefits occur. And, we have to
> have some sense that it is unlikely, and this is tough, that there
> aren\'t unintended mechanisms that can influence outcome not captured
> by the marker.
>
> Those are clinical insights that are important to supplement the data.
> The data, as you point out, can also though be very helpful and it
> needs to be analyzed in a much more sensitive way. It is only the
> first step to see that people who respond live longer than
> non-responders, have a better quality of life, blah, blah, blah. What
> I really want to know is if you have 20, 30 or 50 or 100 studies that
> have been done, and these need to be randomized, controlled trials,
> and those studies have measured treatment-induced effect on the
> marker\--let\'s say it is response, let\'s say it is time to
> progression, and treatment-induced effect on the clinical endpoint,
> what we need to understand is what is the functional relationship
> between the level of treatment-induced effect on that marker, such as
> response, and the level of treatment-induced effect on the clinical
> endpoint, which is other than what that meta-analysis of 176 studies
> did. It is a different issue. An example of this is the analysis that
> was presented on November 12, looking at whether disease-free
> survival\--this as Dan Sergeant\'s analysis\--could be a surrogate
> endpoint for survival in the colon adjuvant setting. They at least did
> a meta-analysis on all potentiated 5-FU colon adjuvant trials and
> showed a fairly strong relationship between the magnitude of treatment
> effect on, in that case, disease-free survival and the magnitude of
> treatment effect on survival.
>
> So, the kind of thing that would be very informative here, in this
> setting if we were talking about time to progression for example, is
> this meta-analysis looking at an array of studies to see whether or
> not when you achieve a given level of reduction in failure rate and
> time to progression, does that translate reliably to a given level of
> reduction in survival.
>
> My biggest concern is to be able to rule out cases where when I
> achieve a certain response rate or when I achieve a certain reduction
> in time to progression, does that ever translate into no benefit? How
> big do those effects have to be such that we don\'t get no benefit on
> survival? Those are answerable questions. We can go to the data and
> start doing those meta-analyses. They will give us very important
> insights. Those, however, have to be supplemented. Just to quickly
> repeat what I said before, we really do need to have a clear sense of
> mechanism. So, if we are talking about biomarkers, is the biomarker
> the result of the tumor burden and it is not mediated through the
> change in the biomarker that the patient has worse survival? I suspect
> that is the case. So, that wouldn\'t be a classic example of what we
> would go for. But basic measures of tumor burden would be the likely
> candidates that we would be looking for, and if we have interventions
> that are thought to be fairly safe so that it is unlikely that there
> would be major unintended negative effects, then we are in the ball
> park of the kind of evidence that we would be needing to see and the
> kinds of settings we would need to be in.
>
> DR. PRZEPIORKA: Any burning questions before we move on? Dr. Temple?
>
> DR. TEMPLE: Actually I have a burning question for Dr. Gralla. Most of
> the time when you study symptoms you make sure the people entering the
> trial have one. You wouldn\'t study headaches in people who didn\'t
> have the headache but you thought might get one some day. A lot of the
> quality of life efforts we have seen do not make sure that the people
> who are entering the trial are impaired in those dimensions and, even
> more, even if they have one of the things on your list of physical
> symptoms they don\'t have all of them. So, anybody trying to show
> improvement is starting out with a huge disadvantage because there is
> no prominence to the symptom.
>
> So, my question is this, we have urged people to think about this, for
> each patient identify a target symptom, namely, one that they actually
> have and try to focus on that, even if it was actually different for
> each patient in the trial. I wonder if you have any thoughts about
> that. I mean, if I were doing it that would seem the way to find an
> effect if there is one because you are at least identifying people who
> have the problem, whereas in so many of the trials we have seen the
> people don\'t even have that problem. It is hard to win.
>
> DR. GRALLA: Yes, I understand your point and I think that is another
> reason why we have to be careful about setting an absolute number on
> improvement. Three percent of patients are asymptomatic, three
> percent. When people ask me how do you treat the asymptomatic patient,
> I don\'t worry about it, I just wish more would walk in the door. So,
> everyone has symptoms.
>
> The question of looking at symptom burden, how do your symptoms affect
> you is not a bad one to look at in that way because, therefore, it
> doesn\'t matter whether it is pain, cough or dyspnea.
>
> DR. TEMPLE: But you want to be sure they are having an effect. It
> wouldn\'t be a good question to ask if they said, no, it doesn\'t
> bother me, I get through it.
>
> DR. GRALLA: No, no, everyone rates that question from zero to 100. You
> can rate it zero, you can rate it 100. So, you can see the whole
> group. If you have 200 patients in an arm, you make up the number and
> you can see what the scores are. If you start out at baseline with one
> group being much more symptomatic than the other, then you have big
> problems but that is not what usually happens. And, what you can see
> here are differences, real differences when you see drugs that work.
> So, what you can see is patients rate the effects of their symptoms as
> being improved more on treatment A versus treatment B. It is not a
> huge effect but it is there.
>
> If you want to, you can start with those patients. People have
> correlated different scores on a visual analog scale with mild, severe
> and marked. So, if you want to say I only want to look at those
> patients who rate their pain above 25 at baseline and what happened to
> that group, you can do that from this same set. But now what we are
> doing is getting to Dr. Fleming told us. Maybe you don\'t want to go
> there; now you are looking at a subset analysis.
>
> DR. TEMPLE: Yes, but I could also stratify and I could make that my
> primary hypothesis.
>
> DR. GRALLA: You could; you could.
>
> DR. TEMPLE: You could say to yourself if they don\'t have a whole lot
> of impairment in this dimension I am not likely to say much benefit.
> So, I want to make my primary hypothesis people who are very impaired
> in this dimension.
>
> DR. GRALLA: Yes, I like to think of the opposite criticism. So, you
> only looked at those patients who rate their pain. So, is your drug no
> good for people who don\'t have pain?
>
> DR. TEMPLE: It doesn\'t improve their pain.
>
> DR. GRALLA: But what I showed you before, looking at the difference
> between pemetrexed and CIS, even within responders was eight out of
> eight parameters favored the combination, a significant difference in
> itself. This is what the patients say and, to me, that is very
> compelling. I don\'t know how the FDA would see that but to me that
> was very compelling. But no one of those was hugely different but in
> each one of those areas people looked at it being different. Your
> suspicion would have been that many of them would have been the same.
>
> DR. TEMPLE: I am only asking because we see so many \"unsuccesses\"
> and one of the possible explanations for that is that there isn\'t
> much room for improvement. You know, if you have ten items in a score
> and only one of them is capable of being improved, that is pretty
> tough. If all ten are, well, you are much more likely to show
> something.
>
> DR. GRALLA: But the differences in the areas that are looked at
> here\--for example since we were talking about mesothelioma, there are
> only five. In the validation studies for the instrument there were
> only five that were important. When you think of pain and dyspnea and
> cough and anorexia and this sort of thing\--I can\'t remember the
> other one, you know it is not too surprising when you get a tumor
> response. The problem is lung cancer comes up with dyspnea where you
> have COPD as a concomitant illness. If we have a drug that fixes the
> COPD we are really in good shape. There you have the confounding
> variable problem.
>
> DR. PRZEPIORKA: Thank you. Thank you to all the speakers. I would like
> to now open the open public hearing and call to the podium Mr. Mark
> Scott. While he is coming up to the podium I have been asked to read a
> statement about financial disclosure.
>
> Both the FDA and the public believe in a transparent process for
> information gathering and decision-making. To ensure such transparency
> at the open public hearing session of the advisory committee meeting,
> the FDA believes that it is important to understand the context of an
> individual\'s presentation. For this reason, the FDA encourages you,
> the open public hearing speaker, at the beginning of your written or
> oral statement to advise the committee of any financial relationship
> that you have with any company of any group that is likely to be
> impacted by the topic of the meeting. For example, the financial
> infection may include a company\'s or a group\'s payment for your
> travel, lodging or other expenses in connection with your attendance
> at this meeting. Likewise, FDA encourages you at the beginning of your
> statement to advise the committee if you do not have a financial
> relationship. If you choose not to address this issue of financial
> relationship at the end of your statement, it will not preclude you
> from speaking. You may go ahead.
>
> **Open Public Hearing**
>
> MR. SCOTT: My name is Mark Scott. I am the executive director for
> development in the U.S. and I work for AstraZeneca Pharmaceuticals so
> that would be the financial interest, and they did pay my way here
> today.
>
> \[Laughter\]
>
> Madam Chairman, members of the committee, ladies and gentlemen, thank
> you for the opportunity to speak. I am representing actually
> AstraZeneca Oncology for this presentation today and I believe in your
> package you received a seven-page document outlining a number of
> points we intended to make as part of this committee meeting.
>
> I believe that most of the points have already been discussed today so
> I want to go into them with the detail I had originally intended. Some
> of the points were made this morning and some of the points are
> directly relevant to the discussion you will have after this with
> respect to the questions that are being addressed.
>
> The first point is that we wanted to endorse the committee discussion
> on symptomatic improvement as used as the basis for full approval for
> oncologic agents, and especially for non-small cell lung cancer as it
> is a disease of symptoms. With well validated scales that are
> available, including the lung cancer symptom scale, a demonstration of
> relief of these symptoms as determined by well conducted and
> controlled patient-reported outcome studies could be acceptable as a
> sole basis for full approval of new agents.
>
> The next area was in trials in subsets of patients, specifically
> performance status II. This wasn\'t necessarily directly germane to
> the discussion but, given that you are talking about lung cancer, we
> thought it to be important. Inclusion and exclusion criteria for many
> clinical trials in non-small cell lung cancer exclude performance
> status II patients because of their short life expectancy and because
> many are considered unsuitable for cytotoxic chemotherapy.
>
> Novel agents with better tolerability may offer a chance to bring
> clinical benefit to this ill-served patient population. The FDA has
> recently granted fast-track status for a compound to be investigated
> in a trial in performance status II patients and we are asking the
> committee do they agree that a PS-II population in advanced non-small
> cell lung cancer is an identifiable population worthy of clinical
> study, and for whom an indication could be written? If the answer was
> no, how would they propose to define the population of patients often
> considered too unfit to tolerate chemotherapy and, therefore, being
> excluded from many current clinical trials?
>
> Another area that we wanted some debate about which got covered this
> morning is that we are very encouraged that there was a recommendation
> by the committee that progression-free survival could serve as the
> sole basis for approval in certain situations.
>
> The last area we wanted to discuss was the efficacy standard, and I
> will not go into it in great detail but it has to do with
> non-inferiority trials, which I will talk about at the end. We would
> briefly like to reinforce the implications for oncologic drug
> development as raised by Dr. Williams this morning. It is actually
> through an article by Rothman et al. that was published in the
> January, 2003 edition of [Statistics in Medicine]{.underline} on
> non-inferiority trials. The methods described in this article are
> increasingly used by regulators in the United States and Europe to
> evaluate the design analysis of trials of new agents. The consequences
> for trial size are enormous as a result of this paper.
>
> In this context, there has been something of a paradigm shift though
> in the approach to cancer treatment over the recent years. Academia
> and industry alike are now fully engaged in the discover, research and
> development of novel, well tolerated, biologically targeted
> anti-cancer agents. It is hoped that these new treatments will offer
> significant advantages to patients in terms of improved tolerability,
> but they may not always demonstrate increased efficacy. This naturally
> leads to the use of active control in non-inferiority trials to
> compare the new agent standard to standard agents, with the
> conventional aim being to show no clinically relevant loss of
> efficacy.
>
> But the key problem for researchers, physicians and patients alike is
> that with Rothman\'s approach there is a dramatic increase in the size
> of the trial required to determine non-inferiority. We don\'t believe
> that the answer is to avoid non-inferiority trials. We believe that
> there are situations that are clinically relevant where a
> non-inferiority trial would be the trial of choice to define efficacy.
>
> We don\'t believe that the scientific statistical debate about how to
> best draw inferences from active control, non-inferiority trials
> should be considered complete. Rothman\'s approach serves to highlight
> that considerable statistical, methodological and philosophical issues
> remain, and failure to consider these issues constructively will, at
> the very least, lead to ever-increasing drug development costs, time,
> and delay the availability of new therapeutic options to patients with
> life-threatening diseases. At worst, the barriers posed will
> discourage drug development where it otherwise might have been
> feasible and so prevent potentially useful new medicines from becoming
> available to patients.
>
> We sincerely hope the scientific community, together with regulatory
> bodies worldwide will give this important area further careful
> thought, and we, at AstraZeneca, recommend that the advisory committee
> here, as well as academic interest and industry interest have a panel
> like this meeting to address this issue. Thank you.
>
> **Questions for Discussion**
>
> DR. PRZEPIORKA: Any questions for Mr. Scott?
>
> \[No response\]
>
> Thank you. Our hosts have provided some guidance, if you will, on the
> importance of the questions and, given the hour, we will be taking
> these out of order.
>
> The first question to be discussed will be question seven, under the
> surgical adjuvant setting. The FDA has stated that disease-free
> survival can support regular drug approval in cancers where the
> majority of recurrences are symptomatic. Others propose that
> prolongation of disease-free survival should support regular approval
> in all clinical settings because a delay in cancer detection or a
> delay in the need for toxic cancer treatment is of clinical benefit.
>
> In non-small cell lung cancer, should a disease-free survival
> improvement from adjuvant chemotherapy support regular drug approval?
> If so, clarify why you consider disease-free survival an established
> surrogate for clinical benefit in this setting.
>
> Part b) is if not, could a disease-free survival improvement support
> accelerated approval? Would a survival advantage ultimately be
> required for conversion to regular approval?
>
> So, the question before us is should disease-free survival in the
> adjuvant setting be a primary endpoint or a surrogate for survival.
> Dr. Johnson?
>
> DR. B. JOHNSON: I think this is a more a philosophical than a real
> question in that adjuvant therapy hasn\'t yet been proven to play a
> role in lung cancer, and I can\'t imagine\--I don\'t know of any
> company that has a plan to look at this. So, it is not something that
> is going to come up for three to five years. So, I think yes is
> probably the answer but I don\'t think it is terribly important to
> define the answer at this time.
>
> DR. PRZEPIORKA: Just to question you, you indicated that there has
> been no drug that has been shown to have an advantage in that setting.
> Was that based on survival as opposed to disease-free survival, and
> would you be willing to suggest that disease-free survival would be an
> appropriate endpoint rather than survival?
>
> DR. B. JOHNSON: There are two studies that have been presented in
> abstract form that Paul talked about, and it looks like there will
> likely be an advantage for at least one of those two studies when it
> gets published and the disease-free survival fits with the actual
> survival. The point I was trying to make is I can\'t imagine that
> somebody is going to submit for approval a new drug unless you are
> going to be approving it for a new indication.
>
> DR. PRZEPIORKA: Dr. Johnson?
>
> DR. D. JOHNSON: Dr. Bruce Johnson and I decided ahead of time to avoid
> the confusion that the good-looking Johnson\--
>
> \[Laughter\]
>
> DR. PRZEPIORKA: You are also in alphabetical order!
>
> DR. D. JOHNSON: I would say yes, disease-free survival can be used as
> a primary endpoint and I would say that I would interpret the two
> studies that have been presented slightly differently. One will be
> published in [The New England Journal]{.underline} soon, which was
> presented at a plenary session at ASCO this year. It is really the
> only study that is sufficiently large to address this question. It was
> an international study, done largely out of France. The disease-free
> survival essentially mirrors the overall survival. This is essentially
> identical to what we see in breast cancer adjuvant trials.
>
> The second trial, which shows the same pattern, is a trial out of
> Japan which used a drug that is not available in the U.S., UFT. It too
> showed a disease-free survival that was reflected in the overall
> survival.
>
> So, I personally think that this is a worthwhile endpoint. If it is
> going to be used in future trials, I think DFS can be used as it is in
> breast cancer adjuvant trials.
>
> DR. PRZEPIORKA: Other comments from our experts?
>
> DR. BONOMI: I agree and I think you are going to see that there is
> going to be a lot more activity in this area with these trials,
> especially with the ALT trial turning out to be positive. I know the
> cooperative groups are gearing up to do new studies.
>
> DR. ETTINGER: There are two studies. One is the Canadian study that
> has been completed with vinorelbine/CIS that we await with bated
> breath in early disease, stage I actually, and there is the CALGB
> study that is very similar with a different set of drugs, hopefully,
> going in the same direction otherwise we will have a real problem on
> our hands. Right now we have the ALPI study, although there was a
> trend that was negative, and we have the ALT study that obviously is
> positive.
>
> So, I agree that disease-free survival in that study as well as the
> UFT study in Japan show that the disease-free survival and survival
> are in the same direction and should be able to use either one of them
> or both.
>
> DR. PRZEPIORKA: Other questions? Comments? Ms. Ross?
>
> MS. ROSS: Just a quick comment because my duty here is to represent
> patients, and the status quo is not acceptable. We can\'t remain with
> a 14 percent survival rate with lung cancer. We have to open this up.
> Yes, I would agree with that position. Please open it up.
>
> DR. PRZEPIORKA: Do you have other points you want us to discuss with
> that question? No? Okay.
>
> DR. WILLIAMS: There is one other issue though. I would like you to
> vote on it.
>
> DR. PRZEPIORKA: To vote on it?
>
> \[Multi-member discussion\]
>
> DR. WILLIAMS: What we are asking for, call it what you want, is would
> you grant full approval for this? That is the question before you\--or
> regular approval.
>
> DR. PRZEPIORKA: If we get a positive vote on a) we won\'t need to vote
> on b) then. Going around the table then, the question before us is in
> the surgical adjuvant setting would one accept disease-free survival
> improvement to support regular full approval for a drug. Dr. Ettinger?
>
> DR. ETTINGER: Yes.
>
> DR. PRZEPIORKA: Dr. Saxon?
>
> DR. SAXON: No.
>
> DR. BONOMI: No.
>
> DR. D. JOHNSON: Yes.
>
> DR. B. JOHNSON: Yes.
>
> DR. GRILLO-LOPEZ: Although I don\'t have a vote, if I had one I would
> like you to know that I would vote yes.
>
> \[Laughter\]
>
> DR. GEORGE: Yes.
>
> DR. CHESON: Yes.
>
> DR. DOROSHOW: Yes.
>
> DR. RODRIGUEZ: Yes.
>
> DR. BRAWLEY: Yes.
>
> MS. ROSS: Yes.
>
> DR. FLEMING: Conditionally yes. Sorry, I have to give a condition
> because it wasn\'t totally clear to me. If we can say consistently
> that at recurrence there are symptoms, then that makes it what I would
> call a level one outcome. Short of that, if we can put forward data
> that would indicate that there is a clear consistency between effects
> on disease-free survival and effects on survival that would also be
> the basis.
>
> DR. LEVINE: Yes.
>
> DR. REAMAN: Yes.
>
> DR. PRZEPIORKA: Yes.
>
> MS. HAYLOCK: Yes.
>
> DR. CARPENTER: Yes.
>
> DR. REDMAN: Yes.
>
> DR. TAYLOR: Yes.
>
> DR. PRZEPIORKA: It is overwhelmingly yes so we will forego b).
>
> Back to the first page of the afternoon session, first-line non-small
> cell lung cancer treatment setting, approval based on demonstrating
> superior time to progression. So, considering the pros and cons that
> we all discussed this morning in the time to progression session, for
> approval of drugs for first-line treatment of advanced lung cancer,
> could time to progression benefit of a new drug compared to a standard
> first-line regimen justify regular full approval? Assume that the
> standard control arm has a known small, two-month, benefit. Comments?
>
> DR. CHESON: So, we are really keeping this at time to progression and
> not progression-free survival?
>
> DR. WILLIAMS: Why don\'t you change it to progression-free survival?
>
> DR. PRZEPIORKA: Progression-free survival.
>
> DR. WILLIAMS: Thank you, you have made it easier.
>
> DR. PRZEPIORKA: Dr. Johnson?
>
> DR. D. JOHNSON: Actually, my comments were relative to time to
> progression, but actually I just want to make one other point that may
> be self-evident to everybody at the table but it may be more germane
> to Dr. Bunn\'s comments vis-a-vis response. One of the problems I
> think in lung cancer studies is the tremendous heterogeneity of the
> population that we study. I think one of the problems that FDA faces
> and this advisory committee faces when it comes to lung cancer is the
> fact that there has been a stage creep that affects us. Stage IV
> disease is very much more homogeneous and a lot of the data that I
> think that Dr. Bunn presented really applies principally to stage IV
> disease. When you start including unresectable stage III disease,
> first of all, you have to define unresectable and then you have to
> define which stage III disease one is dealing with. At least in
> cooperative group trials, a review of the database shows as much as a
> three-month difference in median survival in various so-called
> unresectable stage III patients relative to stage IV. That is actually
> the difference that many trials are designed to see. None, as Dr.
> Bruce Johnson has shown, actually has quite achieved that level in
> advanced disease. Typically, the best one sees is about a two-month
> improvement in the so-called statistically positive trials in stage
> IV.
>
> So, I just want to make this point. It also has to do with response
> rates because response rates are consistently higher in patients with
> unresectable but locally advanced disease as compared to patients that
> have metastatic, extrathoracic metastases. So, there is a huge issue
> here that I didn\'t really hear addressed but I am assuming, maybe
> incorrectly, that this particular committee is familiar with and knows
> about.
>
> DR. PRZEPIORKA: Would you feel more comfortable asking this question
> in a metastatic setting versus the non-metastatic setting separately?
>
> DR. D. JOHNSON: I think it would be helpful to our colleagues at FDA
> but maybe they can answer that question for themselves.
>
> DR. PRZEPIORKA: Would you like to hear that?
>
> DR. WILLIAMS: Certainly, if it makes a difference, we would.
>
> DR. PRZEPIORKA: Other comments before we move to vote? Dr. Fleming?
>
> DR. FLEMING: I would be interested to know if there is more evidence
> to put on the table than what I have heard thus far. The distinction
> here between what I have been calling a level two as a marker versus
> level three is profound. Level three means it is reasonably likely to
> predict clinical benefit. Level two is, is it reliable? It is reliable
> evidence; it is established. Across clinical areas the number of
> established surrogates is really small. They are very rare. It takes
> striking evidence to be able to reliably say that the effect on this
> marker will tell us the effect on the clinical endpoint.
>
> When this FDA/ASCO group met, after several meetings the summary of
> the conclusions, which are presented in this document, basically were
> it has not been established that the benefit on TTP reliably predicts
> benefit on survival\--reliably predicts. Listening to Paul\'s
> presentation, the vast majority of it was advocating for greater
> attention to response. His comments indicated, if anything, some real
> skepticism, pointing out a number of inconsistencies in time to
> progression prediction of survival. So, I would consider that a fairly
> negative summary that, in fact, endorsed what the FDA/ASCO summary
> indicated after its sessions. But maybe there are more comprehensive
> analyses other people have done that can give a more positive view
> than this.
>
> Essentially I am trying to summarize what I heard at FDA/ASCO and what
> I heard from Paul. It sounds as though for time to progression these
> data are well short of what we would typically think of as necessary
> to say reliable.
>
> DR. WILLIAMS: Tom, I think some of those things we were talking about
> this morning really need to be discussed a little bit here. Does it
> matter that there is a short difference between time to progression
> and survival, and which way does it matter? Does it make it more
> acceptable or less acceptable? Do you think there are symptoms when
> people progress and, therefore, is that the reason you would accept
> it? You know, what would be the pros and cons of accepting it here?
> So, I think a bit of discussion on that point would be helpful.
>
> DR. B. JOHNSON: One of the potential means for this is that this will
> pick up an important endpoint that survival misses. The length of time
> between time to progression and death in advanced disease is very
> short. So, the help of that would be very small as a surrogate to
> outcome.
>
> The second potential problem is that now with therapies in the second-
> and third-line you would have problems in interpreting data that the
> randomized did not take care of. To me, that is a hypothetical
> problem; not a problem that has been proven to be shown. So, I don\'t
> see that adding a time to progression or progression-free survival
> would be particularly helpful in interpreting the trials.
>
> DR. D. JOHNSON: I don\'t know if this helps, Tom, but one thing that
> we have done over the last several years is to do a detailed analysis
> of the ECOG database for advanced disease, with all of the recognized
> limitations of such an analysis. But what I can say is that at least
> in stage IV disease\--which is fairly reliably diagnosable, perhaps
> even more so today but certainly in the \'80s and \'90s with CT scans
> one could pretty reliably diagnose stage IV disease\--one thing we
> observed is at the time of progression, as documented by the
> individual taking care of the patient, typically by a physical finding
> or a new radiographic finding, before widespread availability of
> second-line treatment or the widespread acceptability of that, the
> median survival of patients from that point forward was approximately
> 14 weeks or so. That was borne out in the docetaxel study that Dr.
> Cohen alluded to where the median survival of patients after
> first-line therapy was four months. What docetaxel did was extend that
> by approximately two and a half months, more or less, in one study not
> in the second study.
>
> We did an analysis which we then presented this year at ASCO, looking
> at the ECOG trials subsequent to the approval of docetaxel. That is,
> presumably the widespread availability of second-line therapy. What we
> found was that the median survival of patients from progression was
> extended by approximately six weeks beyond what it had been according
> to the data prior to that. Again, this more or less validates in my
> mind the data that we saw in that relatively small trial of docetaxel.
>
> Another thing we did during that same analysis which was of interest
> to me, and I presented this at the forum, were two separate analyses.
> Again, we are talking almost exclusively about stage IV disease. These
> data were developed in patients, 85-90 percent of whom had documented
> stage IV disease. Patients that had disease control\--forget about
> whether their tumor got smaller or not but they didn\'t progress, did
> as well regardless of whether their disease got smaller by X amount,
> 30 percent, 40 percent or whatever. Those patients had virtually
> identical survivals.
>
> The other thing we looked at was percent of progression at various
> time points. We chose time points when physicians would have evaluated
> patients according to the protocol. So, that would be every three
> weeks or every four weeks, whatever. It didn\'t really matter whether
> one chose three weeks, six weeks, nine weeks or whatever. If one
> selected a time point and then calculated the percent of progressors,
> non-progressors, in only those studies where there was a statistically
> significant survival benefit was there a difference in percent of
> non-progressors in favor of the arm that did better, if you follow
> what I am saying.
>
> So, it is a little bit different than progression-free survival, but
> it is a fixed time point where one can say X amount of patients are
> progressing at this point in time, fewer in this group and this group
> does better. And, that was surrogate, if you will, of survival. So, we
> looked at those. I think that was something you were talking about
> earlier, could one use some marker of that nature to do that.
>
> DR. FLEMING: The evidence that we really need here would be a wide
> array of studies, conducted in a given setting where we are advocating
> the use of a given marker as the reliable evidence of benefit that
> would show treatment-induced effects on that marker at a certain level
> which are always going to tell us that we have treatment-induced
> effects on survival and, more generally, that the relationship between
> those two is very strong. Some of the examples that Paul gave were
> ones that gave very inconsistent results in progression from survival.
> He also mentioned the ECOG 1594, saying that the GC arm was a month
> and a half longer in time to progression, suggesting a difference but
> the survival effects were the same.
>
> DR. D. JOHNSON: Actually, those survival results are not the same.
> They are not statistically significantly different but actually the
> better survival is in that arm. But that is a whole other argument. I
> would disagree with Paul\'s analysis of that particular data.
>
> But let me say this, that what we did was develop those markers in one
> set of data, 5592 which was the predecessor trial and was a three-arm
> trial, and we tested the model in the 1594 data. We also went back and
> tested it in another data set, 1583, which was a study that Dr. Bonomi
> chaired back in 1983. He is not that old; he just looks that old\--
>
> \[Laughter\]
>
> \--and again validated those endpoints in the same direction. There
> was a survival advantage in his study with carboplatin as a single
> agent and, yet, it had the lowest objective response rate. But the
> percent of patients who progressed at various time points was lower in
> that particular arm. There was \"crossover\" but only a small
> percentage of patients actually crossed over. But it was that percent
> of noon-progressors that actually best correlated with outcome in that
> particular study.
>
> DR. FLEMING: But you are saying the aggregate data showed a lower time
> to progression in the arm\--
>
> DR. DL. JOHNSON: No, what I am saying is the objective response rate
> in 1583 for carboplatin as a single agent was nine percent. That was
> the lowest overall response rate. The highest response rate was 27
> percent, as I recall, a three-fold difference in response rate, and
> yet the 27 percent group had the lowest, statistically less survival
> compared to carboplatin. But then when we applied our rule of
> non-progression, and you could pick the point you want, after two
> cycles, after three cycles or whatever, not looking at objective
> response rate but non-progression it comes out in favor of the
> carboplatin arm, just as we had predicted from the 5592 data and 1494
> data and then applied to the 1583 data. So, there were three separate
> databases.
>
> DR. FLEMING: It is this kind of data that certainly gives one concern
> about the reliability of the response predictor where you are telling
> us it goes in the wrong direction. More broadly, for time to
> progression or any other measure of tumor burden what one needs is
> much more evidence than what I am hearing, and it may exist but just
> needs to be looked at in a meta-analysis framework to understand
> whether treatment-induced effects on whatever measure you are
> advocating\--time to progression right now\-- is reliably telling us
> treatment-induced effects on clinical endpoints such as survival.
>
> DR. PRZEPIORKA: Dr. Bonomi?
>
> DR. BONOMI: I want to make one comment. The MBP regimen is a peculiar
> regimen. I don\'t know if Dick Gralla is still here. We used a very
> low dose of cisplatin, 40 mg/m^2^, and some people would say, and I
> think Dick would be one of them, that dose might be below or right at
> the minimum effective dose. The point I want to make is there is
> discordance between response and survival in the study but that
> particular regimen isn\'t a good one to base it on because in three
> consecutive studies it gave the highest response rate, statistically
> significant in I think two out of the three, and a trend for a shorter
> survival. In fact, when it was lumped together it actually gave a
> significantly lower one-year survival rate, MBP did. So, higher
> response rate, lower survival. We thought that regimen either was
> doing something detrimental in people or possibly the platinum dose
> was too low. Mitomycin might have been detrimental. We thought it was
> a combination of toxicity and the actual anti-tumor effects. That is a
> peculiar regimen. I wouldn\'t want to base any correlation response
> and survival on that particular one.
>
> DR. FLEMING: But that really gets at the essence of what leads these
> predictors to not be reliable. It is not that they are irrelevant;
> they are relevant but are they adequately relevant? Are they
> adequately capturing the complexities of how the disease process
> influences the outcome, and are they adequately capturing some of the
> unintended effects? This is the heart of why these are often
> misleading.
>
> DR. GRALLA: If I could make a comment?
>
> DR. WILLIAMS: You need a mike.
>
> DR. PRZEPIORKA: Will you take the podium?
>
> DR. GRALLA: There are other aspects, suck as Lucio Guino\'s study
> where, with different doses of cisplatin, he finds that the same drugs
> put together differently equal, for example, gemcitabine/cisplatin
> which is approved.
>
> I think that we can find exceptions, but what I think Paul was trying
> to do was to put them all together. He was looking at single agents.
> When you put single agents together at the doses at which they are
> used, you do find exceptions but what you find is a fairly strong
> correlation between response and survival. You know, we can put
> together regimens in ways that don\'t have duration of response, that
> are too low to do that. So, I think Paul was looking at single agents,
> not combinations that are more subject to that because when you put
> that together differently you can get a different result.
>
> DR. FLEMING: But, Richard, a lot of that single agent was Phase II
> data and that is not the kind of data that you need to have to
> validate a surrogate because that is just getting at correlation of
> response and the outcomes. That is just a foot in the door step.
>
> DR. GRALLA: It may be. I mean, you are right, many of those were Phase
> II studies. I think if you looked at the randomized studies looking at
> single agents though you would come up with a clearer correlation
> between survival and response but we only have about 15 or 20 of those
> in the last few years.
>
> I must say, in my heart of hearts I believe really ultimately response
> does agree with survival. The question is are the data robust enough
> to agree with that at this time, and that I am not sure of and why
> wouldn\'t we want to look at the data to see that rather than just
> have an opinion?
>
> DR. PRZEPIORKA: We will get back to the question of progression-free
> survival. Dr. Johnson, before I could answer this question the
> question I really have for you or anyone else in the expert row there
> is would you limit enrollment in such a study on the basis of
> performance status? If, in fact, we want to use progression-free
> survival as the ultimate reason for approval and we think
> progression-free survival is actually a measure of clinical benefit,
> is it going to be likely in somebody who has ECOG performance status
> II or are we looking for people who are pretty healthy looking people?
>
> DR. D. JOHNSON: Well, I think most of the data that have been
> developed in the last decade has really been restricted to patients
> with performance status 0 or I. We could debate about II should be
> allowed or not but, frankly, the numbers here are not generally a
> problem. So, I personally think restricting to 0 or I is still the way
> to go. There is a higher level of toxicity associated with performance
> level II. Actually, response rates tend to be fairly similar across
> the performance status and we have shown that several times in the
> ECOG database but the toxicity levels are much different. So, I
> personally think it should be preferentially in patients with
> performance status 0 and I. I wouldn\'t mandate that it be limited
> that way but I would certainly urge that that be done in that fashion.
>
> DR. PRZEPIORKA: Dr. Ettinger?
>
> DR. ETTINGER: Since progression-free survival in my opinion is a fuzzy
> endpoint, it seems to me the quality of life issue becomes paramount.
> Therefore, I would say you want patients that are symptomatic if you
> are going to use that as an endpoint because then there is clinical
> benefit, and I think that is critical and I think that is what the
> patient wants. If the survival didn\'t come out to be statistically
> significant, at least there was a clinical benefit and that is enough
> to approve a drug, especially if the progression-free survival was in
> the right direction that was statistically significant.
>
> DR. TEMPLE: Just to make the point, we have long said that improvement
> in symptoms is a basis for full approval. That is why we haven\'t been
> asking you about that. So, that is already true and we haven\'t had
> any reason to debate it. The question here is suppose you don\'t have
> that. So, if you have that along with whatever it is, you are fine;
> that is not an issue.
>
> DR. PRZEPIORKA: Dr. Williams?
>
> DR. WILLIAMS: First, I believe Dr. Johnson is saying that you believe
> there probably is a correlation, at least that it could be that
> progression-free survival could be a substitute or a surrogate for
> survival. Perhaps we don\'t have all the data yet to validate it as
> such. So, I would like to pursue a little bit further also whether or
> not in these patients you believe that progression is an indicator of
> symptoms and that would be the other basis where you might consider
> this endpoint\--a little discussion on that matter.
>
> DR. D. JOHNSON: Well, I got off in a little o- bit of a tangent. The
> point I was trying to make when I was talking with Dr. Fleming is the
> fact that I do believe progression-free survival is a valid endpoint,
> and I do think that upon progression, even in this era when we have
> second-line therapy, the overall survival after that is not that good.
> I mean, it is really pretty modest and those patients are for the most
> part symptomatic. Most of the recurrences take place because the
> patient walks back in your office not on a scheduled visit but because
> they have new lung pain, or they had a seizure, or they are short of
> breath, or they are coughing up blood, or they are coughing their
> lungs out. So, this is not a subtle thing in most instances. We don\'t
> find it on screening PET scans. It is the type of thing that patients
> are really quite symptomatic.
>
> So, I do think prolonging their progression-free is almost tantamount
> to their symptom improvement, not symptom free because they rarely
> completely resolve their symptoms.
>
> I might add that the first drug that showed benefit in non-small cell
> lung cancer that we know about was published in 1948 in
> [Cancer]{.underline} by David Karnofsky and it was nitrogen mustard.
> Nitrogen mustard actually\--the reason that he recommended its usage
> was not because it induced tumor regression but because it improved
> symptoms in 70 percent of patients. I am mindful of the fact that the
> FDA did approve gefitinib because of its objective response in symptom
> improvement, and the rapidity with which that occurred I think was on
> average eight days. If you go back and read Dr. Karnofsky\'s paper you
> will note that nitrogen mustard which, by the way, most of us don\'t
> use to treat lung cancer these days, improved symptoms in
> approximately six to seven days. Procarbazine has been shown to do the
> same thing too in non-small cell lung cancer. So, this is not a new
> concept. This has been going on for 55 years.
>
> DR. PRZEPIORKA: Other discussion that you need before the vote?
>
> \[No response\]
>
> As recommended by Dr. Johnson, we will split this out looking at
> locally advanced versus metastatic disease, and we will start with the
> metastatic patients. So, would you consider progression-free survival
> as an appropriate endpoint for full approval for a patient with
> metastatic non-small cell lung cancer? We will start with Dr. Taylor
> and work our way around.
>
> DR. TAYLOR: no.
>
> DR. REDMAN: Yes.
>
> DR. CARPENTER: yes.
>
> MS. HAYLOCK: Yes.
>
> DR. PRZEPIORKA: Yes.
>
> DR. REAMAN: Yes.
>
> DR. LEVINE: Yes.
>
> DR. FLEMING: No, and just to amplify a bit, there is a correlation
> here but I still think that the essence of the nature of what we need
> still maybe hasn\'t gotten clarified adequately. There is a
> correlation between those people who have a longer time to progression
> and those people who have a longer time of survival. The evidence, at
> least as was brought forward before the ASCO/FDA group and the
> evidence that Paul Bunn brought forward today certainly brings out
> that there are serious concerns about whether we can rely on time to
> progression effects to predict survival effects. Symptomatic effects
> have been mentioned. I wonder if the best way to measure symptom
> improvement is through time to progression or whether it would be
> through some of Richard\'s approaches that he has indicated using
> PROs.
>
> But, in essence, the number of truly validated surrogates are rare in
> clinical practice. I think the data that we would need potentially
> could be out there but they haven\'t been brought forth to be
> analyzed.
>
> DR. PRZEPIORKA: Ms. Ross?
>
> MS. ROSS: Yes.
>
> DR. RODRIGUEZ: Yes.
>
> DR. DOROSHOW: No.
>
> DR. CHESON: No.
>
> DR. GEORGE: Yes.
>
> DR. B. JOHNSON: No.
>
> DR. D. JOHNSON: Yes.
>
> DR. BONOMI: Suggestive but no.
>
> DR. SAXMAN: No.
>
> DR. ETTINGER: No.
>
> DR. PRZEPIORKA: So, it is 8 no and 11 yes.
>
> DR. WILLIAMS: Can we do a subgroup analysis? Any particular group
> occur to you?
>
> \[Laughter\]
>
> DR. PRZEPIORKA: Let\'s do the second part and see if that changes.
>
> DR. WILLIAMS: Okay, go ahead.
>
> DR. PRZEPIORKA: So, those with inoperable, locally advanced disease,
> would you use progression-free survival as your primary endpoint for
> approval? We will start with Dr. Ettinger.
>
> DR. ETTINGER: No.
>
> DR. SAXMAN: No.
>
> DR. BONOMI: No.
>
> DR. D. JOHNSON: No.
>
> DR. B. JOHNSON: No.
>
> DR. GEORGE: No.
>
> DR. CHESON: No.
>
> DR. DOROSHOW: No.
>
> DR. RODRIGUEZ: No.
>
> MS. ROSS: Yes.
>
> DR. FLEMING: No.
>
> DR. LEVINE: No.
>
> DR. REAMAN: No.
>
> DR. PRZEPIORKA: No.
>
> MS. HAYLOCK: Yes.
>
> DR. CARPENTER: No.
>
> DR. REDMAN: Yes.
>
> DR. TAYLOR: No.
>
> DR. PRZEPIORKA: Overwhelming no. So, clearly that reflected the
> discussion earlier regarding a slightly better prognosis group that
> you want to get good, hard endpoints in.
>
> DR. WILLIAMS: So, in patients that might be more symptomatic or more
> likely to be symptomatic upon progression the \"non-lungers\" said yes
> and the \"lungers,\" except for one, said no. That is what I heard.
>
> DR. PRZEPIORKA: Do you want us to continue on question two regarding
> the metastatic patients?
>
> DR. WILLIAMS: No, why don\'t we move on?
>
> DR. PRZEPIORKA: Well, we can move on because we have said no. If it
> doesn\'t support full approval, would it support accelerated approval?
> We will again start with Dr. Ettinger.
>
> DR. ETTINGER: No.
>
> DR. SAXMAN: I think that would depend on the magnitude so I guess the
> answer is yes.
>
> DR. WILLIAMS: Let me just give a little guidance here now. The
> accelerated approval regulations say that you must show an advantage
> over available therapy. Let\'s say this is a first-line therapy with a
> survival advantage and you are showing a TTP advantage over it so what
> you need to ask is, is this endpoint reasonably likely to predict
> clinical benefit. You don\'t have to show that there is clinical
> benefit. So, that is the call for accelerated approval, to feel that
> this is reasonably likely to predict clinical benefit. So, you can
> also discuss the magnitude but I just wanted to make sure that that
> was clear.
>
> DR. SAXMAN: That is TTP.
>
> DR. WILLIAMS: Or progression-free survival, or we will substitute that
> for each of these.
>
> DR. SAXMAN: What about accelerated approval?
>
> DR. WILLIAMS: Accelerated approval. In other words, you are getting
> the best thing out there with respect to time to progression or
> progression-free survival.
>
> DR. SAXMAN: With the idea that full approval was intended upon
> subsequent survival advantage.
>
> DR. WILLIAMS: Right.
>
> DR. BONOMI: I will say yes on that one.
>
> DR. D. JOHNSON: Yes.
>
> DR. B. JOHNSON: Yes.
>
> DR. GEORGE: Yes, assuming all those methodologic issues are addressed
> that we discussed.
>
> DR. CHESON: Yes.
>
> DR. DOROSHOW: Yes.
>
> MS. ROSS: Yes.
>
> DR. FLEMING: Abstain.
>
> DR. REAMAN: Yes.
>
> DR. PRZEPIORKA: Yes.
>
> MS. HAYLOCK: Yes.
>
> DR. CARPENTER: Yes.
>
> DR. REDMAN: Yes.
>
> DR. TAYLOR: Yes.
>
> DR. PRZEPIORKA: That is overwhelmingly yes. Then we have to answer the
> more important question which is what would be the interval that you
> would want to see to say that your progression-free survival was of
> clinical benefit. It is open for discussion. Dr. Johnson?
>
> DR. B. JOHNSON: About three months beyond control.
>
> DR. WILLIAMS: We are talking about accelerated approval now, right?
> So, we are talking about what would be a surrogate reasonably likely
> to predict clinical benefit.
>
> DR. PRZEPIORKA: Dr. Carpenter?
>
> DR. CARPENTER: All the differences in therapy we have heard about were
> all either in the two-month or the three-month range of any therapy
> over another, if I understand the experts. It would seem unrealistic
> to expect anything larger than that of a new therapy, or not very
> likely. So, David mentioned the biggest difference in survival and the
> disease-free survival threshold level usually pretty closely parallels
> that. I think that the data needed for accelerated approval would have
> to be pretty compelling and there would need to be a large,
> well-controlled study that showed a difference that is larger than we
> typically see for survival with best supportive care with a doublet. I
> think it would need to be at least three months.
>
> DR. PRZEPIORKA: Dr. Johnson?
>
> DR. D. JOHNSON: Just to give some context and, again, I think you have
> to think about this in stages and stage IV I would argue is the most
> homogeneous group in a group about whom we have the most data
> accurately in terms of these numbers. So, median survival in stage IV
> disease is about seven and a half, maybe eight months with PS-0 in one
> patient. If you throw II\'s in that drops down. The median time to
> progression in SWOG and ECOG trials is pretty reliably\--the time to
> progression, not progression-free survival\--is about three and a half
> months. You saw that in the 1594 data. That is unbelievably
> reproducible. I use that all the time. You can just about double the
> time to progression in most of the cooperative group trials and you
> can come up with the survival, median survival. That is what it is
> going to be.
>
> Now, progression-free survival is a little bit harder to come up with
> because those data haven\'t been as well characterized, at least
> within the cooperative group data. But I would agree with Bruce. I
> think if one is looking for accelerated approval one needs to see
> something that is more than just a few weeks difference in
> progression-free survival, and I think three months may be
> unattainable. I don\'t know but you are talking about accelerated
> approval here and I would agree with that number.
>
> There is one method-logic question that has been posed which I think
> may be germane even in the accelerated approval setting and that is
> should the trial be blinded and, if it is not, or even if it is,
> should progression be verified by a blinded central reading of scans.
> One shakes their head yes, one, no.
>
> DR. BONOMI: I don\'t think so. David has pointed out it is pretty
> obvious when these people are progressing and I think probably you
> don\'t need to go to that degree of rigor. Maybe David might dissent.
>
> DR. D. JOHNSON: No; I don\'t dissent. I just want to point out that,
> in the studies, at least the ones I have been involved in, where there
> has been a review committee that reads the X-rays, there is as much
> disagreement amongst the review committee as there is amongst the
> original investigators. So I am not sure who is truly accurate in
> reading these.
>
> Actually, it is my personal view that the way to get better rigor is
> not to have someone else read the films but to have someone
> consistently read the films at one\'s institution. That way, I think
> one gets more accurate. But that is a debate for another day, I think.
>
> DR. BONOMI: One other thing. I think more and more places now have
> digital radiographs with a cursor and you can measure it. There was
> just a paper in JCO that is what Dave said; it should be one person
> reading these things consistently. You can keep it, put it in a power
> point presentation. If somebody wants to look later and see what you
> did, they can see exactly what they did. The reading stays right on
> there in millimeters. It is much more reliable than it used to be but
> it should be one person.
>
> DR. B. JOHNSON: One point of clarification. When you talk about
> blinded, is it blinded to the treatment or is it blinded for
> determining the time of progression?
>
> DR. PRZEPIORKA: Either.
>
> DR. B. JOHNSON: One of the things, and I think we have heard this
> consistently, it is nice to blind you to the treatment but, if you are
> getting some kind of I.V. infusion, I don\'t think it is going to be
> ethically or practically possible to blind you to the treatment.
>
> So I think it depends on the circumstances. If it is a pill,
> certainly. If it is a 14-day infusion, no.
>
> DR. PRZEPIORKA: Dr. Temple.
>
> DR. TEMPLE: I am having a disconnect. The question here is about time
> to progression irrespective of whether the person is symptomatic. What
> you are all saying is they are always symptomatic, or almost
> symptomatic, and that is what makes you know they have progressed. But
> we never see that. We are never given data that show symptomatic
> progression. If it is that easy, why isn\'t everybody collecting it
> because then there would be regular approval. It wouldn\'t be
> accelerated. There wouldn\'t even be a discussion.
>
> DR. D. JOHNSON: I am reminded of the time that I sat in this committee
> informally as a member and this is like deja vu because I remember
> your comments many times, Bob\--
>
> DR. TEMPLE: Sorry.
>
> DR. D. JOHNSON: No, no. I am glad to find you are consistent. In my
> after-ODAC life, I have been involved in advising folks and I have
> made that point many times that it is something. I think Richard has
> made the point many, many times as well. We, basically, agree with
> you. We do think that that is a reason for approval of drugs and we
> would like to see more of it ourselves.
>
> So I can\'t answer why people don\'t do it. But I am also reminded of
> one of my favorite quotes. I actually put it\--after I heard you make
> this quote, I actually had my wife embroider it and it is on my wall.
> It is listed there, \"Bob Temple, FDA, Survival Trumps Everything.\"
> That was a quote from you and I have never forgotten that. So we
> always remind people when they\--
>
> DR. TEMPLE: Just one other observation; we have also asked people,
> even if you are not absolutely sure that, at the time of radiologic
> progression, there are symptoms. It has always been our assumption
> that, in something like lung cancer, symptomatic progression must be
> fairly near at hand, even if they have crossed over or stopped the
> drug.
>
> We have invited people to look for symptomatic progression at any
> time, even if they are off therapy or moved out and, again, gotten
> very little interest in doing that.
>
> DR. B. JOHNSON: Let me make a comment about this. It has to do with
> the clinical practice of it. One of the things that happens is, when
> we go in to see somebody and they tell us they have shortness of
> breath, you examine them and they have decreased breath sounds half of
> the way up, you send them for a chest X-ray and you get the chest
> X-ray and it shows a new pleural effusion and enlarging nodules. The
> thing I always tell the patient\--well, usually I tell them when they
> are responding, responding, getting better, it is easier to make jokes
> when they responding.
>
> But we say, well, one of the things that\'s nice about being an
> oncologist is it is not that complicated because 95 percent of the
> time the radiographs agree with the symptoms. Now, we have grown up
> with radiographs as our objective criteria for assessing disease
> progression. So that gets categorized not as a symptomatic progression
> but it gets categorized as a radiographic progression because that is
> what has been reviewed in every cooperative-group study.
>
> Now, one of the things that Richard has talked to us about is that the
> symptom scales have evolved so that they may be more objective than
> assessing radiographic response which will be a step forward in being
> able to recognize and use the data. That hasn\'t been something that
> hasn\'t been easily available to us outside of a clinical-study
> setting.
>
> DR. GRALLA: One of the problems has been feasibility. The point is if
> you see the X-ray that Bruce is pointing to, you say, well, why do I
> need to validate this on a scale. I have this. Unfortunately, we have
> often gone from the chest X-ray to the CAT-scan so it is \$1,000
> procedure that you wait for a little while on.
>
> It has been necessary to convert these scales to easy ways. They are
> not like on a palm-pilot, some of them. They are just being rolled out
> in trials. This should make it easy. But how do we now adopt that into
> clinical practice because we are not used to doing that and, God
> knows, getting us to change is the hard part.
>
> So you have got this case-report form that is 40 pages long and the
> rest of this and now you want to add something else to it. That is why
> I think you haven\'t seen it but I think it is up to us now, from the
> cooperative group and from other areas, to get this so you so you can
> see it in a way where most of the patients have it.
>
> DR. PRZEPIORKA: Dr. Temple, just to bring his point back to you and
> your definition of symptomatic progression. Would you be looking for
> something on a scale that is objective and you can measure or, as he
> points out, the patient says, I\'m short of breath? Is that enough to
> say this is a symptomatic progression?
>
> DR. TEMPLE: That is a fair question. If we are all blinded, it would
> be a much easier question because then you could accept a lot of
> things. But there are people here much better able to think about that
> than me, but somebody showed the five or six things that are most of
> what bother patients.
>
> If there were some systematic question that even asked them on a
> ten-point scale, how is your fatigue, your this, your this, your this,
> your this, and that was done regularly. When it looked worse, you then
> sent them out for an X-ray. That would greatly help the persuasiveness
> of that finding of progression as a meaningful thing.
>
> The other thing, of course, is if, in several studies, it always came
> out that way, you would have at least some case for saying that
> progression pretty much always means symptomatic progression. Then we
> wouldn\'t have to do all that anymore.
>
> DR. GRALLA: I think Dr. Taylor pointed out in second line, where we
> saw these response rates of 6 to 10 percent, do we need to send all
> these patients for X-rays for this? When the patient tells you that
> they can\'t breathe, and you have got a valid way of measuring it,
> that they have more pain, that they are using more pain medicine and
> they are dropping weight like a stone, I am just not sure that we need
> the chest X-ray, the MRI, the PET scan.
>
> DR. TEMPLE: We totally agree because symptomatic progression is a
> no-brainer approval, if you believe it\--if you believe it. That\'s
> important
>
> DR. GRALLA: These instruments do that now. The problem is getting them
> incorporated into trials in a feasible way. It is the feasibility that
> is the problem.
>
> DR. B. JOHNSON: There is one other problem that comes up with this.
> Richard may want to address this. We have gone through the design of a
> trial now where the symptoms as being assessed on one of the formal
> scales and the design want to withhold that information from the
> physician because they think it will bias the physician\'s
> decision-making.
>
> We are wrestling with the ethical dilemma about do you withhold
> patient information from the treating physician with the potential of
> biasing the outcome. I would like to hear Richard\'s comments on this.
>
> DR. GRALLA: It is a great point, Bruce. We are doing a 200-patient
> trial in Ontario right now trying to look at that, trying to look at
> how these data affect\--did these data affect the physician
> decision-making. So I hope we have some information there. I think it
> is going to be difficult to say because the patient comes in and has
> pain. As David said, it is not at the regular visit that the patient
> comes in with this. The patient comes in telling you this. It wasn\'t
> on the screening PET scan.
>
> But we have a 200-patient study looking at this where the physicians
> are given this prospectively and they are given the data each time. We
> will see what they tell us. It will also be interesting to see the
> average number of cycles that they use.
>
> DR. WILLIAMS: I guess the biggest problem in my mind is what about
> blinding. Can we believe it? How do we know we can believe it. These
> validations of this and that, they don\'t seem to be taking into
> account the placebo effect or the effect of knowing your treatment.
>
> So how do we address that? If can\'t blind trials, then can we use
> these endpoints? We have basically moved down to No. 7 and 8 with this
> discussion, I think. Can we? I wonder what Dr. Gralla would have to
> say about that.
>
> DR. GRALLA: So, by \"these endpoints,\" you mean these subjective
> endpoints, the pain, et cetera?
>
> DR. WILLIAMS: Right.
>
> DR. GRALLA: Let\'s look. We have talked about 1594, this four-arm
> lung-cancer trial. Was the patient supposed to feel that they should
> mark it better because they were getting the docetaxel or the
> paclitaxel? Most of these trials are in that way.
>
> Now, if the patient is getting the gemcitabine or the or the
> paclitaxel, my guess is that we could tell which one the patient was
> getting if we were blinded. So I think that actually maintaining the
> blind is unlikely and that these are, to me, almost moot points
> because we are usually looking at Treatment A versus Treatment B. The
> patient is usually told if we are using the best standard versus a new
> agent, well, you are getting the very best that we know of.
>
> I don\'t think that patients answer that their cough or pain is
> different six, eight, twelve weeks into a study because of this. Now,
> I think it is important, such as in the gefitinib study, et cetera,
> that the patient then being given a pill is given a placebo on the
> other arm when they maybe are getting nothing in second line. I think
> that that really is important.
>
> But, in most of these first-line Stage IV patients\--and that is the
> other reason that the normative data will be important, also, to be
> sure that this is a group.
>
> DR. KEEGAN: Dr. Gralla, I guess having lived through enough of the
> hype of certain drugs\--Herceptin was one, Iressa and Gleevec were
> others\--in a lot of trials, some patients actually are concerned
> about which arm they are randomized to and do have a strong feeling.
> Perhaps patients might not be as concerned about being on a certain
> arm and declaring symptoms as patients who are on the \"unfavorable\"
> arm, or what they perceive to be unfavorable, and want to hurry up and
> declare their symptoms so they can be crossed over. Is that a concern
> in an unblinded trial, because I think that has been a concern we have
> had.
>
> DR. GRALLA: I certainly think whenever possible to blind, why not.
> There is absolutely no reason not to. The are many studies where we
> didn\'t see that being done. However, I must say that, in most of the
> trials that we have done in the \'90s, this really hasn\'t been where
> people have been so excited and where they have dropped out in that
> way.
>
> If you look at the \*pemetrexed study that I showed, basically, you
> can see a lot of patients showing improvement on the cisplatin study,
> et cetera. There is a strong correlation with response there, on the
> cisplatin arm, et cetera.
>
> I agree that it is an issue and whenever possible to blind, it is
> reasonable to do. But maybe the burden of proof is on us to show that
> your concern actually occurs because it is like the placebo effect,
> when they looked at it carefully, it was pretty hard to show it was
> really there.
>
> DR. WILLIAMS: That is kind of our tradition to have the sponsor show
> that something exists. That is hard to get around.
>
> DR. PRZEPIORKA: Dr. Bonomi.
>
> DR. BONOMI: Just very brief. One other objective thing that could be
> done in every Stage IV lung-cancer trial is just measure the serial
> weights. Obviously, people with edema would throw that off. But,
> otherwise, if I had one thing I could look at in a patient, just show
> me their serial weights and pretty much that is going to tell you what
> is happening to them.
>
> DR. PRZEPIORKA: Is performance status still a valid\--
>
> DR. BONOMI: Oh, absolutely but it is\--you know, the weights are
> so\--it is a quantitative\--one, two is not\--Karnofsky is a little
> bit more detailed.
>
> DR. GRALLA: These are all valuable. But they are not surrogates for
> quality of life. So they are all valuable. They are components of
> quality of life. But they are not, by themselves, that. So performance
> status is really a function scale. It is of real value, what is your
> ability to do things.
>
> Actually, we like now the patient-generated activity scale where they
> fill that out. That can be useful. These are all valid points that are
> very helpful in clinical management. It is pretty hard to see a
> patient who is losing weight like crazy and think that you are doing
> something good for that patient.
>
> DR. PRZEPIORKA: Dr. Saxon.
>
> DR. SAXON: Getting back to the original question which was to choose a
> magnitude of progression-free survival that one would think would be
> clinically relevant, it seems to me that the problem with that, and
> maybe I don\'t understand this correctly\--but the problem with that
> is that it dissociates that endpoint from the toxicity issue.
>
> Whereas, I think a three-month progression-free survival advantage in
> a minimally toxic drug may be quite interesting and important, a
> three-month progression-free-survival advantage with a very highly
> toxic drug probably wouldn\'t be. So my own opinion is you can\'t
> choose an absolute magnitude that is of clinical relevance, that you
> have to take into account the toxicity of the agent. So it is going to
> be a judgment call each time this comes up.
>
> So I guess, in that regard, I disagree with Dr. Johnson, B. Johnson. I
> don\'t think it is going to be possible, quite frankly, to choose an
> absolute magnitude. That consideration is too important, I think.
>
> DR. PRZEPIORKA: Dr. Fleming.
>
> DR. FLEMING: I had voted against use of time to progression as a full
> reliable endpoint because of the uncertainties we have talked about. I
> abstained on the issue of its use as an accelerated approval because I
> am a bit on the fence. I think we are getting at some very good
> discussion that I think are the relevant factors that would pull me
> off the fence one way or the other.
>
> If we are conducting these studies with a high level of rigor that
> minimizes bias due to unblinding which does concern me, and minimizes
> missingness, those are issues that certainly are important. I am very
> favorably persuaded by my colleagues\' comments that, if we were
> relying on time to progression as an accelerated-approval endpoint, it
> would have to be based on a very substantial evidence of benefit.
>
> I think Scott makes the good point; ultimately, it is benefit to risk.
> So what that level of benefit is going to have to be will be dependent
> on what the overall safety profile is. That is certainly relevant
> although it is helpful to get Dr. Johnson\'s sense, three months. My
> own sense here is it should be something very substantial taking into
> account, of course, the toxicity profile.
>
> We didn\'t talk about statistical strength of evidence, but it should
> be strong statistical strength of evidence. Traditionally, we call it
> strength of evidence of two trials, 0.25 squared, something on that
> order, something on that order. It should be strong evidence than I
> might have asked for for survival because, in fact, it is not as
> reliable a measure.
>
> The study presumably will give us some information on PROs or
> survival. Certainly seeing some suggestive evidence that those results
> look to be trending in the right direction, obviously, would be also
> very importantly reinforcing.
>
> The final point that I would make is a very important issue; is
> accelerated approval tantamount to full approval and, if it is, then I
> would argue we should be using criteria close to that for a full
> approval. But, if accelerated approval really is to get early access
> while we complete the validation trial in a timely way and, if we have
> procedures in place that would give us a process to withdraw the
> accelerated approval if the validation study shows lack of benefit,
> then I am much more willing to say yes, this lower level of evidence
> that we would have is, in fact, a basis to providing an accelerated
> approval.
>
> So I guess I am saying under all of the conditions that we have talked
> about, I would also support the accelerated approval. But those
> conditions mean that we need to have considerable strength of evidence
> on time to progression. It would be useful to have supportive evidence
> on survival and it would be important to know that, if the validation
> study, when completed, showed lack of benefit, that this wasn\'t going
> to lead to indefinite access. If it were, then we should be looking at
> full approval criteria.
>
> DR. PRZEPIORKA: Dr. Johnson.
>
> DR. B. JOHNSON: I wanted to get back to Dr. Williams\' point about
> being concerned about using the PROs and the blinding issue. One of
> the things that we don\'t have a lot of examples of in lung cancer is
> a big dissociation between patient-related symptoms or patient
> outcomes and what is happening with the underlying disease.
>
> The duration of time is relatively short that we typically see so,
> until we come up with some examples where there is a moderate
> dissociation between the patient\'s perception of outcome and what we
> typically measure in the disease, I think it should be okay. It is not
> something I would lay awake at night worrying about.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: I guess something I want to flag for a later discussion is
> the difference between what we usually measure, which is medians or
> the shape of the curve, and the possibility that there are widely
> different results from one piece of the patient population to the
> other; that is, a small responder set.
>
> I don\'t want to try to resolve that now, but has is always sort of
> bothered me because I have always been struck by the end of the tail
> that goes out real far. That seems, in some ways, more important than
> the median. None of our analyses really reflect that. But I don\'t
> want to talk about it now. I just want to flag it for later. Much
> later.
>
> DR. PRZEPIORKA: In that case, we will move on to the Question No. 6
> which we are now getting into dreaded territory. First-line
> non-small-cell lung-cancer treatment setting approval based on the
> noninferiority analysis of time to progression or progression-free
> survival and/or response rate.
>
> So, specifically addressing the following situation; a less toxic
> experimental drug demonstrate noninferiority of both response rate and
> progression-free survival compared to the standard toxic regimen. The
> standard toxic regimen has previously demonstrated an estimated
> two-month survival benefit one trial comparing it to best supportive
> care.
>
> In the current trial data, 95 percent confidence intervals cannot
> establish whether the experimental therapy retains the survival
> benefit of the standard regimen. Could approval be based on
> noninferiority analyses of response rate and/or progression-free
> survival in situations where the noninferiority analysis of survival
> cannot be performed.
>
> Examples would be when there are insufficient patient numbers to allow
> the survival noninferiority analysis or when there is confounding of
> the survival analysis by crossover.
>
> Discussion? Dr. Fleming?
>
> DR. FLEMING: 5 and 6 are related. They are both noninferiority
> questions. 5 was on survival, 6 was on surrogate for survival. I am
> just wondering, since 5 lays out the fundamental issues that have to
> be considered for a valid noninferiority trial which also have to be
> considered in Question 6, is it okay to consider those two questions
> together, or can we start with 5?
>
> DR. WILLIAMS: I would prefer not to get into the details. Let\'s
> suppose that we have everything we need for a noninferiority trial,
> for time to progression and response rate. I don\'t want to get into
> whether we do and how you would do that, but let\'s suppose we do.
>
> Not a likely situation, but let\'s suppose. Given that, and given that
> we can\'t deal with survival compared to this marginal survival
> benefit of this other agent, but it is less toxic\--I mean, this is a
> real situation that we definitely will face with several drugs in the
> near future. The question is can you do noninferiority comparison with
> response and time to progression.
>
> Certainly, you can do it with response rate. And they are less toxic.
> So that is the question. I don\'t want to get into the details of what
> are the various numbers of trials we have in order to demonstrate the
> time-to-progression effect and the response-rate effect. Let\'s just
> assume that we have a margin that we can establish and we can
> establish that we have the same noninferiority rate and time to
> progression.
>
> I would like to take that as a given, in this question.
>
> DR. TEMPLE: It didn\'t say noninferiority on the surrogates.
>
> DR. WILLIAMS: Right. Response rate and time to progression.
>
> DR. TEMPLE: But not for the survival, but tolerability advantages.
>
> DR. WILLIAMS: Yes. This is an extremely real example. All of the
> doublets have very poorly documented survival effects. It is very
> difficult to do an noninferiority survival analysis. So you have
> either got to beat them or the other alternative would be to say, I
> have the same response rate, time to progression with some sort of
> rigor and that I am less toxic.
>
> So it is sort of a value judgment. You have already said\--part of
> committee said they wouldn\'t take progression-free survival as a
> benefit anyway. On that basis, maybe it seems obvious. But the
> situation may be that you cannot deal with survival here unless you
> beat the drug. So I would just like you to kind of struggle with what
> we are struggling with.
>
> DR. PRZEPIORKA: So, if I can reinterpret the question, if you have a
> drug that is really not toxic and it gives you the same response rate
> and time to progression as your current standard which is, come in,
> get your white count wiped out and have lots of nausea, vomiting and
> throwing up and, on the basis of numbers, response rate and time to
> progression are exactly the same for the toxic and nontoxic drugs and
> there is no way you could look at survival\--
>
> DR. WILLIAMS: We have to go a little better than just on the numbers.
> We would have to satisfy Dr. Fleming they are noninferior.
>
> DR. PRZEPIORKA: But there is no way you could look at survival in
> those patients because there is just not enough. Would you be willing
> to recommend approval?
>
> DR. D. JOHNSON: Regular approval.
>
> DR. PRZEPIORKA: Regular approval.
>
> DR. WILLIAMS: Or even accelerated approval. That would be a
> possibility.
>
> DR. SAXON: But that is not exactly what this says. What this says is
> that you cannot establish whether the experimental therapy retains the
> survival benefit. So the confidence intervals here are overlapping
> null.
>
> DR. WILLIAMS: Well, no. When we are talking about with respect to
> survival, you are correct. But we cannot establish it either because
> we don\'t have enough data or because the effect is so poorly
> established historically that it could never be practically done.
>
> DR. TEMPLE: Realistically, if you have a two-month survival, the lower
> bound for confidence interval is added somewhere less than that, and
> you want to preserve 50 percent of it, you would have to rule out a
> loss of half a month or something. The size of study that could do
> that is not really thinkable.
>
> DR. B. JOHNSON: Can you give us an example of the sizes. The unspoken
> thing here is that it would take a huge trial to do that with a
> two-month difference.
>
> DR. WILLIAMS: I would say 2,000 or 3,000. I don\'t know what the
> statisticians would say.
>
> DR. B. JOHNSON: Can you give us an idea about the size we are talking
> about?
>
> DR. FLEMING: It is easier if you go with me for a moment. It is easier
> to start with the perspective of survival and then move into the
> perspective of time to progression. But the size, just to jump ahead,
> of the trial is going to be dependent on what alternative you are
> presuming.
>
> The way this would frequently be done, if it were survival, for
> example\--let\'s suppose we have a three-month advantage in survival
> and it is estimated with considerable precision, plus-or-minus a
> month. So it is three months, plus or minus a month.
>
> Now, by the way, that clearly is going to be based on a metaanalysis
> because three months plus-or-minus three months is what you get when
> you have a p-value that is two-sided 05. So you are talking about very
> strong evidence to be three months plus-or-minus a month.
>
> Then the typical approach is to say, all right, that means it is at
> least two months. I will preserve half the benefit so I will have a
> one-month margin.
>
> DR. TEMPLE: In that case, you could do it.
>
> DR. FLEMING: In that case, it is like the iridia\* Zometa example
> where this is the exact approach that was used. But, clearly, it takes
> a metaanalysis. There has to be substantial evidence of some benefit.
>
> However, I would even say here the sample size may not be as
> horrendous as you would think because, if we are somewhat better, we
> can rule out we are somewhat worse. There was an noninferiority
> survival improvement and that was \*docetaxel against \*navalbine. In
> essence, the docetaxel median survival was a month longer. You can
> rule out that you are a month worse when you are a month longer
> without it being an extraordinary sample size.
>
> Where it becomes extraordinary is if you truly are not any better and
> then you are having to rule out a small margin. Then it takes a big
> sample size.
>
> I would hope we would learn from experience, and I think we are
> learning from experience. The temptation is to say, if I have an
> effective standard of care and I can come along with something that is
> less toxic, if the curves are overlapping, if their
> time-to-progression curves, survival curves, whatever, it is very
> tempting to say, come on; efficacy is the same and safety is better.
>
> It brings me back to March 14, 1986 when ODAC was meeting and we were
> looking at advanced breast cancer with adriamycin as the standard and
> mitexantrum was being considered and everybody was impressed by the
> fact that it was less nausea, vomiting, cardiotoxicity,
> myelosuppression. The committee voted 9 to 2 in favor of approval
> because there wasn\'t anything that was compellingly different in
> survival.
>
> Yet, the fact that the curves are close together doesn\'t really mean
> we can rule out that it is worse. Fortunately, Bob Temple and others
> at the FDA came back and said, let\'s revisit this in a year. It was
> revisited in December of \'87 and, at that point, the differences were
> significant favoring the control, now adriamycin, and the committee
> completely reversed its vote and it was 11-nothing against approval.
>
> The relevance of what we learned fifteen years ago was it is important
> to understand what levels of rigor we have to have in order to judge
> that we can rule out that it is meaningfully worse. These margins are
> not just a statistician\'s configuration of something to make
> clinicians\' lives complicated. It does do that, but there is much
> more of an intention than that, and that is to be able to say, what is
> the difference between evidence that looks consistent with
> noninferiority versus evidence that really establishes noninferiority.
>
> For superiority, if you had 30 patients on an arm and you had a
> two-month survival difference, we wouldn\'t claim that superiority if
> the p-value is 0.15. We have to be as rigorous, if not more rigorous,
> in a noninferiority setting.
>
> So the conclusions that are actually derived and the points that are
> made in Paragraph 5 for Question 5 are relevant for Point 5 and Point
> 6. It is very important that we understand that we have active
> comparators that truly provide substantial benefit that is precisely
> estimated and where those estimates apply to the setting in which the
> noninferiority trial is going to be done. That is called the constancy
> assumption.
>
> A lot of methods are out there. The Rothman method was referred to by
> Mark Scott in his open-session discussion. I would just point out,
> that method or any other needs to adjust for the constancy assumption.
> Mark Rothman was mentioned that to me also at lunchtime. The method is
> now frequently being applied when it doesn\'t adjust for the validity
> of the constancy assumption which, again, clinically means,
> historically, I may have estimated my active comparator to have a
> certain level of effect, but it may not have that level of effect as
> an imputed placebo in my noninferiority trial if I have different
> sensitivities for efficacy, if I have different ways of measuring, if
> I have different supportive care.
>
> The analysis that is being brought before this committee, I hope one
> question people would ask is, are we using rigorous methods to truly
> rule out meaningful differences and is that constancy assumption
> factor being factored in.
>
> Moving to Question 6, we make our life far more complicated when we
> now try to do a noninferiority analysis on a surrogate endpoint. That
> is where we are in Question 6. If one is looking at ruling out a
> certain level of difference in time to progression\--let\'s say you
> have got these combination regimens that have been established in
> first-line as standard of care on survival and we now want to look to
> see whether we are not meaningfully worse in time to progression.
>
> We are not even saying are we better. We are saying, are we not
> meaningfully worse. Then what we have to be able to say\--I have
> registered concerns in using time to progression as a superiority
> because I haven\'t seen the evidence here presented that indicates
> that if we achieve a certain difference, beneficial effect in time to
> progression, that reliably means a treatment-induced effect in
> survival.
>
> To answer Question 6 positively, you need far more information. You
> have to be able to know that if you give up a certain fraction of the
> benefit in time to progression, that will translate into the fraction
> of survival benefit that you are willing to give up. That type of
> functional relationship is extraordinarily hard to get at.
>
> We talked about lipids as an example where FDA has used this as an
> acceptable surrogate. We have myriads of studies showing you can get a
> 10 percent reduction in cholesterol. It doesn\'t provide any kind of
> benefit. But a 30 to 40 percent does provide major benefit.
>
> You have got to understand the functional relationship that says how
> much time to progression difference translates into the amount of
> survival difference I am willing to give up. I would argue that is
> wishful thinking. That level of insight and the data that we would
> need to be able to do that just doesn\'t exist.
>
> DR. PRZEPIORKA: I think a key question here that he brought out was
> making sure that survival doesn\'t pay the price. If there is a way
> that you could keep the confidence intervals\--or predict how much you
> have to keep the confidence intervals down so that you don\'t lose
> survival, if you know the correlation between the surrogate and
> survival, that would be one way to say, okay; it is kind of safe to do
> this since it is less toxic.
>
> But if you can\'t predict, I think everybody would have a difficult
> time knowing the history of the drugs that we have seen in the long
> run to say yes, this would probably be okay to approve.
>
> DR. TEMPLE: In some ways, probably the example we are more likely to
> see is where response rates may be a little better, time to
> progressions may be a little better than the control and we don\'t
> really have much data on survival. That would raise an interesting
> question about accelerated approval, I think. That is probably more
> likely to face us.
>
> It is not easy for me to imagine how we would be able to do successful
> noninferiority on time to progression if we didn\'t have a clue about
> survival. I am not sure how you could do that.
>
> DR. PRZEPIORKA: I guess from our earlier discussion that if this
> little bit better is less than three months, as far as we are
> concerned, it is not inferiority, it is not superiority.
>
> DR. TEMPLE: Right. Thanks.
>
> DR. WILLIAMS: Perhaps we could go to the last area about symptoms
> again and have a little bit of discussion. We have heard all of Dr.
> Gralla\'s presentation about the merits of these endpoints, but what
> are we ready for now and how should they be used in the studies we are
> doing? Do we think that they are ready to be a primary endpoint? Is
> there a specific area we need to go with these endpoints? Do we need
> to include them in all the studies?
>
> DR. PRZEPIORKA: We will go ahead and go through the second No. 7 and
> No. 8. But, before we do that, I just wanted to make a statement of
> concern that I had regarding the meaning of validation in these
> quality-of-life tools that are used since they seem to be validated
> against other quality-of-life tools.
>
> I work with these patients. I understand their quality of life needs
> to be good but what is the definition of quality of life. I sit in the
> chair under a cover and don\'t move but my pain is better or it is I
> can take the cover off, fold it up, do some laundry. So I am
> disappointed to hear that these are not validated against a functional
> scale which I think would be a meaningful clinical benefit.
>
> DR. GRALLA: I\'m sorry, but I think that is incorrect. These are not,
> but my pain is a little better, I am shivering. How much pain do you
> have? None at all or as much as it could be? These are validated in
> ways that are quite clear. If you, certainly, take an example of the
> FACT-L, there is looking at physical symptoms and how that affects
> functionality. So these are strongly validated. The Melzack-McGill
> scale looks at these issues and looks at the quality of pain.
>
> We don\'t look at the quality of pain. So there is strong correlation
> with these if you look at how they are looked at. For instance, the
> observer scale, as part of the LCSS, correlates with what type of pain
> medicine you now need. So, have you gone more or less down the WHO
> ladder or are you just taking tylenol?
>
> So these are validated in ways that correlate with function, et
> cetera, but the main answer is do they tell you whether a person has
> pain or not. So a pain questionnaire answers the pain question. They
> have predictive validity for survival and maybe even for response as
> well.
>
> But we don\'t ask that of survival, does this give us a function
> answer. We don\'t ask it of response, does it give us a function
> answer. Now we are asking of pain? I think the validity methods, the
> gold standards that are used are those that are used elsewhere and
> that, if you look at the function analysis, especially in the FACT, it
> really gives you a lot of information as to how people function. And
> they all correlate with performance status.
>
> DR. PRZEPIORKA: That was not clear in your presentation, but we would
> certainly like to know more about how the quality-of-life scales
> predict function. I think that is really important.
>
> DR. GRALLA: Again, if you just look at the validation study for the
> FACT-L, and it would have taken half an hour to discuss that alone,
> you can see that it is divided into social functioning, physical
> functioning, psychological functioning. All these areas are right
> there. So these address exactly the points that you wish to look at.
>
> DR. PRZEPIORKA: Dr. Bonomi?
>
> DR. BONOMI: In the FACT instruction, they have a thing Dr. Cella calls
> a Trials Outcome Index. It has 21 questions and it addresses the
> things that Dick just talked about. It has lung-cancer symptoms. It
> has functional symptoms. And it does get all of that stuff. In fact,
> David alluded to it earlier. That was the best predictor of survival
> in the study, 5592 study. It was better than performance as the
> initial Trials Outcome Index score was the best predictor.
>
> The problem is, and this I would like to raise, it has 21 questions
> that the patients have to answer. I think that the things that are
> probably most valuable are the lung-cancer symptom scale or the FACT-L
> which is just seven questions about lung-cancer symptoms.
>
> That is something you can get pretty reliably. You start going to 21,
> it starts getting a little tougher. But maybe Dick has a comment about
> that.
>
> DR. GRALLA: I agree. If you want detail\--there are always tradeoffs.
> How much detail do you wish to have? If you will accept the fact that
> these validity studies that are done and published in the
> psychometrics that show all these outcomes that you want, and are
> boring as hell to read, these 20-page papers, or whatever, they go
> into these issues.
>
> The question is when you get this ready for prime time, you don\'t
> want to be doing all those scales that they did because there is
> correlation with each one of these areas. So Dave Cella has developed
> this 7-question subscale which some people like, et cetera. The LCSS,
> which is supposed to address these, has only nine items to be done.
>
> So these get to the questions, is there really pain relief, et cetera.
> The basis has already been done as to what this means to patients.
> There is a lot of information on that. It is like looking at a
> CAT-scan and saying, but how do I know it really works each time.
> There are other studies that have shown what it really means, as far
> as that is concerned.
>
> So I would have to say that if you want to look at the full scale
> which is what really Phil is talking about, and you take the T, O, I
> out of that, you get 21 items, et cetera. You can do these. But you
> can get answers that tell you that patients are improving in the areas
> that are most important to patients just by using the smaller areas.
> For the LCSS, it is whole instrument. For the FACT-L and for the
> EORTC, it is a subscale.
>
> DR. PRZEPIORKA: Dr. Temple?
>
> DR. TEMPLE: One of the areas in which we think we have made progress
> is we don\'t call these quality-of-life scales anymore. We call them
> patient-reported outcomes because quality of life captures\--you have
> got to check the spiritual nature of it all and we are not so such
> cancer treatment fixes that.
>
> But we think it is at least plausible that it might fix a good scale
> of lung-cancer symptoms. So the focus there is on those and they have
> a certain amount of face validity. They seem at least as valid as the
> typical questions a physician will be put to the patient, like, how is
> your breathing or how are you feeling.
>
> They are pretty solid. Those seem like the most promising things.
> Whether performance in the community for someone with advanced lung
> cancer is as relevant as how is your breathing these days, I think
> could be debated. But at least some of them seem very plausible on
> their face and we would be very happy to see effects on those things,
> I think.
>
> DR. PRZEPIORKA: I think a question came up earlier regarding
> performance status II patients and whether or not there should be
> quality-of-life instruments are PROs as a primary outcome for studies
> in that subset of patients with lung cancer. Any comments?
>
> DR. D. JOHNSON: You mean as separate studies altogether and is it
> something that is valid. I think the answer to that is yes. We have
> data from, again, prospective studies, one from Michael Cullen which I
> think is a really nice trial that was done in the U.K. in which they
> included patients with advanced disease who had performance status II,
> and they did patient-reported-outcome analyses.
>
> What he demonstrated was what ECOG, SWOG and CALGB and others have
> demonstrated, that the better your performance status at diagnosis,
> the greater is your \"survival benefit.\" Again, just to give
> everybody some baseline data who aren\'t lung-cancer docs here, if you
> get a platinum-based therapy and you are Stage IV, your median
> survival will be nine months if you are 0 performance status, six
> months if you are 1, and three months if you are 2. That I call my
> Rule of 3s.
>
> In Cullen\'s study, he showed really exactly the same thing. It was
> the exact reverse of that in terms of symptom benefits. Obviously, if
> you are asymptomatic, you can\'t get better. You can\'t get more
> asymptomatic.
>
> The amount of benefit in terms of symptom improvement was greatest in
> the patients who were PS-2. So there was a balance. Their survival
> benefit was not as great. It is one-and-a-half months to two months
> with no treatment, three months to four months maximally with
> treatment.
>
> But, by contrast, their improvement, however you chose to define that,
> was a higher percentage of improvement relative to the PS-1 patients
> although their survival, the PS-1s, was better than the PS-2s. That
> makes sense. The more symptomatic you are, the more likely you are to
> improve.
>
> DR. GRALLA: Dr. Przepiorka, in the validation studies, Dr. Holland, in
> Cancer in 1994, looked at \"known groups.\" So we know that survival
> varies by each decline of the Karnofsky scale. So she looked at very
> low performance-status group patients, performance status 30 to 50.
> She found validity for the very low performance-status group, the
> median, the Karnofsky 50 to 70, and then the better 80 to 100. So part
> of the validation is looking at known groups and then seeing if this
> goes true.
>
> This sort of paradoxical finding that David has explained to us seems
> to exist through that as well. So these instruments have all looked at
> those groups and these instruments, to some degree, have been looked
> at in the hospice population as well.
>
> DR. PRZEPIORKA: Are there any other lung-cancer settings where the
> symptom-based endpoints can then serve as the primary endpoint for
> approval?
>
> DR. B. JOHNSON: One of the things I would like to address is one of
> the reasons why\--we work quite a bit with mesothelioma patients. One
> of the reasons why they generated that\--why the symptom scale\--and
> we participated in that study where we assessed that\--is that it is
> very difficult to assess responses in mesotheliomas because it is
> pleural based and you can\'t do Recist criteria. So you have either
> got to come up with a new way of doing it which has since been better
> validated.
>
> But when those trials started, they didn\'t really exist. So they
> embedded that symptom scale in there. We got experience doing it and I
> agree with Dick. I think that was one of the first times we were
> really consistent about it and got it short enough so the patients
> could reproducibly do it.
>
> And so mesothelioma would be a very good one to take a look at. But
> the thing that happened there is that the symptoms very closely
> paralleled what they saw radiographically which is what you see in
> almost every situation.
>
> The other thing that happened that we learned in there is that, and
> this may be shocking to some people, but they don\'t always tell the
> doctor everything. If you took a look at what they filled out, they
> say, I feel great. Everything is going wonderful. And they have got it
> all maximally symptomatic.
>
> So it does collect information, no matter how thorough we try to be,
> that does not otherwise exist in the medical record.
>
> DR. PRZEPIORKA: That is No. 7. Moving on to No. 8, discuss the role of
> quality of life as a drug-approval endpoint. Are quality-of-life
> results meaningful in single-arm studies? I think Dr. Gralla actually
> addressed that a little, if he wants to reiterate his opinion.
>
> DR. GRALLA: My opinion on this would be that it is very interesting to
> see it is exploratory, but, for drug approval, I have real difficulty
> with it.
>
> DR. PRZEPIORKA: Does anyone disagree with that? Okay. We also talked
> about blinding a little bit so I will skip b. and go to c.; should
> quality-of-life instruments be routinely included in lung-cancer
> studies and, if so, which ones.
>
> DR. B. JOHNSON: If it is routine, then why would you have to pick
> them?
>
> DR. D. JOHNSON: Actually, I am not sure I would mandate that they be
> included. There are circumstances where, if we are curing 100 percent
> of the patients and their quality-of-life drops a little bit, I think
> they might accept that to some degree. I am being facetious, but I do
> think that there are circumstances where quality of life is really not
> going to be necessarily beneficial to the outcome of the trial.
>
> Again, if you are powering for survival benefit, it seems to me
> redundant to look at the quality of life and then try to come in for a
> drug approval on the basis of that later on, as a secondary endpoint.
> Now, maybe FDA would feel differently about that, but, to me, if you
> want to use it, you should use it in the proper way.
>
> DR. PRZEPIORKA: Dr. Bonomi.
>
> DR. BONOMI: I agree with Dr. Johnson completely. I would not make it
> mandatory. You would pick it and, if it is your primary objective,
> great, and make it simple. It has got to be simple, lung-cancer
> symptom scale or something like that.
>
> DR. PRZEPIORKA: Dr. Saxton.
>
> DR. SAXTON: I agree with Dr. Johnson.
>
> DR. PRZEPIORKA: Dr. Ettinger?
>
> DR. ETTINGER: I agree.
>
> DR. PRZEPIORKA: Do you have other questions you want us to look at?
>
> DR. WILLIAMS: No. I just want to thank everybody for all their input.
> I think it has been a great discussion. It is a great way to sort of
> kick off the endpoints process.
>
> DR. PRZEPIORKA: Ms. Ross.
>
> MS. ROSS: Thank you, Madame Chair. Would it be in order for me to make
> a motion to have a vote on objective response rate as an acceptable
> endpoint for accelerated approval?
>
> DR. WILLIAMS: We have already used it. The reason we didn\'t ask is
> because we already did it with Iressa. I guess you could. The only
> thing that could happen is that it would turn around that decision
> which isn\'t what you want, I don\'t think.
>
> MS. ROSS: Drop the motion. Okay. Thank you.
>
> DR. PRZEPIORKA: Just as a point of information, our next meeting will
> be March 4 and it will be one day. It might be one day, it might be
> two, but it is a different day than originally planned so please check
> your calendars and this meeting is now adjourned. Thank you.
>
> \[Whereupon, at 4:43 p.m., the meeting was adjourned.\]
>
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