# Presentation: 505505

## Meeting Agenda

- Presentations on endpoints
- Regulatory issues
- Scientific issues
- Pros and cons of end points
- Classical end points
- Non-classical end points
- End points and trial designs according to lung cancer stage

## Presentations	

- Regulatory background
- General regulatory requirements
- US lung cancer approvals
- International lung cancer approvals
- Classical lung cancer end points
- Non-classical lung cancer end points

## Outline of Presentation

- FDA requirements for new drug approval
- Regular approval of cancer drugs: end points used
- Accelerated approval
- Endpoints and issues

## Requirements for Drug Approval

- Safety (FDAC, 1933)
- Efficacy demonstrated in adequate and well controlled studie_s_ (1962)
- Basis for efficacy:
- Regular approval
- Clinical benefit, or
- Established surrogate for clinical benefit
- Accelerated approval
- Surrogate (reasonably likely to predict CB)

**Notes:**
Drug approval requires adequate and well-controlled studies demonstrating that the drug is safe and is effective for the approved indication. The safety requirement comes from the Federal Food Drug and Cosmetic Act of 1938.  The efficacy requirement is from a 1962 amendment to the Act.   
   There are two routes to new drug approval.  The traditional route which I will call regular approval requires the demonstration of clinical benefit, or an established surrogate for clinical benefit.  Clinical benefit is usually considered to be tangible benefit of obvious worth to the patient, such as prolongation of survival or relief of pain.  Sometimes FDA has accepted surrogates as the basis for regular approval, usually after much clinical experience with the surrogate and widespread acceptance by patients and physicians.  Examples are lowering blood pressure and lowering cholesterol.   On occasion these assumptions have been wrong, such as the benefit of suppressing some arrhythmias. 
	Another mode of approval is accelerated approval, approval which can be based on a surrogate endpoint considered to be reasonably likely to predict clinical benefit.  I will discuss accelerated approval in a later slide.

## How many trials?

- 505(d) of the Act:
- Substantial evidence: “Adequate and well-controlled investigations”
- Single trial1:
- “generally only in cases in which a single multicenter study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit... and a confirmatory study would have been difficult to conduct on ethical grounds.”
- 1Efficacy Guidance, May 1998

**Notes:**
We hold innumerable end of phase II meetings with drug companies.   In the division of oncology, we have for years been involving advisory committee members in our end of phase II meetings.  This allows us to get expertise, and also to get some buy-in from the committee.  In the past, most of our NDAs have also been taken to the committee. 
One of the central questions we address at these meetings is how many trials are needed.  The usual answer is more than one, and this is based on this clause in the Act.  There are occasions when one trial may suffice, and this was expressed in our efficacy guidance that was finalized in May of 1988....This occurrence is actually not that rare in oncology.  I believe this practice is probably more defendable in oncology.  Often in oncology have data from more than one objective endpoint, such as tumor response or time to progressoin, supporting that the drug is active, and that the efficacy finding was not a statistical fluke.

## Oncology Efficacy Supplements

- Only one additional trial may be needed for closely related indications:
- Advanced cancer and earlier cancer
- Different dosing regimens
- New combinations of drugs
- 1Draft Guidance on New Cancer Treatment Uses, 1997.

**Notes:**
The field of oncology may be somewhat different in that there are a large number of potential indications.  First, there are all kinds of different cancers, such as lung cancer (large cell, small cell), breast cancer, etc. We treat each of these as different diseases.  But also, each disease may occur at a different stage, each with its own clinical considerations.  So we may consider adjuvant therapy, first line therapy, and refractory therapy as separate indications.  For these latter classifications we often will consider whether one trial may suffice for an efficacy supplement and whether we can utilize data from other stages of disease to serve as the supporting data. This philosophy was expressed in a draft guidance in 1997.

## Regular Approval Endpoints in Oncology

## Clinical Benefit Endpoints Supporting Oncology Drug Approval

- Survival
- Improvement in tumor-related symptoms
- Disease-free survival (selected settings)

## Established Surrogates Supporting Approval

- Complete response rates in some settings (e.g., acute leukemia)
- Partial response rate in some settings (e.g., hormonal treatment of breast cancer)

## DODP: Endpoints for Approval (1/1/90 - 11/1/02)

- Approvals not based on Survival:
- 73% (48/66) of all approvals
- 67% (37/55) excluding accelerated approvals

**Notes:**
As we begin the discussion of this drug, and of the endpoints proposed to support its effectiveness, it is useful to reflect upon endpoints used by the FDA to support cancer drug approval. It has often been stated in the media or in the oncology literature that FDA  only approves cancer drugs based on survival as an endpoint, however, this is clearly not the case.  Recently, the Division of Oncology Drug Products evaluated the basis of approval  for drugs in our  division since 1990.  As shown on this slide, survival was the approval endpoint in the minority of approvals.  73% of all approvals were not based on survival....and if you exclude accelerated approvals, 67% of approvals were not based on survival.

## Slide 11

**Notes:**
This table displays a survey of endpoints used by our division for regular approval of cancer drug indications over a 12-year period.  As you can see, only 18 out of 57 utilized survival as the approval endpoint.  

## Examples of endpoints in oncology

- Idarubicin	-Prolonged remission in leukemia
- Zinecard		-Protection from cardiac toxicity
- Photofrin		-Dysphagia scale
- Aredia		-Skeletal morbidity scale
- Daunozome	-Visible lesions of KS
- Novantrone	-Pain

**Notes:**
You might think that reviewing cancer drugs would be pretty boring... monitoring whether patients die of cancer, looking at tumors, and evaluating toxicities such as causing patients to lose all of their hair.  On the contrary, I have found that review of cancer drugs is anything but routine.  Here are some of the different efficacy endpoints we have seen.  My first NDA was for Idarubicin in the treatment of Acute Leukemia.  The endpoint was complete response with disappearance of leukemia cells.  This was fairly routine from an endpoints standpoint, although it was my first introduction to the concept of non-inferiority trial design, something that we are still struggling with today at an Agency level.  With zinecard we had our first example of a “chemoprotection agent” that is, a drug given to ameliorate or prevent the toxicity of another agent.  For this drug the main endpoint was cardiac toxicity as manifest by changes in MUGA scans during treatment with doxorubicin.  Photofrin was in a completely new class of agents, photodynamic drugs.  With this treatment patients are given an IV injection with a photosensitizer and then Laser light is shined on the local area of cancer.  In this case, patients with esophageal cancer that was causing dyphagia, or problems swallowing, were evaluated both for shrinkage of tumor, but more importantly an improvement in ability to swallow.  The scale had a functional element to it, such as “I can swallow solids, I can swallow liquids, I cannot swallow anything, “etc.  
Daunozome was approved for treatment of Kaposi’s sarcoma on the basis of tumor responses.  Although we do not often consider shrinkage of tumor to be sufficient evidence for full approval, with Kaposi’s sarcoma, where tumor is on the surface of the skin including the skin, it was felt that improvement in tumor was of obvious benefit to the patient’s self image, ant therefore represented clinical benefit.  
Finally, Novantrone was approved for treatment of refractory prostate cancer  on the basis of an improvement in pain in a randomized but unblinded trial.  I am sure many of you would not consider pain to be a valid endpoint in an unblinded trial, but these studies required a large individual patient increment in pain and were supported by data on antitumor effect.  

So one of the important jobs of the medical reviewer is to assist in the evaluation of which endpoints represent clinical benefit or efficacy endpoints.  Ideally this is done during review of the protocol at the end of phase II stage so that FDA and the sponsor are in agreement regarding this point when the NDA is submitted.  At the time of NDA submission, reviewers new to the application must review the division files to ascertain what FDA has agreed to regarding this critical point.  

## Accelerated approval 

- Serious or life-threatening disease
- Drug must provide _benefit over available therapy_
- Surrogate endpoint may be used
- Surrogate endpoint must be _reasonably likely to predict clinical benefit_
- Post marketing studies must verify clinical benefit

**Notes:**
Lets return to regulatory considerations.
We are considering this application under the 1992 accelerated approval regulations. This slide lists the major issues. 
These regulations are for diseases that are serious or life-threatening where the new drug appears to provide benefit over available therapy. 
The key point for our consideration is that AA can be granted on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit.  After AA, the applicant is required to perform a post-marketing study to demonstrate that treatment with the drug is indeed associated with clinical benefit.  If the post-marketing study fails to demonstrate clinical benefit or if the applicant does not show due diligence in conducting the required study, the regulations describe a process for rapidly removing the drug from the market..

- Regular approval:   _clinical benefit or established surrogate_
- Accelerated approval (AA):	_surrogate endpoint __*reasonably likely to predict clinical benefit*_.
- AA used only when new treatment represents *benefit over available therapy*
- Sponsor must do phase 4 trial showing clinical benefit

- New Drug Approval Efficacy Requirement

**Notes:**
Drugs may be approved by two different mechanisms and using two different types of endpoints.  
For traditional approval, you must show a drug provides clinical benefit.   The exact meaning of clinical benefit involves clinical judgment and is a critical issue when designing a trial for new drug approval.  
The other mechanism for new drug approval is accelerated approval.  Accelerated approval is based on a surrogate endpoint that is judged reasonably likely to predict clinical benefit.  There are two other important differences with accelerated approval.  First, the accelerated approval mechanism can only be used if the new drug represents a benefit over available therapy.  And second, after accelerated approval, drug companies must perform a phase 4 trial demonstrating that the drug produces clinical benefit.  If not, the drug can be removed from the market.  

## Evidence for Accelerated Approval

- _Substantial evidence_ from well controlled clinical trials regarding a surrogate endpoint
- NOT: _Borderline evidence_ regarding a clinical benefit endpoint

**Notes:**
I want to emphasize an important point about  accelerated approval, one you have likely heard from our  office director, Dr. Temple. 
The quality and amount of evidence required is no different for accelerated approval than for regular approval. We still expect substantial evidence from well controlled clinical trials.  We cannot accept borderline evidence. ... the difference is that evidence may focus on a surrogate endpoint rather than a clinical benefit endpoint.

## ODAC Meeting on: Accelerated Approvals(March 2003)

- 19 NDAs or BLAs for new treatment indications (involving 16 drugs)

## DODP Accelerated Approvals

## ODAC Meeting on: Accelerated Approvals(March 2003)

- Confirmatory studies should be part of drug development plan
- Early discussion of confirmatory studies with Agency
- ODAC wanted to be consulted on confirmatory study plans

## Single Arm Trials (SAT)  and Accelerated approval (AA) 

- SAT require few patients
- SAT for AA limit study to refractory disease
- SAT have limited ability to evaluate valuable endpoints such as TTP, QOL, and Survival

## Randomized Trials (RT) and Accelerated approval (AA) 

- More patients and time
- Allows AA at any disease stage
-  	(surrogate beats available therapy)
- Allows “add-on” design
- 	(A vs A + B)
- Allows a variety of endpoints
- Time to event (TTP, survival)
- Endpoints requiring blinding (symptoms, QOL)
- Defines individual drug contribution
- (oxaliplatin vs 5FU/LCV versus oxaliplatin + 5FU/LCV)

## Endpoints and Issues

## Survival

- Gold standard
- Superiority design: beat anything
- The crossover problem
- Non-inferiority design: problematic with current regimens

## <footer>

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**Notes:**
So, here is an example of a design problem that we are grappling with, that problem is how to assess efficacy when the sponsor wants to claim that his drug is as good as the standard drug.  We term these trials non-inferiority trials rather than equivalency trials.  Dr. Temple has been writing about this for years, in fact, in 1989, when I first encountered this issue in the evaluation of my first NDA for Idarubicin, a leukemia drug, I used his a copy of a presentation he gave to the DIA as the basis of my review of this endpoint.
You can never statistically prove that two treatments are equivalent.  You can prove that one is better than the other, or you can prove that one is not worse than another... but you have to qualify that statement, you have to say, not worse than by some amount, perhaps 20%, or 50%, etc.  A critical question that arises in determining this non-inferiority margin  is how do we know that the standard drug works, and how well do we know this.   Lets think of a new cancer drug C that we think has some toxicity advantages compared to  the standard drug A.  The company claims it is just as good as A for treating cancer, but it has a toxicity advantage, it does not make your hair fall out.  Looking back 10 years ago, we find this survival curve of Drug A compared to placebo.  Quite impressive, nearly a 50% difference in median survival.  But, how well do we know these data?  First, we look at the hazard ratio, and the 95% confidence intervals.  The 95% confidence intervals only give us assurance that the hazard ratio is at least 0.8 compared to placebo.  So the size of the effect is known with less confidence here.  

Now we do the study comparing A to the new drug C.  In the first example the hazard ratio is 1, but the confidence interval extends to 0.7.  This suggests that there is a reasonable chance that this drug might be no better than placebo.  In the next two cases, the confidence intervals assure us that at least some fraction of the treatment effect has been maintained.  In the first case, the point estimate suggests that the new drug C is better than A, but not significantly so.  Even with wide confidence intervals,  retention of effect is assured.  In the next example, the hazard ratio estimate is 1, and because a large number of patients were studied, the confidence intervals are narrow, and we are assured of retention of activity.  
There are numerous other issues to consider with these designs, such as whether the populations are similar between the historical data and the current data, and whether the trials were carefully performed in order to minimize variation in the data. The Agency has a working group that is evaluating various methods for evaluating the results of such studies.  However, it is clear that we feel much more secure evaluating trials that demonstrate superiority of one drug over another. 

## Tumor Response Rate	

- Can be assessed in single-arm study
- Documents activity in a subset of patients
- When can it be considered an established surrogate?
- Suggested as such by ODAC for topotecan treatment of refractory small cell lung cancer
- When can it be considered a “reasonably likely surrogate”?
- ODAC, lung cancer discussion 2002

- Does it measure clinical benefit?
- Is it reliable?

- TTP: Critical Regulatory Questions

**Notes:**
So, from a regulatory standpoint, there are two very important questions to ask about an endpoint for traditional approval.  First, Does it measure clinical benefit.  We will not address that point for TTP today.

Second, can it be reliably measured?

- Measured in all patients
- Measures cytostatic activity
- Progression is often the basis for change in therapy
- Assessed before crossover
- Requires smaller studies
- ?Face validity

- TTP: Advantages

**Notes:**
Here are some of the positive qualities of TTP.   It is useful to consider how it compares to common endpoints such as response rate or survival.

TTP is measured in all patients and might therefore be a better measure of overall benefit than response rate.  TTP does not require massive tumor shrinkage, and might be a better measure of benefit for cytostatic agents.  

From a practical standpoint, progression is often the basis for oncologists changing therapy.  Therefore, an advantage of TTP  compared to survival as an endpoint,  is that TTP is measured before patients change therapies or cross over.  This is of growing importance as more good therapies become available.  And, because progression often occurs months to years before death, smaller studies are required when TTP is the endpoint compared to survival as the endpoint.
Finally, some would argue that delalying progression has face validity as an indicator of clinical benefit... that benefit seems relatively obvious because progression is a necessary step between cancer growth and patient morbidity and/or death.

-represents necessary step between cancer growth and death
-usually measured before crossover (vs. survival)
-MDs use it as basis for therapy change 
-Less patients needed (vs. survival)

Traditional approval:   Based on clinical benefit

Acclerated approval (AA):	Based on a surrogate endpoint reasonably likely to predict clinical benefit.
	-AA used only when new treatment represents benefit over available therapy
	-Sponsor must agree to phase 4 trial demonstrating clinical benefit

- _Indirect_ measure of patient benefit.
- Unclear clinical meaning of small TTP difference
- Expensive to measure carefully
- Reliability in unblinded setting?
- Unknown reliability of small TTP difference with usual trial monitoring

- TTP: Problems

**Notes:**
Here are some problems with TTP:   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.  Careful assessment of progression at frequent intervals is often  labor-intensive  and expensive.  
And then there are the questions we want to address today: How reliable is TTP?  There are the obvious concerns regarding ascertainment bias in unblinded trials and there are questions regarding the the reliability of the small TTP differences often observed in our trials.

## Determining Event Dates

- Visit 1

- Visit 2

- Randomization

- = Date of Death or actual tumor progression

- Survival Event Date

- Visit 1

- Visit 2

- Randomization

- TTP Event Date

- Survival Analysis

- TTP Analysis

**Notes:**
We must remember a critical difference between analyses of survival and of  tumor progression.  The date of death, represented by the star in this cartoon, will not change regardless of the evaluation schedule or the censoring.  

With 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 a longer time to progression.  

## Tumor-Related Symptoms

- Evaluation of patient morbidity has supported many NDA approvals
- Major impediments
- Lack of blinding
- Missing data
- Time to symptomatic progression
- Frequently discussed, not yet successful

**Notes:**
This slide discusses tumor related symptoms, one class of non-survival endpoints that FDA has used for approval of cancer drugs.  The FDA considers improvement in tumor-related symptoms to be clinical benefit, not just a surrogate.  Therefore, studies adequately demonstrating improvement in tumor symptoms can support regular approval, not just accelerated approval.  Tumor-related symptom observations were important in the approval of several oncology drug NDAs including symptom improvements in patients with obstruction from lung or esophageal cancer, patients with cutaneous or subcutaneous tumors, and patients with painful bone metastases.    

## Review of Presentation

- FDA requirements for new drug approval
- Regular approval of cancer drugs: end points used
- Accelerated approval
- Endpoints and issues

## Slide 31

## Endpoints Discussion

- Classical end points
- (pros and cons)
- Non-classical end points
- (pros and cons)
- Discussion  according to stage
- (End points and trial designs)

**Notes:**
Drug approval requires adequate and well-controlled studies demonstrating that the drug is safe and is effective for the approved indication. The safety requirement comes from the Federal Food Drug and Cosmetic Act of 1938.  The efficacy requirement is from a 1962 amendment to the Act.   
   There are two routes to new drug approval.  The traditional route which I will call regular approval requires the demonstration of clinical benefit, or an established surrogate for clinical benefit.  Clinical benefit is usually considered to be tangible benefit of obvious worth to the patient, such as prolongation of survival or relief of pain.  Sometimes FDA has accepted surrogates as the basis for regular approval, usually after much clinical experience with the surrogate and widespread acceptance by patients and physicians.  Examples are lowering blood pressure and lowering cholesterol.   On occasion these assumptions have been wrong, such as the benefit of suppressing some arrhythmias. 
	Another mode of approval is accelerated approval, approval which can be based on a surrogate endpoint considered to be reasonably likely to predict clinical benefit.  I will discuss accelerated approval in a later slide.

## 1. 	What are the Pros and Cons of 	each end point:

- As a regular approval endpoint?
- (A measure of clinical benefit  or a reliable surrogate)
- As an accelerated approval endpoint?
- (A surrogate reasonably likely to predict clinical benefit)
- As a secondary end point for labeling?

## 2. 	For each endpoint, what are the 	important trial design issues?

## Classical Endpoints

- Survival
- Response Rate
- Time to progression
- Disease-free Survival

## Non-classical endpoints	

- Specific quality of life instruments
- Assessment of tumor-specific symptoms

## Treatment settings	

- Neoadjuvant
- Adjuvant
- First-line therapy
- Second-line and subsequent therapy

## Trial designs	

- Superiority design
- (A beats B)
- Add-on design
- (A+B beats A)
- Non-inferiority design
- (e.g., A + B is non-inferior to A + C)