ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTIVIRAL DRUGS ADVISORY COMMITTEE**
>
> Tuesday, March 19, 2002
>
> 8:00 a.m.
>
> Holiday Inn
>
> Two Montgomery Village Avenue
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Roy M. Gulick, M.D., M.P.H., Chair
>
> Tara P. Turner, Pharm.D., Executive Secretary
>
> MEMBERS:
>
> Brian Wong, M.D.
>
> Victor G. DeGruttola, Sc.D.
>
> Princy N. Kumar, M.D.
>
> Sharilyn K. Stanley, M.D.
>
> Janet A. Englund, M.D.
>
> Lauren V. Wood, M.D.
>
> Jonathan M. Schapiro, M.D.
>
> Courtney V. Fletcher, Pharm.D., Consumer Representative
>
> VOTING CONSULTANTS:
>
> Robert L. Atmar, M.D.
>
> Eric P. Brass, M.D., Ph.D.
>
> Jacqueliine S. Gardner, Ph.D., M.P.H.
>
> Fred M. Gordin, M.D.
>
> Erik A. Henchal, Ph.D.
>
> L. Barth Reller, M.D.
>
> Eugene Sun, M.D.
>
> FDA
>
> Russ Fleischer, PA-C, M.P.H.
>
> Debra B. Birnkrant, M.D.
>
> Thomas Hammerstrom, Ph.D.
>
> Mark Goldberger, M.D.
>
> NON-VOTING MEMBERS:
>
> Eugene Sun, M.D.
>
> [C O N T E N T S]{.underline}
>
> Call to Order, Roy M. Gulick, M.D., M.P.H. 4
>
> Introductions 4
>
> Conflict of Interest Statement,
>
> Tara P. Turner, Pharm.D. 6
>
> Introduction/Opening Remarks,
>
> Debra B. Birnkrant, M.D. 7
>
> Sponsor Presentation: ViroPharma, Incorporated:
>
> Introduction, Mark McKinlay, Ph.D. 12
>
> Impact of the Common Cold,
>
> Frederick Hayden, M.D. 14
>
> A New Option for Treating Colds,
>
> Mark McKinlay, Ph.D. 20
>
> Clinical Efficacy and Safety,
>
> Ellen Cooper, M.D., M.P.H. 27
>
> FDA Presentation:
>
> Overview of NDA and Issues,
>
> Russ Fleischer, PA-C, M.P.H. 58
>
> Statistical Review of Efficacy,
>
> Thomas Hammerstrom, Ph.D. 71
>
> Safety Review and Summary,
>
> Russ Fleischer, PA-C, M.P.H. 82
>
> Questions to the Presenters 95
>
> Charge to the Committee, Debra B. Birnkrant, M.D. 187
>
> [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. GULICK: Good morning, everybody. I am Tip Gulick, from Cornell
> University. I am happy to call to order this meeting of the Antiviral
> Advisory Committee. We would like to start by going around the table
> and introducing the members of the committee. So please, state your
> name and your affiliation. Dr. Sun, shall we start with your?
>
> **Introductions**
>
> DR. SUN: Eugene Sun, Abbott Laboratories.
>
> DR. BRASS: Eric Brass, Harbor-UCLA Medical Center.
>
> DR. RELLER: Barth Reller, Duke University Medical Center.
>
> DR. HENCHAL: I am Erik Henchal, US Army Medical Research Institute for
> Infectious Diseases, Fort Detrick.
>
> DR. GARDNER: Jacqueline Gardner, University of Washington, in Seattle.
>
> DR. ATMAR: Robert Atmar, Baylor College.
>
> DR. WONG: Brian Wong, VA Connecticut Health Care System and Yale
> University.
>
> DR. FLETCHER: Courtney Fletcher, from the School of Pharmacy,
> University of Colorado Health Sciences Center.
>
> DR. TURNER: Tara Turner, executive secretary for the committee.
>
> DR. SCHAPIRO: Jonathan Schapiro, Stanford.
>
> DR. GORDIN: Fred Gordin, VA Medical Center, Washington, D.C. and
> George Washington University.
>
> DR. KUMAR: Princy Kumar, Georgetown University, Washington, D.C.
>
> DR. DEGRUTTOLA: Victor DeGruttola, Harvard School of Public Health.
>
> DR. ENGLUND: Janet Englund, University of Chicago.
>
> DR. HAMMERSTROM: Tom Hammerstrom, FDA.
>
> MR. FLEISCHER: Russ Fleischer, FDA.
>
> DR. BIRNKRANT: Debra Birnkrant, FDA.
>
> DR. GULICK: Thanks, everyone. I believe we have Dr. Sharilyn Stanley.
>
> DR. STANLEY: Hello, good morning.
>
> DR. GULICK: Hi. You are coming in loud and clear.
>
> DR. STANLEY: Good. Then, I won\'t yell.
>
> DR. GULICK: You can yell a little if you like. Dr. Stanley will be
> participating by teleconference for this meeting. I would like to turn
> to Tara Turner to read the conflict of interest.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: Thank you. The following announcement addresses conflict
> of interest with regard to this meeting, and is made a part of the
> record to preclude even the appearance of such at this meeting. Based
> on the submitted agenda for the meeting and all financial interests
> reported by the committee participants, it has been determined that
> all interests in firms regulated by the Center for Drug Evaluation and
> Research present no potential for an appearance of a conflict of
> interest at this meeting.
>
> We would like to disclose for the record that Dr. Eugene Sun, from
> Abbott Laboratories, is participating in this meeting as an industry
> representative, acting on behalf of regulated industry. As such, he
> has not been screened for any conflicts of interest.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participants are aware of the need to exclude themselves
> from such 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 products they may wish to comment
> upon. Thank you.
>
> DR. GULICK: Thanks. We will turn to Dr. Birnkrant for some opening
> remarks.
>
> **Introduction/Opening Remarks**
>
> DR. BIRNKRANT: I would like to welcome everyone to today\'s advisory
> committee meeting on pleconaril for the treatment of the common cold.
>
> In addition to our Antiviral Advisory Committee members, I would like
> to acknowledge our guests and other members participating from other
> FDA advisory committees, including Dr. Reller from the
> Over-the-Counter Drug Products Advisory Committee, Dr. Gardner, from
> the New Risk Management Advisory Committee, and Dr. Brass, formerly of
> the Over-the-Counter Drug Products Advisory Committee. I would also
> like to thank ViroPharma for their efforts in developing this product.
>
> \[Slide\]
>
> The marketing application we bring before you today represents a
> departure from the indications we usually present before our
> committee. Generally we present an application for a serious or
> life-threatening disease, such as HIV or hepatitis C. Today, though,
> we will be discussing an application for a disease that is acute and
> self-limited, with an average duration of illness of about 7 to 11
> days, but one that repeatedly affects the entire population.
>
> \[Slide\]
>
> Why, then, are we bringing this application before you today? At
> previous advisory committees we have reviewed our processes for
> bringing applications before the advisory committee and today I will
> do the same.
>
> \[Slide\]
>
> In general, we bring applications before the committee for the reasons
> you see on this slide: either it is a new chemical entity or first
> drug in its class; it has a novel mechanism of action and it poses
> complicated analytic and safety issues. In my brief comments I will
> explain how pleconaril fits into these categories.
>
> \[Slide\]
>
> Pleconaril is a new chemical entity and first drug in its class.
> Whereas other treatments for the common cold, such as decongestants
> and nonsteroidal anti-inflammatory agents provide relief of individual
> symptoms, pleconaril\'s novel mechanism of action prevents viral
> attachment to susceptible cells and prevents encoding of rhinoviruses
> and enteroviruses, thus, impacting multiple cold symptoms through its
> antiviral effects.
>
> \[Slide\]
>
> This application also poses several complicated analytic issues. The
> two principal studies were double-blind, placebo-controlled studies of
> pleconaril or placebo for five days. Treatment had to begin within 24
> hours of onset of symptoms. Both trials had the same endpoint of time
> to resolution of rhinorrhea and alleviation of five other symptoms,
> such as cough and nasal congestion, to absent or mild sustained for
> approximately 48 hours. Even though both studies were identically
> designed, the treatment effect varied to about half a day in study 043
> and one and a half days in study 044. Further, there was a treatment
> differential in smokers versus non-smokers.
>
> \[Slide\]
>
> With regard to safety issues, we are bringing this application before
> you today because pleconaril induces CYP3A4. This was brought to our
> attention through reports of menstrual irregularities in a six-week
> prophylaxis study of pleconaril. This was further investigated through
> a drug interaction study of a single dose of an oral contraceptive and
> five days of pleconaril, where it was shown that concentrations of
> ethinyl estradiol were reduced by 35 percent. Safety issues related to
> CYP3A4 induction relate to the effect of pleconaril on oral
> contraceptives, possibly resulting in breakthrough bleeding and the
> potential for unintended pregnancy. In addition, there is concern that
> there is potential for other drug interactions such as those of
> protease inhibitors. We will also be discussing safety findings of
> palpitations and tachycardia and my colleague, Russ Fleischer, will
> elaborate on these issues.
>
> \[Slide\]
>
> In sum, we are asking you to discuss the safety and efficacy findings
> presented in the application today. When you discuss efficacy, please
> consider the following: the totality of the data from Phase II and
> Phase III trials, considering the treatment effect across the studies
> as well. Please also consider the results in subgroups and the need to
> use pleconaril within 24 hours of symptom onset. In your discussions,
> also please address the empirical use of an antiviral agent without a
> diagnostic assay.
>
> \[Slide\]
>
> With regard to safety, we will ask you to discuss the safety of
> pleconaril as it relates to CYP3A4 induction with the potential for
> other drug interactions, as well as drug interactions with oral
> contraceptives.
>
> \[Slide\]
>
> Lastly, given that the effectiveness standard for approval requires
> substantial evidence from adequate and well-controlled trials, as
> outlined in the Amendments to the Food, Drug and Cosmetic Act in 1962,
> what we are asking you today is what level of risk is acceptable in
> this setting of using pleconaril for the treatment of the common cold.
>
> \[Slide\]
>
> With this slide I would like to turn to the agenda for today\'s
> presentation. We will start off with a presentation by ViroPharma.
> This will be followed by the FDA presentation by Russ Fleischer and
> Dr. Tom Hammerstrom. Then we will take a break. We will return from
> the break for a discussion of the presentations. This will be followed
> by lunch and an open public hearing. Following the open public hearing
> we will continue our discussion and pose the questions to our advisory
> committee. Thank you very much.
>
> DR. GULICK: Thanks, Dr. Birnkrant. Now will turn to the sponsor,
> ViroPharma, for their presentation.
>
> **Sponsor Presentation**
>
> **Introduction**
>
> DR. MCKINLAY: Good morning.
>
> \[Slide\]
>
> My name is Mark McKinlay, head of research and development at
> ViroPharma. Today represents a significant milestone both in the
> develop of pleconaril and the field of antiviral chemotherapy. Until
> now there has not been a drug that treated the viral cause of the
> cold, reducing multiple symptoms and reducing the overall duration and
> severity of the illness.
>
> \[Slide\]
>
> Following this brief introduction, Dr. Frederick Hayden will discuss
> the impact the cold has on patients. I will return to review the
> preclinical profile and the clinical pharmacology of pleconaril,
> including the drug interaction data. The rest of the presentation will
> be given by my colleague, Dr. Ellen Cooper, who will summarize the
> safety and efficacy of pleconaril for this indication. Dr. Cooper will
> conclude with an overall assessment of benefit/risk of pleconaril for
> use in the treatment of the common cold.
>
> \[Slide\]
>
> Pleconaril was rationally designed to be a specific inhibition of
> picornaviruses, the predominant cause of the common cold. Pleconaril
> has activity across the human picornaviruses including the
> rhinoviruses and enteroviruses. It is a potent, orally bioavailable
> compound that inhibits viral replication and reduces symptoms.
>
> \[Slide\]
>
> The indication that we are seeing is for the treatment of acute
> picornaviral upper respiratory illness, or the common cold, in adults.
>
> \[Slide\]
>
> At this time I would like to introduce Dr. Frederick Hayden to discuss
> the impact that colds have on patients.
>
> **Impact of the Common Cold**
>
> DR. HAYDEN: Thank you, Dr. McKinlay and good morning, ladies and
> gentlemen.
>
> To start, I would like to disclose that I have been a paid consultant
> to ViroPharma since the founding of the company and I have also served
> as an investigator on the majority of the Phase II and Phase III
> studies of pleconaril for the viral respiratory indication. My
> background is in internal medicine and infectious diseases, and my
> laboratory has engaged in studies of antiviral drugs and vaccines for
> over two decades.
>
> \[Slide\]
>
> During that time there has been considerable progress with regard to
> the development of interventions for influenza virus. Indeed, we
> currently have four approved antiviral drugs and the agency is
> actively reviewing a new attenuated vaccine.
>
> With regard to RSV infection, there is aerosolized ribavirin and
> passive immunoprophylaxis, and there are several kindred vaccines that
> are in active clinical testing right now. In contrast, for
> picornaviruses and rhinovirus colds specifically there is no approved
> antiviral drug. The large number of immunotypes make the prospect for
> a vaccine very unlikely, and our current treatments have significant
> limitations which, I think, clearly indicate that there is a need for
> an effective antiviral option.
>
> \[Slide\]
>
> The picornavirus family causes the majority of colds. Most of these
> are due to rhinovirus infection but it is worth bearing in mind that
> between five and ten percent of colds are due to enteroviruses. In
> addition, rhinoviruses cause a substantial number of other
> complications, involving both the upper and lower respiratory tract,
> many of which are then associated with antimicrobic use. On an average
> basis, a person in this country will experience about one rhinovirus
> infection annually. The number of colds experienced in this country
> has been estimated to be as high as a billion episodes annually.
>
> \[Slide\]
>
> We know that the incidence of common cold is clearly age related so
> that children have the highest attack rates. In younger adults the
> rates average about two to three episodes per year. Then, in older
> individuals the rates drop, in part because of increasing immunity but
> also decreasing exposure. Rhinoviruses are year-round pathogens and
> they account for about half of colds episodes on an annual basis. In
> addition, there are seasonal peaks of activity in the spring and the
> fall months, during which rhinoviruses have been implicated in 80
> percent or more of colds episodes.
>
> \[Slide\]
>
> Several years ago we undertook a study of approximately 350 adults who
> had self-diagnosed colds. Over 80 percent of these individuals had a
> documented rhinovirus infection. These individuals were able to
> rapidly self-recognize the onset of their illness so that 69 percent
> were able to make a self-diagnosis within eight hours of the onset of
> their symptoms.
>
> Sore throat was the most common initial symptom occurring in about 40
> percent of these individuals. But, as the illness evolved, other
> symptoms predominated so that rhinorrhea became the most bothersome
> symptom. Indeed, this is one of the rationales for its inclusion in
> the outcome measure used in the Phase III studies of pleconaril. Fever
> is uncommon during rhinovirus colds and, indeed, predicts against the
> presence of a rhinovirus infection. The degree of morbidity associated
> with these illnesses was substantial so that the average duration of
> sleep disturbance was four nights and this may, in fact, contribute to
> some of the daytime performance problems that have been documented in
> common cold sufferers. The overall duration of symptoms until
> resolution of the illness was 11 days in this particular cohort. The
> other studies have found, depending on the particular definition of
> illness used, durations ranging from 7 to 11 days, but it is worth
> noting that about a quarter of cold sufferers will have symptoms into
> the second week of their illness.
>
> \[Slide\]
>
> It is worth looking at the pathogenesis of these illnesses in some
> greater detail because this has important implications with regard to
> our therapeutic interventions. Clearly, colds start with viral
> infection of the nasal mucosa. These in turn, then, drive certain host
> responses in terms of the elaboration of proinflammatory cytokines and
> chemokines and also neurogenic reflexes, but then lead to the familiar
> symptoms associated with colds episodes.
>
> Current treatments are directed against specific host responses, such
> as vasodilation or mucus secretion, and by doing so they provide them
> relief of individual or small numbers of symptoms. In contrast, what
> has been recognized in studies of experimental antiviral drugs,
> including pleconaril now, in the natural cold setting is that
> treatment of the viral etiology itself can lead to treatment benefit
> for the whole range of cold symptoms. Indeed, this is consistent with
> the hypothesis that ongoing viral replication is important in driving
> the symptoms associated with colds.
>
> \[Slide\]
>
> The morbidity of these illnesses is also reflected in current practice
> patterns. We know that 75 percent of patients will seek self-treatment
> so that they will use a high frequency of over-the-counter
> medications, of which there are over a thousand available in this
> country currently. The most common ones that are used include cough
> preparations; combination, multi-ingredient, cold products; as well as
> analgesics. Over half of individuals will use sedating type
> antihistamines as well as decongestants. Of course, the benefits with
> these over-the-counter remedies are variable, tend to be temporary in
> nature and focused on individual symptoms. It is important to
> recognize that they don\'t reduce the duration of these illnesses, nor
> have any impact on the likelihood of complications. In addition, of
> course, a number of these, particularly antihistamines which have
> sedating effects and oral decongestants, have significant side effects
> and there is appropriate precautionary wording in the labels for these
> drugs.
>
> \[Slide\]
>
> Colds are also a leading cause of visits to physicians. Indeed, the
> estimates are anywhere from 25 million to 52 million physician visits
> in this country annually for colds episodes. About 15 percent of cold
> sufferers will seek a physician contact. When they do so, they
> commonly leave the office with a prescription either for a
> prescriptive remedy with a combination cold product or an antibiotic.
> About 30-50 percent of individuals will actually receive an antibiotic
> prescription, based on recent trials and, of course, we know from the
> basis of carefully controlled studies that antibiotics neither benefit
> the symptom profile of colds, their duration or reduce the likelihood
> of complications associated with these episodes. So, I think this is
> an important problem in terms of driving the excess use of antibiotics
> in this country and the potential for emergence of drug-resistant
> respiratory bacteria.
>
> \[Slide\]
>
> To summarize then, colds cause significant morbidity. Patients
> commonly seek treatment. Our current treatments are targeted to host
> responses and do not address the cause of colds. Indeed, in some
> instances these treatments are harmful. Again, this is a problem
> associated with excess antimicrobic use.
>
> I think this background indicates that there is a need for a safe and
> effective antiviral option for common cold treatment. Thank you.
>
> **A New Option for Treating Colds**
>
> DR. MCKINLAY: Thank you, Dr. Hayden.
>
> \[Slide\]
>
> Pleconaril was designed to be a specific inhibitor of picornavirus
> replication. Pleconaril is shown here, on the left, and a cut-away
> view of the virus is shown here, on the right. In blue is the outer
> capsid protein shell of the virus that surrounds the single-stranded
> RNA core. Picornaviruses attach to their cellular receptor via a deep
> depression or canyon that surrounds each five-fold axis asymmetry on
> the virus. Pleconaril interacts in a specific hydrophobic pocket in
> this capsid. This pocket is highly conserved across the susceptible
> viruses in terms of its shape, presumably because of the critical role
> that it plays in determining the overall stability of the virus and
> its participation in the encoding process. When pleconaril interacts
> in this site it blocks the encoding or the release of the RNA into the
> cytoplasm to initiate infection. Pleconaril blocks encoding of all
> susceptible picornaviruses.
>
> In addition to encoding, for those rhinoviruses, the 90 percent that
> use ICAM of the cellular receptor, when pleconaril binds in this site
> it causes a conformational shift in the floor of this canyon, blocking
> attachment to ICAM. While this pocket is highly conserved across the
> rhinoviruses and enteroviruses that are susceptible to pleconaril,
> subtle changes in shape lead to changes in susceptibility to
> inhibition.
>
> \[Slide\]
>
> The inhibitory concentrations, measured in micrograms per mL, are
> shown here for the rhinoviruses and enteroviruses. They range in
> susceptibility from single digit nanograms per mL to approximately 10
> percent of viruses, both rhino and entero, that are not susceptible to
> inhibition at 3.8 mcg/mL, the highest testable concentration in cell
> culture. Because pleconaril is specific to the picornavirus family,
> viruses outside the picornaviruses are not inhibited by pleconaril.
> Inhibitory concentrations are achieved following a single 400 mg dose
> of pleconaril.
>
> \[Slide\]
>
> Plasma concentrations reach a maximum of 2 mcg/mL approximately three
> hours after dose, and decrease in two distinct phases, a short alpha
> phase of approximately 2.8 hours and a terminal elimination phase of
> 180 hours. At eight hours, which approximates the Cmin in a TID dosing
> regimen, the plasma concentration exceeds that required to inhibit
> replication to 75 percent of rhinovirus serotypes. Plasma
> concentrations increase with increasing dose.
>
> \[Slide\]
>
> These increases are dose proportional across the range of 50-1000 mg.
> We learned early on in the program that the bioavailability of
> pleconaril is significantly increased when administered with food. In
> subsequent studies, all Phase II and III studies, patients were
> advised to take pleconaril following a meal. Despite its high protein
> binding, pleconaril has a high volume of distribution. Very little of
> the drug is excreted intact in the urine. Phase I studies have
> demonstrated no clinically significant effect of renal impairment, age
> or gender on the pharmacokinetics of pleconaril.
>
> \[Slide\]
>
> Pleconaril is metabolized predominantly through reductive processes.
> Intestinal microflora cleave the oxadiazole ring to the ring open
> benzenamine derivative. Subsequent metabolism occurs via the
> conjugation and opening of the isoxazole ring. Since p450 enzymes are
> not predominantly involved in the metabolism of pleconaril, drugs that
> induce or inhibit p450\'s would not be expected to affect pleconaril
> pharmacokinetics.
>
> \[Slide\]
>
> To investigate the potential for an interaction with drugs that are
> metabolized by p450, we investigated the effects of pleconaril [in
> vitro]{.underline} and in humans on CYP450 activity. We first
> evaluated the effects of pleconaril [in vitro]{.underline} on purified
> CYP isozymes and found that pleconaril had no effect on five isozymes
> and only weakly inhibited three isozymes, 1A2, 2C9 and 2C19. We
> followed this with probe molecules for 1A2 and 2C9 and found no effect
> on the pharmacokinetics of S- and R-warfarin, and a small effect on
> theophylline AUC and t1/2, and I will show you these data shortly.
>
> As Dr. Birnkrant mentioned, in the course of the six-week prophylaxis
> study conducted last fall, we noted an interaction between oral
> contraceptive use and pleconaril. To determine the mechanism of this
> interaction, we very rapidly implemented studies to determine the
> mechanism of this interaction. The results of these studies showed
> that pleconaril increased 3A activity, using two probes for 3A,
> midazolam and the ethinyl estradiol component of the oral
> contraceptive Ortho-Novum.
>
> \[Slide\]
>
> First, beginning with theophylline interaction, this being the probe
> molecule for 1A2 inhibition that we saw [in vitro]{.underline}, in
> this study theophylline-naive patients were given a single dose of
> theophylline followed by pleconaril TID for five days. Another single
> dose of theophylline was administered, followed by pleconaril again
> TID for two days. The pharmacokinetics of theophylline were measured
> before and after exposure to pleconaril. We saw no change on Cmax, a
> 15 percent increase in the AUC, and less than a 20 percent increase in
> the t1/2 of theophylline. Other than this interaction with
> theophylline, we would not expect any interaction with pleconaril with
> any other drug as a result of inhibition of p450 enzymes.
>
> \[Slide\]
>
> The investigation of CYP3A increase in activity was conducted with
> midazolam and the oral contraceptive Ortho-Novum. First the IV
> midazolam study, IV midazolam was administered before and after a
> five-day course of pleconaril. The pharmacokinetics were compared and
> we noted a 28 percent decrease in the AUC of midazolam and a 16
> percent decrease in the t1/2.
>
> \[Slide\]
>
> A similar magnitude of effect was seen with the estrogen ethinyl
> estradiol component of the oral contraceptive Ortho-Novum. In this
> study subjects were administered a single dose of Ortho-Novum,
> followed by five days of pleconaril TID. Another single dose of
> Ortho-Novum was administered followed by two more days of pleconaril
> TID. The plasma concentration of the estrogen ethinyl estradiol and
> the progestin norethindrone were compared before and after exposure to
> pleconaril. We noted no clinically significant increase in the Cmax of
> ethinyl estradiol, a 34 percent decrease in the ethinyl estradiol AUC
> and, importantly, no effect on the progestin norethindrone
> pharmacokinetics were noted in this study. No evidence of CYP
> induction was seen in the preclinical studies. In fact, preclinical
> studies showed pleconaril to have an excellent safety profile.
>
> \[Slide\]
>
> The safety profile preclinically is shown here. Pleconaril has low
> acute toxicity at doses up to 2 g/k. We saw no significant effects in
> rats or dogs administered pleconaril for one or six months. Pleconaril
> is not genotoxic, teratogenic, and has no effect on male or female
> fertility. We also noted no effects on the growth, development or
> reproductive performance of rats exposed to pleconaril [in
> utero]{.underline} through weaning.
>
> At this time, it is my pleasure to introduce Dr. Ellen Cooper, who
> will summarize the safety and efficacy of pleconaril in the treatment
> of the common cold.
>
> **Clinical Efficacy and Safety**
>
> DR. COOPER: Thank you, Mark.
>
> \[Slide\]
>
> Good morning. My name is Ellen Cooper. I am the vice president of
> clinical and regulatory affairs at ViroPharma. It is my privilege to
> be here to summarize the clinical data supporting the safety and
> efficacy of pleconaril for treatment of the common cold.
>
> \[Slide\]
>
> The clinical development program for pleconaril for treatment of the
> common cold began in 1996 with the proof of concept virus challenge
> study in normal volunteers. The results of this placebo-controlled
> study demonstrated that pleconaril lowers virus levels in nasal mucus
> and reduces the severity and duration of cold symptoms.
>
> Following this study, a Phase II program in adults, with naturally
> acquired upper respiratory illness, was initiated. The criteria for
> enrolling patients with a high likelihood of picornavirus colds, the
> definition of the primary efficacy endpoint and the frequency of
> self-assessment of cold symptoms evolved over the course of these
> studies, culminating in the design and conduct of two pivotal Phase
> III studies. ViroPharma also has an ongoing program investigating the
> safety and efficacy of pleconaril for the treatment of colds in
> children, and we recently completed a six-week prophylaxis study in
> adults.
>
> \[Slide\]
>
> From the Phase II treatment studies we gained important insights in
> three major areas. First, we developed a better understanding of the
> clinical manifestations of colds that are caused by picornaviruses.
> These characteristics include significant rhinorrhea in the absence of
> fever. Second, we found that certain co-factors, including smoking,
> allergic rhinitis and the use of concomitant cold symptom relief
> medications, tend to obscure the ability to evaluate the primary
> symptom-based endpoint. Third, it was determined that alleviation,
> rather than complete resolution of all symptoms, is a more appropriate
> endpoint for evaluating the clinical benefits of the antiviral drug in
> the earlier, more bothersome phase of illness.
>
> \[Slide\]
>
> These insights were incorporated into the design of the two Phase III
> studies which were conducted during the fall of 2000. The two
> placebo-controlled Phase III studies enrolled over 1000 patients each
> at almost 200 centers across the United States and Canada. Both
> studies used identical entry criteria.
>
> \[Slide\]
>
> The target population was otherwise healthy adults. To reduce
> enrollment of patients with non-infectious causes of upper respiratory
> symptoms, patients were required to answer \"yes\" to the question
> \"do you have a cold today?\" All patients were required to have
> moderate or severe rhinorrhea and another upper respiratory symptom. A
> systemic symptom was not required. The maximum time from onset of
> symptoms to first dose of study drug was 24 hours. Patients with
> fever, active allergic rhinitis or asthma were excluded. Patients were
> randomized equally to pleconaril 400 mg three times daily or to
> matching placebo.
>
> \[Slide\]
>
> Randomization was stratified by smoking status and prior use of cold
> symptom relief medication. Because earlier studies indicated that
> smoking and the use of concomitant cold symptom relief medications
> confounded the ability to detect a treatment effect, stratification on
> these variables was considered important to ensure balance between the
> treatment groups. Concomitant use of cold symptom relief medication
> during this study was discouraged but acetaminophen and
> dextromethorphan were provided to all patients for their use if
> necessary. The primary outcome variable in these studies was based on
> patient self-assessments of their cold symptoms.
>
> \[Slide\]
>
> Patients were provided with study diaries in which they were
> instructed to record twice daily the severity of each of six cold
> symptoms as absent, mild, moderate or severe, and whether or not they
> felt they still had a cold. In addition, they were asked to record
> once daily the number of tissues they had used, whether or not their
> sleep had been disturbed, and whether or not their normal level of
> activity had been impaired by their cold symptoms. Use of concomitant
> cold medications was also reported. These were the first pleconaril
> studies in which virologic testing was performed on all patients.
>
> \[Slide\]
>
> Blow-nasal mucus samples were collected at baseline, which was study
> day one; two days later, which was study day three; and at the end of
> treatment, which was study day six. RT-PCR testing was performed on
> all nasal mucus samples. If the baseline sample tested positive, it
> was cultured. If the baseline culture was positive, post-baseline
> samples from the same patients were also cultured. All
> culture-positive samples were tested for susceptibility to pleconaril.
> Patients who were infected with the picornavirus, as detected by
> RT-PCR, comprised the primary efficacy population.
>
> \[Slide\]
>
> The intent-to-treat infected, or ITT-I population, consisted of the 63
> percent of patients enrolled in study 043 and 67 percent of patients
> enrolled in study 044 who tested PCR positive, for a total of 65
> percent picornavirus infected patients across both studies. The
> intent-to-treat, or ITT, population consisted of all randomized
> patients. All of our safety analyses were performed in this
> population. Pleconaril was not expected to have any benefit in
> PCR-negative patients who do not have picornavirus colds. Efficacy
> analyses were performed on all three populations. This presentation
> focuses on the results of the primary efficacy population.
>
> \[Slide\]
>
> Baseline demographics were similar across both treatment groups in
> both studies. Overall, the patients were relatively young, mostly
> female, predominantly white, and a little over a quarter were smokers.
> Demographics in the intent-to-treat population were similar. At
> baseline disease characteristics in both the intent-to-treat and the
> intent-to-treat infected populations were evenly matched.
>
> \[Slide\]
>
> The median time from onset of cold symptoms to first dose of study
> drug was 20 hours in both treatment groups in both studies.
> Approximately one-third of patients reported using cold symptom relief
> medication prior to enrollment. The median total symptom severity
> score in all groups at baseline was 9 out of a theoretical maximum of
> 18 if all 6 symptoms were assessed as severe. The primary endpoint
> measured sustained improvement across multiple cold symptoms.
>
> \[Slide\]
>
> The primary efficacy endpoint was defined as the time from initiation
> of study drug to the absence of rhinorrhea and all other cold symptoms
> to absent or mild for at least four consecutive half-day reporting
> periods without the use of cold symptom relief medication. Analyses of
> the primary endpoint in the primary efficacy population in both
> studies demonstrated the clinical benefits of pleconaril in reducing
> the duration and severity of picornavirus colds.
>
> \[Slide\]
>
> The median treatment benefit was 0.6 days in study 043 and 1.5 days in
> study 044. The results of both studies, based on the prespecified
> primary endpoint, were statistically significant. The magnitude of the
> differences at the 25th and 75th percentiles indicates similar
> variability of outcomes in the two studies.
>
> \[Slide\]
>
> The Kaplan-Meier graphs of the primary endpoint show sustained benefit
> in both studies. In this self-limited viral infection pleconaril
> caused a more rapid alleviation of illness in both of the studies.
>
> \[Slide\]
>
> To explore the apparent differences between the two studies in the
> size of the treatment benefit as measured by the primary endpoint,
> post hoc analyses using slight modifications of the primary endpoint
> were performed.
>
> The required duration of sustained symptom alleviation was modified
> from the 48 hours in the prespecified endpoint to 24 hours and to 72
> hours. The results of these post hoc analyses indicated that the
> median treatment benefit of pleconaril in reducing the duration of
> illness was approximately one day in both studies. While the treatment
> benefit was larger in study 044 than in study 043 using the
> prespecified endpoint, requiring 48 hours of sustained symptom
> alleviation, the analyses using 24 hours of sustained alleviation
> showed a greater benefit in study 043. When sustained alleviation of
> 72 hours was used, the size of the treatment benefits in the two
> studies were almost identical, one day. These results support the
> consistency of the treatment benefit across both studies.
>
> \[Slide\]
>
> Analyses of the primary endpoint in the intent-to-treat population
> also favored pleconaril. As expected, the magnitude of the treatment
> benefit in the ITT population was slightly less than in the ITT-I
> population, with a median benefit of 0.5 days in study 043 and 0.9
> days in study 044. The addition of PCR-negative patients diluted the
> treatment effect observed in the ITT-I population. As anticipated,
> patients who did not have picornavirus colds received no benefit from
> pleconaril. The median duration of illness in the PCR-negative
> patients was approximately 6 days in both treatment groups in both
> studies.
>
> \[Slide\]
>
> The antiviral activity of pleconaril was assessed using virus culture.
> Of those patients who were culture positive at baseline, proportions
> of patients who remained culture positive during or at the end of
> treatment were calculated. Fewer patients in the pleconaril groups in
> both studies had positive cultures on study day three, the first
> post-baseline sampling day. Analyses of virus levels relative to
> baseline, as measured by the TaqMan PCR assay, indicate the virus
> levels were less than one percent of baseline on study day six. In
> study 044 fewer patients treated with pleconaril than placebo remained
> culture positive on day six. The antiviral efficacy of pleconaril
> parallels the clinical efficacy across a broad range of symptoms.
>
> \[Slide\]
>
> The prespecified secondary clinical endpoints included time to
> resolution of individual cold symptoms; time to patient-assessed \"no
> cold;\" tissue use; the proportion of nights of sleep disturbance and
> days of impaired activity due to cold symptoms; the number of days of
> concomitant use of cold symptom relief medication; and the sum of the
> total symptom severity score.
>
> \[Slide\]
>
> Time to resolution of each of the six cold symptoms was shorter in
> pleconaril patients than in placebo. \[Slide\]
>
> Time to resolution of each of the four respiratory and two systemic
> symptoms demonstrated that pleconaril reduces the duration of multiple
> cold symptoms. The asterisk indicates significant differences between
> the treatment groups, which favored pleconaril in all cases. In
> addition, analyses of the other secondary endpoints consistently
> favored pleconaril.
>
> \[Slide\]
>
> For each of the endpoints shown on the X axis the bars represent the
> percent change in the pleconaril group compared to the placebo group.
> The treatment differences for study 043 are shown in white, and in
> green for study 044. For example, the last bar on the right indicates
> a 22 percent reduction in the total symptom severity score in patients
> on pleconaril compared to placebo. The green bar, next to it,
> indicates the 16 percent reduction in study 044. The asterisks
> indicate a statistically significant benefit of pleconaril compared to
> placebo within a study. In all cases the direction of the change
> favored pleconaril.
>
> \[Slide\]
>
> To explore the clinical action of pleconaril post hoc analyses of
> changes in symptom severity by day were performed. This analysis
> focuses on differences in the proportions of patients in the two
> treatment groups each day who reported any symptom as moderate or
> severe which was defined as bothersome or interfering with normal
> activity. The horizontal axis shows the half-day reporting intervals
> through day six, and the vertical axis shows the percent of patients
> in each treatment group who reported any symptom as at least
> bothersome. In both studies significant differences in favor of
> pleconaril were observed in the proportion of patients who assessed
> any cold symptom as bothersome, beginning on the second day of
> treatment.
>
> This approach to analysis is conservative in that it requires all
> symptoms to be mild or absent for a person to achieve non-bothersome
> status. Despite this strict definition of improvement, the results
> support the efficacy of pleconaril in providing early and sustained
> reduction in the severity of cold symptoms.
>
> \[Slide\]
>
> Another post hoc analysis of symptom severity explored the differences
> between the treatment groups in the percent change from baseline in
> the total symptom severity score, which consisted of the sum of all
> symptoms, scored from zero for absent to three for severe, for each
> reporting interval. This approach to analyzing the morbidity of
> picornavirus colds also showed that the decrease in symptom severity
> was faster in pleconaril patients than in placebo in both studies,
> beginning on the second day.
>
> \[Slide\]
>
> The data from our pivotal studies were analyzed to investigate the
> consistency of treatment outcome between subgroups, defined by the
> prospectively determined strata of smoking status and prior use of
> cold symptom medications, and by age, gender and race.
>
> \[Slide\]
>
> The results indicate no evidence of inconsistency of treatment outcome
> in the subgroups based on prior use of cold symptom relief medication
> or in the subgroups defined by age, gender and race. However, a
> significant interaction between treatment and smoking status was
> found. Therefore, efficacy analyses were performed separately in
> non-smokers and smokers.
>
> \[Slide\]
>
> Analyses of the primary endpoint in the pooled data set of smokers
> showed no evidence of a treatment benefit of pleconaril, whereas in
> non-smokers a median benefit of 1.3 days was observed. The 25th and
> 75th percentiles indicate similar variability in outcome in both
> subgroups. Analyses of the proportion of patients with positive
> cultures at baseline and on study days three and six demonstrate the
> antiviral activity of pleconaril in both smokers and non-smokers.
>
> \[Slide\]
>
> Analyses of the pooled data showed that fewer patients in the
> pleconaril groups remain culture positive in both the non-smoker and
> smoker strata. Post hoc analyses of the differences in total symptom
> severity scores indicate that pleconaril reduces symptom burden more
> rapidly than placebo in both smokers and non-smokers, consistent with
> its antiviral activity.
>
> \[Slide\]
>
> These analyses of differences between the treatment groups in the
> total symptom severity score as a percent of the baseline score show
> that symptom severity declined faster in pleconaril than in placebo
> patients during the early treatment period, regardless of smoking
> status. Although a treatment benefit of pleconaril, as measured by the
> primary endpoint, was not apparent in smokers, pleconaril has
> antiviral activity in both smokers and non-smokers, supporting the
> biological activity of pleconaril independent of smoking status.
>
> One hypothesis to explain the differences in the observed benefit in
> smokers and non-smokers is that the chronic symptoms of smoking may be
> difficult to distinguish from resolving cold symptoms, obscuring the
> treatment benefit.
>
> \[Slide\]
>
> Virological testing was performed on all patients enrolled in the
> pivotal studies. All nasal mucus samples that were PCR positive were
> cultured for the presence of picornaviruses. All culture-positive
> samples were tested for susceptibility to pleconaril in a cell culture
> assay.
>
> \[Slide\]
>
> Of the 744 patients in the two pivotal studies who had positive viral
> cultures at baseline, 87 percent had viruses that were susceptible to
> pleconaril at concentrations less than or equal to 3.8 mcg/mL, the
> highest testable concentration, and 13 percent had viruses that were
> not susceptible. This spectrum of sensitivity is similar to that
> reported in the literature from other patients with naturally acquired
> picornavirus colds. The clinical benefit of pleconaril was evaluated
> separately in patients whose viruses were susceptible and
> non-susceptible at baseline.
>
> \[Slide\]
>
> In patients with drug-susceptible viruses, analyses of the primary
> efficacy endpoint showed a median treatment benefit of 1.8 days in
> study 043 and 2.1 days in study 044. In the relatively small
> proportion of patients with baseline viruses that were not susceptible
> to pleconaril there was no evidence of a treatment benefit.
>
> To determine the incidence of post-treatment viruses with reduced
> susceptibility, virus cultures that were positive at baseline and at
> days three or six were tested for susceptibility to pleconaril.
>
> \[Slide\]
>
> Paired isolates from the same patients were compared. Among the 294
> placebo patients with positive virus cultures at baseline and at least
> one post-baseline positive culture for which susceptibility could be
> determined, two patients had post-baseline viruses with at least a
> ten-fold reduction in susceptibility. Among the 263 pleconaril
> patients, 28 or 10.7 percent had post-baseline viruses with reduced
> susceptibility. Because drugs with a specific antiviral mechanism of
> action exert selective pressure on susceptible viruses, co-existing
> variants with reduced susceptibility have the opportunity to
> predominate in the virus population. The possible consequences of
> post-treatment viruses with reduced susceptibility on the clinical
> benefit of pleconaril was assessed.
>
> \[Slide\]
>
> The duration of illness, based on the primary endpoint and on time to
> patient-assessed \"no cold\" was analyzed in the 28 patients with
> post-baseline viruses with reduced susceptibility, and in the larger
> groups of pleconaril and placebo patients in whom a ten-fold change in
> susceptibility was not observed. These results indicate that the
> duration of illness in these patients is no longer than in patients
> without a change in susceptibility.
>
> \[Slide\]
>
> The viruses with reduced susceptibility were characterized [in
> vitro]{.underline}. These viruses were found to be physically less
> stable than wild type susceptible viruses. Genetic characterization
> revealed amino acid substitutions at positions 98, 122 and 180 in the
> hydrophobic pocket into which pleconaril binds. The genotypic and
> phenotypic profile of these viruses is similar to that observed in
> lab-derived Coxsackie B3 viruses that were selected [in
> vitro]{.underline} for reduced susceptibility to pleconaril. These
> viruses were shown to be attenuated for replication and were less
> virulent in a lethal murine model. The virological profile of
> pleconaril indicates that post-treatment viruses are unlikely to
> result in adverse clinical consequences for individual patients, and
> that viruses with reduced susceptibility appear to be less fit than
> wild type viruses.
>
> \[Slide\]
>
> The pivotal clinical trials demonstrated that pleconaril reduces the
> median duration of picornavirus colds by about one day. Importantly,
> the clinical benefits of pleconaril in reducing total symptom severity
> are evident by the second day of treatment. As expected from an
> antiviral drug, pleconaril reduces the severity and duration of
> multiple cold symptoms in parallel with its antiviral activity.
>
> \[Slide\]
>
> The clinical safety of a new drug for the treatment of the common cold
> is an important part of a benefit/risk assessment. The pleconaril
> safety database summarized in the NDA consists of nearly 3900
> individuals who received pleconaril, most of whom were adults.
>
> \[Slide\]
>
> These patients participated in 39 adult and pediatric studies that
> were completed prior to June, 2001. Safety analyses were performed on
> the following subsets of patients: adults in any Phase II/III study;
> adults in the six cold treatment studies; and adults in the three
> Phase II/III cold treatment studies in which the tablet formulation
> was used. This presentation focuses on analyses of patients enrolled
> in the cold tablet studies since the safety profile is very similar in
> all data sets.
>
> \[Slide\]
>
> The patients enrolled in the cold tablet studies, which includes the
> two pivotal studies, better represent the proposed dose formulation
> and target population. In addition to the five- to seven-day treatment
> database, over 700 adults received six weeks of pleconaril in a
> recently completed cold prophylaxis study. Adverse events were
> reported by approximately 55 percent of patients in both treatment
> groups in the five- to seven-day treatment studies.
>
> \[Slide\]
>
> Thirteen patients experienced serious adverse events, six in the
> placebo group and seven in the pleconaril group. One woman died in an
> automobile accident 30 days following completion of pleconaril
> treatment. Headache was the most common adverse event reported,
> followed by diarrhea and nausea. Frequencies were similar in
> pleconaril and placebo patients, with a slight excess incidence
> associated with pleconaril. Nearly all adverse events were classified
> as mild or moderate.
>
> \[Slide\]
>
> Less than five percent of patients reported any severe adverse event.
> Discontinuations due to adverse events were also low.
>
> \[Slide\]
>
> Discontinuations were reported in 2.7 percent of placebo patients and
> 3.4 percent of pleconaril patients. Headache, diarrhea and nausea were
> the most common reasons, with less than one percent of patients
> discontinuing study drug for any of these reasons.
>
> \[Slide\]
>
> Analyses of the laboratory safety database revealed no clinically
> significant changes. Testing performed prior to and at the conclusion
> of treatment revealed no clinically significant changes in hematology,
> renal or liver function or in other laboratory safety values.
>
> \[Slide\]
>
> To assess the safety of pleconaril administered over a longer period
> of time, over 1000 healthy adults were enrolled in a cold prophylaxis
> study that was conducted this past fall. This study had two major
> objectives. The first was proof of concept of the ability of
> pleconaril, given once or twice daily, to prevent the development of
> picornavirus colds. The second was to obtain clinical safety data on
> exposure to pleconaril of longer than one week. The total dose
> administered in the pleconaril BID group in the six-week study was 5.6
> times larger than in the proposed treatment dose of 400 mg three times
> daily for five days. Preliminary analyses of the safety database from
> the prophylaxis study were performed. However, efficacy and
> pharmacokinetics data have not yet been analyzed.
>
> The incidence of adverse events in the clinical laboratory safety
> profile of pleconaril following six weeks of exposure was similar in
> the five- to seven-day treatment database, underscoring the safety of
> a five-day treatment regimen. The one exception was a higher frequency
> of menstrual disorder adverse events in women taking oral
> contraceptives and pleconaril in the longer study.
>
> \[Slide\]
>
> The first reports of breakthrough bleeding in two women taking oral
> contraceptives resulted in notification of all women enrolled in the
> study of the apparent increased risk of menstrual disorders, the
> possibility of decreased oral contraceptive efficacy, and the need for
> re-consent to continue participation in the study. All women were
> queried regarding their interval menstrual histories at the biweekly
> clinic visits.
>
> When the study was analyzed the incidence of menstrual disorder
> adverse events was found to be higher in the pleconaril groups than in
> placebo. Most of these adverse events were reported as spotting or
> early withdrawal bleeding in women taking oral contraceptives. Review
> of all menstrual disorder adverse events in the five- to seven-day
> treatment database indicated a higher incidence of 3.5 percent in
> women taking oral contraceptives and pleconaril, compared to placebo.
> In both the five- to seven-day treatment studies and in the six-week
> prophylaxis study none of the menstrual disorder adverse events in
> women taking oral contraceptives and pleconaril were severe.
>
> \[Slide\]
>
> In the five- to seven-day treatment studies none of the menstrual
> disorder adverse events resulted in discontinuation of study drug. In
> the six-week prophylaxis study less than one percent of women in each
> treatment group discontinued study drug as a result of a menstrual
> irregularity. In the five- to seven-day cold treatment studies the
> incidence of menstrual disorder adverse events in women taking
> pleconaril and oral contraceptives was 3.5 percent, almost identical
> to that in all Phase II/III treatment studies.
>
> A Phase I study to investigate the mechanism of the increased
> incidence of menstrual disorders in women taking oral contraceptives
> indicated that treatment with pleconaril results in a modest induction
> of CYP3A enzymes, causing increased clearance of ethinyl estradiol.
> There was no change in the pharmacokinetics of the progestin component
> norethindrone.
>
> \[Slide\]
>
> We carefully reviewed all pregnancies that were reported in the five-
> to seven-day treatment studies and in the six-week prophylaxis study.
> Among the 722 women enrolled in the prophylaxis study, seven
> pregnancies were reported during the 12-week observation period. One
> woman each in the placebo and low-dose pleconaril groups and five in
> the BID pleconaril group became pregnant. Two of these pregnancies
> occurred in women taking oral contraceptives.
>
> \[Slide\]
>
> The incidence of pregnancies reported by patients in the five- to
> seven-day treatment studies was also low. Six pregnancies were
> reported among the 3400 women who received pleconaril in the five- to
> seven-day treatment studies, two-thirds of whom were between the ages
> of 18 and 40 years. Approximately 300 women in the placebo and 400
> women in the pleconaril groups were taking oral contraceptives. Four
> of the six pregnancies occurred among women who received placebo, one
> of whom was taking oral contraceptives. Two pregnancies were reported
> among women who received pleconaril, both of which progressed to
> delivery of normal infants.
>
> While the incidence of pregnancies was too low to draw definitive
> conclusions regarding the possible effect of pleconaril in reducing
> the efficacy of oral contraceptives, there is no indication of
> increased risk of pregnancy in women taking oral contraceptives in
> five to seven days of pleconaril.
>
> The safety database of over 4500 adults and children who received
> pleconaril in our placebo-controlled studies demonstrate that
> pleconaril is safe and well tolerated for the proposed five-day
> treatment regimen.
>
> \[Slide\]
>
> The most common adverse events were headache and GI symptoms. The
> frequency of these adverse events in the pleconaril group was slightly
> higher than in placebo, and were not related to dose or duration of
> treatment, indicating that most are background incidence in the
> population studied.
>
> No clinically significant changes in laboratory safety parameters were
> observed in either of the five- to seven-day treatment studies or in
> the six-week prophylaxis study, demonstrating that pleconaril does not
> adversely affect any major organ system.
>
> Although the incidence of menstrual irregularities was higher in women
> using oral contraceptives who were also taking pleconaril, the total
> incidence reported in the five- to seven-day treatment studies was
> low. Similarly, there was no evidence of an increased incidence of
> pregnancies in women taking five to seven days of pleconaril, and none
> were reported in women taking oral contraceptives. Thus, the safety
> profile of pleconaril supports empiric treatment of patients with
> colds.
>
> \[Slide\]
>
> Because colds affect people with many different conditions, ViroPharma
> understands the importance of thoroughly pursuing the safety of
> pleconaril in a wide variety of settings and medical circumstances. To
> this end, we are committed to conducting appropriate additional
> studies to characterize further the safety and efficacy of pleconaril
> in adults and in children.
>
> \[Slide\]
>
> A PK/PD study in chronic theophylline users is under discussion with
> experts. To further characterize the modest induction of CYP3A
> enzymes, two additional drug interaction studies are under way. A
> two-cycle oral contraceptive interaction study will assess the maximum
> PK and PD effects of pleconaril. Another study, using oral midazolam,
> will determine the duration of the increased CYP3A activity. A large
> post-marketing study is planned to track the safety of pleconaril in
> ongoing use by practicing physicians in an expanded range of patients.
>
> \[Slide\]
>
> This Phase IV trial will be designed to confirm the safety and
> efficacy of pleconaril in patients with underlying respiratory
> conditions and other medical co-morbidities. In addition, we will
> conduct a post-marketing study of the potential impact of pleconaril
> in reducing antibiotic use in the outpatient setting. We are also
> committed to continuing our pediatric program and to expand it to
> include children with asthma.
>
> To explore approaches to further investigate post-treatment viruses
> with reduced susceptibility, we are in active discussion with a
> variety of experts. Three possible designs include a family
> transmission study, a virus challenge model, and a cohort study in
> immunocompromised patients.
>
> The results of all of these studies will provide treating physicians
> with additional guidance for the use of pleconaril in a broader range
> of patients.
>
> \[Slide\]
>
> In summary, we have demonstrated that pleconaril is an important first
> in class antiviral that is safe and efficacious for the treatment of
> the common cold. We have demonstrated in well-controlled trials that
> pleconaril reduces the duration of picornavirus colds and causes more
> rapid symptom alleviation than placebo, beginning on the second day of
> treatment. Pleconaril shortens multiple cold symptoms simultaneously,
> and the antiviral activity in patients with picornavirus colds
> parallels its clinical benefits. Pleconaril has been shown to be safe
> and well tolerated at the proposed dose of 400 mg three times daily
> for five days. The risks associated with the treatment course of
> pleconaril are few and manageable.
>
> \[Slide\]
>
> Patients taking pleconaril and theophylline may experience a slight
> increase in steady-state plasma concentrations of theophylline. Women
> using oral contraceptives may experience an increased incidence of
> menstrual irregularities. Pleconaril has the potential to cause a
> modest reduction in concentrations of drugs with narrow concentration
> response relationships that are metabolized predominantly by CYP3A
> enzymes.
>
> \[Slide\]
>
> ViroPharma will provide specific guidance to physicians in managing
> their patients with colds. First, patients should be convinced that
> their upper respiratory symptoms are the result of a cold and not to
> allergic symptoms or to some other non-infectious cause. The clinical
> presentation should include significant rhinorrhea without fever.
> Treatment with pleconaril should be initiated within a day of onset of
> symptoms. Patients should be instructed to take pleconaril with food
> three times daily. They should be advised that pleconaril may result
> in a slightly increased risk of headache or nausea. To be cautious,
> women taking oral contraceptives should be advised to use an
> additional form of birth control.
>
> Because pleconaril increases the activity of CYP3A enzymes, patients
> taking drugs with narrow concentration response relationships, such as
> cyclosporine and HIV protease inhibitors, may experience a decrease in
> efficacy of these drugs. The physician should be aware that there are
> limited data at the present time on the safety and efficacy of
> pleconaril in the elderly and in patients with significant medical
> co-morbidities. However, there are no signals in our overall safety
> database to indicate increased risk.
>
> \[Slide\]
>
> The development of the first antiviral drug to treat the predominant
> cause of the common cold is a landmark achievement in the history of
> anti-infectives. I remember quite clearly the review and approval of
> acyclovir nearly twenty years ago. Acyclovir was the first antiviral
> drug to treat chronic herpes simplex infections that caused recurrent,
> painful outbreaks. Fifteen years ago the development and approval of
> zidovudine, the first anti-retroviral drug for the treatment of AIDS,
> brought new hope to patients with HIV. Zidovudine was the first in a
> series of advances to transform AIDS from a fatal disease into a
> manageable chronic illness.
>
> Now we have the opportunity to reach a new milestone in antiviral drug
> therapy, the approval of the first antiviral agent to reduce duration
> and severity of picornavirus colds. Although colds are neither chronic
> nor serious, they cause substantial acute morbidity and can be highly
> contagious. The development of each of these first in class antiviral
> drugs represents important achievements. None were easy and all
> required new ways of thinking. In each case, not only was a new
> chemical entity with a new mechanism of action developed, but new
> standards for the design and interpretation of Phase III clinical
> trials were determined for diseases that had never been treated.
>
> In conclusion, pleconaril is the first antiviral drug that has been
> shown to be safe and efficacious in the treatment of the common cold.
> The demonstrated clinical benefits outweigh the potential risks. Thus,
> pleconaril represents an important new option for physicians in
> managing their patients with upper respiratory infections. Thank you
> for your attention.
>
> DR. GULICK: Thanks, Dr. Cooper, Dr. Hayden and Dr. McKinlay. We are
> going to hold questions from the committee and we will proceed right
> with the agency\'s presentation. Russ Fleischer is going to kick it
> off.
>
> We have some people joining us on the committee. So why don\'t we have
> them introduce themselves and state their affiliation? Dr. Wood,
> welcome.
>
> DR. WOOD: Thank you. I am with the National Cancer Institute.
>
> DR. GULICK: And Dr. Goldberger?
>
> DR. GOLDBERGER: I am the Acting Director of the Office of Drug
> Evaluation IV.
>
> DR. GULICK: Thanks. Dr. Stanley, can you hear us? We will take that as
> a no.
>
> **Agency Presentation**
>
> **Overview of NDA and Issues**
>
> MR. FLEISCHER: Good morning, committee, guests and members of the
> audience.
>
> \[Slide\]
>
> I am pleased to be here today to lead the FDA\'s presentation on the
> NDA for pleconaril for treatment of acute picornaviral VRI in adults,
> known as the common cold.
>
> \[Slide\]
>
> This morning I will start by giving you an overview of the NDA and
> some of the issues we identified in the review. Dr. Hammerstrom will
> present the statistical review of efficacy and then I will return and
> go into some depth on the safety, and provide an overall summary.
>
> \[Slide\]
>
> The clinical development program for pleconaril for the VRI indication
> consisted of six trials, two pivotal trials, studies 043 and 044,
> where pleconaril was administered 400 mg three times a day for five
> days, and four Phase II studies, studies 010, 013, 020 and 032. We are
> not going to talk about studies 10 and 13 today but we will go into a
> lot more detail about 20 and 32 as they were two very large Phase II
> studies.
>
> \[Slide\]
>
> I will review the application and identify a number of regulatory and
> scientific issues. The big ones are listed on this slide and in our
> presentation we will cover each one of these in some detail.
>
> \[Slide\]
>
> The overall study results was the first thing we looked at, and
> pleconaril has been investigated for treatment of a couple of other
> viral infections, enteroviral meningitis and hand, foot and mouth
> disease. In both these cases consistent efficacy was not demonstrated
> for a variety of reasons. The company moved on to the early VRI
> studies. In a few of them there was difficulty in establishing
> efficacy, and we are going to go into those trials a little bit more
> in detail. We now have the results of the two large Phase III studies,
> studies 043 and 044, and in these trials pleconaril provided about
> half a day faster time to resolution in the all randomized patient
> population, and about a day faster time to resolution of VRI in
> infected patients.
>
> \[Slide\]
>
> In a large Phase II study and both Phase III pivotal trials pleconaril
> failed to produce a treatment effect in smokers. The pivotal trials
> were open to enrollment of patients over the age of 65 but only a very
> small number of elderly patients actually entered the trials so it was
> difficult to draw any conclusions about efficacy in that
> subpopulation. The pivotal trials enrolled otherwise healthy adults
> and patients with any kind of cardiac or respiratory disease, or any
> kind of immunosuppression were excluded.
>
> \[Slide\]
>
> You have heard about the all randomized patient population and you
> have heard about the infected population, and both are legitimate
> populations for assessing efficacy of an anti-infective agent. To look
> at the infected population one has to have some confidence that you
> can reliably identify infected patients, demonstrate a treatment
> effect in those patients, but not harm patients who do not have the
> infection.
>
> Arguably, all randomized patients is also a valid population as they
> are more reflective of actual use. We believe that in this case, if
> pleconaril is approved, it will probably be prescribed to all-comers
> based on presenting symptoms, and there are no rapid diagnostic assays
> available to identify infected patients. Alternatively, pleconaril
> could be prescribed to an asymptomatic patient with instructions to
> initiate at the time of self-diagnosis of a cold.
>
> \[Slide\]
>
> The human picornaviruses, as you heard, encompass over 170 different
> serotypes. This is a flow chart of what the applicant did to identify
> infected patients. At entry into the two pivotal studies a nasal mucus
> sample was collected, and it was run on a real-time TaqMan RT-PCR
> assay. If the result was positive, it was sent for viral culture. If
> it was negative, it was retested on an ELOSA, an experimental ELOSA
> RT-PCR assay. Again, positive samples were sent for culture and a
> negative was considered really negative.
>
> So, at baseline 61 percent of the patients went into the two pivotal
> trials who were considered infected by a positive PCR. Then, 63
> percent of this 61 percent actually had a positive culture. So, the
> total patient population in the pivotal trials that had a positive
> culture was about 40 percent.
>
> On days three and six additional or repeat virologic testing of nasal
> mucus was done, but only with the TaqMan assay, and this identified
> another approximately three percent of infected patients, but these
> patients had tested negative at baseline. So the overall population of
> patients infected, as the applicant showed you, was about 64 percent.
>
> \[Slide\]
>
> We evaluated the qualitative and quantitative aspects of the RT-PCR
> assay to see how well they were identifying infected patients. The
> applicant reported that the TaqMan could detect 90/100 rhinoviruses;
> 3/53 enteroviruses; and none of the parechoviruses from laboratory
> isolates. Sensitivity of the assay was reported at 93 percent, and the
> sensitivity was determined using nasal mucus samples from symptomatic
> patients enrolled in one of their large Phase II studies. The assay is
> run for 60 cycles and any sample that crossed the 0.1 fluorescence
> level was considered positive. Appropriate controls were not included
> in the design of the assay and there was a lack of reproducible
> sampling. Therefore, we could not validate the assay\'s ability to
> quantify viral nucleic acid.
>
> \[Slide\]
>
> This is an example of the TaqMan readout. The number of cycles, up to
> 60, is down here. The 0.1 fluorescence level is right here. Any sample
> that crossed any time during the 60-cycle run was considered positive
> for picornavirus.
>
> \[Slide\]
>
> A modified experimental ELOSA assay was used to re-test TaqMan
> negative samples. This assay was reported to identify all rhinoviruses
> and all enteroviruses, and 1/2 parechoviruses with 97 percent
> sensitivity.
>
> \[Slide\]
>
> This slide shows a representative sample of a TaqMan and an ELOSA gel.
> The M is the molecular standard. The negative is the negative control.
> This arrow points to where the 68 base paired expected product showed
> up for these different samples.
>
> This is an ELOSA gel. Again, M is the molecular standard. The minus is
> the negative control. Here, the arrows are pointing to a 388 base
> paired expected product.
>
> \[Slide\]
>
> The baseline PCR positive samples were cultured and HeLa cells
> expressing ICAM at 33 degrees Celsius. Cultures were considered
> positive or negative based solely on the presence of cytopathic
> effects, and there was no serotyping of positive cultures conducted.
>
> \[Slide\]
>
> As you heard, about 24 percent of patients had resistance to
> pleconaril, 13 percent at baseline and about 11 percent by the end of
> treatment. The isolates were not serotyped so there is no data to
> determine if certain serotypes were more or less likely to be
> resistant to pleconaril. Molecular analysis of four viruses that
> lacked baseline susceptibility to pleconaril demonstrated that three
> had the same mutation at amino acid position 98 of the binding pocket.
> We also saw that single amino acid substitutions could result in up to
> 100-fold decrease in susceptibility to pleconaril.
>
> \[Slide\]
>
> This is basically a repeat of what the applicant showed you. These are
> patients who had treatment emergent resistance. There is a very small
> number, but it does not appear that there was an adverse outcome for
> those patients.
>
> \[Slide\]
>
> When we looked at susceptible versus not susceptible for placebo and
> pleconaril, you can see that for patients with not susceptible virus
> to pleconaril at baseline, and again the numbers are small, there was
> a delay in time to resolution of VRI. Remember, these are in patients
> and viruses that have never been exposed to pleconaril before so this
> was out in the community already.
>
> \[Slide\]
>
> Pleconaril needs to be administered with food. Exposures are increased
> 4 to 6.5 fold with a high fact, high caloric meal. We don\'t have any
> data on any other meal compositions because no other ones were
> studied.
>
> In patients with hepatic impairment exposures of pleconaril increased
> by 40 percent, and this may have been due to subjects not completing
> their meals or because the meals were lower in fat content.
>
> In the pivotal trials patients were instructed to take pleconaril
> three times a day with meals, within 15 minutes of the meal or, if
> they missed a meal, with a snack. We don\'t know to what extent
> patients adhered to these recommendations or if there was any kind of
> impact on the assessment of efficacy.
>
> \[Slide\]
>
> Generally pleconaril was well tolerated. Headaches, nausea, vomiting,
> abdominal pain and diarrhea were observed. The major things that we
> became concerned about was the CYP3A4 induction. We believe this is
> directly tied to the occurrence of menstrual disorders in the
> treatment trials and in the six-week prophylaxis study. We believe
> there is an increased risk for unintended pregnancies, and there is a
> potential interaction with other medications for which no data is
> available.
>
> There are also a few cases of tachycardia and palpitations that were
> triggered by a review of the theophylline interaction study. When I
> come back I will talk about these in a lot more depth during my safety
> review.
>
> \[Slide\]
>
> As I said, there were four Phase II trials in the application. The two
> biggest ones were study 20 and 32. Both were similarly designed. Study
> 20 looked at two doses of pleconaril compared to placebo; 32 looked at
> one dose of pleconaril compared to placebo. Patients were to present
> with symptoms of VRI of less than 36 hours. The endpoint was slightly
> different, time to resolution for 48 hours in 20, and for 24 hours in
> 32.
>
> Here you can see the results. In the all randomized patient population
> there was no difference between pleconaril and placebo in 20; the same
> in the infected populations. In 32 there was no difference in the all
> randomized. There was about a half day in the infected. In these two
> trials, using the ELOSA assay, the applicant was only able to identify
> about 40 percent of patients being infected with picornavirus and Dr.
> Hammerstrom will go into more detail in his presentation.
>
> \[Slide\]
>
> Post hoc analyses of these big studies identified a number of problems
> that adversely affected the demonstration of a treatment effect. The
> applicant was not able to identify a high rate of infected patients
> using the ELOSA assay. Even with changing the sampling method from a
> nasal wash in study 20 to a nasal blow in study 32, still about 40
> percent of patients were considered PCR positive.
>
> Uncontrolled and undocumented cold medication use, inclusion of
> smokers, inclusion of patients with fever, allergic rhinitis, overly
> stringent endpoints which required all symptoms to be completely
> resolved, and the recognition that treatment needed to be given
> probably within the first 24 hours of symptom onset all impacted the
> assessment of outcomes in these studies.
>
> \[Slide\]
>
> Based on what was learned in Phase II, the applicant designed studies
> 43 and 44. Just to briefly review them, they were double-blind,
> placebo-controlled and enrolled healthy adults over the age of 18.
> Patients presented with moderate to severe rhinorrhea, with symptoms
> less than 24 hours. They had to answer \"yes\" to the question, \"are
> your symptoms due to a cold?\" Patients with allergic rhinitis, fever,
> underlying pulmonary, cardiac, immunocompromised patients or other
> serious illnesses were excluded from the trial.
>
> \[Slide\]
>
> Randomization was stratified on smoking status and pre-treatment use
> of cold medication, both of which appeared to influence assessment of
> efficacy in Phase II. A patient was considered a smoker if they were
> actively smoking or had stopped smoking within three months of study
> entry. Patients were randomized to pleconaril or placebo three times a
> day for five days. They had a clinic visit on days 3, 16 and 18, and
> completed diaries for the 18-day study period. Acetaminophen and
> dextromethorphan were provided but patients were instructed to use
> them only as necessary.
>
> \[Slide\]
>
> All the symptoms were scored on an ordinal severity score of zero for
> absent to three for severe. Then, the virologic testing method was as
> I previously described it.
>
> \[Slide\]
>
> About 2100 patients entered the two trials. This is the all randomized
> patient population, about 69, 70 percent female, 36 years of age;
> about 30 percent were smokers; 30 percent had used pre-treatment cold
> medication. The median time to first dose of study medication was
> about 20 hours. The baseline severity score was nine out of a maximum
> of 18. Again, at baseline the PCR positive status was about 61 and 62
> percent in the two arms respectively.
>
> \[Slide\]
>
> With that background, I am going to turn it over to Dr. Hammerstrom to
> present some perspective on pleconaril\'s efficacy.
>
> **Statistical Review of Efficacy**
>
> \[Slide\]
>
> DR. HAMMERSTROM: In addition to the two pivotal Phase III trials, 43
> and 44, the applicant also provided data from one small Phase II
> trial, number 10, and two larger Phase II trials, 20 and 32. These
> latter two trials differ in several ways from trials 43 and 44.
> Concomitant cold medication use was allowed. Subjects were recruited
> up to 36 hours after symptom onset. PCR positivity was determined only
> by the ELOSA assay, without the use of TaqMan. There was no record of
> OTC co-medication use, and the duration of recording of symptoms was
> not exactly the same in all four trials.
>
> The applicant originally required all symptoms to be absent in trial
> 20, but we recalculated the endpoints to require the five symptoms
> other than rhinorrhea to be merely mild or absent. In trial 32 the
> applicant required one day of resolution. We recalculated to require
> two days of resolution. We also attempted to make the endpoints in
> trials 43 and 44 more comparable by doing the sensitivity analysis in
> those two trials in which cold medication use was omitted from the
> computation of the primary endpoint. The results in these two trials
> were nearly identical to the results of the protocol primary endpoint,
> which will be given below.
>
> \[Slide\]
>
> The next two slides show the status of two pivotal trials by arm with
> respect to the assay and viral culture results at baseline and during
> the trial. There is one problem with these data. Specifically, no
> viral culture was taken for subjects who were negative on the PCR
> assay. So one column of the 2 X 2 table for assay cross-culture is
> missing.
>
> \[Slide\]
>
> This is the same thing for trial 44. Overall, the rate of baseline PCR
> positivity in trials 43 and 44 was 60 percent consistently across all
> four arms. In addition, about three percent of patients became
> positive during treatment. In our analysis, because pleconaril is
> supposed to be antiviral, we decided not to include patients who only
> became PCR positive while on treatment. Furthermore, the day three
> assay has been used as a secondary endpoint, so it should not also be
> used as a baseline covariate. We have looked at the analysis both ways
> and neither estimated quartiles of time to resolution nor peak values
> changed consequentially.
>
> \[Slide\]
>
> This slide shows the primary endpoint for the two pivotal trials using
> the PCR positive population. For each arm the table shows the number
> who were included, that is, were PCR positive at baseline, three
> quartiles of time to resolution of symptoms and cold medication use
> and the p values for the comparison of placebo and pleconaril.
>
> For example, in trial 43 the Q1 equals four shows that 25 percent of
> subjects on pleconaril had complete symptom resolution within four
> days. The Q2 equals seven shows that 50 percent of subjects on
> pleconaril had complete symptom resolution within seven days. The Q3
> equals 11 shows that 75 percent of pleconaril subjects had complete
> healing by day 11, and that 25 percent took 11 days or more to heal.
>
> When we calculated this, we rounded off all the times to the half day
> so our numbers are not exactly the same as the applicant\'s. We
> didn\'t think subjects could really identify symptom disappearance to
> the nearest hour. The p values here were computed stratifying on the
> same variables used to stratify the random assignment, pre-treatment
> cold medication use, and smoker, non-smoker. One can see a fairly
> consistent pattern. The pleconaril arm is one to one and a half days
> ahead of the placebo arm for all three quartiles in both trials,
> except the median in trial 43. Statistical significance was achieved
> in both trials.
>
> \[Slide\]
>
> This slide shows the primary endpoint for the two pivotal trials for
> the full ITT population. The layout of information is the same as in
> the previous slide. One should notice that the size of the pleconaril
> effect is about half a day smaller than it was in the PCR positive
> population. That is, it is about half a day instead of one day in
> trial 43, and it is about one day instead of one and a half days in
> trial 44. Also, the statistical significance has been lost in trial
> 43.
>
> \[Slide\]
>
> This slide shows the corresponding results for the two larger Phase II
> trials, 20 and 32. Trial 10 was much smaller and is not included here.
> Recall that the endpoint here is slightly different. Over-the-counter
> cold medication use was not recorded. It is noticeable that in trial
> 20 pleconaril showed no benefit in the PCR-positive population. All
> three quartiles are as long or longer on pleconaril than on placebo.
> In trial 32 there was a benefit of half a day at the median but not at
> the other quartiles, and a slight benefit also at the third quartile
> but neither of these was statistical significant.
>
> As I mentioned, we did attempt to check whether this occurred solely
> because of the absence of cold medication data, and in trials 43 and
> 44 one gets no consequential differences in the estimates of the size
> of pleconaril benefit or in the strength of its statistical
> significance if one omits cold medication use from the computation of
> the endpoint.
>
> \[Slide\]
>
> This slide shows the results from the same two trials, 20 and 32, for
> the full population. It is noticeable that there is a pleconaril
> benefit found in trial 20 but not in 32. The finding in trial 20 is
> somewhat contrary to the results in the two pivotal trials where the
> PCR-positive supopulation shows a much clearer pleconaril benefit than
> does the full population.
>
> It is most plausible that the larger concomitant use of cold
> medications and the longer delay in recruitment after symptom onset
> accounts for the lack of treatment effect. These trials may contain
> more information about the expected effects in general use since
> longer days in recruitment and wider use of anti-symptom drugs will
> occur in that setting.
>
> \[Slide\]
>
> This slide shows the loss to follow-up in the two pivotal trials. One
> thing to notice is the bimodal shape of the distribution of dropouts.
> Five to 11 people per arm decided not to participate after being
> randomized. Four to 11 people per arm dropped out on days one to five,
> most for adverse events. Only one to three patients per arm dropped
> out in the long interval, from day 6 to 15. Then, about 50 per arm
> left after day 16 or later without resolution of the symptoms. That
> includes everyone who reaches day 18.5 in their diary and is still
> sick.
>
> \[Slide\]
>
> The next several slides show the results for the PCR-positive
> population stratified by number of baseline covariates. Results are
> laid out as before, except that p values are omitted. This is because
> the trials are not large enough to detect real effects in subsets. In
> all these slides only the PCR-positive population is used. In the full
> population pleconaril benefits become slightly smaller.
>
> \[Slide\]
>
> This and the next slide show stratification by pre-treatment cold
> medication use, which was one of the two covariates used to stratify
> the randomization. The non-users are given here. There is an estimated
> pleconaril benefit of one and a half to two days in trial 44, and one
> to one and a half days in trial 43.
>
> \[Slide\]
>
> This slide shows the pre-treatment cold medicine users. Here, the
> pleconaril benefit is zero to one days in trial 44; one to two and a
> half days in trial 43. The overall impression is that the benefit is
> similar across both strata, possibly slightly smaller but still
> positive in this stratum.
>
> \[Slide\]
>
> This and the next slide shows the results of stratifying by smoker and
> non-smoker. Here we have included one of the two Phase II trials,
> trial 32, which was one of the two trials for which we had smoker and
> non-smoker data. Here are the results for non-smokers and one sees an
> estimated benefit of one to one and a half days in trial 43; one and a
> half to two days in trial 44; half a day to two days in trial 32.
>
> \[Slide\]
>
> The results for smokers are given here. One notices that the
> pleconaril subjects actually take longer to heal than the placebo
> subjects within this stratum in all three trials. All of the quartiles
> for all three trials are as long or longer on pleconaril as they are
> on placebo.
>
> \[Slide\]
>
> This slide shows the results stratified by gender. Both trials 43 and
> 44 have been pooled together in order to increase the sample size
> within each gender and to eliminate the need for two slides. The
> females are estimated to have a pleconaril benefit of one and a half
> to two days. The males have a smaller but still positive benefit of
> zero to one days.
>
> \[Slide\]
>
> This slide shows the results for smoker stratified by gender. Again,
> trials 43 and 44 have been pooled. One sees the same pattern as shown
> for smokers previously. Both for females and for males pleconaril is
> estimated to increase the time to symptom resolution. All of the
> quartiles in both genders are at least as long or longer for
> pleconaril.
>
> \[Slide\]
>
> The next four slides give the results for the time to resolution of
> each of the individual symptoms and for the time to end of cold
> medication use. Notice that the primary endpoint was achieved when all
> symptoms, except for rhinorrhea, were no worse than mild. This table,
> in contrast, requires each individual symptom to be reduced all the
> way to absent so it contains a little bit different information than
> the primary endpoint itself.
>
> The p values have been put back in here because the PCR-positive
> sample is not being subdivided into several too small subsegments. The
> sample sizes are not exactly the same because only subjects who have
> the given symptom baseline are included. Even so, most of these
> samples are large enough to be able to detect treatment effects of the
> size detected for the primary endpoint.
>
> From this slide, one can see that rhinorrhea, congestion and malaise
> showed statistically significant benefit from pleconaril in trial 43.
> Cough shows sort of a tie here. One quartile is better, one is worse
> and one is equal.
>
> \[Slide\]
>
> This shows the other three symptoms from trial 43. One can see that
> myalgia and sore throat also showed statistically significant
> pleconaril benefit in trial 43.
>
> \[Slide\]
>
> This and the next slide cover trial 44. Here, one can see that
> rhinorrhea alone showed a statistical significant benefit. Although
> congestion and cough showed non-significant benefits, the quartiles
> are smaller for pleconaril. There was no benefit for malaise, except
> possibly in the first quartile.
>
> \[Slide\]
>
> Finally, one can see that myalgia and cold medication use also showed
> pleconaril benefits, although they did not achieve statistical
> significance. There was no benefit for sore throat. I should also
> remark that it makes no sense to look at percent reduction in total
> symptom score. Symptoms are ordered but they are not numeric. Severe
> may be conveniently coded as a 3 but is not equal to 3 times mild. One
> could have used the codes 1 to 4 instead of 0 to 3 and gotten quite
> different results. Furthermore, separate symptoms cannot be combined
> in this way and be clinically meaningful. A severe sore throat is not
> equal to mild rhinorrhea plus moderate cough.
>
> \[Slide\]
>
> This slide shows the comparison of secondary endpoints, days of normal
> activity compared, nights with sleep impaired, and incidence rate for
> complications of colds. Of these, only one was statistically
> significant in one trial. Although the first two showed a small
> estimated pleconaril benefit in both trials, one-sixth to one-third of
> a day with less impairment of normal activity; one-third to two-thirds
> of night\'s sleep improved.
>
> \[Slide\]
>
> Here are the efficacy conclusions, pleconaril is statistically
> significantly superior to placebo in the PCR-positive population. If
> the assay has a low false-negative rate, then the PCR-positive
> population includes most infected subjects and the statistical
> significance there confirms pleconaril benefit.
>
> \[Slide\]
>
> Pleconaril showed no statistically significant benefit in the PCR
> population of trials 20 and 32, which had slightly different endpoints
> and slightly different recruitment criteria. Pleconaril will be used
> in the whole population for which the estimated benefit in the two
> pivotal studies was approximately one half day.
>
> \[Slide\]
>
> Finally, pleconaril has no effect in smokers. This absence of benefit
> has been confirmed in three separate studies, 43, 44 and 32.
>
> I will now turn the podium back over to Russ, who will continue with
> the safety analysis.
>
> **Safety Review and Summary**
>
> MR. FLEISCHER: Thank you, Dr. Hammerstrom.
>
> \[Slide\]
>
> I would like to turn to a discussion of safety of pleconaril. The VRI
> safety database that we looked at consists of approximately 4500
> patients who received pleconaril or placebo, about 2500 of which
> received pleconaril. There were no treatment-related deaths or
> significant lab abnormalities noted during the clinical trials. The
> adverse events were generally similar, with headaches and
> gastrointestinal events being the most bothersome and present. They
> also led to the most discontinuations, but the discontinuation rates
> were similar between the treatment arms and I will show you that in a
> minute.
>
> \[Slide\]
>
> This is a table of the adverse events occurring greater than two
> percent in the two pivotal trials. Here the placebo and pleconaril
> arms are pooled. Headache was the most frequent adverse event, and it
> was slightly more frequent in the pleconaril arm. We really still
> don\'t have a great explanation for why headache occurred so
> frequently in these trials. Gastrointestinal events, diarrhea, nausea,
> vomiting, abdominal pain were essentially similar but they led to the
> most discontinuations and the discontinuations fit an interesting
> pattern, where patients would complain of gastrointestinal events
> within one to two days of the onset of dosing. They would stop the
> medication, either placebo or pleconaril, and their GI adverse events
> would go away within a day.
>
> This also occurred with similar frequency between P-seropositive and
> P-seronegative patients. we didn\'t think it was an effect of a
> particular virus being present. So, we hypothesized that one
> explanation might be something in the formulation of pleconaril.
> Pleconaril and the placebo formulations were exactly the same, with
> the exception that the pleconaril formulation contained pleconaril.
> Each capsule contains sodium laurel sulfate, which is an emulsifying
> detergent, which is used as a tablet wetting and lubricating agent and
> this is an agent that is known to cause irritating effects to eye,
> skin, upper respiratory tract and the stomach.
>
> \[Slide\]
>
> The first significant adverse event I would like to talk about is
> menstrual disorders. These were seen in mild to moderate severity of
> early menses, intermenstrual bleeding, menorrhagia and menstrual
> disorders not otherwise specified. They were observed at three to
> three and a half percent in the five- to seven-day treatment studies.
> But then there was a significant increased frequency noted in the
> six-week prophylaxis study, as outlined by the applicant. They also
> increased sequentially or exponentially as duration of exposure to
> pleconaril increased during the six-week study. Women were
> re-consented. A barrier method was recommended and menstrual disorders
> became a targeted question at each clinic visit.
>
> \[Slide\]
>
> These two table show the frequency of menstrual disorders in the five-
> to seven-day treatment studies and the six-week prophylaxis study. You
> can see here that in the pleconaril it is three to three and half
> percent among oral contraceptive users compared to essentially nothing
> in the placebo arm and women who were taking pleconaril and were not
> taking oral contraceptives.
>
> In the prophylaxis study, among oral contraceptive users the rate was
> 27 percent in the placebo arm, 58 percent in the pleconaril once daily
> arm and 81 percent in the pleconaril BID arm. Across the non-OC users
> it was consistent, between 13 and 16 percent. These rates may be
> overestimation since the menstrual disorders were events that women
> were specifically asked about during the remainder of the six-week
> trial.
>
> It was also interesting to note that the prevalence of menstrual
> disorders was three percent during the first week of the prophylaxis
> study, which correlates with the three percent in the one-week
> treatment studies. After that time they increased significantly.
>
> \[Slide\]
>
> To investigate possible mechanisms, the applicant conducted a five-day
> intravenous midazolam study and a five-day oral contraceptive
> interaction study. We believe the results conclusively demonstrate
> induction of CYP3A4 by pleconaril. It is evidenced by rapid decreases
> in midazolam and ethinyl estradiol levels by 28 percent and 35 percent
> respectively. There was no significant change in the norethindrone
> pharmacokinetics.
>
> Pleconaril has a long terminal half-life. It is approximately 180
> hours after a single dose and after multiple dose it is well over 1000
> hours. Also, since the oral contraceptive interaction study was only
> five days in duration, we do not know if maximum suppression of
> ethinyl estradiol was achieved, or how long it takes for ethinyl
> estradiol levels to return to an effective range following cessation
> of exposure to pleconaril. The applicant does have an ongoing PK/PD
> interaction study which may or may not help address this issue.
>
> CYP3A4 induction by pleconaril could potentially impact exposure and
> effectiveness of a number of important drugs, such as
> immunosuppressants, antiarrhythmics, calcium channel blockers,
> protease inhibitors and Viagra, but there are no data on pleconaril\'s
> effects on these drugs to date.
>
> \[Slide\]
>
> The obvious concern was that these menstrual disorders in the presence
> of decreased hormone levels might increase the risk of unintended
> pregnancies. In the treatment studies approximately 20 percent
> patients were oral contraceptive users and in the six-week study about
> half of the women were using them. So there are another about 230
> women who were oral contraceptive users between the two studies.
>
> Thirteen pregnancies were reported in this database. The ones of
> interest, there were two pregnancies among 156 oral contraceptive
> users both in the BID arm of the six-week study. One is ongoing and
> one ended in an abortion. There were five pregnancies reported in
> placebo users, one of which was an oral contraceptive user and the
> outcome of this pregnancy is unknown since the patient was lost to
> follow-up.
>
> \[Slide\]
>
> The CYP3A4 induction of ethinyl estradiol probably compromises the
> oral contraceptive effectiveness for at least an entire cycle. We
> believe that a backup method of contraception will be necessary for a
> prolonged duration of time. We attempted to characterize the potential
> public health risk of unintended pregnancies that could result from
> widespread use of pleconaril.
>
> A 1998 report from the Guttmacher Institute said that about 10.4
> million women between 15 and 44 years of age use some kind of pill
> form of contraception. Unfortunately, there is no data on the type or
> duration of those pills. We looked at data that has been submitted to
> the FDA to support the approval of oral contraceptives ever since the
> 1960\'s. Based on those data, the expected oral contraceptive failure
> rate is approximately one pregnancy per 100 women per year of use. We
> believe that the two pregnancies in 156 women in six weeks of
> pleconaril exposure appears higher than what would be expected in the
> general population of oral contraceptive users. It is important to
> note that plasma was shown not to be teratogenic, mutagenic of
> genotoxic in animal studies.
>
> \[Slide\]
>
> The next thing that kind of popped up on the radar screen is
> tachycardia and palpitations. In the theophylline probe study, 15
> healthy theophylline-naive volunteers were enrolled. During the second
> co-administration phase of theophylline and pleconaril, three of these
> 15 patients complained of palpitations and tachycardia. In general,
> there was an increased frequency of abdominal pain, nausea, dizziness
> and syncope during the co-administration phase, and although across
> the entire study population there was a 15 percent increase in the
> theophylline area under the curve, there were no significant PK
> changes in the three patients who complained of palpitations.
>
> \[Slide\]
>
> We looked at the VRI database and identified seven pleconaril treated
> patients who complained of tachycardia, with or without palpitations.
> Three reported a pattern of onset within one hour of ingestion,
> lasting for about an hour. Four patients discontinued study because of
> these events. One was serious enough that the patient presented
> himself to an emergency room but no cardiac etiology was identified.
> No patient underwent a pleconaril rechallenge so we don\'t know
> whether these might have recurred. There were two patients in the
> placebo database. One complained of tachycardia and palpitations on
> day five, and the other on day two. Both remained on study with
> resolution of their events. Overall, there was no appreciable change
> in heart rate or blood pressure noticed in the database. Since none of
> these clinical patients were on theophylline or had a history of
> respiratory or cardiac disease, a clear etiology for these events is
> still not known.
>
> \[Slide\]
>
> Let me summarize and go through each of the points that I identified
> in the beginning of my talk. Efficacy in Phase II was essentially not
> demonstrated based on a number of design problems, including
> difficulty in identifying infected patients.
>
> The results of the two pivotal trials demonstrate approximately a half
> day benefit in the all randomized population, and about a one day
> benefit in infected patients. Efficacy in smokers was not demonstrated
> across three clinical trials, and there were no data in patients with
> co-morbid conditions such as cardiac or respiratory disease. We also
> don\'t have very much data in elderly patients.
>
> \[Slide\]
>
> The methods used by the applicant appear to be able to identify
> infected patients. However, quantitative measurement of viral nucleic
> acid by the TaqMan assay could not be determined. Positive cultures
> were not serotyped so although the results suggested rhinovirus, we
> have no data to confirm actual virus present in the cultures.
> Resistance was present in 13 percent of patients prior to any exposure
> to pleconaril and these patients experienced a much longer time to
> resolution of their VRI than patients with susceptible virus. Patients
> with treatment emergent virus did not appear to be adversely impacted
> by that, but the numbers in those analyses are very small. Again,
> single amino acid substitutions were identified that led to greater
> than 100-fold decrease in susceptibility to pleconaril.
>
> I just want to take this opportunity to thank Dr. Kathleen Whitaker,
> from the Center for Devices, who assisted in the analysis of all the
> clinical virology data.
>
> \[Slide\]
>
> We believe the efficacy should be considered the way the drug may be
> used. Essentially infected and all randomized patients both represent
> legitimate populations for assessing efficacy, but we believe
> pleconaril will be prescribed to symptomatic patients who present with
> symptoms of VRI and there is no diagnostic assay that will be
> available to identify who has an infection with picornavirus and who
> does not.
>
> We also believe that it is possible that patients would obtain a
> prescription for pleconaril, with the instruction to hold onto it and
> use it at the time of initial self-diagnosis of a cold. This could
> impact any kind of risk communication that would be necessary for this
> drug.
>
> Pleconaril requires administration with food three times per day, but
> how much has not been fully characterized. Since pleconaril is highly
> lipophilic, the fat content might be important. Finally, pleconaril
> needs to be initiated early in the illness, within 24 hours of symptom
> onset.
>
> \[Slide\]
>
> Pleconaril induces CYP3A4, leading to clinically demonstrable and
> rapid decreases in ethinyl estradiol levels, leading to breakthrough
> bleeding that appears to have resulted in two unintended pregnancies.
> The maximal amount and duration of induction are not known. Although
> treatment of VRI would be for only five days, pleconaril has a long
> terminal half-life. Thus, we believe the effectiveness of at least an
> entire oral contraceptive cycle would be impacted and women would be
> required to use a backup method of birth control but, again, for how
> long we really don\'t know yet.
>
> Also, CYP3A4 induction could negatively impact the effectiveness of
> many other medications and we have no data to know how much, or which
> drugs at this time.
>
> Palpitations and tachycardia were observed in the theophylline
> interaction study in some patients in the treatment trials. In
> general, pleconaril was well tolerated, with headaches and
> gastrointestinal adverse events being the most bothersome.
>
> Finally, I would just like to acknowledge the other members of the
> review team. We look forward to your questions and your discussions.
> Dr. Birnkrant will return later and she will give you your specific
> charge and review the questions that we are seeking your input on.
> Thank you very much.
>
> DR. GULICK: Thanks, Mr. Fleischer and Dr. Hammerstrom. That completes
> the presentations this morning. We are going to take a 15-minute break
> now. We will reconvene at 10:20 for the question period. Thanks.
>
> \[Brief recess\]
>
> DR. GULICK: Welcome back, everyone. Dr. Stanley, are you still with
> us?
>
> DR. STANLEY: I am with you.
>
> DR. GULICK: You are a trooper! This is an opportunity for the
> committee members to ask questions either of the sponsor or the
> agency. People are jumping right in. Dr. Gordin, would you like to
> lead us off?
>
> **Questions to the Presenters**
>
> DR. GORDIN: I was wondering, Dr. Hayden, if you could talk a little
> bit about the common cold in terms of who gets it. Looking at the
> groups that were excluded from studies here, how many people with a
> common cold do actually have a temperature over 100? How many people
> with a cold would have had a cardiac or respiratory illness that would
> have been excluded? Also, if you could talk about how many days of
> work are really missed by people with a common cold. I am not sure if
> that was even looked at here as an endpoint or data collected? Did
> people not go to school or not go to work? Could you talk a little bit
> more about kind of populations as a whole in the country versus what
> was studied here?
>
> DR. HAYDEN: Well, I think that the patients enrolled in these two
> clinical trials were really representative of the young and
> middle-aged general civilian adult population. As I indicated, the
> incidence of colds decreases with increasing age. We know that
> co-morbidities increase with increasing age so the likelihood of colds
> developing in those with underlying cardiac or respiratory conditions
> is diminished in terms of frequency relative to younger individuals,
> although their likelihood of having complications from those illnesses
> and more protracted symptoms is increased.
>
> You asked about fever specifically. In the study that we did in 1994,
> where we enrolled 346 self-diagnosed adult cold sufferers, 82 percent
> of those were picornavirus positive. The proportion with fever was
> less than five percent. Rhinoviruses can cause febrile respiratory
> illness but it is a very small proportion of these illnesses and that
> helps, in fact, in terms of trying to make a distinction between a
> rhinovirus cold and, for example, influenza where fever is a predictor
> of influenza infection and also response to antiviral therapy. So I
> think there can be some useful clinical criteria that will help
> identify appropriate target populations.
>
> DR. GORDIN: What about the question of people who do get colds, how
> many miss work or school? And, was that specifically looked at in
> these studies? I know impairment was looked at and the FDA, in their
> presentation, showed I believe that in five of the six parameters
> there was no statistical difference, but did anybody specifically look
> at missed work, missed school, missed activities?
>
> DR. HAYDEN: The clinical trials did incorporate a self-report of the
> number of days of impaired activity. Unfortunately, that is a very
> insensitive measure of the effects of an acute respiratory illness on
> performance. Prior studies of cold sufferers in general have not found
> reduction in work time as much as altered performance while on the
> job. In order to capture effects on quality of life or more detailed
> psychomotor abnormalities, one would need to use specific instruments
> to examine those things, and those were not incorporated into these
> studies of otherwise healthy individuals. I think that is reasonable,
> given that the likelihood of seeing effects on those endpoints in an
> otherwise healthy group might be lower than in older individuals or
> those who have some co-morbidities.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: My question is to Dr. Cooper. Dr. Cooper, I am certain you
> recognize that for most practicing clinicians to administer the drug
> within 24 hours would be problematic. So, I wanted to ask you a couple
> of very practical questions on how you did this trial.
>
> My first question to you is how did you manage to get about 2000
> patients in just about three months? Did you have somebody sitting at
> a phone and as soon as they said \"I\'ve got rhinorrhea,\" \"come
> right in?\" I would just like to have a flavor of how you managed to
> get patients within 24 hours into your clinical trials.
>
> DR. COOPER: Well, we identified the sites beforehand, of course, who
> had investigators to participate in these studies. Then, as the fall
> season began or just prior to the fall season there were
> advertisements, radio announcements \-- each site did it differently
> but basically got the word out to the community that there was a trial
> that was looking to enroll patients with colds within 24 hours of
> onset. So we were very pleasantly surprised at how easily we were able
> to enroll these studies.
>
> DR. KUMAR: Can I ask you a follow-up question? Among the patients that
> called in and came in, what percentage of them were within the 24-hour
> period of time?
>
> DR. COOPER: It was very high, between 95-98 percent. If you want an
> exact number, Dr. Villano can give you the specifics.
>
> DR. VILLANO: Stephen Villano, clinical research at ViroPharma. To the
> specific question about how patients were screened and enrolled within
> the 24-hour window, I would note that approximately three patients
> were screened for every one that was enrolled in a clinical study.
>
> DR. KUMAR: That is what I wanted to know.
>
> \[Slide\]
>
> DR. VILLANO: In fact, the number one reason for not being enrolled in
> the study was not being within the 24-hour window, which accounted for
> approximately 60 percent of the people that were not allowed to be
> entered into the study.
>
> DR. KUMAR: Thank you. That is exactly what I wanted to know. Thank
> you, Dr. Cooper.
>
> DR. GULICK: Dr. Brass?
>
> DR. BRASS: I would like to ask, hopefully, a quick series of questions
> about some basic toxicology and pharmacology of the compound. First,
> do you have any data on whether or not the compound interacts with any
> of the PPAR class of receptors in the liver or elsewhere? Is that a
> \"no?\" I heard a \"no.\" Okay.
>
> Next, Dr. McKinlay\'s slide 19 showing metabolism of the compound \--
> is it easy to get that slide back on? What is the other product of
> that first metabolic step where the ring is open?
>
> DR. MCKINLAY: What is the other product? I will ask Dr. Rhodes to come
> up to address that.
>
> DR. RHODES: Gerry Rhodes. I am with drug metabolism and clinical
> pharmacology at ViroPharma. If I understand your question correctly,
> you are asking what is the other product formed. Trifluoracetic acid
> would be the loss.
>
> DR. BRASS: And, does that reach systemic circulation? And, what do you
> know about the toxicology of it?
>
> DR. RHODES: It does reach systemic circulation. We have found
> trifluoracetic acid in the urine of patients in a C14 ADME study. I
> would like to ask Dr. Hincks to comment on the pharmacologic profile
> of trifluoracetic acid.
>
> DR. HINCKS: Jeff Hincks, preclinical development at ViroPharma. As far
> as studying specifically trifluoracetic acid, we have not. However, we
> have seen that in rats as well, and under those auspices we have
> studied, I guess, the metabolism profile that we saw with pleconaril
> in rats and dogs. We saw similar metabolic profiles.
>
> DR. BRASS: But from the literature elsewhere, is trifluoracetic acid a
> benign compound?
>
> DR. HINCKS: It is fairly well tolerated at high levels, yes.
>
> DR. BRASS: Next, I just want to emphasize that on slide 17 of the
> initial presentation \--
>
> \[Slide\]
>
> \-- I just want to emphasize that trying to estimate a terminal
> half-life of greater than 100 hours in duration from that data set is
> impossible, and when we talk about the duration of potential induction
> or other pharmacologic actions of this compound, do we have a better
> way to estimate the half-life, other than that particular figure?
>
> DR. RHODES: The graph in the presentation was clearly for presentation
> purposes. We have characterized the terminal elimination and half-life
> of pleconaril to much later time points.
>
> \[Slide\]
>
> This graph shows the plasma concentration time profile following the
> last dose of a five-day treatment regimen of 400 mg TID. Again, there
> is a long terminal half-life, even difficult to estimate here. We
> sampled out to over 600 hours, so to even estimate it at 1000 is a bit
> of a stretch. It is difficult to determine accurately but we do fall
> very rapidly from Cmax concentrations over a 24-hour period to
> concentrations that are relatively low, about 0.5 mcg/mL, and then
> there is a long terminal elimination of drug from that point.
>
> DR. BRASS: Is that the data set that the 1000 hours was derived from?
>
> DR. RHODES: Estimated from, yes.
>
> DR. BRASS: So to the degree these numbers matter, 100 is probably, if
> anything, an underestimate and one shouldn\'t be tied into that number
> quantitatively. Do you agree that is fair?
>
> DR. RHODES: Yes, I agree that is fair. There is going to be, you know,
> quite a bit of play in that number of 1000. The half-life of 180 hours
> that was quoted was determined after a single dose where, again, you
> may not be able to fully describe the terminal phase to the same
> degree.
>
> DR. BRASS: My last question of this series is when you look at drug
> interaction data, I think it is very important to think about the drug
> interaction data as safety data, not kind of efficacy equivalent data.
> As such, it is the outliers, particularly in small data sets, that
> often contain the signal about the magnitude of a potential drug
> interaction in subpopulations that were exposed to the drug. You
> showed us mean data for the 3A4 interaction induction experiment. I
> would be interested to see what the maximal range of effects was in
> terms of AUC reduction, and how that might relate to a prototypic
> inducer like rifampin, which is accepted to have a substantive
> interaction with oral contraceptives.
>
> DR. RHODES: If you don\'t mind, I would like to start with a
> comparison with rifampin first.
>
> \[Slide\]
>
> I would just like to review quickly what we do know about pleconaril
> and then compare it and contrast it to other potent inducers. We have
> seen an increase in CYP3A activity with IV midazolam confirmed in an
> interaction study with an oral contraceptive agent. Ethinyl estradiol
> levels did drop 34 percent, with a half-life decrease of 18 percent.
> We didn\'t see any effect on norethindrone pharmacokinetics. In
> interaction studies we conducted with theophylline and warfarin which
> are probe substrates for 1A2 and 2C9, we didn\'t see any inductive
> effect there.
>
> \[Slide\]
>
> The potent inducers of 3A \-- again, I am going to use terms like
> potent, moderate and modest with respect to current categorizations in
> the literature, and this is data drawn from the literature \-- potent
> 3A inducers, like carbamazepine, phenobarbital and rifampin have a
> potent effect on midazolam. I think they drop the AUC of oral
> midazolam by approximately 95 percent. These potent inducers of 3A
> don\'t just affect 3A, however. They also affect 2C9 with drug
> interactions with warfarin, also drug interactions with theophylline
> mediated through 1A2. So, the activity of those enzymes also
> increases.
>
> Some of these inducers also increase phase two drug metabolizing
> enzymes UDP, glucurosyl transferase activity. Some also induce P
> glycoprotein synthesis. There are other classifications for 3A
> inducers where this general pleiotropic sort of induction isn\'t
> observed. Topiramate would fall into that class; felbamate would, and
> with the data we currently have with pleconaril, we believe it would
> fall in that class as well. But the effect is mainly on CYP3A.
>
> \[Slide\]
>
> What I have done on this table is really compare and contrast the
> literature data for characterizations of potent moderate and modest
> based on literature precedent. You know, two positive sites indicates
> a change greater than 50 percent on average. One, less than 50
> percent, and at least for the [in vivo]{.underline} data we currently
> have with pleconaril, summarized across the top with midazolam,
> warfarin, theophylline and then the CYP enzymes are mainly involved in
> their biotransformation.
>
> So again, this potent class of inducers has significant effects on
> midazolam, 95 percent; about 60 percent decrease in ethinyl estradiol
> AUC. Effects on warfarin, effects on theophylline. There is a group of
> 3A inducers that have less of an effect on 3A, ritonoavir, rifabutin,
> troglitazone, St. John\'s wart, for instance, where this is
> approximately 30-40 percent for ethinyl estradiol. This more moderate
> classification in terms of the broader spectrum of what they also
> induce is that you do see some other signals for warfarin and
> theophylline interactions, and also rifabutin and troglitazone
> pharmacokinetics. Topiramate, felbamate, these are 30 percent drops in
> ethinyl estradiol AUC. Again, there is not much data here, at this
> point, although there is nothing reported for interactions with
> warfarin and theophylline, and pleconaril seems to fit into this class
> where we have about a 30 percent change in ethinyl estradiol but no
> effect on warfarin, theophylline or norethindrone pharmacokinetics.
>
> Now, with respect to data in our individual studies and the confidence
> intervals around them, the geometric means, there is individual
> variability in those studies, of course, and we have seen, you know,
> higher clearances in some subjects. I think the maximum range in the
> midazolam study \-- and Joe can correct me if I am wrong \-- is
> roughly almost a doubling of clearance in some subjects. Others are
> affected less. I think that is typically what you do see in drug
> interaction studies. There will be some individuals that will be more
> affected than others, yes.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: There are two issues that I would like to ask about. The
> first is for the resistance in the virology, are there any data on
> other compounds that work with a similar mechanism of action being
> developed by the company or other companies, and which mutations are
> seen if any cross-resistance studies were done with the isolates that
> were found here?
>
> DR. MCKINLAY: Yes, I will ask Dr. Hayden to come up and discuss that.
>
> DR. HAYDEN: There has been a series of compounds that are so-called
> capsid binders, different chemical entities but all targeting the same
> structure in VP1. Some one years ago, the workers at the common cold
> unit, under the direction of Dr. David Turrell, actually took one of
> these selected A-resistant variant [in vitro]{.underline} and compared
> the relative infectiousness of that variant to the wild type virus.
>
> \[Slide\]
>
> This shows you the results of the clinical trial. These individuals
> were inoculated intranasally with the parenteral susceptible strain
> and with a variant that was roughly seven-fold or more less
> susceptible. You can see that the proportion of individuals developing
> cold symptoms was relatively low with both viruses, but less than half
> with the drug resistant compared to the wild type. Viral shedding was
> seen in 27 percent compared to 67 percent. Seroconversion, another
> marker of infection, was substantially lower with the drug-resistant
> variants. The overall infection was documented in 27 percent of those
> inoculated with the drug-resistant variant compared to 92 percent,
> over a three-fold reduction. This reduction in infectiousness then is
> correlated with some of the laboratory studies of such drug-resistant
> variants where they have shown reduced stability to pH and in some
> cases heat.
>
> I can\'t comment directly on the cross-resistance profiles of the
> pleconaril less susceptible variants compared to these older agents,
> but perhaps other individuals can.
>
> DR. SCHAPIRO: The question is really regarding other agents, to what
> degree what mutations were seen.
>
> DR. MCKINLAY: The data in the literature indicates that there is
> cross-resistance. For example, the chalcone is cross-resistant with
> pleconaril, etc. The actual mutation in this particular mutation was
> not characterized in this study.
>
> DR. SCHAPIRO: One more question. The issue of complications, I saw
> some data in the background information. The appearance of acute
> complications in patients treated or not treated. I think it was Table
> 17 and 50.
>
> DR. MCKINLAY: Right, I will ask Dr. Villano to comment on the
> complications.
>
> DR. VILLANO: I believe you are referring to the projectable version of
> the respirator complications in the intent-to-treat populations.
>
> \[Slide\]
>
> Is this what you are referring to?
>
> DR. SCHAPIRO: Yes.
>
> DR. VILLANO: This slide demonstrates the respiratory complications of
> otitis media, bronchitis, sinusitis and pneumonitis, as was asked of
> the investigators to report had they occurred at any time during the
> course of the study. It is important to point out that in these
> studies we did not provide specific definitions for these events, but
> laid out that if they were to occur during this study, specifically
> tell us if they occurred.
>
> As shown here, the overall incidence of any respiratory complications
> was relatively low, which probably reflects the fact that the
> population was otherwise healthy and generally at low risk for
> developing these complications.
>
> DR. GULICK: I will come back to you, Dr. Brass. I will give everyone
> an opportunity to ask questions and then we will have people repeat if
> they like. Dr. Fletcher?
>
> DR. FLETCHER: Three questions for the sponsor and then one joint one
> for both the sponsor and the agency. My first is about the
> pharmacokinetic/pharmacodynamic basis for the dose selection. Dr.
> Brass has already commented about slide 17 with the profile. In the
> presentation it was noted that the eight-hour concentration was
> approximately 0.5 mcg/mL, about the 75 percent inhibitory value. But
> that is based on total concentrations, and the drug is 99 percent
> protein bound so the free drug concentration would be considerably
> less than that 75th value. So, I don\'t see from those data a
> pharmacologic basis for the dose that has been selected, the 400 three
> times daily. So I am wondering what other pharmacologic data you have,
> correlations with dose and antiviral effect or emergence of
> resistance, correlations with concentrations and antiviral effect and
> emergence of resistance.
>
> DR. MCKINLAY: Let me call Dr. Rhodes to explain the rationale for the
> dose selection.
>
> DR. RHODES: Our dose was selected based on an appropriate combination
> of preclinical and clinical Phase I pharmacokinetic data. Data from
> Phase II trials were not conclusive with respect to antiviral activity
> with respect to PK/PD and it wasn\'t traditionally sampled in that
> way. However, we did have an appropriate combination of data from
> which to decide on a dose selection. Our dose is 44 mg TID for five
> days.
>
> \[Slide\]
>
> The slide that Dr. McKinlay showed you with the classic concentrations
> at eight hours, what we did, we had preclinical data suggesting that
> the tissue to plasma ratio, partitioning of drug from plasma to
> tissue, nasal tissue, was approximately five-fold. So we looked at a
> range of Phase I data, at the eight-hour time point, the end of a
> dosing regimen; looked at the plasma concentrations in individual
> subjects at that point. We took those subjects with the lowest plasma
> concentrations, dose over the individual variability, and with that
> projected five-fold ratio of plasma to nasal tissue concentration,
> patients with the lowest plasma concentrations at eight hours,
> applying that factor would project the nasal tissue concentrations at
> MIC90 for rhinovirus serotypes. So our dose was selected based on
> those criteria.
>
> DR. FLETCHER: My second question is about food. In the data the FDA
> presented they indicated that the food effect increases the AUC by
> about four- to six-fold. To understand that there must have been some
> study that was done, drug given fasting or drug given with food. I
> would like to know what that meal looks like. How many eggs, how much
> bacon?
>
> DR. RHODES: The study that has been referred to was a comparison of
> fasting subjects to those getting a standard English breakfast. So it
> would have been eggs, bacon, hash browns, toast and butter \-- a
> rather heroic meal!
>
> \[Laughter\]
>
> DR. FLETCHER: And that was done in healthy volunteers or in
> individuals that were in a study that had a cold?
>
> DR. RHODES: That was done in healthy volunteers.
>
> DR. FLETCHER: So in the pivotal studies, 43 and 44, what were the
> recommendations there for meals?
>
> DR. RHODES: In the Phase III trials patients were asked to take
> pleconaril with food. The meal was not specified so it was an open
> dietary regimen.
>
> With respect to protein binding, the drug is highly protein bound,
> granted. But it is not like many drugs that are highly protein bound
> with a very low volume of distribution at, say, just extracellular
> water volume. Pleconaril\'s volume of distribution is considerable
> even with the high protein binding.
>
> DR. FLETCHER: Another drug interaction question. In Dr. Cooper\'s
> presentation, she indicated, I believe, that these drug interactions
> were manageable. I am curious how they were manageable. What are the
> guidelines by which you would manage the oral contraceptive
> interaction or the theophylline interaction, or the potential
> interactions with other CYP substrates?
>
> DR. MCKINLAY: I would like Dr. Joe Bertino to address this, as an
> individual with a lot of experience in this area.
>
> DR. BERTINO: I am Joe Bertino. I am the section chief of clinical
> pharmacology at Bassett Healthcare, in Cooperstown. We did the
> midazolam study.
>
> \[Slide\]
>
> Dr. Fletcher, in terms of your question, I think that in terms of
> manageable there are some different issues that I would raise. The
> immunomodulators, cyclosporin, protease inhibitors \-- we, clearly, on
> this slide have a break where I think that these are the interactions
> that I would be most concerned about.
>
> The oral contraceptive issue, I think there is an expert in the
> audience here today, Dr. Mishell, that can probably comment on that a
> lot more. The question really is do you lose contraceptive efficacy?
> In the rifampin-rifabutin studies in the literature, a very potent
> inducer of both ethinyl estradiol and norethindrone, in those studies
> in the literature in two separate groups of women, women never spiked
> their progesterone so they never ovulated even in the face of a drug
> interaction, but there is a lot of variability in the population in
> terms of estrogen/progesterone exposure.
>
> These agents I have put down here, I think drugs like amiodarone that
> have very long half-lives, 40-50 hours, the only thing that is
> reported in the literature for that drug is a case report of a woman
> with TB that got five weeks of rifampin and then had a ventricular
> arrhythmia on amiodarone.
>
> Calcium channel blockers, again, probably for hypertension I would
> think this would be less of an issue if patients were being treated
> for angina. There is a report in the literature of a
> rifampin-nifedipine interaction with variant angina coming back into
> the patient as being a concern.
>
> Benzos, you know, once again the effect was about 30 percent with
> midazolam. Presumably a drug like alprazolam might show a similar
> effect. It would be hard to know what the overall implications are for
> those drugs.
>
> Clarithromycin \-- opiate analgesics \-- we have alfentanyl here,
> alfentanyl is also a 3A substrate, and there is probably not a real
> concern with the statins.
>
> So I think that my concern lies in this group of drugs, here, mostly
> these two in terms of managing, I probably would be reluctant to use
> the drug in patients getting cyclosporin and protease inhibitors.
>
> DR. FLETCHER: I suspect we will come back to the drug interaction
> topic again, but let me get to my last question, which is a joint one
> for both the sponsor and I would like the agency to comment as well.
> That is on whether there is a possibility of ethnicity/race difference
> in effect with this drug. In study 043 you enrolled about 80 percent
> whites and in 044 about 90 percent. In the intent-to-treat analysis
> there was a beneficial effect in 44 but not in 43. Then, in one of the
> sponsor\'s subgroup analyses, on page 73 of your briefing booklet, you
> actually did an analysis looking at the effect of the drug in whites
> and in non-whites. We realize the sample size issue, but for the white
> population there was a benefit; for the non-white there was not. So,
> my question first for the sponsor, and I would like to know if the
> agency looked at that issue as well, you know, is the reason you found
> an effect in 44 with intent-to-treat and not in 43 because it has a
> higher population of whites enrolled? So, the bottom line is are there
> data here telling us that there may be an ethnicity/race differential
> effect with this compound?
>
> DR. HAMMERSTROM: We did look at the analysis stratified by race. There
> was a smaller effect in blacks. In fact, if I remember correctly,
> there wasn\'t much of one at all. But it is a very small subset and it
> is difficult to decide. You could say there is a signal there. In a
> perfect world where clinical trials could be run free of charge, we
> would like to say 500 black patients treated with this drug to find
> out whether that signal is just noise or not. The way it is now, it
> looks like it could be just noise but we can\'t prove it is not. I
> don\'t remember whether there was a difference in ethnicity percentage
> between the two trials.
>
> There is an effect in the ITT population even in trial 43. All of the
> quartiles are shifted downward about half a day. It is not
> statistically significant. I think the p value was \-- what? \-- about
> 0.2. But there have been other drug approvals where we have approved a
> drug on the basis of one pivotal trial getting a p value comfortably
> below 0.05 and the other trial getting a p value that is around 0.09
> or something like that. It didn\'t make the nominal p value. Remember,
> p values, for all the popularity of the 0.05 cut-off point, do not
> drop. It doesn\'t suddenly change from effective to ineffective as you
> cross that border.
>
> DR. MCKINLAY: Dr. Villano?
>
> DR. VILLANO: The analysis that we performed looking at the efficacy in
> the primary endpoint based on race was an analysis that we performed
> in the pooled data set because, as was mentioned, although we did not
> enroll patients with any restrictions as to race there were, as it
> turned out, very, very small numbers in the non-white group.
>
> \[Slide\]
>
> This slide shows these pooled results that were mentioned in the
> briefing book. In the large group of subjects who were white there
> clearly is a demonstrable treatment benefit, whereas, we could not
> make this conclusion in the non-white subgroup. However, to the extent
> that we could try to analyze whether there were true differences
> between these groups or not, we did apply a Cox regression model to
> try to analyze whether there was consistency that could be
> demonstrated within these groups. Obviously, it is very difficult
> because of the very small group. That value was insignificant,
> suggesting that there was no inconsistency of effect between those
> groups to the extent that that analysis can help.
>
> However, in addition, to help support the activity of pleconaril in
> both subgroups we also looked at a supporting endpoint, the viral
> culture results based on race as well.
>
> \[Slide\]
>
> That is shown in this slide. Looking at the white and non-white
> population on the right and left-hand side of the screen, there was an
> interesting difference between the white and non-white groups in that
> the non-white population actually, at day three, had a notably lower
> viral culture positivity rate, although in both groups there was
> treatment effect seen. So to the extent that we could analyze it, we
> have not seen notable differences between those groups although,
> again, our numbers are very small.
>
> DR. GORDIN: To follow-up, I was also concerned, in the same Table, 25,
> that gender appears to be a major factor as well. Where the numbers
> are substantially larger, it appears that, again, the effect is seen
> in women but not in men. I was wondering if you could show that. I was
> also, again, interested in the agency\'s opinion on this, and how much
> of the gender race is intermixed with smoking as a factor. If you
> could kind of talk a little bit more about the subgroups.
>
> DR. BRASS: You might as well add age to that too.
>
> DR. VILLANO: First let me show you the analogous slides with regard to
> gender. Again, I will stress that the protocols were enrolled without
> restriction as to gender, although based on some of the epidemiology
> that you might have heard about colds, they are certainly more
> prevalent in women which probably reflects the enrollment in our
> studies.
>
> \[Slide\]
>
> This also shows the viral culture results based on gender, also
> showing that both women and men had a demonstrable effect in terms of
> antiviral activity, culture positivity reduction on day three compared
> to the placebo groups.
>
> \[Slide\]
>
> With regard to the primary endpoint, we did the exact same type of
> analysis, looking at the primary endpoint, pooling the studies
> together to, again, maximize the numbers. In this instance we see that
> women had the greater result in terms of reduction compared to
> placebo. The direction clearly was also in favor of pleconaril in men,
> although the magnitude of the change was not as large.
>
> We attempted the same Cox regression analysis to see if that could
> demonstrate significant differences between those groups. We did not
> find that difference in that particular analysis.
>
> You also mentioned smoking as well. What I would like to do is just
> give an overall view, again, of our ability to try to discern which of
> these variables, prestratified variables and demographics might have
> had influence on the primary outcome measure.
>
> \[Slide\]
>
> This slide demonstrates, again, our attempt to use a Cox regression
> model to evaluate each of these variables in turn as to whether or not
> there was effect on the treatment efficacy of pleconaril. As shown
> here, looking for any p value that showed significance, the
> interaction was positive only for smoking status, suggesting that of
> all these variables, including demographics, that was the one that
> clearly had an effect on treatment outcome based on the primary
> efficacy endpoint.
>
> DR. HAMMERSTROM: Our analysis pretty much confirms the sponsor\'s
> analysis. We did have, if you remember, a slide up there crossing
> gender with smoking and there didn\'t seem to be a three-way
> interaction of treatment, gender and smoking. The absence of effect
> among smokers was about the same. There is a smaller effect in males
> estimated, but it is still positive. There is not enough N to get a p
> value and say that it is small at 0.05 even when you pool the two
> studies together because, remember, only a third of the patients are
> males.
>
> We didn\'t look that much at age, but there is not that much variation
> in age. Most of these people are working age adults. There are not
> that many elderly and there are no children.
>
> DR. GULICK: Dr. Englund and then Dr. Wong.
>
> DR. ENGLUND: Yes, I wanted to discuss a little bit more about the
> diagnosis, specifically the PCR diagnosis you used. Although it was
> not for the primary endpoint, in fact, slide after slide you have
> shown us is showing culture as an indicative endpoint. In fact,
> culture was only attempted when PCR was done. I am not an expert in
> rhinovirus PCR but, in fact, based on what I do know about some of the
> TaqMan systems, you have chosen a lower threshold of 0.1, I believe,
> and doing it for 60 cycles, whereas most of, at least the flu things,
> have been 45 cycles. So perhaps could someone discuss the methodology
> and why this was done, and if there was even a subset analysis if
> there are any culture positive with PCR.
>
> DR. MCKINLAY: Right, we can show you the clinical data by subset by
> culture positives. But, first, let me have Dr. Collett come up and
> talk about the assays.
>
> DR. COLLETT: Marc Collett, virology, ViroPharma. The TaqMan assay that
> you are specifically referring to, we used a 60-cycle assay run. All
> the performance data were generated using that cycling run. We have
> demonstrated that the results from both the performance evaluations
> and supplementary testing, which may not have been provided in your
> book, indicate that the TaqMan assay maintains its high level of
> sensitivity and specificity throughout the cycles.
>
> \[Slide\]
>
> Shown on this slide is a breakdown by cycle, and confirmation by
> cycles of TaqMan positive samples, grouped here at less than 20
> cycles, 30 cycles, 40 cycles, 50 and 60 cycles, showing the number of
> TaqMan positive samples in this collection of clinical specimens
> tested from the three studies. The confirmation rate by the
> independent RT-PCR assay, which uses different primers and is a
> different methodology, the assay agreement is quite high. The assay
> agreement is high across all levels of CT values or threshold crossing
> values. So it appears that the specificity is maintained at the higher
> cycles.
>
> DR. ENGLUND: But you have no culture data. In fact, there are study
> samples which might include patients receiving therapy or not
> receiving therapy. Correct?
>
> DR. COLLETT: Yes, these are baseline samples.
>
> DR. ENGLUND: Oh, this is baseline?
>
> DR. COLLETT: Yes.
>
> DR. GULICK: Dr. Atmar?
>
> DR. ATMAR: In the description of the assays in the application the
> ELOSA was said to be more broadly reactive an assay. There really
> aren\'t any data describing what the relative levels of detection of
> the two assays are in terms of amount of viral genome. Do you have
> information about that for us, and what is your explanation for the
> apparent lower number of positives in the ELOSA column compared to the
> TaqMan column?
>
> DR. COLLETT: Are you referring to these particular data, here?
>
> DR. ATMAR: I am referring to these data in terms of comparison of the
> TaqMan to the ELOSA and then just a question about what the relative
> level of detection is in terms of the number of genomic copies per
> sample need to be present.
>
> DR. COLLETT: Let me first start with the spectrum of detection by the
> two assays because that differs slightly. As we get that slide up, for
> the TaqMan assay the primers were derived based on an analysis of
> rhinovirus sequences. So the TaqMan assay turns out to be more
> rhinovirus specific than more broadly cross-reactive to picornavirus
> encompassing both rhinoviruses and enteroviruses.
>
> \[Slide\]
>
> Shown here, the TaqMan assay identified 89 percent of the 101
> prototypic serotypes but very few enteroviruses, whereas the ELOSA,
> using the different primer set, was able to detect all the prototypic
> viruses, both the rhinoviruses and the enteroviruses.
>
> Going back to the assay agreement between the two assays, there is
> some disagreement, as shown in the previous slide, that could relate
> to differences in the viruses that were being detected, as well as
> differences in the efficiency of the two assays since they are using
> different primer sets and, actually, different assay technologies.
>
> DR. ATMAR: But my question is how much viral genome per mL or per
> sample needs to be present? You use 1B I guess \--
>
> DR. COLLETT: We use the 1B as a standard but we have also looked at
> five prototypic serotypes and looked at the lower limit of detection,
> which I believe is what you are asking.
>
> \[Slide\]
>
> This slide is showing it for the TaqMan assay in two units, either the
> traditional or more customary PFU, which these viruses are all
> quantified by. We see that the lower limits of detection are less than
> PFU. If we then calculate based on estimations of absolute RNA
> quantities, we get, as you can see, a variation of genome detection
> sensitivities across the five serotypes. This doesn\'t appear to be
> unexpected. We would expect this type of diversity due to their
> genetic diversity as well.
>
> DR. ENGLUND: But just one more follow-up though, but that assay is
> done using viruses grown in tissue culture, or something like that.
>
> DR. COLLETT: That is correct.
>
> DR. ENGLUND: My other concern about all this is you are using frozen
> mucus collected in Saran wrap or other methods, and do you have any
> data? There is actually good data about the inactivation with the
> thick mucus of other viruses and I just haven\'t seen any data on
> rhinoviruses.
>
> DR. COLLETT: Excuse me, other viruses?
>
> DR. ENGLUND: Other viruses when TaqMan procedures are used, that it
> will actually limit the detection by PCR. So I am concerned because we
> are getting an endpoint \-- not an endpoint, excuse me, but we are
> analyzing our data and we are all thinking critically based on the
> culture results which are determined by PCR, for which I see no good
> standardization or even increased data on the methodologies.
>
> DR. COLLETT: The data collection paradigm was that individuals were
> evaluated for PCR positivity and then those individuals were
> subsequently cultured. Based on performance evaluations prior to the
> pivotal studies, we did an assay agreement analysis, a three-way
> comparison of all the assays to determine what number of virus culture
> positives we might get outside of the TaqMan detection sphere, and
> that turned out to be quite low. This was an evaluation of 855
> baseline samples from the 032 study. There, we found 0.6 percent of
> the sample were virus culture positive but scored negative by both
> RT-PCR assays. So we would have missed some patients in the pivotal
> trials because we didn\'t do virus culture on all samples, but we
> estimate that would be a very low number, approximating about six to
> eight individuals.
>
> DR. ENGLUND: But in that early study, how were those samples
> collected? Were those washes as opposed to mucus blows?
>
> DR. COLLETT: It was blown mucus collection, very similar to what was
> done in the pivotal studies.
>
> DR. ENGLUND: I thought the pivotal studies were done two different
> ways. No? They were done both with nose blows?
>
> DR. MCKINLAY: Right, it was blown mucus in study 32 and a swab was
> taken \--
>
> DR. ENGLUND: Yes.
>
> DR. MCKINLAY: \-- of the sample, whereas in 43 and 44 the whole sample
> was taken.
>
> DR. GULICK: Did we get to all your questions, Dr. Englund? I thought
> you had one more.
>
> DR. ENGLUND: I did, but now I have forgotten it. You can go on.
>
> DR. GULICK: Thanks. Dr. Wong and then Dr. DeGruttola.
>
> DR. WONG: I want to return to the safety profile of the drug. I think
> I have a reasonably good flavor for the efficacy, but I was concerned,
> when I read the book and then also during the presentation, about the
> possibility that this drug really may cause excess unintended
> pregnancies in women taking oral contraceptives. When I looked at the
> data that would really bear on that question I couldn\'t really make
> an assessment for myself because some of the denominators, for
> example, were missing in some of the groups. I was wondering if you
> could reassure me that that is not the case. I mean, show us the data
> that bears directly on that point.
>
> DR. MCKINLAY: First I will ask Dr. Villano and then we have an expert
> in our midst, Dr. Mishell, who can comment on this as well.
>
> DR. VILLANO: Specifically, I would like to review again the data that
> we presented with regard to the pregnancies that occurred in both the
> five- to seven-day treatment studies and then distinctly in the
> six-week prophylaxis study.
>
> \[Slide\]
>
> This slide summarizes the pregnancies that occurred in all five- to
> seven-day treatment studies that were conducted with pleconaril. Among
> placebo patients there were 1500 women, 303 of whom were using oral
> contraceptives. There were four pregnancies reported in this group,
> one of which occurred in an oral contraceptive user. Among the
> patients receiving pleconaril the number was greater, 415 women were
> using oral contraceptives during any of these studies and there were
> two pregnancies, neither of which occurred in women who were using
> oral contraceptives.
>
> As presented earlier this morning, we don\'t have outcome on this
> particular woman. We tried several times. The patient refused
> follow-up despite several contacts.
>
> \[Slide\]
>
> In distinction, the incidence in the six-week prophylaxis study
> obviously encompasses a longer treatment period and follow-up period.
> This slide shows these results. On the top, we see the placebo
> patients. I can reiterate the numbers here. We have approximately 100
> women on oral contraceptives in each of the first two groups. I am
> sorry, they are not on the slide, but approximately 100 women on
> placebo; approximately 100 on 400 mg once a day; and approximately 60
> on 400 mg BID. The pregnancy rate is shown here. We had one in the
> placebo group, one in the 400 mg Q day group and five in the 400 mg
> BID group, and this is where we had two pregnancies that occurred in
> women who were receiving oral contraceptives. One had an elected
> abortion; one is still ongoing, outcome to be determined in several
> months.
>
> Specifically with regard to any implications as to pleconaril\'s
> effect on the efficacy of oral contraceptives, we find that our data
> are actually fairly limited with regard to numbers to make
> conclusions. But I would like to invite Dr. Mishell to come up and
> comment on these results.
>
> DR. MISHELL: Thank you. Good morning, everyone. My name is Dan
> Mishell. I am the professor and chairman of the Department of
> Obstetrics and Gynecology at the Keck School of Medicine, University
> of Southern California.
>
> I would just like to start off by telling you my qualifications for
> commenting on this. I have been involved with contraception as my main
> area of interest since I entered academic medicine in 1963. I have
> been a consultant to the Population Council in New York and am a
> consulting senior scientist to them. That is the organization that
> developed the copper T intrauterine devices, as well as the Norplant
> implantable contraceptives. I have also been a consultant to the World
> Health Organization on their contraceptive development program in the
> 1970\'s. I edit the medical journal [Contraception]{.underline}, which
> is a monthly journal, and since its inception in 1970 I have been the
> editor in chief. It is a peer reviewed journal dealing exclusively
> with contraception. I have also chaired the NIH symposium on
> contraception that was held here, in Bethesda, last summer, and I have
> written chapters on contraception for numerous medical texts,
> including Cecil\'s textbook of medicine.
>
> I would like to just tell you about oral contraceptives. They are
> composed of two steroids, progestin which is the steroid in the oral
> contraceptives that is mainly responsible for their contraceptive
> effect. What progestin does is inhibit the mid-cycle LH surge which is
> a stimulus release of the egg from the follicle so ovulation doesn\'t
> occur. The progestins have been used by themselves as very effective
> contraceptives. There is an injectable agent which is a progestin,
> which has no estrogen and is extremely effective in preventing
> pregnancy.
>
> The implants that I just mentioned are also composed of just
> progestins. There is no estrogen, and they also have an extremely high
> effectiveness rate. Both of these types of progestin only
> contraceptives have failure rates less than half of one percent per
> year.
>
> The progestins also prevent pregnancy by secondary mechanisms, keeping
> the cervical mucus such that the sperm doesn\'t ascend to the upper
> genital tract to fertilize the egg, and also alters the endometrium,
> suppressing the growth of the glands which make the glycogen which
> supports the growth metabolism of the blastocysts while in the
> endometrial cavity so it really prevents implantation if fertilization
> happens to occur.
>
> The other steroid in oral contraceptives is estrogen. In most
> combination oral contraceptives there is an estrogen and it is called
> ethinyl estradiol. It is a synthetic steroid. There are a couple of
> pills that are progestin only pills but they are not used very
> frequently but they are fairly effectiveness, low dose progestins.
> This estrogen in the oral contraceptives, its main action is to
> maintain the endometrium and prevent intermenstrual bleeding and to
> prevent bleeding except after the pills are stopped and then the woman
> has withdrawal bleeding for several days. The estrogen also has a
> contraceptive mechanism that inhibits follicular growth by suppressing
> FSH, but its main effect is maintaining the endometrium.
>
> This agent, pleconaril, stimulates the enzyme that helps metabolize
> the estrogen, ethinyl estradiol. That is why the area under the curve
> of ethinyl estradiol is reduced. There is increased metabolism of the
> estrogen. But it has really no effect on the progestin in the study.
> That is to be expected because of the mechanism of action of the
> enzyme and how the estrogen and progestin are metabolized differently.
>
> \[Slide\]
>
> Let me just sort of summarize what I have said. The main action of the
> steroids in the oral contraceptives, progestin, is to inhibit
> ovulation. That is the way it works, it inhibits the LH surge and
> thickens the mucus. So progestins alone are contraceptives and this
> agent does not interfere with the metabolism of the progestins. So, I
> would expect it to not have any effect on contraceptive efficacy. The
> numbers we saw, as far as pregnancies, are pretty reassuring. In the
> 400 women who used the oral contraceptives and were taking pleconaril
> for five to seven days there were no pregnancies. That is really quite
> reassuring to me.
>
> In the six weeks there were two pregnancies. The numbers are really
> small, and typical use of oral contraceptives, in contrast to the
> studies that were submitted for the approval to the FDA in which the
> pregnancy rate was around one preclinical, in typical use in the first
> year the failure rate of combination oral contraceptives is around
> five percent. Those are studies that were done by Jim Trusseller,
> published in [Contraceptive Technology]{.underline}, based upon
> national surveys of family growth.
>
> The estrogen\'s main mechanism is to decrease the breakthrough
> bleeding or intermenstrual bleeding. It also inhibits follicular
> growth. So by decreasing the levels of estrogen, one will have an
> increased incidence of intermenstrual bleeding, which is what has been
> found in the studies of short-term and long-term use.
>
> \[Slide\]
>
> Just to remind you of the interaction study in which an oral
> contraceptive was given alone, in the yellow line, and then after six
> days of pleconaril another single tablet of oral contraceptives, and
> this is the estrogen showing significantly reduced levels in the
> circulation. Then pleconaril was given again at one and two days
> thereafter and showed that there was still a decrease in estrogen
> levels, decreased area under the curve. Therefore, one would expect an
> increase in breakthrough bleeding which was observed in the clinical
> studies
>
> \[Slide\]
>
> If we look at the progestin, I think this is what is reassuring to me
> because this is what prevents pregnancy. You can see that these two
> curves are superimposable. It is the same study. This is progestin
> levels, and the yellow and blue lines are superimposable even after
> two more days of pleconaril, after giving it on the six day. So I am
> really reassured about this data and the pharmacokinetics. This agent
> will be associated with an increased incidence of intermenstrual
> bleeding, which is more what we call a nuisance side effect. It is
> really not a health side effect. Women don\'t like to have unscheduled
> bleeding, but as the dose of estrogen has declined in oral
> contraceptives formulations there has been an increase in the
> incidence of intermenstrual bleeding. With the low estrogen dose pills
> that we have today, the lowest that is approved in the United States
> and marketed is 20 mcg of estrogen and about ten percent of the women
> have breakthrough bleeding or spotting. As I said, it is an annoyance
> but it doesn\'t cause anemia, doesn\'t need blood transfusion. As
> shown in the studies, no woman discontinued use in the five- to
> seven-day study because of abnormal menses.
>
> There is a drug marketed in Europe with 15 mcg of ethinyl estradiol,
> 25 percent less than we have here. It is not marketed in the United
> States, and one of the reasons is because it has a lot of breakthrough
> bleeding. But I have to say that it is still effective as a
> contraceptive because it has sufficient progestin to prevent
> pregnancy. So that is my interpretation of the data. I appreciate the
> opportunity to address it. If you have further questions, I will be
> happy to answer them.
>
> DR. GULICK: Could we also ask the agency to respond to the same
> question?
>
> DR. BIRNKRANT: Sure, I will begin with that response. I think one
> thing we have to keep in mind is that in the six-week clinical trial
> of prophylaxis women were re-consented to use a backup barrier method
> during the clinical trial. So, it is not just that we are seeing a
> handful of pregnancies. We may have seen actually more had they not
> been re-consented to use barrier methods as a backup.
>
> The other thing I wanted to mention is we don\'t really know how long
> this induction lasts. We only have this drug interaction study of five
> days. We don\'t really know how much longer it goes, and how long it
> takes to recover. The applicant will be conducting further studies to
> help shed additional light in that area.
>
> In addition, I just wanted to comment that the pregnancies that we saw
> were only in the six-week trial period, and it is my understanding
> that typically for oral contraceptive development these trials are
> approximately a year long, with low levels of contraceptive failure
> rates and here we are seeing failure rates after only six weeks.
>
> MR. FLEISCHER: I would like to chime in. The other thing is that in
> the five- to seven-day treatment trials there was no targeted
> questioning of menstrual disorders and we may actually have
> under-reporting because, if the woman had some breakthrough bleeding
> she may not have thought it was anything because it was just part of
> her cycle. We don\'t know. In the six-week study they were
> specifically asked so we may actually have an overestimation.
>
> The other thing that is interesting in the six-week study is that
> there appears to be a dose response. If you look at the once daily
> pleconaril and compare that to the twice daily and compare that to
> pleconaril, it is increasing exponentially as the dose of pleconaril
> increases.
>
> The other thing in the five- to seven-day treatment trials is that
> there was no long-term follow-up so we don\'t know what happened maybe
> a month later with women who may or may not have gotten pregnant.
>
> Then, in the pharmacokinetic studies the slope remains decreasing at
> 48 hours when the measurements were made. As Dr. Birnkrant said, we
> don\'t know when that plateaus and we don\'t know when they come back.
>
> So, we agree that we don\'t have hard data to know what the risk is,
> but we believe there is a potential risk that has to be dealt with
> somehow in the labeling and communicated to patients in a way that
> they would not freak out.
>
> DR. GULICK: People had a couple of follow-up comments. Dr. Wood and
> Dr. Kumar?
>
> DR. WOOD: One of the questions I had was concerning potential repeat
> exposure to pleconaril after you had an initial exposure. Since the
> half-life is so long, the question then becomes is there any idea, in
> terms of whether or not there would be a continued reduced
> effectiveness of contraception, if a woman were to be re-exposed.
> Let\'s just say she took a five- to seven-day course as she would if
> she had a cold, and then maybe developed cold symptoms five weeks
> later or six weeks later where conceivably the drug might still be
> around from her initial dosing. Could you comment on that at all? Are
> any studies planned?
>
> The other issue is in the studies planned by the pharmaceutical
> sponsor of interactions with oral contraceptive pills, there is only a
> BID dose that is going to be studied, not a TID dose. It didn\'t seem
> like there was a TID dose of pleconaril, which is the therapeutic dose
> in the 043 and the 044 studies.
>
> DR. MISHELL: Could I just respond to the agency\'s comment before that
> question is answered? Yes, I agree that warnings need to be put in the
> labeling about the chances of increased bleeding, similar to what
> occurs with other drugs such as the anticonvulsants which sort of do
> the same thing. But as far as the numbers of pregnancies, you are
> dealing with two pregnancies in oral contraceptive users. I mean, the
> N is so small you can\'t really make any conclusions about that. As I
> said, in typical use of oral contraceptives the failure rate is five
> per hundred women in the first year of use. So, in six weeks, which is
> a quarter of that, it would be a little bit more than one. You know,
> the numbers are so small we can\'t really interpret it.
>
> DR. GULICK: Dr. Birnkrant?
>
> DR. BIRNKRANT: Our consultant from the agency, Dr. Leslie Furlong,
> will respond.
>
> DR. FURLONG: With due respect to Dr. Mishell, I don\'t think you can
> actually use the typical use rates in this setting. Dr. Trusseller\'s
> typical use rates are based on retrospective survey data where women
> were asked for the preceding four years, month by month, what they
> were using as a birth control method. We are talking about a clinical
> trial here, and we thought an appropriate comparator would be
> contraceptive efficacy clinical trials in which we see actually, on
> average, 0.7 pregnancies per 100 women per year in all our currently
> approved products.
>
> The five-day studies, I don\'t believe, were designed to detect
> pregnancies. The six-week studies were modified. There was a protocol
> modification once the breakthrough bleeding data came along, and they
> were looked at from the standpoint of pregnancy detection. In those
> studies we see no pregnancies in the placebo group in patients who
> were on oral contraceptives. We see none on the low dose pleconaril
> group on oral contraceptives, and we see two in 156 women who were
> using pleconaril and oral contraceptives.
>
> We agree that the numbers are too small to state anything with
> statistical significance, however, it is interesting that we see none
> in placebo, zero also in the low dose pleconaril and two as the dosage
> increases. In addition, we, at the agency, are not as sure about which
> of the two components of the combination birth control pills is
> responsible for efficacy. We believe it is an interaction. I don\'t
> believe that the progestin only pills are simply watered down versions
> of combination oral contraceptives for many reasons. One obvious
> reason is that the progestin only pills are taken on a daily basis.
> There is no seven-day window of non-use. The combination oral
> contraceptives must continue to be effective through a seven-day
> window in which women are not taking the pill. So there is a very
> large difference there.
>
> In addition, we know that ethinyl estradiol induces sex hormone
> binding globulin, which is a protein to which man of the progestins
> are highly bound. We don\'t reach steady state levels of norethindrone
> in some of our pills until they have been taken for two weeks. So, a
> single dose midazolam study is not adequate to address even
> norethindrone concentrations in an average pill user.
>
> So for those reasons we think there is still concern about the two
> pregnancies that were detected in the six-week trials, and we think
> that the drug should be labeled that way.
>
> DR. GULICK: Mr. Fleischer?
>
> MR. FLEISCHER: You mentioned that you agreed that information should
> be contained in the labeling about this interaction, should it be
> approved. What would you recommend putting in there? A mention in the
> adverse events section, a precaution, a contraindication, a warning or
> a black box?
>
> DR. MISHELL: Well, I would use something similar to what is in the
> anticonvulsant drugs. I believe it is in the warning section and also
> in the patient package insert, as well as the physician\'s insert. I
> guess it depends on whether you want to put a warning in against
> unwanted pregnancies based upon two pregnancies or not. I still think
> that the data are very reassuring in the initial study, the way the
> drug is being given and also the pharmacokinetics of the progestin. It
> is not something that is going to cause a great number of pregnancies,
> I don\'t think, if it actually does enhance the pregnancy rate, and I
> don\'t think there is evidence that it does from the data that we have
> right now.
>
> DR. GULICK: First Dr. Kumar and then Dr. Wood. We got a little
> sidetracked.
>
> DR. KUMAR: First I want to make a comment and then ask a question. I
> want to move a little bit away from pregnancy to intermenstrual
> bleeding. You alluded to the fact that intermenstrual bleeding is more
> an annoying problem than something that is clinically worrisome. I
> think that is in the context of which drug is given for what
> indication. For an anti-epileptic that is given for a serious
> condition, then I would agree with you, sir, that it is more annoying
> and that the benefits far outweigh the risk. But for something like a
> common cold about which we are talking, the intermenstrual bleeding,
> in those circumstances you are giving up one set of annoying
> complaints for another set of annoying complaints. So, I do wish to
> point out a woman\'s perspective on that.
>
> DR. MISHELL: I totally agree with you, but I think most of the
> intermenstrual bleeding or spotting doesn\'t require sanitary
> protection. I think it has to be put in the labeling, as the agency
> said, that this does occur.
>
> DR. KUMAR: You certainly have more expertise than I ever had but I
> just wanted to point out my view.
>
> The second thing, and this is to Mr. Fleischer, I just wanted to make
> sure I understood from the briefing document and from the slide that
> you showed on menstrual disorders, is there more intermenstrual
> bleeding in patients who took pleconaril but did not take oral
> contraceptives? That is the way I understood it.
>
> MR. FLEISCHER: No.
>
> DR. KUMAR: Even patients who did not take oral contraceptives, was
> there increased intermenstrual bleeding?
>
> MR. FLEISCHER: In the six-week study?
>
> DR. KUMAR: In the prophylaxis study, yes.
>
> MR. FLEISCHER: Remember, they became targeted adverse events. So it is
> possible that women, when they started to ask about them, they
> answered more positively. It ran about 13-16 percent across the
> pleconaril and placebo arms. That was very consistent across the three
> arms in non the non OC users.
>
> DR. MISHELL: But in women taking oral contraceptives in the placebo
> arm there was no increased intermenstrual bleeding than in women
> taking pleconaril. The incidence was the same. In the women taking
> pleconaril and on placebo the incidence was the same, identical.
>
> DR. KUMAR: In the prophylaxis study, in women not taking oral
> contraceptives was there an increased intermenstrual bleeding in the
> pleconaril arm?
>
> DR. MISHELL: You probably ought to look at the data.
>
> DR. VILLANO: There were several questions of a related nature. Let me
> just address the latter and we may want to come back to the former. I
> am going to show a slide that depicts all menstrual disorder events in
> both the five- to seven-day and the six-week prophylaxis studies. I
> would like to divide the women into those who were receiving any
> estrogen or progestin component of any kind. We further subcategorized
> those women into those who were receiving an oral contraceptive and
> those who were receiving any other estrogen or progestin compounds,
> such as hormone replacement or Depo-Provera and those who were
> receiving no estrogen or progestin of any kind, to show you the
> difference between those groups.
>
> \[Slide\]
>
> To your specific question, I will focus on the right-hand of the slide
> with the longer-term follow-up in the sex-week prophylaxis study.
> Among all women in the six-week prophylaxis study the three groups are
> shown here. The incidence of any menstrual disorder ranged between 21
> and 32 percent. The differences clearly lie in the oral contraceptive
> use group, with a difference of between two and three times greater
> incidence in those receiving pleconaril.
>
> Of note, of those receiving any other estrogen or progestin, there
> were actually no episodes of menstrual disorders in those who received
> pleconaril; three in those receiving placebo. Among those women who
> were receiving no estrogen or progestin of any kind, the rates are
> shown here, between 18 and 21 percent, with no significant difference.
> I think that was the question.
>
> DR. KUMAR: Thank you.
>
> DR. GULICK: Dr. DeGruttola?
>
> DR. DEGRUTTOLA: I just had a technical question on the subgroup
> analyses of how the estimate or how the testing of the consistency of
> results across subgroups was done. Was that a test of interaction
> between the subgroup and question like sex or the effect and question
> like sex and treatment?
>
> DR. MCKINLAY: I will ask Dr. Hudson to come up.
>
> DR. HUDSON: Good morning. Spencer Hudson, biostatistics ViroPharma. I
> would like slide 1812.
>
> \[Slide\]
>
> These are the results of a series of Cox regression models that were
> used to look for inconsistency between the effect of treatment and the
> individual subgroups. All these were done on the pooled data so we
> maximized the power of these tests. The first one we did was simply
> looking at the consistency between treatment effect in the two
> studies. You can see here that that is not significant.
>
> DR. DEGRUTTOLA: Could I ask what you mean by consistency? Was there an
> interaction term, a study by treatment interaction term?
>
> DR. HUDSON: Exactly, yes. Then we went down to the two prespecified
> strata of smoking status and cold medication, and then we followed up
> with the three demographic variables, age, race and gender. Of all
> those tests, only the smoking status came out as being significant.
>
> DR. DEGRUTTOLA: I just want to comment I think that is the appropriate
> way to look at it. I get a little concerned when people look at
> subgroup analyses and say for certain groups it looks significant, a p
> value less than 0.05, and for other groups it looks not significant
> because the p value is greater than 0.05. I just want to point out
> that even if the predictor in question has no effect, like gender for
> example, just by chance you are going to see that situation arising.
> So I think that those results are interpretable.
>
> Then, I have one question for the agency. There was a comment of an
> exponential increase by dose, I believe, in the prophylaxis study for
> the risk of bleeding, I think it was. I just wanted to comment, if
> that was referring to the slide that was on immediately previous to
> this.
>
> MR. FLEISCHER: I used exponential without an exponent. It was a big
> increase between what we saw in the placebo compared to pleconaril
> once day, to pleconaril twice a day.
>
> DR. DEGRUTTOLA: Is that referring to the Tables 46 and 47?
>
> MR. FLEISCHER: What page was that?
>
> DR. DEGRUTTOLA: It is page 98 in the book and Dr. Hammerstrom just
> told me the lower slide on page 17.
>
> MR. FLEISCHER: Do you have it? Are you happy?
>
> DR. DEGRUTTOLA: Yes. I assume the increase you were referring to was
> in OC users, menstrual disorders going from 27 percent to 58, to 81
> percent.
>
> MR. FLEISCHER: Yes.
>
> DR. DEGRUTTOLA: Thank you.
>
> DR. MCKINLAY: Dr. Wood, I apologize. We didn\'t answer one of your
> questions.
>
> DR. WOOD: My concern was about individuals who may get repeated doses
> of pleconaril, with the long half-life, who are taking oral
> contraceptives.
>
> DR. MCKINLAY: I will ask Dr. Rhodes to come up. Dr. Cooper? Ellen had
> a comment first.
>
> DR. COOPER: First of all, regarding both the increased incidence of
> spotting and breakthrough bleeding in women on oral contraceptives and
> pleconaril, and also the concern about decreased contraceptive
> efficacy, again, it is important to differentiate between five-day
> treatment and the six-week study.
>
> In terms of Dr. Wood\'s question about repeated dosing, let\'s say a
> month later a woman takes five days of pleconaril and then a month
> later gets another cold and takes another course of treatment, the
> half-life, the long half-life is the terminal half-life. As Dr. Rhodes
> showed, for the initial half-life the levels really fall off quite
> quickly. So, there really are very low levels. They are there but they
> are very low for prolonged periods of time. So, we really wouldn\'t
> expect any substantially different effect with the second course a
> couple of weeks or a month later.
>
> I would just like to say that we certainly, at ViroPharma, agree that
> the numbers are small in terms of the pregnancies both in the five- to
> seven-day and in the six-week. We do have two pregnancies in women
> taking oral contraceptives and pleconaril in the six-week study. But I
> think that we can\'t draw conclusions one way or another, absolute
> conclusions one way or another from this data.
>
> We certainly agree that there is a need to look at the duration of the
> increased induction of the enzymes, and we are in the process of doing
> that. We also certainly expect to include in the labeling advice to
> physicians and to patients to use a backup form of birth control.
>
> DR. WOOD: So how long would you recommend that they use that backup
> form of birth control if they had a single course of pleconaril?
>
> DR. COOPER: For a minimum, for the remainder of the cycle. Whether we
> would recommend it for an additional month would depend on the outcome
> of the study in terms of looking at the duration of the induction of
> the CYP3A enzymes.
>
> DR. GULICK: Dr. Reller, then Dr. Sun.
>
> DR. RELLER: This will be for Dr. Cooper, Dr. Hayden or anyone they
> choose. The primary endpoint in smokers versus non-smokers, could you
> explain again why it seems that the smokers who get pleconaril have
> prolonged symptoms that are at about the same magnitude of the people
> who are non-smokers had a decrease in symptoms? What is the
> pathophysiology of that relative to placebo?
>
> DR. MCKINLAY: Dr. Villano?
>
> DR. VILLANO: In terms of the results we have seen in smokers versus
> non-smokers, what we started with in our analyses was looking at the
> results showing that we do, in fact, have antiviral efficacy in both
> subgroups, as demonstrated during the primary presentation. However,
> we did analyses to try to understand why that antiviral activity did
> not translate into efficacy in the primary endpoint which required
> that all symptoms be at least mild and, in fact, rhinorrhea resolved
> to absent.
>
> In reviewing this, we considered the natural history that is known
> about smokers and non-smokers in terms of their symptoms of the cold.
> Smokers are known to have colds associated with greater mucus
> production and are also known, at baseline, to have more chronic
> symptoms, such as rhinitis and cough. We hypothesized that the primary
> endpoint in particular that was utilized in these studies, which
> required all symptoms to be mild and at least the rhinorrhea to be
> resolved completely, may not be the best endpoint to analyze the
> efficacy that may be seen in smokers. We showed earlier that the
> symptoms score is reduced early in the course of illness. That is a
> post hoc analysis and, again, we did not demonstrate efficacy in the
> primary endpoint.
>
> In terms of your specific question regarding the differences between
> the pleconaril and the placebo groups, basically we are cautious about
> conclusions in this subgroup in that there were only 28 percent of
> patients who were, in fact, smokers. While we can conclude that we
> don\'t see any efficacy in the primary endpoint, we cannot further
> differentiate that magnitude of change between the two groups.
>
> DR. GULICK: Follow-up?
>
> DR. RELLER: Another thing that was paradoxical, at least for my
> assessment, is slide 16 that was shown by the agency that looked at
> time to primary endpoint, comparing those whose isolates were
> susceptible or resistant to pleconaril. I don\'t know if it is
> possible to put that up.
>
> DR. MCKINLAY: We actually have the same slide that they do.
>
> DR. RELLER: It is slide 16, on page 6 of the handout from the agency.
>
> \[Slide\]
>
> DR. MCKINLAY: This is a little different format but it is the same
> thing.
>
> DR. RELLER: So the question is in the susceptible isolates, those
> patients given pleconaril had decreased duration of symptoms, whereas
> in the non-susceptible isolates there was actually an increased
> duration of symptoms. Why might that be?
>
> DR. VILLANO: We can specifically look at this group of 13 percent
> overall of subjects who had baseline isolates that were
> non-susceptible to pleconaril. Not only were, obviously, these groups
> relatively small, in which case the primary endpoint value is somewhat
> sensitive because of the small numbers to the median, but also we
> found small imbalances in the percentage of patients who were smokers,
> an excess of patients on pleconaril versus placebo, and also slightly
> higher baseline total symptom scores in those in the pleconaril group
> compared to the placebo group. Again, probably the largest influence
> on this is the relatively anomalous low duration of illness as
> determined in the placebo group which is probably sensitivity to the
> relatively low numbers of subjects in those categories.
>
> DR. RELLER: If one looked at the susceptible strains, one would be
> trying to infer that if you got an agent that is active it works. But
> is it just small numbers? Just luck of the draw that those patients
> with resistant strains who received pleconaril actually had more
> symptoms, greater persistence of symptoms? How do you get there?
>
> DR. ENGLUND: Did you identify what those viruses were? I mean, we have
> kind of a lack of knowledge if they were even rhinoviruses versus
> enteroviruses. At least those specimens, do we know what those were?
>
> DR. MCKINLAY: Well, we tested a cross-section and actually sequenced
> the viruses. Of the subset we tested, 99 percent were rhinoviruses.
>
> DR. ENGLUND: Of these resistant ones?
>
> DR. MCKINLAY: Well, no, they were a subset of what we tested. Marc
> Collett, could you come up?
>
> DR. COLLETT: In the combined studies there were 95 patients who were
> infected with viruses that were not susceptible. We are in the process
> of looking through those and we have recent data on the sequencing of
> amplicons derived from those viruses. We have sequenced, I believe,
> about 44 of them so far and they are all rhinoviruses.
>
> DR. GULICK: Dr. Schapiro, follow-up?
>
> DR. SCHAPIRO: Along those lines, it did seem quite impressive that
> there was about a four-day increase. Russ, you mentioned earlier that
> the vehicle there is an irritant. I think you mentioned also to the
> respiratory tract. Was there any consideration that if the virus is
> not sensitive there is some background irritation? I think you said
> there is a concentration of the drug in the epithelium. Why are we
> seeing in some cases an additional effect?
>
> MR. FLEISCHER: We didn\'t really look at the vehicle.
>
> DR. GULICK: Dr. Sun and then Dr. Atmar.
>
> DR. SUN: I have two questions. The first is actually continuing this
> thread. What struck me is that you seem to have two sets of resistant
> viruses, those that are present at baseline and those that are
> post-baseline, and it sounds like you are doing some genotypic
> analysis. But from your preliminary data, do you identify differences
> in the mutation patterns in those two sets? Because it is striking
> that the clinical course of the baseline resistant viruses appears to
> be longer than either the sensitive virus treated with pleconaril or
> placebo, whereas, as you referred to in your presentation, the
> post-baseline resistant viruses may have perhaps trended towards a
> shorter course. You evoked at that time an argument about reduced
> fitness. So there is a little bit of a disconnect here which could
> potentially be sorted out by some genotypic analysis. I think it is an
> important question because you have a fairly high rate of treatment
> emergent resistance. So, with successive seasons of use you might
> induce actually a population prevalence of resistant virus. So, it is
> important to know the biologic characteristics of that virus. Then I
> have a second question.
>
> DR. MCKINLAY: Dr. Collett?
>
> DR. COLLETT: Indeed, I am happy to have the opportunity to clarify the
> viruses that we were observing that have reduced drug susceptibility
> to pleconaril. Indeed, there are two types of viruses that we have
> been referring to. Those are viruses that are observed at baseline
> that are not susceptible and these are naturally occurring viruses
> that turn out to be just not susceptible. They are picornavirus
> viruses or rhinoviruses. Then there are the viruses that are
> identified in patients that are treated with pleconaril that appear
> post-baseline in individuals that are infected at baseline with
> sensitive viruses.
>
> \[Slide\]
>
> In referring to that group of viruses, as was indicated earlier, we
> identified 28 individuals in the combined studies that had viruses
> that exhibited greater than ten-fold change in drug susceptibility
> relative to their baseline samples. It is important to note that these
> viruses actually preexist in the baseline samples at a low frequency.
> We know this because workers have done this in working with these
> types of inhibitors in the literature, and we have done this with
> pleconaril and we have actually done it with patients in the pivotal
> trials. If we look at susceptible virus populations at baseline, we
> can find these types of viruses that have reduced drug susceptibility.
>
> \[Slide\]
>
> If we go on to slide 1760 and continue looking at the samples from the
> 28 patients, we find that 21 of the 28 are still susceptible to
> pleconaril, with a median IC50 value of 270 ngm/mL. So these would
> expected to be inhibitable at readily achievable plasma
> concentrations. There are seven that are no longer inhibited by
> pleconaril at the highest testable level in the cell culture assay. We
> have gone on to characterize these viruses and we are still working in
> this area, but it is important to note, which has been shown earlier,
> that these patients had no unusual clinical outcome.
>
> \[Slide\]
>
> If we go on to slide 1440, we have gone on to characterize these
> viruses both molecularly and physically. We have so far sequenced 22
> viruses with reduced drug susceptibility post-baseline, sequenced
> across the drug binding pocket, and we find a very interesting, very
> clear story. There are two amino acid positions that appear to be
> changed relative to the baseline sequence in these patients, and that
> is at position 98 and 122 and we find two other viruses at position
> 180. The location of these mutations are all in the drug binding
> pocket.
>
> \[Slide\]
>
> I show in this rendition or depiction of the drug binding pocket the
> position and location of these mutations, and how they impinge on
> pleconaril. Isoleucine 98 is at the top of the drug binding pocket
> into which pleconaril is integrated, and interacts with the isoxasole
> ring of the compound. Isoleucine 122 is below, at the bottom of the
> pocket, also interacting with phenoxy ring. Serine 180 actually causes
> a change in the position of the two adjacent amino acids, causing a
> distortion of the pocket. By substituting larger, bulkier amino acids
> at these positions, such methionine, it impinges in the pocket, thus,
> preventing or decreasing the affinity of the drug for the binding
> pocket, thus, explaining the means by which these viruses are now less
> susceptible to pleconaril.
>
> If we look at the physical characteristics of the viruses with these
> mutation in the drug binding pocket, we find that in 29 of the 30
> cases that we have evaluated so far from samples from the pivotal
> studies, in those cases the viruses are more labile to acid exposure.
>
> \[Slide\]
>
> Here we show an example of the baseline virus isolated from a patient
> and its infectivity inactivation as a consequence of exposure to
> decreasing pH, and in two isolates a 122 mutation and a position 98
> mutation. You see the instability of the virus under these conditions.
>
> These observations are totally consistent with all preclinical data in
> studying viruses that we have selected in cell culture that are of
> reduced drug susceptibility to pleconaril. It seems that they all have
> mutations in the drug binding pocket and in large part at that
> position, 98.
>
> \[Slide\]
>
> In patients that we have observed with these viruses, again, there
> seems to be no unusual clinical outcome. The amino acid changes are
> all in the drug binding pocket. The viruses are all unstable, either
> from clinical studies or the preclinical work that we have done. So it
> appears that the development of reduced drug susceptibility as a
> consequence of pleconaril treatment results in a virus that is less
> stable and likely to be less competitive in nature.
>
> When we look at these viruses in an animal model, some of the [in
> vitro]{.underline} viruses, in particular the Coxsackie virus that
> have these mutations in the drug binding pocket, we find that those
> viruses are attenuated for replication in the animal model, as well as
> attenuated for virulence in that model. So, it appears that viruses
> acquire the reduced drug susceptibility are definitely enfeebled, as
> we can tell with data to date. So, we feel that the treatment emergent
> viruses don\'t pose any threat to individuals.
>
> DR. GULICK: A follow-up from Dr. Schapiro.
>
> DR. SCHAPIRO: I would disagree with that comment. I think there is a
> concern. If these are viruses which are seen in wild type and these
> are viruses which have specific mutations, I don\'t think we can
> assume that they are not going to be pathogenic. I think that from
> other models in viruses and bacteria we have seen mutated resistance,
> and I think we have had bad experiences assuming that these viruses
> would not be pathogenic. That is the model we have consistently seen
> when we have hoped that these would be crippled pathogens. It is also
> not surprising that for the first treatment you would still have the
> same outcome if this was an emerging resistance which happened after a
> couple of days of treatment.
>
> So, I would like the company to address a concern that I have, that
> this is a high rate of generation of mutations which in viruses that
> have these mutations or that are resistant we do not see an effect. I
> think that the fact that there is possible cross-resistance to other
> compounds that work with a similar mechanism of action, and here we
> are giving it for a minor indication \-- if these are viruses which
> are now resistant and ultimately we do develop more potent compounds
> against serious infection by the picornavirus, I think this is an
> issue which is very concerning to me. I would like that to be
> addressed. I mean, wouldn\'t there be a potential that by treating a
> relatively mild disease \-- we repeatedly see one million infections a
> year in the States \-- after a few years we generate a mutant
> population against not only this compound might not work but other
> compounds, and if we have serious infections down the road we won\'t
> be able to treat them. That is a concern I would like to hear
> addressed.
>
> DR. GULICK: Let me hold that. Let\'s resist the temptation to jump
> into discussion and just finish up off the question and answer session
> this morning. That will be one of the topics that I think we will
> address after lunch, if that is okay.
>
> DR. SUN: Can I just clarify what your response was? You showed us
> primarily data on the post-baseline resistant virus. Are you still
> working on characterizing the 26, or I think actually you have 50
> isolates, from the two studies?
>
> DR. COLLETT: Yes, we are. As I mentioned earlier, there are 95
> patients in which we isolated those viruses that were not susceptible
> at baseline. We are working our way through that. As you can imagine,
> these viruses are all different and finding the appropriate probes to
> do the appropriate sequencing is a challenge. We have gone through
> about 45 so far. We haven\'t completed work on the sequencing across
> the drug binding pocket so right now we don\'t know the molecular
> basis for their non-susceptibility but those studies are ongoing.
>
> Again, not to de-emphasize this issue, we believe it is very important
> and we are very committed to studies that are under consideration
> which, perhaps during the discussion session, we can go through and
> elaborate on those.
>
> DR. GULICK: Dr. Reller, did you have a follow-up comment?
>
> DR. RELLER: Not a comment, a question. I realize the numbers are
> probably small but related to Dr. Schapiro\'s inquiry, a question from
> the epidemiological standpoint, did you happen to enroll in this study
> any family members or subsequent patients in the household, or
> dormitory or fraternity, sorority, etc. that may have been a second or
> third exposure?
>
> DR. MCKINLAY: I don\'t think we have any information on that. That
> wasn\'t specifically excluded.
>
> DR. RELLER: It wasn\'t excluded but it might be worth going back and
> looking. I mean, there may be only a few such patients or a small
> number but it may provide some interesting information, given the
> incredible amount of sequencing and molecular work that has been done
> on the basic biology of these viruses.
>
> DR. GULICK: We have time for a few more questions. Dr. Sun, did we get
> to your second question?
>
> DR. SUN: No. Can I ask it now? This may be a question that you may not
> have data on, so if you don\'t maybe you could just speculate, but I
> was wondering how you think treating the common cold with pleconaril
> might affect the development of serotype specific immunity.
> Specifically, I think you did show some data suggesting that viral
> titers and viral burden is decreased in patients receiving the drug.
> To the extent that neutralizing antibody is important in acquired
> immunity, and this may be something Prof. Hayden might like to
> address, what do you see as the effect of the development of
> neutralizing antibody, which is particularly relevant given your
> introductory comments about the decreasing incidence of the cold with
> increasing age, and might that reflect the building of a repertoire of
> neutralizing antibody earlier in life to a variety of common cold
> serotypes?
>
> DR. HAYDEN: To my knowledge, there aren\'t specific data to address
> the question of the effect of pleconaril treatment on the development
> of serotype specific neutralizing antibody. There are data from
> earlier capsid binding type agents in the experimental model, showing
> that there is no effect on the frequency or height of antibody
> response when those proof of principle studies were tested.
>
> Also, I think if one would look at the precedent with regard to
> influenza infections, treatment of acute respiratory illness is not
> associated with a diminution in the HAI antibody response in terms of
> frequency or height of that response. So, when used for treatment in
> an acute illness where there is already substantial antigenic exposer
> there is likely going to be an adverse effect on the humoral immune
> response.
>
> The other side of this, of course, is that there are so many
> immunotypes, over 100 recognized immunotypes for rhinovirus, that an
> effect, even if it were there which I doubt would occur, would mean
> that it would probably be lost in the broad number of potential
> viruses that these individuals could be exposed to in the future.
>
> DR. GULICK: Dr. Atmar and then Dr. Gardner.
>
> DR. ATMAR: I have a follow-up question related to the smoking cohort.
> You learned from your Phase II studies that your endpoints were not
> appropriate so you modified those for the entire population in Phase
> III. My question is have you looked at the data for the smoking cohort
> to see if there was a particular symptom that was responsible for the
> apparent lack of effect? There was an allusion to baseline increased
> rhinitis. Was it persistent rhinitis, or was it moderate cough, or is
> there some hint?
>
> DR. MCKINLAY: Dr. Villano?
>
> DR. VILLANO: We did evaluate the population based on smoking status
> and tried to determine if there was one or a group of symptoms
> specifically that was leading to the attainment of primary endpoint.
> As a reminder, the primary endpoint is defined as the time point at
> which all rhinorrhea is completely resolved, other symptoms having
> achieved a level of mild or absent. In all of our analyses of any
> subpopulation the criterion for complete resolution of rhinorrhea has
> in all cases been what we call the driver of achieving the primary
> endpoint. That is the case in smokers and non-smokers as well.
>
> \[Slide\]
>
> However, on this slide, for your interest, we have another depiction
> of the characteristics that contributed in various degrees to
> achieving the primary endpoint. Just to describe this slide for you,
> based on smokers and non-smokers in each treatment group, this slide
> shows the percentage of patients who had a given symptom in the time
> period immediately before reaching the primary endpoint. That is, what
> was still there just before they reached the primary endpoint.
>
> As you can see, the presence of rhinorrhea, although somewhat less
> prominent in smokers than in non-smokers, is by far the biggest
> contributor to achieving the primary endpoint. The notable difference
> among smokers is in the presence of cough. Cough was somewhat more
> prevalent just before reaching the primary endpoint in smokers than in
> non-smokers.
>
> Again, we actually analyzed the primary endpoint even excluding cough.
> If we just took that symptom out of the equation altogether, the
> results are virtually the same because that resolution of rhinorrhea
> is still so important to our specific primary endpoint.
>
> DR. GULICK: Dr. Gardner then Dr. Henchal.
>
> DR. GARDNER: I have two questions. Dr. Gordin asked about who gets the
> common cold. I didn\'t hear anything about smokers. Can you tell us
> whether smokers are considered to be more susceptible to infection
> with rhinoviruses?
>
> Secondly, in considering risk management alternatives, I wonder if it
> is fair to ask the company whether the marketing plan for pleconaril
> includes direct to consumer advertising.
>
> DR. MCKINLAY: On the first question, Fred, do you have an answer, or
> Dr. Black?
>
> DR. BLACK: I am sorry, I don\'t know whether smokers are at increased
> frequent risk of having colds because of their smoking status.
> Certainly, when they do develop illness, as you have heard, they tend
> to have more protracted symptoms and have more morbidity associated
> with those illnesses, but I am just not certain, from the
> epidemiologic data that I am familiar with, whether there is any
> alteration in the frequency. Again, in the older smoking cohort the
> individuals with co-morbidities, where there might be underlying
> chronic airways disease, the frequency of these illnesses does
> diminish but it relates heavily, of course, to exposure in the
> household setting.
>
> DR MCKINLAY: Then the question about direct to consumer advertising, I
> will ask Dr. Wickler to comment.
>
> DR. WICKLER: Matt Wickler, ViroPharma medical affairs. Although we
> have not yet finalized the pleconaril communications plan, it will
> focus almost exclusively on educating healthcare providers. So we do
> not currently have any large efforts under way or plans to do any DTC
> promotions.
>
> DR. GULICK: Dr. Henchal?
>
> DR. HENCHAL: Yes, my question is for Dr. Collett with regard to the
> RT-PCR assays that were used for these studies. When the endpoint
> limit of detection results were shown, it appeared to me that there
> may be two to three orders of magnitude difference in the ability of
> your assay to detect different serotypes. I wondered if there is a
> possibility that this would introduce unfortunate bias in your
> studies, especially your clinical virology studies.
>
> DR. COLLETT: The viruses we are trying to detect, the rhinoviruses and
> picornavirus, are a large group of genetically diverse viruses. We
> would expect that any assay would have a range of detection
> sensitivities. Certainly cell culture, which is the traditional or
> historical standard, is very variable in its ability to detect these
> viruses and we found similar variation with both of the RT-PCR assays
> which, again, use different primers and are distinct. The range of
> detection sensitivities with the viruses that we have looked at
> closely, and that represents five serotypes, you are correct, it does
> range over three orders of magnitude in detection sensitivity on a
> genome basis. On a PFU basis they are within ten-fold of one another.
>
> With respect to your question about introducing a bias, I don\'t know
> that we have any information that would bear on that.
>
> DR. HENCHAL: It appears that you are doing some sequence analysis of
> isolates. Does it appear that the viruses that you are sequencing fall
> in any particular serotype groups?
>
> DR. COLLETT: We did not serotype viruses in this study. Serotyping is
> useful for determining the serotypic or immunotypic diversity of the
> viruses that you encounter. We did look at the drug susceptibility
> across all the viruses that indicated a wide range of drug
> susceptibilities, which actually mimics that of the drug
> susceptibility profile for the 101 serotypes, the prototypic
> serotypes.
>
> You mentioned that we are in the process of sequencing, and I alluded
> to it several times, a number of these viruses. We have sequenced the
> amplicons of 146 of these viruses and we see quite a wide range of
> genetic diversity and we are continuing those studies to further
> characterize the viruses, but it doesn\'t look like there is any bias
> introduced. It is quite a diverse range of gene sequences that we are
> observing.
>
> DR. GULICK: Dr. Stanley, you are out of sight but not out of mind. Do
> you have questions?
>
> DR. STANLEY: Thank you. Actually, most of mine have been answered. I
> did have concerns about the resistant viruses. I guess we will talk
> more about that this afternoon. So I think my fellow committee members
> have covered most of my issues.
>
> DR. GULICK: Okay. I think all the committee members have had a chance
> to ask questions. I have a couple myself. Could the sponsor please
> review specifically what the exclusion criteria in terms of
> concomitant illness and concomitant medications?
>
> DR. MCKINLAY: Dr. Villano?
>
> DR. VILLANO: I will just run through the specific exclusion criteria
> as they were set forth in both protocols and, again, both 43 and 44
> were identically designed studies. All these criteria apply to both
> studies.
>
> \[Slide\]
>
> I will just run through them. The exclusion criteria exactly as set
> forth in the studies, we excluded any known pregnant or nursing
> females; persistent cough or rhinitis. We excluded temperature over
> 100 F; a cold that was suspected to be caused by any other virus;
> allergic rhinitis requiring medical treatment within two weeks before
> the study start; and asthma requiring treatment within two months
> before the study start; any prior participation in a pleconaril
> treatment trial and participation in any other research study within
> the previous 30 days.
>
> \[Slide\]
>
> As far as any other medical conditions that the investigator or
> sponsor may have been aware of; any evidence of significant hepatic,
> renal or GI disease that could interfere with absorption; any other
> underlying medical history that was deemed significant requiring
> treatment with systemic, nasal or inhaled corticosteroids; any
> symptomatic respiratory disease or acute or chronic medical condition
> that could have confounded the evaluation of the cold symptom score
> because of those symptoms; any known immunodeficiency, HIV status;
> recent history of alcoholism or use of illicit drugs; and any other
> psychiatric disorders that could have compromised compliance with the
> study. I believe that is it.
>
> DR. GULICK: And concomitant medications that were excluded up front?
>
> DR. VILLANO: The only criterion was that cold symptom relief
> medications, as a general class, were discouraged. They were not
> specifically ruled out altogether. We provided patients with both
> acetaminophen and dextromethorphan specifically with the idea that
> those particular medications would be least likely to interfere with
> the most prominent nasopharyngeal symptoms that we were studying in
> the course of the studies. In fact, that provision was very successful
> in that of all the patients who used any cold medication during the
> study, only one to two percent used any other medication other than
> the acetaminophen or dextromethorphan.
>
> DR. GULICK: That was my second question actually, what percentage of
> patients ended up using the medications that you provided in each
> group?
>
> \[Slide\]
>
> DR. VILLANO: This slide reviews the cold medications that were used
> during the study. We pooled together the results in those patients who
> were picornavirus infected, and 58 percent of those in the placebo
> group used any cold medication during the study, 52 percent in the
> pleconaril group. As shown here, the most prominent medications used
> were, in fact, those provided. Acetaminophen use in 45 percent of
> those on placebo, 39 percent of those on pleconaril, and
> dextromethorphan, 39 percent of those on placebo and 29 percent of
> those on pleconaril. The median duration of use of any cold symptom
> relief medication during the study was one day.
>
> DR. GULICK: My last question is for the agency. Is there a method for
> quantitating the risk of unwanted pregnancy that is accepted?
>
> MR. FLEISCHER: I will let Dr. Furlong answer. The answer is yes.
>
> DR. FURLONG: The data that the company has collected from these trials
> doesn\'t allow you to quantitate with statistical certainty, if that
> is what you are asking. Do we have methods for calculating pregnancy
> rates? Yes, we do but they are for large contraceptive trials
> involving a thousand women at least starting out and continuing for a
> year. So, we are talking about different data sets.
>
> DR. GULICK: So everyone has had the opportunity to ask questions. Dr.
> Brass, I am going to come back to you. I just want to let everybody
> know that we have to wrap up but you have patiently waited.
>
> DR. BRASS: Thank you. I will just ask two very quick questions. The
> first has to do with this very unusual finding of palpitations in the
> theophylline group. Your data says it is clearly not a PK interaction.
> I was wondering if you looked for PD interactions with any other
> chronotropic drugs to see whether or not this was a recurrent theme of
> drug interactions in terms of drug with intrinsic chronotropic
> activity.
>
> My second question has to do with the QT interval prolongation that
> was observed in two patients and not well detailed, just so that we
> can be reassured.
>
> DR. MCKINLAY: Dr. Villano?
>
> DR. VILLANO: With regard to your first question with respect to the
> events of palpitations and tachycardia, I am going to focus on the
> theophylline interaction study that you mentioned. These are the data
> that we have exclusively.
>
> DR. BRASS: You don\'t have to go through the whole thing again. I
> specifically wanted to know whether or not you have thought about
> potential other interaction. We don\'t have to rehash all the data.
>
> DR. VILLANO: Fair enough. The second question that you asked with
> regard to data from EKG collection, we have actually recently even
> expanded the database of EKG data from what was provided in the
> briefing book. Actually, I would like to invite Dr. Morganroth to come
> up and present this information to you.
>
> DR. MORGANROTH: Thank you very much. My name is Joel Morganroth. I am
> a cardiologist from Philadelphia, clinical professor at the University
> of Pennsylvania, and also the key scientist at Ewey Search Technology.
> I have dedicated a lot of my current years in consulting to
> pharmaceutical companies, particularly about the cardiac safety issues
> of non-cardiac drugs and, in particular, the QT interval in terms of
> how to manage it and how to analyze the data.
>
> \[Slide\]
>
> The information that is provided by the sponsor in terms of
> electrocardiographic data comes from a total of 127 subjects in the
> following six protocols that you have been discussing today.
>
> \[Slide\]
>
> If you look specifically at the heart rate data, you see a very small
> change in heart rate on pleconaril given either singly for seven days,
> BID, or for five to seven days TID. Essentially no significant effects
> on PR, QRS and the QT interval, of course, should not be looked at
> individually because we have to look at the potential effect of heart
> rate correction.
>
> \[Slide\]
>
> The studies looking at the 65 subjects, when pooled from the single
> dose studies, compared to the 56 subjects when given for five to seven
> days, shows that there is actually a mean decrease in the QTc interval
> when looked at in this particular data set. The single maximum
> increase of 47 milliseconds in both sets is better looked at on the
> next slide.
>
> \[Slide\]
>
> The use of the CPMP and draft Canadian guidance on ECGs suggests that,
> from our original data looking at the placebo likelihood of
> spontaneous variability, the most specific criterion is a 60
> millisecond change from baseline, and no subject reached that
> criterion. You can see, if you look at the 30-60 millisecond group,
> which is somewhat overly sensitive and not terribly specific, you see
> that, although there are very small numbers of patients on placebo in
> these trials, there is no evidence of even a sensitive effect.
>
> I probably could stop there. If you actually go on to look at other
> slides with gender and age, you also see no evidence of an effect. I
> will just comment for one second about this issue of tachycardia and
> palpitations, since I am up here since it hasn\'t really been
> discussed before. I think that, as a cardiologist looking at cardiac
> safety issues, if you want to determine the effect of a drug on the
> heart the first question, of course, is what is the preclinical data.
> There is no signal in this database, as you know. The next question
> would be is there an effect on blood pressure or heart rate in the
> thousands of patients that are studied and, as you have been told by
> both the sponsor and the agency, there is no effect on blood pressure
> or heart rate. The third issue is do you see an effect on the
> echocardiogram? The data has shown that it doesn\'t appear to
> demonstrate any evidence.
>
> Then, when you go in and you look at the specific cases, it is very
> apparent that there isn\'t a single case that has any objective
> information, other than that the patients had sinus tachycardia for a
> short duration and the few that had, in fact, any evidence of cardiac
> finding that might correlate with palpitations, the majority of the
> cases had no effect on heart rate that had palpitations and no likely
> pathophysiologic basis, many being many days after pleconaril and some
> being within 11 minutes of pleconaril\'s ingestion. So if you look at
> any objective findings, there are none. So I think these very
> non-specific low rate symptoms are something that I personally didn\'t
> find worrisome at all. Thank you.
>
> DR. GULICK: We need to finish up, but are there any last burning
> questions for the sponsor or the agency from the panel members?
>
> DR. WOOD: I just have one question for the agency regarding antiviral
> effects of other drugs. One of the things that I was impressed by,
> even though there was a statistically significant difference in the
> treatment group compared to the placebo, was that 50 percent of the
> patients were still culture positive. I just wondered how that
> compared historically to other antiviral agents in terms of culture
> positivity for therapeutic intervention.
>
> MR. FLEISCHER: How about if we address that after lunch when we put
> our heads together?
>
> DR. GULICK: Sounds like a good place to stop, doesn\'t it? It is 12:30
> and we will take 55 minutes for lunch. We will reconvene at 1:25.
>
> \[Whereupon, at 12:30 p.m., the proceedings were adjourned, to
> reconvene at 1:30 p.m.\]
>
> AFTERNOON PROCEEDINGS
>
> DR. GULICK: Welcome back from lunch. Dr. Stanley, are you with us?
>
> DR. STANLEY: I am with you.
>
> DR. GULICK: Let\'s see, Dr. Wood ended the last session with a
> question. Mr. Fleischer?
>
> MR. FLEISCHER: Without getting into too much detail, I talked to the
> reviewer for the Tamiflu studies. Approximately 80 percent of patients
> or 80-plus percent of patients who were responders had a negative
> qualitative culture on day three of treatment.
>
> DR. GULICK: That was for influenza.
>
> DR. WONG: How about the placebo in that study?
>
> MR. FLEISCHER: I don\'t have that. I am looking for the reviewer; she
> was here just a minute ago. She may be able to tell us.
>
> DR. GULICK: Dr. Hayden?
>
> DR. HAYDEN: The data from the influenza may not be entirely applicable
> to the rhinovirus situation. It is noteworthy though that the duration
> of viral shedding in the influenza trials is not significantly reduced
> compared to placebo, although titers were reduced. In rhinovirus colds
> the best quantitative data come from studies in experimentally
> infected volunteers where it is possible to do multiple samples over
> time. Viral titers are highest at the peak of symptoms, generally two
> days after virus exposure, and then rapidly decline thereafter. We do
> know that in both the experimental colds as well as those studied
> naturally about 50 percent of adults would be virus positive, either
> without treatment or in a placebo treatment setting, at a week, and
> replication can be detectable if one really looks hard for it into the
> second week. The main point is that this is a self-limited virologic
> and clinical illness so that virus is eliminated by specific host
> immune responses at two to three weeks.
>
> DR. WONG: Thanks.
>
> MR. FLEISCHER: I have the answer. We know that there are differences
> between flu and rhinovirus VRI but we don\'t have any other data in
> rhinovirus drugs. So the answer to Dr. Wong\'s question is that the
> placebo rate is about the same.
>
> DR. GULICK: Are there any other questions from the committee that came
> up over lunch that need clarification? If not, Dr. Birnkrant will
> review the charge to the committee. Oh, I am sorry, it turns out we
> are to go into the open public hearing portion of the meeting. No one
> has signed up in advance to speak at the open public hearing. Are
> there any members of the audience who would like to make a statement
> at the open public hearing?
>
> \[No response\]
>
> This concludes the open public hearing and we are back to Dr.
> Birnkrant.
>
> \[Laughter\]
>
> **Charge to the Committee**
>
> DR. BIRNKRANT: Just to emphasize the point that we have not made a
> regulatory decision yet, and we are actually looking to this advisory
> committee and our guests to help shape our regulatory decision.
>
> \[Slide\]
>
> With that, what we are really looking for is a thorough discussion of
> the points that will appear on the following slides with regard to
> efficacy and safety.
>
> \[Slide\]
>
> To be able to determine the risk/benefit of pleconaril for treatment
> of the common cold, with regard to a discussion of efficacy what we
> are asking you to consider is the totality of the data from the Phase
> II and II clinical trials, given that within these clinical trials are
> examples of perhaps how this drug will be used if it is approved.
>
> In addition, we would like you to consider issues related to the
> timing of administration, the need to administer with food, the
> results in smokers, etc.
>
> \[Slide\]
>
> When you discuss safety, we would like you to focus on pleconaril\'s
> effects on CYP3A and the potential for the drug interactions that we
> discussed today and others, as well as the overall tolerability
> profile.
>
> \[Slide\]
>
> In the third point what we are really asking is do the safety and
> efficacy profiles of pleconaril support its approval for the treatment
> of VRI in adults. With that, I will turn it back over to Dr. Gulick
> and we can address the other questions once we approach question
> three. Thank you.
>
> DR. GULICK: Thanks. Could we have question one back up on the screen?
> Committee members, let\'s address the bullet points one at a time as
> we begin to discuss efficacy. There may be other parts of efficacy
> that we also wish to bring up. Who would like to jump in? Dr. Brass?
> We are focusing initially on the efficacy results from the Phase III
> studies.
>
> DR. BRASS: Could I request your indulgence and talk a little bit more
> globally about the efficacy?
>
> DR. GULICK: Sure.
>
> DR. BRASS: Because I think it might speed things along if we look at
> this in totality.
>
> DR. GULICK: All right.
>
> DR. BRASS: My personal reaction as I reviewed this data is that it
> took a while for the sponsor to figure out how to design a clinical
> trial that would sufficiently enrich the patient cohort in a responder
> type of way, and then in a carefully conducted trial could identify
> that there was relief of symptoms.
>
> What I have some concerns about is how generalizable the conclusion of
> efficacy is, assuming that I accept that one-day decrease in symptoms
> is clinically meaningful. Assume that I accept that, I still have
> problems with the generalizability. For example, this was done in a
> time of year that, even for the symptomatic inclusion which were
> carefully screened for, enriched the number of viral positive
> isolates. I don\'t think the intent by the sponsors is to limit its
> availability to the three months of the year on the calendar when the
> study was conducted.
>
> As well, there are very small numbers in a variety of subsets of the
> population which, as everybody has said, is uninterpretable because of
> the small numbers but raise questions about, again, the
> generalizability of even the symptomatic relief, most dramatically in
> smokers versus non-smokers, but the issue of race and gender was
> talked about. In fact, with respect to race, Hispanic populations were
> grossly under-represented and the elderly were substantially
> under-represented. To some degree that reflects the demographics and
> epidemiology of the illness, but in terms of allowing one to conclude
> that the efficacy is generalizable, there is some concern.
>
> Perhaps my greatest concern is how well this relates to extrapolation
> to the use of this drug. In the OTC world, the FDA requires something
> called an actual use trial, where the use of the drug in the setting
> where consumers/patients will actually access the drug and use it
> without supervision, is assessed to see whether or not the label
> indications, warnings, patient selection criteria, etc. are, in fact,
> utilized in the general population.
>
> Implicit in that use of the actual use study was the assumption always
> that in the Rx setting it is not necessary because you can tell the
> doctors what to do and they do it right. I think in recent years we
> have become increasingly cynical about physicians\' ability to heed
> directions and, in particular, non-direct warnings on the label of
> drugs to maximize their efficacy and minimize their toxicity. When one
> talks about the variety of decisions that need to be made to select
> the patient for whom selection for prescription of this drug exactly
> mirrors the patient population in the clinical trials, I think that I
> have great concern about the generalizability and the ability of a
> physician to replicate that patient cohort in order to reproduce the
> efficacy as was demonstrated in the clinical trials.
>
> DR. GULICK: Dr. Gordin?
>
> DR. GORDIN: Similarly, my main concern was really the cohort. To me,
> it was kind of a proof of concept that in a very narrow group it has
> some, to me, marginal benefit. It is concerning that half the patients
> cannot benefit that we would be giving this to in terms of the
> efficacy because they don\'t have an infection caused by this virus,
> and we, as clinicians, cannot determine which half that is.
>
> I am also quite concerned about all the groups that were excluded, as
> just pointed out. But, then, what does the word efficacy mean? Again,
> I guess it is in the eye of the beholder. I would have liked to have
> seen some effectiveness shown in some of the real parameters related
> to lost time from school, lost time from work. But, in fact, the
> so-called impairment parameters were the same between placebo and the
> drug.
>
> Over-the-counter drugs that are already available may or may not have
> been, therefore, as efficacious as this drug had they been studied in
> a similar way against this drug or against a placebo. As was pointed
> out by the company, those drugs were excluded because, in fact, they
> deal with symptoms. And, what we are looking at here is just that, the
> symptoms of having a cold, being reduced by approximately one day
> because the complications of having a cold, such as otitis media,
> bronchitis etc., were, in fact, no different between the two groups,
> approximately seven percent in each group. So to me, it is
> questionable how efficacious it would really be.
>
> DR. GULICK: Dr. Wong?
>
> DR. WONG: I guess I will go back to the issue of the Phase III
> studies. In my mind, there is really very little doubt that the data
> show that there was a treatment effect. We didn\'t really get to see
> in detail the data from the Phase II studies but I guess both the FDA
> reviewers and the sponsor told us that they were unable to demonstrate
> a treatment effect.
>
> In my mind, it comes down to seeing data on a drug now in which there
> is clear-cut evidence of a treatment effect, but wishing that that
> treatment effect had been more robust and more profound than it was
> because it is, indeed, quite modest. What we have is a reduction in
> symptoms of somewhere between half a day and a day when the natural
> history of this disease is that it gets better in everybody. So, my
> answer to the efficacy question is, yes, it is efficacious. The effect
> is very small. Whether I vote for approvability or not I think is
> going to depend mostly on the safety discussion.
>
> DR. KUMAR: Just taking the question of efficacy, in my mind, in the
> Phase III studies the sponsors did show small but definite efficacy in
> this group. Very much like what Dr. Gordin referred to, this small but
> modest efficacy depends upon the patient population. In somebody who
> just wants to save half a day from not going to work, that may not be
> very significant but for somebody embarking on a vacation trip, that
> may be very relevant to them. So in my mind, it has shown a small but
> definite efficacy in Phase III studies.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: I think it is very important to think of efficacy in
> terms of an antiviral agent for a respiratory virus and we have to
> realign our thinking to thinking of respiratory viruses which are very
> different from the other viruses. This is a very different virus than
> influenza. It is very difficult to design a study and I think the
> company is to be congratulated for working and fine-tuning a study
> which did end up being a homogeneous population to try and get an
> endpoint. I think it is very important that we need some more studies.
> But I think that to demonstrate efficacy you have to actually
> fine-tune the population and focus and target the study so that you
> can demonstrate it.
>
> They have shown, I believe, clinical efficacy. I wish they had been
> able to show some more virologic efficacy, and I think perhaps they
> could have if we had been able to do more studies, and I would
> recommend that for the future. I think, as clinicians, actually many
> of us have the ability to do some PCR but they haven\'t even given us
> an idea of what is culture positive and what is PCR positive for those
> of us who do have the ability to do that, which is not, of course, the
> referring physician. There is a population for which this would be
> beneficial, but I think they have shown us clinical efficacy which was
> their primary endpoint.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: I would agree. I think the question really is if these
> are appropriate studies, if we can consider these approval studies for
> the common cold. I think the company did a very good job in showing us
> the data in a very careful and descriptive way. I am also convinced
> that in this study there was real benefit. I would agree also that
> this study does not in any way mean that you can use it for the common
> cold because, as it will be used for the common cold, I don\'t think
> there will be efficacy and I think that is the real question.
>
> DR. GULICK: Feel free to keep speaking about it, but we have begun to
> address the first two and Dr. Schapiro is moving us towards the third
> bullet, what is the manner in which pleconaril will likely be used in
> clinical practice. Some of the issues surrounding that are symptomatic
> patients, use of diagnostic tools, and then asymptomatic patients. Dr.
> Englund?
>
> DR. ENGLUND: I just want to say that, of course, one would target the
> pediatric patients who are having the most infections and potentially
> might be able to benefit the most, yet, we haven\'t seen data for
> that. I know there are things ongoing, but if you look at the
> epidemiology, it is the children that are suffering a lot from these
> infections, the asthmatics etc.
>
> DR. GULICK: Dr. Reller?
>
> DR. RELLER: If this drug were approved on a prescription basis, not an
> over-the-counter preparation, a patient would need to be sick long
> enough to seek medical attention. I doubt if most people would go to a
> doctor within 24 hours. So the efficacy data that we have is, again,
> emphasizing that this study is perhaps not reflective of real-world
> practice.
>
> Food. People maintain a good appetite or not maintain a good appetite
> when they feel lousy. We know that 25 percent of the patients studied,
> at least, were smokers for whom we do not have efficacy. The most
> objective measure of efficacy was in those patients who had a
> confirmed infection. Quite apart from the ambiguities of how solid
> that confirmation was, but let\'s just assume 50 percent had a
> confirmed picornavirus infection. In real-world practice, when one
> includes all of the patients who, for legitimate reasons, were
> excluded from this trial, then we have a dilution of effect that
> becomes very striking. Although the numbers of patients studied was
> substantial, we are talking about several thousand, at most, for a
> billion event occurrence.
>
> So, I see an incredibly small sample size on which these judgments are
> being rendered relative to the patient population or event, including
> the repeated events in the younger people, and then we drift over into
> the safety issues. We also know, at least from the study sample, that
> about 20 percent of the patients studied among the women were taking
> oral contraceptives, and I will save the other comments until we get
> to the safety discussions.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: I want to come back to the issue of having to take the
> medication within 24 hours of symptoms, and I want to give my clinical
> perspective on that. In this first charge that was given to us by the
> agency, that is the one that I find most troublesome.
>
> I can guarantee you that there is no way that a patient can take this
> medication within 24 hours, unless the patient goes well in advance of
> the particular season and says give me a prescription; I just want to
> keep it in my medicine closet. That is the only practical way to get
> this drug within 24 hours. In any other circumstances, calling the
> doctor, having the doctor or the nurse return your call, then calling
> it into the pharmacy, having the pharmacy prepare it, you then go and
> pick up the drug \-- there is absolutely no way that the drug can be
> taken within 24 hours. And, I think we need to keep that in mind when
> we look at safety issues. It is giving it to a number of patients that
> are going to be keeping it in their medicine cabinets, waiting to take
> it at the onset of symptoms. That is very different from handing it to
> a patient right then and there and reviewing the adverse events with
> the patient.
>
> DR. GULICK: Dr. Henchal?
>
> DR. HENCHAL: I agree with that conclusion, and I wondered if there
> were really at risk populations that would warrant this preparation
> where the physician would actually prescribe the drug and let the
> patient make their own determination when to take it. I can\'t
> identify that population.
>
> DR. KUMAR: But we don\'t have the data for the at risk population.
>
> DR. BRASS: In fact, they were specifically excluded. If you talk about
> patients with asthma, which is an obvious at risk cohort, they were
> explicitly \-- and I understand why because you don\'t want to confuse
> the symptoms, but in terms of whether or not there would be
> symptomatic relief or their endpoint relief, all those populations you
> are most interested in were excluded.
>
> DR. GULICK: Dr. Wood?
>
> DR. WOOD: Just one point, getting back to the issue of efficacy, I
> wanted to go back to the FDA\'s efficacy conclusion slide. I think the
> important statement is regarding the assay to determine infectivity,
> it is a conditional statement that we have not answered and that has
> not been answered, to my knowledge, by the data presented. That is, if
> the assay has low false-negative rates, then the PCR positive
> population includes most infected subjects and the statistical
> significance confirms the effect of the drug. However, if the assay
> has a high false-negative rate, then we would not be able to confirm
> the same level of confirmation based on the statistical results. To my
> knowledge, we have not been able to verify what the true
> false-negative rate is.
>
> DR. GULICK: Dr. Atmar?
>
> DR. ATMAR: Any RT-PCR assay for picornaviruses is going to be
> investigational, and the data presented by the sponsor, looking at two
> different PCR assay using different methodology would suggest that
> there is a high rate of concordance. The issue that came up this
> morning in terms of looking at culture positivity as a primary
> endpoint rather than RT-PCR, there are numerous studies that show that
> RT-PCR assays are two-fold, three-fold or more sensitive than are
> culture assays and it really depends upon the ability of labs to do
> culture. There are people studying this disease in underlying
> respiratory illness, like asthma and COPD, who don\'t even bother to
> do cultures anymore because the additional yield is so low, they have
> to do RT-PCR anyway.
>
> So, as a person who does use this assay or uses or own home-brew assay
> for picornaviruses, I am reasonably convinced that, based on the data
> presented and without getting into all the particulars of exactly how
> the assay is set up, they have shown that they have a reasonably
> sensitive assay that corresponds with what we understand about the
> epidemiology of rhinoviruses or picornaviruses during the fall season.
>
> Regarding efficacy, I agree with what everybody else has said or most
> people have said, that there was efficacy demonstrated in the trials
> and, in fact, for a self-limited illness half a day to a day to a day
> and a half is, though modest, an important or clinically significant
> benefit, as a person, again, who studies respiratory virus infection.
> As some of us were talking over lunch, it is very difficult to measure
> the clinical benefit in an objective fashion, though anecdotally, in
> doing these kinds of studies, even though blinded, one can reasonably
> say this person got drug; this person didn\'t in the flu experience; I
> don\'t have any experience with picornavirus. So, actually being able
> to show a benefit of half a day to a day in a relatively homogeneous
> population I think shows efficacy.
>
> Is it generalizable? Well, we don\'t have the data to say that but, in
> fact, because of the increased variability in symptom duration, the
> population size needed to be studied would grow, if not exponentially,
> at least arithmetically. I mean there would be much larger numbers and
> it would be much harder to prove the efficacy in those groups. That is
> not to say that those studies shouldn\'t be done, but it is not to
> denigrate the sponsor for not having done those studies already. So
> there is clinical efficacy at least in the population that they
> studied.
>
> Then the question as to how it would be used, the same sorts of
> questions were raised about some of the influenza antivirals, and the
> comments were made that the drugs can\'t be prescribed within 36 hours
> or two days, and that is something to be overcome. But, in fact, as we
> get more antiviral agents for respiratory disease, this is going to be
> true of whatever antiviral we are talking about. So, to say that it
> can\'t be done or hasn\'t been done \-- we haven\'t had the agents to
> do it, or the physicians haven\'t had the need to be able to respond
> expeditiously. I think initially it will be difficult but that is not
> to say that it can\'t be done and strategies can\'t be developed.
>
> I think it is efficacious and it then comes back down to the question
> of the safety of the drug because up to half the people who have a
> common cold will not have a picornavirus illness. So, there is no
> short-term likelihood that we are going to get an assay that will give
> us a rapid diagnosis of a picornavirus infection. So, up to half the
> people who have a common cold almost won\'t derive any benefit because
> they will have some other viral etiology. So, I think we will have to
> address those issues when we get to safety.
>
> DR. GULICK: We are going to turn to safety next. Dr. Brass and then
> Dr. Schapiro.
>
> DR. BRASS: If I could just continue on the efficacy, I was confused by
> a point that was just made, two points actually. First of all, if it
> would take considerably larger numbers of patients to demonstrate
> efficacy in these other populations, are you implying that the
> magnitude of the efficacy would be smaller in those other populations
> and that is why it would take more patients? I just don\'t understand
> why it would be hard to have this efficacy extrapolated. Then I have
> one other point after that.
>
> DR. ATMAR: In answer to that, my postulate would be that the
> variability that one would see in these other populations would be
> great enough that in a less homogeneous population \-- I mean, one\'s
> power is affected by the variability in the population, and as the
> variability increases the number of patients that need to be studied
> to show that effect go up. I don\'t remember the statistics well
> enough off the top of my head, but if you had a two-fold increase in
> variability you would need something like four times the number, and
> one of the statisticians could correct me if I am wrong.
>
> DR. BRASS: That is assuming it is symmetric variability, but it seems
> to me that what you are really talking about is low responder rate,
> not more variability in the actual efficacy endpoint.
>
> The second point I was going to make is that the 50 percent number for
> patients who are exposed to this drug, who might potentially benefit,
> I think is optimistic. First of all, it assumes that only patients
> with viral upper respiratory infections as opposed to symptoms that
> seem like they might be upper respiratory infections actually take the
> drug, and that patients can differentiate an allergic rhinitis from an
> oncoming cold within those first critical hours.
>
> So, I think the 50 percent estimate is optimistic and assuming that,
> again, 10 percent of the strains are not susceptible strains and
> whether or not that is a factor as well. So I think the 50 percent
> benefit is an upside estimate, not a realistic estimate.
>
> DR. ATMAR: Well, I will decrease the 50 percent to 45 percent,
> yielding you the 10 percent resistant isolated not responding. But if
> you look at the epidemiologic studies that have been done in a number
> of different populations, not just young healthy adults, consistently
> about 50 percent of what people identify by different definitions in
> different studies, 50 percent are shown to be associated with a
> rhinovirus infection or picornavirus infection.
>
> DR. BRASS: Is that based on the first 12 hours of symptoms or the
> complete course of their symptoms?
>
> DR. ATMAR: Again, the studies are set up in different ways but, for
> example, the study that Dr. Hayden I think alluded to earlier, that
> was done at the University of Virginia, where people self-presented
> during the fall season, admittedly, with what they self-identified
> with a common cold, and 80-plus percent of those patients were shown
> to have a rhinovirus infection. I don\'t remember the details of the
> study and whether they didn\'t include patients who had a history of
> allergic rhinitis.
>
> But, you are right, it is a difficult clinical problem and it is even
> more difficult in patients who have chronic respiratory illness
> because their baseline is higher. So it makes it harder to study and
> it makes it harder to identify when an illness is present.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: Do you want us to move into toxicity?
>
> DR. GULICK: Just a moment, Dr. Stanley?
>
> DR. STANLEY: I just want to echo what a lot of people said, which is
> clearly there is efficacy shown, if I can call half a day to a day
> decrease in symptoms efficacious in this very select population, but
> to try to generalize it and to understand the way the drug is going to
> be used, I think there is a big potential for misuse. We talk about
> inappropriate use of antibiotics and we are going to get into
> inappropriate use of antivirals. I don\'t see anywhere specifically in
> our questions the whole issue of resistance and what was seen in this
> fairly limited exposure to this drug to a population. We were getting
> to it earlier this morning but I don\'t think we can assume that a
> virus developing resistance is something that is ever a good thing.
> So, I just throw that back out as a factor to put in when you are
> considering approving this drug for widespread use.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: I would start also by saying that I agree strongly with
> Dr. Kumar. The only way of mimicking these results is to give the
> patient this drug at the beginning of the season to have in the
> medicine cabinet. There is no way today, even in a very luxurious
> practice, to have the patient in from the beginning of symptoms. That
> is the only way. I do think when we consider toxicity and resistance
> we should realize that is the only way we could mimic these results.
>
> I think also when we start making a decision on an individual patient,
> the risk/benefit decision of who you will give to for their cabinet,
> we do consider from this study those that have really the best results
> were white, young, non-smoking females. Those are the ones where we
> have seen the most efficacy.
>
> Regarding toxicity, and I think that is what Dr. Stanley was referring
> to, there are two issues of adverse events or safety. One is I think
> the global resistance. I think that is a safety issue. Then, there is
> a personal safety issue. Can we talk about the resistance now?
>
> DR. GULICK: Sure.
>
> DR. SCHAPIRO: Or do you want to wait?
>
> DR. GULICK: Let\'s try to completely develop the efficacy question. I
> agree with you to consider resistance as part of the safety, which is
> our second question. We have considered most of the issues up here.
> The one we haven\'t really touched on a lot is the administration with
> food. Dr. Fletcher, you have food there!
>
> DR. FLETCHER: Yes, the cookie got me in trouble! When I think about
> the label, you know, the purpose of it is to communicate to
> prescribers and to consumers how to use the drug in a safe and
> effective manner. You know, the committee has been discussing that
> very issue, how would we write a label to use this drug in an
> efficacious manner? What are the groups that really benefit from it?
> To me, that is where the food part comes in. It seems what we know in
> healthy volunteers is if you take it with that standard English
> breakfast you get a four- to six-fold increase in your area under the
> curve. That is not how the drug seemed to be used in the Phase III 043
> and 044 studies. There seemed to be a recommendation with food. So,
> how do you translate that into information that then can be
> communicated to the prescriber and to the consumer? What do you do
> with food? From at least a pharmacologic basis, if it affects the area
> under the curve that much it has to, in some way, affect efficacy but
> I am lost to know how to translate that into an informative statement.
>
> DR. GULICK: Yes, Dr. Gardner?
>
> DR. GARDNER: Well, most of my concern and what I would like to talk
> about will have to do with safety, but relative to Dr. Fletcher\'s
> statement, part of that is that if the most reasonable way to have it
> available to people who need it when they need it within 24 hours is
> to prescribe it in advance, which is what is the recommendation for
> emergency contraceptives, as you know, which have to be taken within
> 72 hours, then you immediately move away from the ability to
> communicate in standard labeling ways, at best, to a more analogous
> situation to an over-the-counter medication, but you also are
> increasing the likelihood that people for whom it was not prescribed,
> who live in the household, will be using it when they feel symptoms
> coming on. They may or may not have the information about the best way
> to take it for maximum efficacy and then, obviously, that translates
> to anything we are going to discuss about safety as well.
>
> DR. GULICK: Any other last comments about efficacy? Let me try to
> summarize. The committee, in large part, agreed that, yes, clinical
> efficacy has been documented in the Phase III studies here. People
> noted this was really a modest effect, on the order of a day of
> reduced symptoms and that this is a self-limited disease.
>
> The endpoints, people agreed, were difficult to measure. Dr. Englund
> commended the sponsor on developing an endpoint that was measurable.
> It is really focused on symptoms and reduction of symptoms. Other
> committee members regretted that more emphasis wasn\'t placed on
> functional measures, such as return to work or return to school. And,
> there weren\'t really differences demonstrated in complications of the
> acute infection.
>
> People were concerned about the limited virological results and there
> was some discussion about the applicability of the assays.
>
> The biggest concern on the part of the committee was the
> generalizability of the results that we saw. Although these were large
> studies of thousands of patients, it was noted that many of the
> patients were young, white, healthy women and to generalize this to
> the world at large was of concern to many of the committee members.
>
> It was also pointed out that, obviously, people who are truly infected
> with picornavirus are the ones who benefit from this versus others who
> have self-identified cold symptoms and are infected with other
> viruses.
>
> People had concerns about specific subsets. There was no definite
> benefit demonstrated in smokers; benefits in men less than in women.
> Then there were major concerns in terms of groups that were not
> assessed, such as non-whites in large numbers; relatively little data
> in the elderly; those taking concomitant medications or those with
> complicating conditions. So, that limits the generalizability from the
> data that we saw.
>
> The last point that people focused on was the actual use of this drug.
> Again, some limitations and potential for misuse were noted, and the
> concern about actually giving the drug within 24 hours and what that
> would require in terms of the healthcare system; the assumption we
> would quickly move to a system where this is prescribed in advance and
> having patients have it on hand; the point that the PCR assay is not
> something used in clinical practice to try to figure out which
> patients are truly infected.
>
> Then, towards the end of the conversation, concerns about the food
> effects and, as brought up in the question and answer period, the
> likelihood that in the real world people would repeatedly administer
> the drug. I think that is what we covered.
>
> So let\'s move to the second point, which is to discuss safety of
> pleconaril.
>
> DR. BIRNKRANT: We inadvertently left off the issue about resistance.
> If you could discuss that as well we would appreciate that.
>
> DR. GULICK: Yes, I think it fits nicely into the safety discussion
> actually. Who would like to start? Dr. Brass, very reliable.
>
> DR. BRASS: I have four areas of exploration in the safety question.
> The first is the drug interactions, which I think are obviously
> potentially clinically significant, and the issue of the oral
> contraceptives is obviously highlighted because of the patient
> population studied thus far.
>
> It was very interesting to me to hear the lack of consensus about the
> role of the estrogen dose in the efficacy of oral contraceptive
> preparations. I think this point was made, in terms of efficacy of
> oral contraceptives what the drug interaction is going is making it a
> lower dose estrogen preparation effectively. If there is any reason to
> suspect that a lower dose of estrogen is less efficacious than a
> higher dose estrogen combination preparation, that is of serious
> concern. I think we have to remember how this drug is going to be made
> available. We are talking about women who have made a conscious
> decision that they did not want to become pregnant and that the use of
> an oral contraceptive was the optimal way they wanted to avoid the
> pregnancy. Therefore, it seems that any increased risk of an
> inadvertent pregnancy is almost unacceptable in the context of this
> symptomatic indication. So, I think that becomes a very important
> issue.
>
> The second was the cardiovascular. I noted that the sponsor\'s
> consultant indicated there was very little objective data to support
> that concern. I don\'t know if the agency would agree with that
> characterization but, if so, it obviously becomes a non-point. But if
> there are objective data to support the concern, which we haven\'t
> looked at in a lot of detail, then I think further exploration of that
> would become necessary.
>
> The third is the area of resistance, and there are people here much
> more qualified than I to comment on it but I will emphasize that, from
> my perspective, the fact that there is a background rate of resistance
> that makes those genotypes not susceptible, and we don\'t know what
> those genotypes are based on, and experience with other \"less
> virulent\" mutations that were identified early on in antimicrobial
> therapy in general, I think the full scope of the resistance problem
> can\'t be addressed yet based on the information we have right now and
> it is, therefore, of concern.
>
> The final point is, again, that the generalizability, as we talked
> about in terms of efficacy, also plays right into the safety concerns.
> We don\'t have a lot of data about the use of this drug in patients
> with co-morbid conditions and a variety of concomitant medications.
> So, the potential for unrecognized safety concerns in a generalized
> population, and how patients are actually going to use it apropos of
> the oral contraceptive concerns, all remain unaddressed when I think
> about the safety issues.
>
> DR. GULICK: Dr. Henchal?
>
> DR. HENCHAL: Yes, I have the same concerns, especially since the
> studies didn\'t seem to have representative proportions of elderly.
> This might be a target population for the drug in order to prevent
> upper respiratory infections in that population. It might be easy to
> dismiss cardiac effects in a healthy population but when you start
> talking about an elderly population with other health problems, that
> should raise a lot of concern about the use of this drug.
>
> DR. GULICK: Dr. Reller?
>
> DR. RELLER: The very patients who might most benefit from this drug,
> based on the evidence we have here, both in terms of the frequency of
> the entity \-- as you get older it gets less frequent \-- are the very
> ones that I think I have serious questions about balancing the risk
> versus the benefit.
>
> The major objective marker for diminution of symptoms most frequently
> measured was rhinorrhea. So, are we going to trade a day\'s decrease
> in a runny nose for a frequent event of breakthrough bleeding and
> numbers are too small to know the real risk but the potential risk for
> diminished efficacy of oral contraceptives when one extrapolates based
> on question one, these results to a potentially very much larger
> number of patients where even the potential efficacy would be greatly
> diluted.
>
> DR. GULICK: Yes, Dr. Gardner?
>
> DR. GARDNER: I am thinking about risk/benefit ratio really considering
> the substantial group of people who are not expected to derive benefit
> from this drug but would, nonetheless, be assuming what could be
> substantial but currently unknown or perhaps even postulated risks. I
> think we have to take all of those folks into account and that is a
> very large group of people, as we have talked about today.
>
> Even among those who are expected to derive benefit, the benefit may
> be small in comparison to substantial risk, particularly with respect,
> as Dr. Reller said, to oral contraceptives. Although Dr. Mishell
> certainly has fabulous credentials to discuss this, I am, nonetheless,
> unwilling to dismiss the role of ethinyl estradiol and contraceptive
> efficacy quite to the extent he did. Therefore, even if we were to
> believe that it had no role in efficacy, nonetheless, I think that
> women who have been using oral contraceptives for sometime,
> intentionally attempting to prevent pregnancy without intermenstrual
> bleeding, would be very concerned if they suddenly began to have it
> when they took this drug.
>
> In particular, we talked about labeling as being a risk management
> tool and study after study, including some done by the FDA itself,
> have shown labeling to be an ineffective method of controlling risk
> either from the standpoint of directing prescriber behavior or from
> changing or directing consumer behavior. Probably the most notable
> serious example of this is in all of the labeling and warning
> activities that have surrounded Acutane and many years later we still
> continue to have pregnancies on Acutane.
>
> So, for these reasons and the one that we discussed in terms of
> efficacy when this drug were to find its actual use pattern, were it
> to turn out to be that prescribing in advance of need is the most
> effective way to deliver it and have it on the shelf for the sign of
> first symptoms, I think it changes radically our ability to
> communicate and discuss risks with the people who are actually going
> to be taking the drug. Certainly labeling won\'t do it. If the person
> is taking the drug off the shelf to use it at the sign of first
> symptoms did not even hear the prescriber\'s discussion of it at the
> time it was prescribed, then I think we are in serious compromise of
> any ability to communicate either risks or the efficacious way to take
> this product.
>
> DR. GULICK: Dr. Fletcher then Dr. Wong.
>
> DR. FLETCHER: Just to add to that point, I think this is where the
> drug interaction potential comes back again because how long will that
> intervening period be between when the prescription is written and
> when the drug is actually taken? And, what other medications might
> that patient have started in that period of time? So, even though the
> physician may know about them, you have the separation of time now
> that someone could have started on a calcium channel blocker and when
> they started the calcium channel blocker, of course, they weren\'t
> taking pleconaril and then, you know, here comes a cold; take it. So,
> we have, in the way that this drug is likely to be used, a different
> set of drug-drug interaction considerations that will present
> themselves in a way they don\'t normally arise.
>
> DR. GULICK: Dr. Wong?
>
> DR. WONG: I guess I just want to say that I agree with the general
> tenor. I have not seen adequate information, from my point of view, to
> conclude that this drug is safe as we anticipate it will be used.
>
> Over the past few years we have looked at a lot of different sorts of
> drugs on this committee, and most of them have been drugs that are
> directed against life-threatening illnesses. For the most part, we
> have taken that very much into consideration when we have been looking
> at safety data, and I think that is an appropriate thing to do here.
> We are not looking at a drug that is directed against a
> life-threatening illness. The treatment effect here, although there is
> a clear consensus that it exists, I think there is also clear
> consensus that it is not that large. That has to be taken into
> consideration. I would like to see a lot more information and a much
> larger denominator to address the question does this drug decrease the
> efficacy of oral contraceptive drugs, and I would like to see a much
> more thorough evaluation of the effect of antiviral drug resistance
> over time, and also in breadth.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: I would also agree that for the safety I think the major
> issue is the possible drug interaction, as Courtney mentioned. I would
> also agree with what Courtney said, that we are going to give this to
> a patient up front and there would be concern that we have not fully
> understood this induction. I think that has a lot of potential for
> danger. Again, as Dr. Kumar said, even if we accept the fact that
> pregnancy is not increased, the bleeding is a significant issue if
> what we are saving the person is symptomatic relief. It is an
> antiviral but the efficacy we have been shown has dealt only with
> symptoms. We have not been shown any benefit in that we are actually
> reducing any complications or any other issues.
>
> If we can move into the resistance, I don\'t think we have to go into
> it endlessly but I would repeat what I said before lunch. First of
> all, it is a large endeavor to do all these studies and I think, as
> the sponsor mentioned, there is intention to do these. Since we have
> the luxury here of dealing with a non-life-threatening disease, then
> we require more information than we would if this were a drug for
> something which is about to kill our patients. We have learned a lot
> about antivirals, and we have learned that resistance is a major issue
> and we have made mistakes. I think some of the presentations here
> mentioned that when AZT was introduced, I think we did that probably
> the wrong way and, luckily, by the time we introduced NRTIs we learned
> something about it, otherwise they would be of no value had we used
> them differently.
>
> I do think there is concern that we see a ten percent resistance after
> a five-day course. I don\'t think it is surprising that those patients
> did not do worse. I don\'t think that tells us anything that will
> happen ultimately. The baseline samples that were resistant did, in
> fact, not do as well or, in fact, appeared to maybe even do worse.
> Therefore, it is concerning that a drug which would be given so much
> could rapidly produce widespread resistance and this would render it
> ineffective.
>
> The other concern is that there are other agents being developed that
> target the same area. We don\'t know if this will or will not produce
> a degree of cross-resistance. It may or it may not but we have
> absolutely no way of knowing today, and we have to keep in mind that
> this may result in cross-resistance to infections that are
> life-threatening. Viruses of this family in certain instances do
> produce diseases which are life-threatening and if we were to produce
> a population-resistant virus, that could be problematic. There are a
> lot if\'s here. It could be that will not be the situation, but I do
> think for this indication we should have answers to these questions.
>
> DR. GULICK: Dr. Atmar?
>
> DR. ATMAR: In terms of the issue raised about lack of an effect on
> complications, I would point out that the expected complication rate
> of things like otitis media or sinusitis, bacterial sinusitis are
> relatively low, one to two percent for each of those for, I guess, in
> these studies a cumulative total of about five to seven percent, and
> these studies were not powered to look at that endpoint and you really
> need to study many more patients to be able to show an effect there. I
> mean, it was disappointing that there was no apparent trend but,
> because the numbers were small, that is not particularly surprising.
>
> In terms of the resistance issues, I would point out that respiratory
> virus infections like influenza and picornaviruses are acute
> self-limited infections and are different from HIV which is a chronic
> infection. So, some of the same issues that deal with resistance for
> HIV don\'t apply to the respiratory viruses. While I think it is a
> concern, we can be somewhat relieved that with antiviral drugs, even
> though amantadine and rimantidine haven\'t been used extensively,
> resistance to these agents in naturally occurring isolates has not
> increased over time. One could argue that it is because we don\'t have
> a lot of clinical use of the drugs but, nonetheless, it hasn\'t been
> observed.
>
> With rhinoviruses, from city to city we have different serotypes in
> terms of epidemiology in a single season, and they vary from year to
> year within a season. So, I don\'t think, though obviously we don\'t
> have the data, it is likely to be a problem that will have an
> accumulation of resistance within the rhinoviruses over time. With
> enteroviruses I guess it is harder to know whether that would be a
> problem. We don\'t have the data and, short of looking at transmission
> studies which for rhinoviruses are terribly difficult to do, there is
> still a lot of discussion in the literature as to what the most
> important mode of transmission is, whether it is aerosol, and it is
> still open to discussion. So, I am not as worried about the resistance
> issues. It is something certainly to be aware of and to continue to
> look at.
>
> I feel less qualified to address the other safety issues raised in
> terms of the estrogen dose. I guess a question for the committee to
> consider is for the short course. We had zero out of 400-plus women in
> the efficacy trials who were receiving oral contraceptives that became
> pregnant, and two out of 58 or 60, or whatever, in the prophylaxis
> study, which was a six-week study. If we are just looking at the five-
> to seven-day course, the question is what does that denominator have
> to be, zero out of what number? I don\'t know what the answer is. I
> would like it to be a huge number but from a practical standpoint what
> kind of direction could one give to answer that? That hasn\'t really
> been addressed. Everybody wants a bigger number but what should the
> number be?
>
> DR. GULICK: Dr. Brass, Dr. Englund and Dr. Kumar.
>
> DR. BRASS: I agree that getting zero out of a big number is a losing
> battle and that is why I made the point about if I knew, for example,
> what the relative efficacy was of a combined formulation that had half
> the estrogen versus the full dose and I was convinced from that data
> that a half dose of estrogen was associated with no loss of efficacy
> and the clinical data were consistent with that, that would be very
> reassuring to me as opposed to studying 50,000 patients to convince
> myself it was zero.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: I just wanted to speak to the resistance issue because I
> have been interested in that particularly in the hospital setting. I
> do think that rhinoviruses are totally different from the other
> respiratory viruses that I have worked with. I have been very
> concerned about the spread of resistant influenza virus, and have
> published on that, and I am not happy with the use of rimantidine in
> the hospital setting, at least in my hospital setting where there are
> immunocompromised patients. Rhinovirus is not spread by aerosol. The
> resistant variants, and I don\'t know if it is the exact same mutation
> but the ones that we have with similar mutations don\'t spread that
> rapidly, and that is because they are a little bit attenuated because
> they don\'t attach so well, because their attachment mechanism is
> affected.
>
> I am very concerned about the safety and I think the resistance issue
> could be studied more, needs to be studied more and, to hark back to
> me being a pediatrician, it needs to be studied in a pediatric setting
> because those are the kids who are spreading the virus a lot more
> readily and rapidly than adults are.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: I want to come back to the safety issue. At all times it is
> very apparent that not just the agency and the committee members here
> but that sponsors work very, very hard to bring safe drugs forward.
> But in an illness that is self-limited, as the common cold clearly is,
> the bar is much higher where safety issues are concerned.
>
> I want to give you a very simple example. In treatment of syphilis,
> much, much earlier, I still remember being taught and I was told this
> line, that a moment with Venus, the goddess of love, will give you a
> lifetime with Mercury.
>
> \[Laughter\]
>
> I want to go back to this issue and just to think from my perspective,
> to tell patients \-- women on oral contraceptives make that personal
> choice that that is their method of contraception and to say you have
> a common cold; I will prescribe this drug. You may get half a day to
> one day symptom free but you are going to take a whole month of using
> additional barrier methods of contraception. I think that is
> practically going to be very relevant.
>
> I want to preface that to say that I would be accepting of that if I
> knew that I could counsel them right there and then when I write the
> prescription and give it to them, I can sit them down and say these
> are the issues. But many people around the table have said that we
> don\'t think that is the way it is going to be prescribed.
> Prescriptions are going to be given months ahead of time, two or three
> months, and we really don\'t have the face-to-face interactions to go
> through side effects and review, at that moment of time, on what drugs
> they are. Those really are my concerns as a clinician.
>
> DR. GULICK: Dr. Atmar?
>
> DR. ATMAR: Again, I would say that in terms of the way the drug is
> going to be used \-- I mean, we are all speculating as to what seems
> to be practical and it doesn\'t seem likely, certainly in an HMO
> setting, that one could even see a physician within 24 hours. To
> assert that prescriptions will be written ahead of time and given to
> patients, I mean we don\'t know that.
>
> The sponsor certainly, when asked the question, said that they were
> going to target their education towards the primary care physician and
> not towards the public. I guess I am a little bit bothered by making a
> decision based on speculation as to how the drug will be used.
>
> DR. GULICK: Dr. Gordin?
>
> DR. GORDIN: Well, the flip side of that \-- and I agree, it may not be
> that people will have this prescribed ahead of time in their pharmacy
> cabinets, but the opposite, that patients come in on day two or three
> of their common cold and get given this drug, because of pressures,
> beyond the 24 hours. Even in the sponsor\'s own data they presented, I
> believe it was about 60 percent of people who were screened out
> because they showed up too late for the study. It was maybe even
> higher than that. So, I think it is equally likely that instead of
> having it sitting around ahead of time, people will come in, in a
> sense, too late at least in terms of what we understand about the
> efficacy but will be given the drug and, again, experience potential
> toxicity and potentially no efficacy.
>
> DR. GULICK: Other comments about safety? Dr. Stanley?
>
> DR. STANLEY: I just want to reiterate what somebody else said. I
> don\'t think the risk/benefit ratio is there for such a common disease
> that is not life-threatening, and all these questions that are
> answerable but have not been answered yet about toxicity, the
> pregnancy complications and the interactions with other drugs. Those
> are answerable questions.
>
> DR. GULICK: Let me summarize what I think we said about safety. The
> committee really considered safety in terms of four things, the
> context in which we considered safety, the first being that only about
> 50 percent of people would actually be infected with picornavirus; the
> second, again, the generalizability question, that the trials were
> really done in healthy patients and, arguably, these drugs might be
> targeted towards the elderly or people with concomitant disease or
> medications; the point that outside the first 24 hours people might
> also take the drug.
>
> The other context we considered it in was how the drug would actually
> be used. There were some differences of opinion but a growing
> consensus that this would be prescribed in advance and that that
> decreases the opportunity to review safety information with the
> patients, at least in the real world.
>
> The fourth and probably biggest consideration of safety is that, of
> course, the common cold is an acute self-limited illness and that we
> raise the bar for this disease over some of the other diseases that
> the committee has considered over the past years.
>
> The two major areas that people focused on in our discussions were
> drug interactions and resistance. Again, around the table people felt
> that we have incomplete information about both of these.
>
> There were some concerns about the decreased estrogen levels, about
> the breakthrough bleeding, about the potential for unintended
> pregnancy although there was a difference of opinion on that, and the
> requirement for additional barrier protection.
>
> In the area where there is really little data to go on, other than
> some suggestions, there was concern about cardiovascular toxicity and
> symptoms associated with theophylline use.
>
> Then, the point that many people made is that we simply do not have a
> lot of information on other concomitant drugs that people would be
> likely to be taking.
>
> With regard to resistance, a much more controversial discussion
> really, people pointing out that rhinoviruses are not like other
> respiratory viruses and certainly not like viruses of chronic
> diseases. Yet, there was some concern about the ten percent background
> rate of resistance documented on this study. There were differences of
> opinion about the potential for widespread resistance in the community
> given widespread use of this drug, others pointing out that there are
> different serotypes in geography with rhinovirus illness.
>
> Other concerns raised previously were about treatment emergent
> resistance, 13 percent documented in the studies here. Questions that
> we really don\'t have any information on are the cross-resistance
> between this drug and other drugs in development for this and other
> viral diseases and, again, no information about transmission studies
> and whether resistant virus is transmissible among family members or
> other close settings.
>
> Let\'s consider question three. We are going to take a formal vote on
> this question. All members of the committee are eligible to vote, with
> the exception of Dr. Sun. Dr. Brass?
>
> DR. BRASS: Can I make one comment and ask one question?
>
> DR. GULICK: Okay.
>
> DR. BRASS: My comment has to do with the concern about the meaning of
> the efficacy. I would just point out that consumers are currently
> spending an exorbitant amount of money buying products for symptomatic
> relief and complementary medicines of unclear efficacy that they think
> work. So, the value of symptomatic relief to the consumer in the real
> world is actually quite substantial, and I don\'t minimize the benefit
> of cutting the symptomatic period by a day and a half.
>
> Similarly, when we talk about safety, there are no risk-free drugs,
> including those currently available OTC for symptomatic indications.
> They all have risks. We are able to define those risks and make an
> assessment of the risk/benefit ratio. So, a zero risk profile is not
> what is being asked for either in this discussion even for the
> symptomatic indication.
>
> My question, therefore, is when we answer this question do you want us
> to answer it in the context of hypothetically if I imagine that there
> are patients who get benefit and have no risk or little risk
> associated so that in any patient cohort the answer to this question
> is yes, do I vote yes? Or, do I have to vote yes only if I think as I
> extrapolate the data to how it is going to be used and a conceivable
> label to everybody, do I need to vote yes?
>
> DR. GULICK: Would the agency like to respond? Dr. Birnkrant?
>
> DR. BIRNKRANT: We do recognize that this is a complex question, and we
> are looking more for a big picture type of answer. That is, once the
> drug is approved, then is there adequate benefit to support the risk
> that we have discussed today?
>
> DR. BRASS: Given that we can only quantify that in a subset of the
> population based on the data that is presented to us, do we want to
> base the answer on the subset? If I believe what I just said, does
> that mean I automatically vote no?
>
> DR. BIRNKRANT: I don\'t really want to lead you one way or the other.
>
> DR. BRASS: No, I am not asking you to. I have to understand the
> context. I think you know what I mean. You made this question black
> and white so my vote has to be black and white so I just have to
> understand whom I am covering here.
>
> DR. BIRNKRANT: It is focused on approvability, meaning that once the
> product is approved it will be in the general population, and it is
> more a question extrapolated to that population.
>
> DR. GULICK: Just to add, the law says substantial evidence of safety
> and efficacy. That is what we are focusing on. Everyone has to take
> their own risk/benefit into account. Mark?
>
> DR. GOLDBERGER: Just to follow-up on what Debbie said. I think what we
> would like is your take, obviously \-- when I say yours, for each of
> the individuals who will be voting \-- on the discussion that was just
> held with regards to safety and efficacy integrated into your own
> experience, and that certainly can include how the drug perhaps is
> intended to be used and how you think it actually will be used. One of
> the reasons that we have advisory committees is to bring together a
> group of people who have a wide range of expertise, ranging from
> purely scientific to practical aspects, etc. and we would like all
> those factors taken into account in terms of how you decide that you
> would like to vote.
>
> DR. GULICK: Is that clearer? Let\'s pose the question then, do the
> safety and efficacy profiles of pleconaril support its approval for
> treatment of VRI in adults? I am going to go around the table and ask
> people to vote yes or no. We skip Dr. Sun so Dr. Brass, you get to
> start.
>
> DR. BRASS: No.
>
> DR. GULICK: Dr. Reller?
>
> DR. RELLER: No.
>
> DR. GULICK: Dr. Henchal?
>
> DR. HENCHAL: No.
>
> DR. GULICK: Dr. Gardner?
>
> DR. GARDNER: No.
>
> DR. GULICK: Dr. Atmar?
>
> DR. ATMAR: No.
>
> DR. GULICK: Dr. Wong?
>
> DR. WONG: No.
>
> DR. GULICK: Dr. Fletcher?
>
> DR. FLETCHER: No.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: No.
>
> DR. GULICK: Dr. Stanley?
>
> DR. STANLEY: No.
>
> DR. GULICK: Dr. Wood?
>
> DR. WOOD: No.
>
> DR. GULICK: Dr. Gordin?
>
> DR. GORDIN: No.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: No.
>
> DR. GULICK: Dr. DeGruttola?
>
> DR. DEGRUTTOLA: No.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: No.
>
> DR. GULICK: And the chair votes no. So, no votes for \"yes\" and 15
> votes for \"no.\" I suggest we take a break now. We are going to come
> back and consider the rest of the questions but I would like to take a
> ten-minute break. It is 2:40. Let\'s reconvene at 2:50.
>
> \[Brief recess\]
>
> DR. GULICK: We will resume. We have several more questions to consider
> before the end of the day. Dr. Birnkrant, do you want to introduce
> these to us?
>
> DR. BIRNKRANT: Basically, we focused quite a bit on issues related to
> oral contraceptive use and resistance. We were wondering if we could
> perhaps delve into other areas where there would be a need for
> additional studies, as well as again commenting on the areas of
> resistance and drug interactions.
>
> DR. GULICK: Specifically, what additional data would the committee
> like to see? Some things have already been mentioned. Dr. Gordin?
>
> DR. GORDIN: Just to say the obvious, I am sure all of us thought would
> we want to take this ourselves but I do think having much broader
> patient pools studied, and not excluding all the individuals who were
> excluded by age, and also by concomitant medications, diseases, etc.,
> etc. Clearly, at least for me, that was an important factor in
> thinking about would this drug really work if generally used. So, I
> would think that would be an important factor in further studies.
>
> DR. GULICK: Other suggestions about studies? Dr. Englund?
>
> DR. ENGLUND: I really think we need to study the asthmatics and
> children, which might even be the same, asthmatic children.
>
> DR. GULICK: Dr. Henchal?
>
> DR. HENCHAL: Actually, I was going to agree with that but not just
> more studies but studies that have a much broader base to represent
> Hispanics, African-Americans, the elderly, children. All that maybe
> has to be expanded.
>
> DR. GULICK: Dr. Wong and then Dr. Fletcher.
>
> DR. WONG: To me, the issue here wasn\'t efficacy so I will agree that
> it would be very interesting to know the results of use of this drug
> in all those groups but, to me, if they got the safety data in order,
> this would be an approvable drug.
>
> DR. GULICK: Dr. Fletcher?
>
> DR. FLETCHER: I have probably three or four things. First, I think the
> drug-drug interactions. We talked about data with the oral
> contraceptives but there are clearly other drugs for which the
> inductive properties could be very important. I wouldn\'t want to try
> to right now construct a list but I think there do need to be
> interaction studies with other select drugs that are frequently used
> and that would have serious consequences of therapeutic failure.
>
> I think these studies have to go beyond just a numerical
> pharmacokinetic study, in other words, was the area under the curve
> dropped by 30 percent or 20 percent. As we saw, I believe, with the
> oral contraceptive data a 30 percent drop did lead to a clinically
> significant interaction. So, the rules we would like to use, that it
> has to be more than 30 before it becomes clinically important I think
> are ones that we should try to move away from as rapidly as possible
> because it is just not an appropriate standard for us to have.
>
> Second, the food effect. I think we need to understand that in a much
> clearer way. I am probably going to get this wrong but I think the
> rule that our moms taught us was \"starve a cold and feed a fever.\"
> \"Feed a cold, starve a fever?\"
>
> \[Laughter\]
>
> I knew I would get it wrong. Whatever way, if we are using a drug you
> have to take with food, we need to have a much clearer understanding
> of what is really necessary, what kind of a snack; what kind of a
> meal. So, that I think needs to be done.
>
> Third on my list, and these really aren\'t in any particular order,
> would be resistance, I think in particular transmission of resistant
> viruses and response.
>
> Lastly, I am still not willing yet to dismiss the race/ethnicity
> issue. I understand all the hazards about looking at subgroups but, to
> me, when I look at those data I see some signal there that says this
> is worth a little more exploration than has been done to date. I think
> that perhaps could start with some pharmacologic studies to see if
> there is a basis there for any differences in response between
> Caucasians and not Caucasians before you launch into thousands and
> thousands of patient studies. But I think a little more exploration of
> that would be worthwhile.
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: To address some of the issues of resistance, first of
> all by the way, Courtney, my mother also said chicken soup. So, a
> combination of chicken soup with pleconaril I think would be optimal!
>
> Some of the issues that came up in the discussion regarding
> resistance, I think characterizing the patients with resistance
> regarding if this is serotype or point mutation resistance would be
> very helpful. I think also focusing on maybe a pediatric population
> and looking there, and this could be done in a school or in other
> settings, to see to what degree there is transmission. It may be that
> we will find that there is not a lot going on, that there is not a lot
> of transmission and that much of this is not point mutation, but I
> think a pediatric setting might be a good place for a well-designed
> study to look at the virology there and characterizing that I think
> would be helpful. That is something to consider. Of course, we would
> want to see what the cause of resistance is and, to the degree that it
> is possible, I do think we want at least some laboratory studies
> looking at the issue of cross-resistance with other compounds.
>
> DR. GULICK: Dr. Brass?
>
> DR. BRASS: I just want to reinforce the issue of generalizability. It
> is not only an efficacy issue because, again, I do believe the drug
> has efficacy, but it is a safety issue. If you want me to believe that
> as a primary care provider it is okay for me to give this drug to a
> 67-year old man status post-coronary bypass surgery on eight drugs, at
> least one of those has to be some place in a study population. So, I
> think the generalized population is very, very different than what we
> are seeing here. So, unless the label is going to be quite
> restrictive, I think that needs to be taken into account. Again, I
> pick that example because I do think the clarification of the
> cardiovascular adverse events and the theophylline reaction have to be
> at least agreed to, that there is no objective basis for them
> explicitly. And, the oral contraceptive issue I agree with as well.
>
> DR. GULICK: Dr. Wood?
>
> DR. WOOD: I would just like to add in terms of what has already been
> raised regarding drug-drug interactions that the analysis would look
> at repeated exposure since it is likely that individuals will take
> this drug more than once within a cold season since people tend to get
> several colds a season so it wouldn\'t be a one time thing but
> potentially with repeated exposure.
>
> DR. GULICK: Dr. Stanley?
>
> DR. STANLEY: Courtney beat me to it since he is there and I am not,
> but I do want to emphasize again that we really need to understand in
> other ethnicities how this drug works and if it is equivalent. In this
> day and age I think it is unconscionable to just assume that you can
> prove something in a particular Caucasian population and extrapolate
> it to others.
>
> DR. GULICK: Dr. Fletcher and then Dr. Gardner.
>
> DR. FLETCHER: I was just going to add to Dr. Wood\'s comment, I think
> not only repeated exposures but longer duration than five days. I
> think it is likely, if the drug is approved, that some will receive it
> for a course that is longer than five days. Not yet fully
> understanding the time frame of induction, one could imagine that you
> might not have something that appears if you have a five-day course
> and could appear if you have a seven- or ten-day course because you
> reach a different level of CYP induction. So, besides repeat
> exposures, I would probably extend the interval out a little bit
> longer.
>
> DR. GULICK: Dr. Gardner?
>
> DR. GARDNER: A couple of things. First, I hope the sponsor doesn\'t
> get the idea that we are going to try to hold them to pregnancy as an
> outcome or contraceptive interactions because I don\'t think any of us
> are thinking that way. But we would like a whole lot more information
> on the oral contraceptive interaction by analogy, by other studies,
> pharmacokinetically, all kinds of ways that we can get it, but the
> number of pregnancies and powering up for that is not it.
>
> The second thing is that I think possibly we may be struggling with it
> being the first in this class, that is, a prescribed medication, and
> some of what we have talked about today is related to what we would be
> discussing if we had an over-the-counter medication. So, I, for one,
> would like to have some insight from them, possibly from focus groups
> or other kinds of studies, about how this drug is likely to find its
> customary use and what they suggest, other than labeling which I will
> systematically reject every time it comes before me at least, as a
> risk management tool. What are some innovative ways that they might
> find to explain to people the important things about this product once
> it becomes available because even though it may be a prescribed
> product, being first in its class, the sense of all of us that it will
> be prescribed and used very likely, we think, much more like an
> over-the-counter product. I don\'t know about actual use studies but
> certainly label comprehension studies for people who are about to use
> it, or other ways that we could be assured that when it finds its
> usual use some of our concerns will not be magnified, would be very
> helpful.
>
> DR. GULICK: Dr. Brass?
>
> DR. BRASS: I just want to follow-up on something Dr. Fletcher said in
> the context of drug interaction studies, their duration, off/on rates,
> etc., that we not overly focus on mean responses. Because this is
> safety data, it is going to be the outliers that matter, and there
> very well may be ethnicity differences in the drug interactions where
> there are examples too. So I care about the 99th percentile, not the
> mean, and the 30 percent is the mean magnitude.
>
> DR. GULICK: Other comments on additional studies we would like to see?
> Dr. Birnkrant?
>
> DR. BIRNKRANT: With all of these recommendations, would this
> necessarily translate into another Phase III trial for the applicant
> to think about conducting or not?
>
> DR. GULICK: Anyone want to tackle that one?
>
> DR. BRASS: Well, it is usually a bad idea for committees to design
> trials for sponsors. I think if somebody can think of another way to
> do it, more power to them.
>
> DR. GULICK: Dr. Kumar?
>
> DR. KUMAR: I personally think that they have shown efficacy. It all
> comes down to safety. So, in whatever format the sponsor can show
> common drug-drug interactions, intermenstrual bleeding, and reassure
> us that there will not be increased failure of oral contraceptives is
> all that I would look for being able to safely use this agent.
>
> DR. GULICK: Dr. Reller?
>
> DR. RELLER: Since we did not see any data on the effect of this
> compound on prevention of complications, and I am not aware of any
> secondary benefits that might be important or should be considered,
> such as prevention of transmission to other patients, in reality we
> have a drug for an illness where we are talking only about symptom
> reduction. So, the level of safety that I would want to see, however
> it be demonstrated, is basically the same level of safety that would
> be required for an over-the-counter preparation, which means with all
> the ramifications of drug interactions etc., it is a very substantial
> bar because I think the benefit from reduction in symptoms is pretty
> small.
>
> DR. GULICK: Yes, Dr. Stanley?
>
> DR. STANLEY: Which reminds me of another issue we talked about, which
> is more thorough virologic studies to show the effect of actually
> perhaps decreasing viral burden in the secretions. I mean, if you
> could show that more convincingly with a better time decay curve, or
> whatever, now you are looking at a public health impact which gets
> beyond just saving the individual half a day or a day of symptom
> relief.
>
> DR. GULICK: Let me try to summarize. Again, from the committee\'s
> point of view, we were really focused on additional information that
> would fill in the blanks in terms of safety information. That is
> really what we concentrated on.
>
> People noted once again that the generalizability of the current Phase
> III studies should be expanded, and that we need to see additional
> studies in other populations, specifically pediatrics, other non-white
> race and ethnicities, the elderly, people with concomitant diseases
> such as asthma or chronic cardiac or pulmonary disease and
> immunosuppression, also those taking other medications.
>
> We spent a lot of time again talking about drug interactions. As Dr.
> Fletcher pointed out, these aren\'t just changes in numbers but there
> are physiological changes such as breakthrough bleeding. Everyone
> agreed that we need more information on that interaction and, in
> addition, drugs with a high probability of clinical failure. Also,
> just common drugs that are taken quite frequently.
>
> Other issues, pharmacokinetic, better definition of the food effect;
> better definition of longer duration or repeated exposures of the
> medication. Then, as Dr. Brass pointed out, increased characterization
> of the outliers rather than focusing on the mean.
>
> The other major area we touched upon was virological and resistance
> issues. Everyone felt that further characterization of resistance,
> serotypes, point mutations, does this have an effect on transmission
> and people suggested pediatrics or family situations is the best place
> to look for that.
>
> Does the drug really decrease the viral burden, and are there
> subsequent effects on transmissibility? Then, once again,
> cross-resistance among other drugs that are in development right now.
>
> Finally, one other suggestion was from Dr. Gardner, how would this
> drug really be used, and increase the amount of information
> considered, perhaps in a focus group; thinking about innovative ways
> to convey safety information given the likelihood that this drug would
> be prescribed in advance. And, Dr. Brass would like to add.
>
> DR. BRASS: No, I just want to clarify something because you included
> the issue of pediatric populations, and not presuming what the sponsor
> is or isn\'t doing in the pediatric population, I hope the intent was
> not to imply that an adult only indication could not be achieved.
> Because when you say you have to do studies in children or imply that
> you have to do studies in children you are shifting things a lot from
> what we have before us as an adult indication.
>
> DR. GULICK: Yes, let me clarify. I think the spirit of this discussion
> is what kinds of things would the committee like to see done to find
> out more about this drug. Clearly, studies in the pediatric
> population, for the many reasons that were discussed, would be helpful
> and valuable. I don\'t think I meant to imply, or anyone on the
> committee, is that you must do the following things to get your drug
> approved. Dr. Goldberger?
>
> DR. GOLDBERGER: Just to follow-up then on Dr. Birnkrant\'s question
> about an additional Phase III study, we recognize Dr. Brass\' comment
> and we do not expect the committee to go through the detailed elements
> of the design of such a study. Yet, listening to you just summarize
> the discussion about additional data that was required, you spoke
> about the concerns about the generalizability of the information that
> was here; issues about certain ethnic groups not being adequately
> represented; about certain patient populations including the elderly,
> asthmatics, etc.
>
> As you know, we will need to have some discussions with the firm about
> appropriate ways to proceed. It does sound, listening to that, as
> though the committee would like a substantial amount of additional
> clinical trial data, and we would just like as much clarification as
> we can have from you so that when we discuss these issues with the
> firm we can ensure that they have the best possible advice about how
> to proceed.
>
> DR. GULICK: Maybe I can just jump in and say that we all recognized
> around the table is that these were very large studies, thousands of
> people, yet, 80 to 90 percent were white. The elderly were in a very
> low minority; and patients were excluded with many serious concomitant
> diseases. I think I got a consensus from the committee that we are
> concerned about that. There are other diseases, other clinical trials
> that we have seen which may not have complete representation of every
> group but at least are a much more diverse group and you get the sense
> of a performance of a drug in many different populations.
> Generalizability I think is always a concern with clinical trials.
> Having these very large studies be so homogeneous I think gave a lot
> of us pause about trying to apply to the entire world of people that
> get colds. Yes, Dr. Wong?
>
> DR. WONG: I would agree with that with respect to safety but I saw
> enough to conclude that this is an efficacious drug for picornavirus
> infections. So, I would not recommend that efficacy necessarily be
> shown in all those groups, but I would like to see that it can safely
> be used in all those groups.
>
> DR. GULICK: Dr. Reller?
>
> DR. RELLER: I thought the efficacy, when you didn\'t restrict it to
> those who had some evidence of picornavirus infection, was a split
> decision and I don\'t know how you are going to find out information
> in the broad span of patients unless one eliminates some of the
> exclusions and studies those patients. At the same time, in addition
> to safety, with a more diverse patient population you might as well
> see if the efficacy holds up as the drug would actually be used. I am
> not convinced that it would.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: I think that the studies that need to be done do need to
> be broader, but I think you should compare the elderly with the
> elderly, the COPD 50-year old with the 50-year old, and forget to
> compare an 18-year old college student with a 65-year old who is on
> hypertensive meds and has smoked for 50 years. So, I would like to see
> more focused clinical studies in hundreds, not thousands, because I
> think that could be pin-pointed for investigators that have a high
> minority population and it could still get us the right answer. But I
> think you need to keep on comparing oranges with oranges and apples
> with apples because we are never going to get efficacy. With
> rhinovirus I don\'t believe you will get efficacy if you compare a
> huge population unless the sample size approaches 10,000 or 20,000.
>
> DR. GULICK: Dr. Gordin and then Dr. Brass.
>
> DR. GORDIN: I was just going to make the point that if future studies
> are done I think it would be up front, for the FDA and the company, to
> agree whether it is intent-to-treat of all people or only those with
> proven picornavirus, given how difficult it is going to be for any
> clinician to tell the two apart if the drug is marketed.
>
> DR. GULICK: Dr. Brass?
>
> DR. BRASS: My issue with efficacy boils down to what the label
> population is going to be. If the label is going to be limited to
> young, healthy women who are not on oral contraceptives and who are
> not smoking, I think the efficacy has been nicely demonstrated. If we
> want to extrapolate that result to other populations and so reflect it
> in the label, that is where I think the issue of studying other
> patient populations becomes a judgment call. But I am unconvinced that
> the efficacy extends beyond that population in a substantial manner.
>
> DR. GULICK: Dr. DeGruttola?
>
> DR. DEGRUTTOLA: I just want to comment that I would certainly agree
> they have demonstrated efficacy within the restrictions of the
> populations studied, and it would be interesting to go outside those
> populations and learn more about efficacy elsewhere. I also wanted to
> mention that I think that the comment that was made about studying
> families was particularly interesting because, for example, if it were
> feasible to do this, if you could randomize families to use pleconaril
> versus placebo at the time of colds, then you might be able to study
> the resistance issues as well as the transmission issues and find out
> not only if the number of colds in the families were reduced, but also
> something about what viruses they became infected with and so on. So,
> I think that would be a challenging study to do, obviously, and I
> wouldn\'t personally think that would be required for reconsideration
> of the drug. I agree with the concern about focus on safety, as I
> mentioned before, but if there were interest in looking more broadly
> at the questions of resistance and transmission, I think that would be
> a fascinating way to proceed.
>
> DR. GULICK: Have we answered that question to your satisfaction? I see
> a \"yes.\" We have one additional question to consider. This is more
> kind of global, asking the committee to think about rhinovirus
> infections in general.
>
> DR. BIRNKRANT: That is, how to develop a drug for rhinovirus
> infections. In addition to issues outlined on that slide that was up
> there, could we hear some discussion about which population we should
> actually be focusing on for efficacy? Should it be the intent-to-treat
> infected, or should it be the all randomized, or should it be both?
>
> DR. GULICK: Dr. Schapiro?
>
> DR. SCHAPIRO: I would probably agree with Dr. Gordin that it is
> important for this to be clinically relevant. We saw a very nice
> presentation and good data from the sponsor but we were really seeing
> symptomatic relief with a drug that is antiviral, and when we went
> with the risk/benefit that impacted what we were willing to accept. I
> think that was a repeated motif. If we are looking to reduce symptoms,
> then we should also do that in a way that would be widespread. It
> would have to be not diagnosed as the virus but on the symptoms. So,
> as Dr. Gordin said, it wasn\'t appropriate to have here PCR positive
> patients. That just wouldn\'t work. If, on the other hand, we are
> looking at targeting complications and high risk patients, then that
> would.
>
> So, focusing on specific patient patients, of course, depends on what
> diagnostics become available. We may see new and nice improvements but
> I think it has to be relevant to what the sponsor is going for. If it
> is similar to what we saw today, I think it would have to be a general
> population. I think also it would have to be generalizable as far as
> how quickly the treatment was given. We were able to eventually define
> that only a third of those that were screened were able to be
> enrolled. That is clinically relevant. So, I think those are some of
> the things that have to do into the design. I think if we are
> targeting specific populations where maybe you are able to have a
> diagnosis first, in that case it would be applicable. But I think here
> that was a little bit part of the discrepancy between what the sponsor
> was presenting and how we critiqued it. The same I think for toxicity
> and interactions.
>
> DR. GULICK: Dr. Brass and then Dr. Wong.
>
> DR. BRASS: While the endpoint was symptomatic, I think it is worth
> pointing out, as I said before but to reemphasize, that this was a
> very rigorously defined symptomatic endpoint. It was not just a
> composite score of a bunch of things; you had to meet substantive
> standards in multiple categories, and it had to be sustained for 48
> hours. Remember, when you reached the endpoint that really means the
> last day you had symptoms was on day six and so one and a half days
> was a high percentage of the six-day symptomatic period. So, I was
> actually pretty comfortable with the endpoint, as defined, as being
> clinically relevant and rigorous enough to have that kind of meaning.
>
> The issue about the ITT population versus the truly infected
> population goes back to how you make the population risk/benefit
> ratio. Again, if one tries to understand who is actually going to be
> exposed to this drug when it is available 12 months out of the year in
> a more generalized way, what is the percentage of patients who you
> think will be deriving benefit from the universe that is actually
> prescribed the drug? When a physician is making the decision and maybe
> even discussing it with the patient, they have to have some sense of
> what the probability is of even getting that day, day and a half of
> relief.
>
> As I indicated, I think that the 45, 50 percent is a top bar and the
> actual percent in a more generalized population might be much lower.
> That may still be fine, but if one is going to make an informed
> decision with an individual patient about the risk and benefit and
> truly understand what the probability of success is going to be, one
> has to relate it to the overall population that is going to be exposed
> to the drug, not only the subpopulation that has been shown to benefit
> from the drug because you can\'t identify that cohort prospectively.
>
> DR. GULICK: Dr. Wong?
>
> DR. WONG: I guess my answer to Dr. Birnkrant\'s question would be that
> I would ask them for both analyses. I have a hard time imagining any
> circumstance in which I would not want to see them both. Clearly,
> having the intent-to-treat populations compared really does tell you
> the most about the effects that will be seen in real life, but not
> giving the other population takes the risk that you will not be able
> to see a true biological effect and I think that that is something
> that we would want to know. Even if we were not able to extrapolate
> that to a clinically identifiable treatment population today, it might
> well be important to know that a new drug or a class of drugs is
> biologically active in and of itself.
>
> DR. GULICK: Other comments? Dr. Goldberger?
>
> DR. GOLDBERGER: It was, of course, entirely appropriate for the
> company to conduct their clinical trials versus placebo. Nonetheless,
> there are questions that came up here, not surprisingly, perhaps
> intensified a little bit by some of the potential safety issues, about
> how a drug like this would actually compare to the type of
> over-the-counter therapies that are commonly used. Does the committee
> have any perspective or view about clinical trials that would utilize
> that comparison as opposed to simply utilizing a placebo control?
>
> DR. GULICK: Dr. Brass?
>
> DR. BRASS: It would be of interest but should not be required.
>
> DR. GULICK: Do you want to say more about that?
>
> DR. BRASS: Again, we talked about how hard it is to do trials in this
> population. We have referred to the limitations of symptomatic
> therapy, and without understanding all those variables, I think
> demonstrating that the drug was efficacious against placebo would be
> an appropriate standard that would allow physicians and other
> healthcare providers to make an appropriate decision about whether it
> is an appropriate use in an individual patient. Obviously, we would
> all be interested in how it would compare to those other drugs but I
> think all you are doing is adding a series of design complications to
> a problem that we have spent all day talking about how difficult it is
> to study.
>
> DR. GULICK: Yes, Dr. Stanley.
>
> DR. STANLEY: Again, if you are just going to look at symptom relief as
> your endpoint, then there may be some validity to having it compared
> to what is already available over-the-counter. On the other hand, if
> you are looking at an antiviral effect and you can really show a
> significant antiviral effect, then it shouldn\'t be held up next to
> the other standard.
>
> DR. GULICK: Two parts of the question that we haven\'t really touched
> on are the first and fourth, although we have been talking about them
> all day. But do people have general suggestions about diagnostic
> criteria for the potential for drug interactions in a more general
> sense?
>
> DR. BIRNKRANT: We would also specifically like to know if, up front,
> all patients should be cultured, not just those who are deemed to be
> PCR positive.
>
> DR. GULICK: Dr. Englund?
>
> DR. ENGLUND: I think that the sponsor needs to provide us with some
> data, not necessarily on all patients but on a subset of patients, so
> that we can take a look at see. I believe that PCR is a great assay
> and I believe their PCR is probably a good assay. I don\'t believe
> that I have seen it published; I don\'t believe I have seen
> references. I have just read through here and I would like more
> information. So, I would say we wouldn\'t need it on all patients but
> they had thousands of patients and if we could have had a subset of
> that it would have been great. And, I would like to know what the
> effect of the freezing is. I mean, there are things in terms of
> diagnostics that they could provide some information without greatly
> affecting their effort and cost.
>
> DR. GULICK: Dr. Fletcher?
>
> DR. FLETCHER: On drug interaction, for the drugs that we talked about
> that would be very commonly used or that would have serious
> consequences of therapeutic failure, I think those probably ought to
> be discrete drug-drug interaction studies. I don\'t think I would try
> to embed those into another large clinical trial. I think if another
> large clinical trial was done, one could think about an opportunity to
> look for any signals for drug-drug interactions in that study. You
> know, there are population pharmacokinetic techniques that are talked
> about.
>
> The only comment I would have is if you go down that road you would
> need to pay very close attention to the design of that. I think far
> too often we have just said, well, we will collect some random samples
> and try to use that as a screen for drug-drug interactions. I don\'t
> believe that is an adequate way to proceed. If you are going to do
> that you need to pay as much attention to the design of that component
> of the study as you would any other components of a large study.
>
> DR. GULICK: Dr. Atmar?
>
> DR. ATMAR: In addressing the issue of doing the cultures at baseline,
> I think the sponsor did address that issue in their Phase II 032, if I
> remember the number correctly, trial. By my calculation, they came up
> with three additional culture-positive specimens at baseline that were
> RT-PCR negative by the two assays. In an ideal world, sure, do all the
> tests but I think at this time the best method to diagnose
> picornavirus, rhinovirus infection is RT-PCR, and it is an assay that
> has adequate controls to ensure that there is no carryover
> contamination. That is the new gold standard. I think there is
> adequate proof in the literature to substantiate that. So, if I had a
> bottomless pocketbook, yes, I would do cultures on everything but I
> think that the approach that the sponsor took for these two studies is
> realistic.
>
> DR. GULICK: Any other thoughts? Not to belabor it but just to say our
> additional suggestions are for diagnostic criteria. We heard a
> difference of opinion on the use of PCR versus culture, and a plea for
> at least embedding a pilot study into larger studies.
>
> People were convinced that we should look at both intent-to-treat and
> intent-to-treat infected because they tell us different things.
>
> In terms of the population, most of the consensus was that we need to
> have a population for the real world, and consideration about the
> within the 24 hours rule needs to be done, again, looking at the
> intent-to-treat infected as a valuable subpopulation, and then
> consideration of the use of over-the-counter meds since that is so
> common.
>
> In terms of endpoints, people once again complimented the sponsor on
> using a very well thought out symptomatic endpoint which people
> thought was clinically relevant, although many people reiterated that
> we are interested in the virologic effect as well.
>
> Dr. Goldberger\'s question about randomizing people, what is the
> appropriate randomization between a rhinovirus drug and whether it
> should be placebo or over-the-counter meds, and finally drug
> interaction studies and Dr. Fletcher\'s suggestion of doing formal
> small pharmacokinetic studies and then trying to glean signals about
> other possible drug interactions from the larger studies.
>
> Did we do our job? I am getting a \"yes.\" Any final comments from
> anyone?
>
> I would like to thank the sponsor, the agency, the members of the
> committee and the audience, and we will close this session. Thank you.
>
> \[Whereupon, at 3:30 p.m., the proceedings were adjourned.\]

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