> DEPARTMENT OF HEALTH AND HUMAN SERVICES
>
> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> **ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE**
>
> Wednesday, July 10, 2002
>
> 8:30 a.m.
>
> Marriott Washingtonian Center
>
> 9751 Washingtonian Boulevard
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> L. Barth Reller, M.D., Chair
>
> Tara P. Turner, Pharm. D., Executive Secretary
>
> MEMBERS
>
> Gordon L. Archer, M.D.
>
> David M. Bell, M.D.
>
> Alan S. Cross, M.D.
>
> Steven Ebert, Pharm.D. (Consumer Representative)
>
> Mary P. Glodé, M.D.
>
> James E. Leggett, Jr., M.D.
>
> Judith R. O\'Fallon, Ph.D.
>
> Jan E. Patterson, M.D.
>
> Julio A. Ramirez, M.D.
>
> Ciro V. Sumaya, M.D.
>
> Ellen R. Wald, M.D.
>
> CONSULTANTS (VOTING)
>
> Monica Parise, M.D.
>
> Theresa Shapiro, M.D., Ph.D.
>
> GUESTS (NON-VOTING)
>
> Donald Poretz, M.D.
>
> Coleman Rotstein, M.D.
>
> FDA
>
> Renata Albrecht, M.D.
>
> Ruthanna Davi, M.S.
>
> Mark Goldberger, M.D., M.P.H.
>
> Rosemary Johann-Liang, M.D.
>
> Leonard Sacks, MB.B.Ch.
>
> [C O N T E N T S]{.underline}
>
> Call to Order: L. Barth Reller, M.D. 4
>
> Introduction of Committee 4
>
> Conflict of Interest Statement: Tara P. Turner, Pharm.D. 6
>
> Opening Remarks: Renata Albrecht, M.D. 8
>
> **Sponsor Presentation: World Health Organization**
>
> Dr. Melba Gomes 12
>
> Professor Nicholas White 17
>
> Professor Peter Folb 36
>
> Professor Fred Binka 45
>
> **FDA Presentation**
>
> Leonard Sacks, MB.B.Ch. 82
>
> Ruthanna Davi, M.S. 113
>
> Rosemary Johann-Liang, M.D. 124
>
> Renata Albrecht, M.D. 147
>
> Open Public Hearing: Hans Kemmler, M.D. 150
>
> Charge to the Committee: Mark Goldberger, M.D., M.P.H. 178
>
> Committee Discussion 185
>
> Discussion and Vote 238
>
> [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. RELLER: Good morning. I would like to call the Advisory Committee
> meeting of the U.S. Food and Drug Administration Anti-Infective
> Advisory Committee to order. We will begin this morning by the
> introduction of staff from the FDA and committee members for today\'s
> meeting.
>
> We will begin on my right with Dr. Mark Goldberger.
>
> **Introduction of the Committee**
>
> DR. GOLDBERGER: Mark Goldberger from the Office of Drug Evaluation IV.
>
> DR. ALBRECHT: Renata Albrecht, Acting Director for the Division of
> Special Pathogens and Immunologic Drug Products.
>
> DR. SACKS: Leonard Sacks, Medical Officer in the Division of Special
> Pathogens and Immunologic Drug Products.
>
> DR. JOHANN-LIANG: Rosemary Johann-Liang, Medical Officer with the
> Division of Special Pathogens.
>
> MS. DAVI: Ruthanna Davi, Statistical Reviewer, Office of
> Pharmacoepidemiology and Biostatistics.
>
> DR. PARISE: Monica Parise, Medical Officer with the Malaria
> Epidemiology Branch at Centers for Disease Control.
>
> DR. ARCHER: Gordon Archer, Chair of the Division of Infectious
> Diseases at Virginia Commonwealth University.
>
> DR. LEGGETT: Jim Leggett, Infectious Diseases at the University of
> Oregon Health Sciences University.
>
> DR. GLODE: Mimi Glodé, Pediatric Infectious Diseases, University of
> Colorado, Denver.
>
> DR. BELL: David Bell, Assistant to the Director for Antimicrobial
> Resistance in the National Center for Infectious Diseases at CDC in
> Atlanta.
>
> DR. TURNER: Tara Turner, Executive Secretary to the committee.
>
> DR. RELLER: Barth Reller, Division of Infectious Diseases, Duke
> University Medical Center, Director of Clinical Microbiology there.
>
> DR. PATTERSON: Jan Patterson, Medicine and Infectious Diseases,
> University of Texas Health Science Center, San Antonio.
>
> DR. SUMAYA: Ciro Sumaya, Dean, School of Rural Public Health, Texas
> A&M University System Health Science Center.
>
> DR. WALD: Ellen Wald, Division of Infectious Diseases, University of
> Pittsburgh School of Medicine.
>
> DR. EBERT: Steve Ebert, Infectious Disease Pharmacist and Clinical
> Professor at the University of Wisconsin.
>
> DR. SHAPIRO: Terry Shapiro, Division of Clinical Pharmacology, Johns
> Hopkins.
>
> DR. RAMIREZ: Julio Ramirez, Chief, Infectious Diseases, University of
> Louisville.
>
> DR. O\'FALLON: Judith O\'Fallon, statistician at the Mayo Cancer
> Center, Rochester, Minnesota.
>
> DR. PORETZ: Don Poretz, private practice in infectious diseases in
> Fairfax, Virginia.
>
> DR. RELLER: Thank you.
>
> Tara Turner, our Executive Secretary, will read the conflict of
> interest statement.
>
> **Conflict of Interest Statement**
>
> DR. TURNER: The following announcement addresses the issue of 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 and information provided by the
> participants, the agency has determined that all reported interests in
> firms regulated by the Center for Drug Evaluation and Research present
> no potential for a conflict of interest at this meeting.
>
> We would like to note for the record that Kenneth Brown, M.D. 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 interests.
>
> 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.
>
> DR. RELLER: The opening remarks for today\'s meeting will be given by
> Dr. Renata Albrecht.
>
> **Opening Remarks**
>
> DR. ALBRECHT: Good morning. I would like to welcome everyone to
> today\'s advisory committee meeting on artesunate rectal capsules. On
> behalf of both the Division and the Office, I would like to thank the
> committee members, guests and consultants for making the time to be
> with us to lend us your expertise in this deliberation.
>
> May I also extend a welcome to representatives from the World Health
> Organization and to their distinguished consultants who have not only
> undertaken the challenge of developing artesunate rectal capsules as
> initial management in patients with malaria, but have also traveled
> probably the greatest distance to be here. So, for both of these
> efforts, you are to be commended.
>
> I believe it would be appropriate to acknowledge as well that we have
> at this committee meeting representatives from Swissmedic who are also
> reviewing this application and will be making remarks during the open
> public hearing.
>
> Malaria is a serious disease, a life-threatening disease with serious
> social and economic impact. It is estimated to cause perhaps a quarter
> of the billion cases of acute disease annually and about a million
> deaths per year in parts of the world, including Africa, Asia and
> South America. Although it is not a common disease in the United
> States, it does impact U.S. travelers, Peace Corps volunteers and the
> Military who go to those parts of the world.
>
> There are various effective oral and parenteral therapies for the
> treatment of this disease although resistance has developed to some of
> these. However, when these therapies are not an option for the initial
> management of a patient, an alternative is needed. It is with this
> goal in mind that the World Health Organization has developed and
> submitted the application for artesunate. We thank them for bringing
> this application forth and enabling us to present it at the advisory
> committee for discussion.
>
> Let me turn to the scientific aspects of the application. The proposed
> indication, as we will hear, is the initial management of acute
> malaria in patients who cannot take medication by mouth and for whom
> parenteral treatment is not available. The World Health Organization,
> their consultants and FDA staff have prepared a series of
> presentations to provide information on artesunate including its
> activity and safety profile.
>
> Much of this information was also included in the background material
> provided to you before the meeting. As you listen to the
> presentations, we would like you to keep the following issues in mind.
> These issues would also be relevant to the questions that Dr.
> Goldberger will give as the charge to the committee this afternoon.
>
> The first set of issues relate to the differences between the intended
> population that will receive this product in the actual-use setting
> and the population that was studied as part of this NDA. Specifically
> the population studied consisted of patients who were already in a
> hospital setting and, thus, had access to the medical infrastructure,
> medical personnel and ancillary management.
>
> The question would be what is the infrastructure that will make
> artesunate available to the intended population. What education
> program will assure that patients understand how the product should be
> used and what provisions will be available to enable patient transport
> for definitive therapy?
>
> Also, the population that was studied consisted primarily of older
> children and adults, although the anticipated use may involve children
> less than two years of age and then the question of what is the
> potential risk of neurotoxicity in that age group arises.
>
> Also, in clinical studies, the patients had a definite diagnosis of
> moderately severe malaria established on entry while, in the intended
> population, patients may have all levels of severity of malaria or
> they, in fact, may have another febrile illness, for example,
> bacterial meningitis.
>
> The timing of drug administration may also be significant. For
> example, what might be the consequences if the drug is administered
> too soon in the course of disease or, perhaps, too late in the course
> of disease.
>
> The second set of issues relates to the endpoints used in the study
> and their clinical implications. These include the 24-hour parasite
> clearance or parasite-count reduction as a surrogate of clinical
> success or clinical cure and, also, the clinical significance of the
> recrudescence at 28 days that we will see, and what is the impact of
> such recrudescence on the emergence of resistance to artesunate or
> other agents.
>
> So these are some of the issues that we would like you to keep in mind
> as you listen to the presentations this morning. With that, we look
> forward to your discussion and deliberations of the questions and
> issues before you.
>
> I now turn it back to you, Dr. Reller.
>
> DR. RELLER: Thank you, Dr. Albrecht.
>
> We will now have the presentation of the sponsor, the World Health
> Organization, Dr. Melba Gomes.
>
> **Sponsor Presentation: World Health Organization**
>
> DR. GOMES: Good morning. My name is Melba Gomes. I work for the
> Special Program for Research and Training in Tropical Diseases in the
> World Health Organization and am leading a team of experts who come
> independently to act on behalf of WHO in defending this current
> submission.
>
> \[Slide.\]
>
> The first slide essentially repeats what Dr. Albrecht has said that
> infectious and parasitic diseases constitute a large proportion of
> causes of death and, of these, malaria is amongst the highest major
> killer. About 40 percent of the world\'s population is exposed to
> malaria and the death toll is highest in young children.
>
> \[Slide.\]
>
> The estimates are essentially about 1.5 to 2 million deaths in
> children under the age of five. If you go to a pediatric ward in most
> of Africa, Kenya, Malawi, Tanzania, Ghana, half of the wards would be
> filled with children dying of malaria, the majority having symptoms
> that would have progressed fast over 24 hours.
>
> \[Slide.\]
>
> This child would not have been able to take drugs for a period of 24
> hours before the picture was taken. As the disease would have
> progressed, her mother would have needed to choose between taking her
> child to a hospital or not and would have calculated the probability
> that they, the mother and the child, would have arrived at the
> hospital before the child died.
>
> From the data that we have, a small proportion of those who are
> referred to hospital actually reach hospital with a child that is
> alive. The rest, essentially, have died en route to hospital or at
> home. If they have made it to hospital, the disease would have
> progressed to a point at which it is in a very acute stage. This would
> be considered as a medical emergency in a disease considered fatal
> unless treated and most lives are lost from malaria in this way.
>
> \[Slide.\]
>
> In 1997, WHO needed to find a solution for these kinds of children. We
> attempted to respond to this need for a preventable condition by
> developing an antimalarial\--in this case, artesunate\--to be given as
> emergency treatment, emergency management of patients who cannot take
> drugs by mouth but who cannot get to a hospital where definitive
> treatment can be given for several hours, where the risk of death is
> high and we needed to buy them the time to reach definitive treatment.
>
> \[Slide.\]
>
> We will have presented a dossier which is in the hands of the Food and
> Drug Administration, the Swissmedic and the medical-control agency in
> the United Kingdom, the essence of which is in the briefing document
> that you would have, providing what we believe is a coherent case for
> the efficacy, safety and quality of this drug, artesunate, provided in
> a suppository form for the following indication: to manage initially
> acute malaria in patients who cannot take medicines by mouth and for
> whom parenteral treatment is not available.
>
> We see the challenge before us today to defend this indication which
> we have carefully worded to show that the drug is effective for the
> purpose and to discuss safety in relation to the way that we propose
> to give the drug, and to argue that, for this purpose and in the way
> we propose to give the drug, the safety issues for the narrow
> indication can be set aside.
>
> We see it as our responsibility to ensure that any reservations you
> may have regarding safety do not have a bearing on the way we propose
> to use the drug. We will want to show you a future that, if approval
> by the advisory committee and the FDA is given, it will release the
> World Health Organization\'s energy for implementation with a large
> public-health benefit.
>
> The WHO has no intention of releasing its responsibility for providing
> a medicine and undertaking its safe and responsible use following
> approval. It will not be our primary responsibility or aim in our
> presentations to argue on the manner in which the indication applies
> in the U.S. We will be wanting to discuss and to defend this if the
> advisory committee wishes to do so.
>
> It is the first time that WHO has developed a drug and submitted it
> for registration in its own name. In coming to the FDA as a U.N.
> agency, we come in the confidence that the development will meet the
> standards of the highest review process that you will ensure.
>
> I would like to be able to introduce the team who have developed this
> drug. Included implicit in that is the donation of the Chinese who
> have given us their data and the drug. But the first introduction, and
> there would be five members of the team, is Professor Nicholas White,
> Professor Peter Folb, Professor Fred Binka, Sanjay Krishna and Anthony
> Dayan who is not here with us today.
>
> All have contributed their time on a pro bono basis as independent
> experts in this development and they are here as independent experts.
> Professor White and Sanjay Krishna would be the world\'s experts on
> clinical pharmacology and severe malaria. Nick White would have
> devoted the past twenty years of his life to understanding the
> pathogenesis of malaria, the pharmacokinetics and pharmacodynamics
> drugs that can be used in the treatment of malaria.
>
> Professor Peter Folb is normally on the other side, in your position
> in normal life, but he has spent twenty years critically reviewing all
> aspects of drug development dossiers submitted for registration in
> South Africa. He is the person who advised the WHO five years ago that
> we could build a case for this indication, this new indication for
> malaria, and potentially save lives. In large part, he was the
> architect of much of its development.
>
> Fred Binka would have spent the past fifteen years of his life in
> malaria-endemic communities, in Ghana, mainly, quantifying the risks
> and benefits of different interventions that have the potential to
> save lives in malaria.
>
> This is the end of my introduction. I will come back at the end, but I
> will now hand over to Professor White to take you through the clinical
> part of the presentation.
>
> PROFESSOR WHITE: Thank you, Melba.
>
> Mr. Chairman, members of the committee, ladies and gentlemen, I am
> Professor Nick White. I am Professor of Tropical Medicine at Mahidol
> University in Bangkok Thailand and Oxford University in England. It is
> my job this morning to present to you the rationale for rectal
> artesunate and the clinical evidence of efficacy.
>
> \[Slide.\]
>
> I don\'t apologize for repeating the size of the problem,
> approximately one-fifth of the world\'s population infected today and
> various estimates of a higher mortality even than written here of up
> to 3 million deaths per year. So this is the most important parasitic
> disease of man and it is caused by a parasite which invades the red
> blood cell, as you know, and the pathology of malaria is entirely
> related to that process.
>
> \[Slide.\]
>
> So malaria, unlike most other infectious diseases, but, unfortunately,
> as with HIV, has a global mortality that is rising, not falling, and
> we believe that approximately 90 percent of that burden falls in the
> African continent upon children.
>
> \[Slide.\]
>
> This rising mortality is attributed directly to the loss of affordable
> and available drugs.
>
> So, briefly, a summary of the epidemiology of malaria. We
> conventionally define the epidemiology in terms of the
> entomological-inoculation rate. That is the number of times you are
> bitten per unit time\--in this case, a year\--by a mosquito carrying
> malaria parasites. So you can see that there are places in the world
> on this logarithmic scale where you may have malaria every day. You
> may contract this disease every day and everyone has malaria all the
> time.
>
> In this context of high stable transmission, the burden of severe
> disease falls largely on young children and it manifests predominantly
> as severe anemia. This carries, as you have seen, a significant
> mortality.
>
> As the entomological-inoculation rate falls, the intensity of
> transmission falls or becomes more seasonal. We see a change in the
> clinical appearance with a predominant syndrome now of cerebral
> malaria. That is coma in the presence of falciparum malaria in the
> blood. We see also other presentations, predominantly metabolic
> acidosis. These are all linked.
>
> As the entomological-inoculation rate falls further, then the age
> range broadens and everybody becomes susceptible and we now see the
> appearance of different clinical manifestations in adults, notably
> acute renal failure and, to a lesser extent, liver dysfunction and
> pulmonary edema.
>
> But this is a multisystem infection with a different clinical
> epidemiology depending on the intensity and seasonality, to a certain
> extent, of transmission.
>
> \[Slide.\]
>
> So this would be your life if you lived somewhere where you had an
> infectious bite every week. I will show this several times and just go
> through it. This is a logarithmic scale showing the number of
> parasites in your body. If I had a 2 percent parasitemia, I would have
> about 10^12^ parasites in my body. So one is infected all the time.
> The majority of these infections resolve spontaneously but, very
> frequently, they cause fever and debility and every so often you have
> a really serious infection.
>
> \[Slide.\]
>
> Either you survive if you get effective treatment or, if you don\'t,
> you die.
>
> \[Slide.\]
>
> So, falciparum malaria differs from the other three human malarias in
> that it kills people regularly and it does that because it induces a
> phenomenon known as sequestration. What this means is that, once the
> malaria parasite gets inside the red blood cell, it starts to
> manufacture a glue, and adhesive protein, and about 16 to 24 hours
> into 48 hour asexual cycle, these red cells start to stick.
>
> They stick in the microvasculature of vital organs, notably the brain,
> where they cause microvascular obstruction.
>
> \[Slide.\]
>
> The mortality of cerebral malaria ranges approximately from 15 to 20
> percent, so one in five patients treated with available drugs will
> die. We believe that the mortality of untreated cerebral malaria
> approximates to 100 percent.
>
> In adults surviving cerebral malaria, about 3 percent will have some
> detectable neurological sequelae but, in children, about 10 percent
> will have detectable neurological sequelae of which over half will
> resolve within six months. But, nevertheless, given the cumulative
> burden of this disease, this is a major problem.
>
> \[Slide.\]
>
> This may be stating the obvious, but it is very important and it is
> the basis, really, of the rationale for rectal artesunate, and that is
> that antimalarial drugs save lives because they kill parasites.
> Therefore, the reason why people die from malaria is because they
> don\'t get effective treatment early enough in the progression towards
> lethal disease.
>
> \[Slide.\]
>
> The artemisinins are a fascinating and unique family of compounds
> discovered, or rediscovered as you probably all know, by the Chinese
> approximately 30 years ago, a sesquiturpinelactoin peroxides with the
> business end of the molecule being this peroxide bridge and
> substitutions here giving us the different derivatives, in this case,
> a succinate, or hemisuccinate, group forms artesunate.
>
> They are the most rapidly acting of antimalarial drugs. They kill
> parasites faster than any other drugs. They are extremely potent and,
> as I will show you, they have a very important property in that they
> will kill all the stages that circulate in the blood. They will
> prevent the progression from the young and relatively less
> pathological to the mature, more pathological, stages which stick and
> obstruct the microcirculation.
>
> As a bonus, they reduce transmissibility and, to date, despite
> considerable effort in the laboratory, it has not been possible to
> induce resistance and no confirmed evidence of significant resistance
> has occurred despite use in over 3 million patients. That is not a cry
> for complacency, but it is reassuring.
>
> \[Slide.\]
>
> Here we have the 48-hour life cycle of Plasmodium falciparum going
> from the young, so-called ring, forms which circulate in the
> peripheral blood and can be counted by the microscopist to the more
> mature, pathological forms which are sequestered in the
> microcirculation and cause the pathological processes.
>
> So, perversely, it is the parasites that you can\'t see in the blood
> film that are causing the problem, not the ones you can see, and this
> explains some of the discrepancies between parasitemia and severity.
> Nevertheless, there is a general rough relationship between the
> parasitemia counted peripherally and the overall burden in the body.
>
> The artemisinin derivatives affect all these stages and they will
> prevent the progression from the circulating stage to the sequestered
> stage. The other antimalarial drugs, notably the ones that are used
> for severe malaria, are the cinchone alkaloids, quinine and quinidine.
> These drugs do not prevent the development of the circulating ring
> forms to the sequestered pathological stages.
>
> \[Slide.\]
>
> Again, the paradigm of a person, me, perhaps, with 2 percent
> parasitemia. This is to illustrate the different properties of the
> antimalarial drugs. You can treat falciparum malaria with an
> antibiotic such as tetracycline but it is very weak. It will kill with
> a fractional killing rate of 10 per asexual cycle which would mean you
> would have to take tetracycline for about a month to get rid of all
> the parasites in your body.
>
> We can\'t detect parasitemia below about 10^8^ in the body so, below
> this level, we certainly have an infection but we are not able to
> detect it by microscopy. Most of the antimalarial drugs work in this
> sort of area, fractional killing rates or parasite-multiplication
> rates of 10^2^ to 10^3^. So this would be 100-fold to 1,000-fold
> reduction per asexual cycle.
>
> The artemisinins are the most active. They will cause 10,000-fold
> reduction in the number of parasites per asexual cycle, so a single
> dose will cut that parasite biomass by 10,000-fold. Note that it is
> still necessary to expose that parasite population to these drugs or
> an effective antimalarial drug for at least a week. Otherwise, we will
> see recrudescence. So, short-acting drugs need to be present for at
> least a week.
>
> \[Slide.\]
>
> In the worst-case scenario of somebody getting a single rectal
> artesunate administration and then not following up as we believe must
> be done\--in fact, we recommend, of course, must be done\--then this
> is what would happen. You would cut the parasitemia by about
> 10,000-fold and then there would be an uninhibited multiplication. The
> parasite can\'t multiply more than the number of children it has per
> cycle. That is about 10 to 20 maximum. In vivo studies would suggest a
> multiplication rate of 10 maximum per cycle. So it would take nearly
> ten days to get anywhere near the sort of parasitemias that initially
> presented by which time host defenses are mobilized.
>
> Of course, the patient has been ill for all this time, so the
> probability of getting access to antimalarial drugs is much increased.
> This explains, or this simple cartoon, explains why even a single dose
> would be very unlikely to be followed by a recurrence of this rare
> event where one presents with severe or impending severe malaria.
>
> This cartoon is one where there is no mobilization of host defense and
> yet there is rapid nonspecific mobilization of host defenses which is
> why we have people living in the tropical areas of the world. Malaria
> is not uniformly fatal.
>
> \[Slide.\]
>
> What the artemisinin derivatives do is that they cut the parasitemia
> more rapidly than any of the other drugs and they remove those ring
> stages before they progress to the more pathological stages. We can
> actually quantitate this by subtracting the parasite-clearance curve
> after artesunate or another artemisinin derivative from that, from a
> comparator drug such as quinine.
>
> The difference, the area between these two curves, would represent the
> ring forms that have been removed from the circulation before they
> could cause trouble.
>
> \[Slide.\]
>
> This is a summary slide of the pharmacokinetic properties of the
> drugs, the artemisinin derivatives, that we might use in the treatment
> of severe malaria, plasma concentration along here and time. If we
> have artesunate parenterally, intravenously or intramuscularly, in
> severe malaria, it is very rapidly and reliably absorbed. We get
> concentrations well above 1,000 milligrams per kilogram.
>
> The other formulation widely available, in fact the most studied
> formulation, is artemether, which is an oil-based intramuscular
> injection, which is much more slowly and erratically absorbed reaching
> peak concentrations often twelve or more hours after the original
> injection.
>
> Rectal administration occupies a position perhaps more close to the
> intravenous or intramuscular administration where absorption is
> certainly slower but more rapidly than following artemether. Now,
> artemether has been subjected to the largest trials ever in severe
> malaria and it is certainly as effective. In fact, Professor Folb will
> show you some data. It is certainly as effective, if not more
> effective, than quinine. It is because the concentration required of
> these drugs to produce the maximum parasiticidal killing, or minimal
> parasiticidal concentration\--that is the minimum concentration
> producing the Emax or maximum effect\--is very low.
>
> The IC50s would be of the order of 3 to 5 nanograms per ml, IC95s of
> the order of 10 to 20. So, even though these concentrations may look
> very low, very low concentrations are all that is needed to produce
> maximum parasiticidal effect. That is why these profiles are very
> effective and, certainly, these profiles are reliably effective.
>
> \[Slide.\]
>
> Let\'s just briefly examine the relatively unusual, in an individual,
> but, as I have explained, frequent overall path towards lethal
> malaria. After receiving an infected mosquito bite, there is about a
> five- or six-day incubation day in the liver. Then, somewhere between
> 10,000 and 100,000 parasites are released into the blood stream.
>
> Then multiplication rates of approximately six-fold to ten-fold per
> cycle means that the parasites become detectable in the blood
> approximately eleven to twelve days after inoculation. This also
> coincides with the time when fever is usually present. The pyrogenic
> density is quite close to this level.
>
> If no treatment is given and the parasite multiplication continues
> unabated for several more cycles, we enter the dangerous territory
> where lethal disease may occur. Things happen at this point very
> quickly.
>
> \[Slide.\]
>
> In that next cycle, if we manage to stop development of the parasites
> at this stage, then lethal events will not occur. But if the parasites
> mature, sequester and then undergo further schizogony now with a
> burden of 10^12^ in the body somewhere, a parasitemia that may be
> between 1 and 20 percent, then lethal events may occur.
>
> Our objective, therapeutically, is to stop that progression. This is a
> very short time span which explains why children die very rapidly once
> they develop severe malaria.
>
> \[Slide.\]
>
> So if we are on the threshold of developing severe disease, in
> Thailand, if you have more than 4 percent parasitemia but no evidence
> of vital-organ dysfunction, your mortality is 3 percent. That is 30
> times higher than in uncomplicated disease with a lower parasitemia
> but five times lower than once severe disease has developed with
> vital-organ dysfunction.
>
> \[Slide.\]
>
> Then, as I have said, things happen very rapidly and we enter, and we
> very rapidly increase the probability of a fatal outcome.
>
> \[Slide.\]
>
> So the objective of treatment is to interrupt that process and the
> earlier we can do that, the better the probability of saving the
> patient.
>
> \[Slide.\]
>
> Just to summarize our rationale again, as Melba has presented, it is a
> treatment for patients who can\'t take oral treatment. That is a range
> of clinical syndromes from just repeated vomiting through to deeply
> unconscious. Hopefully, we are going to prevent the progression
> towards deeply unconscious.
>
> The trials were designed to assess the antimalarial activity in vivo
> in that high-risk group of patients who had not yet developed
> vital-organ dysfunction. They were on the threshold of developing
> severe disease. Our focus is the immediate life-saving response. This
> is not an assessment of a curative treatment. It is an assessment of a
> life-saving treatment.
>
> \[Slide.\]
>
> Patients were either those who could not take oral drugs or had, as I
> described previously, defined increased mortality. They were given a
> single rectal dose of artesunate and that was followed by the standard
> treatment in the country at the time which varied from an effective
> drug to an ineffective drug, as you will see later, and all cases were
> hospitalized.
>
> \[Slide.\]
>
> The assessment focused on the reduction in parasitemia which reflects
> the main pharmacodynamic effect, parasite killing. It was assessed by
> fractional reductions or total parasite clearance time and the
> clinical response was assessed by the standard ways of fever
> clearance, time to be able to take oral treatment again and, of
> course, prevention of clinical deterioration or death.
>
> \[Slide.\]
>
> There are three types of studies. The first two were randomized
> crossover phase 2b, if you like, dose-finding studies, three phase 3,
> so to speak, studies, one in Thailand, one in Malawi and one in South
> Africa, each with a slightly different design. In Thailand, where
> there was a defined group with a defined mortality, oral artesunate
> was the comparator because that had been shown to be superior to
> intravenous loading-dose quinine in patients with hyperparasitemia.
>
> In Malawi, they were non per os and the comparator was parenteral
> quinine. In South Africa, there were two studies, one in moderately
> severe malaria where the comparator was quinine and one in severe
> malaria where all patients received quinine and some received
> artesunate, while others did not. The randomization was unequal so, in
> each of these trials, the majority of patients received rectal
> artesunate.
>
> Finally, there was a comparability study between the original
> formulation that was used in these studies and the new formulation,
> the one that we are submitting for regulatory approval, we hope.
>
> \[Slide.\]
>
> These studies confirmed the results of all other studies with these
> drugs and that is that there was a reliable and rapid reduction in
> parasitemia when compared with the comparator quinine. This is an
> absolutely consistent finding in all trials with these drugs.
>
> \[Slide.\]
>
> The beneficial effects in terms of parasitological response would be
> the different between those two curves, the parasites that were
> prevented from going on and sticking in these patients\' brains,
> livers, kidneys, lungs and so forth.
>
> \[Slide.\]
>
> A couple of slides just to deal with this question, really, of the
> parasitological outcome, the subsequent treatment response which is
> not the focus of this submission. Once the patients had received the
> rectal artesunate, they were then given so-called consolidation
> treatment which, in Thailand, was mefloquine, which was pretty
> effective. In most of the other countries, it was
> sulfadoxine/pyrimethamine which sadly, although it is national policy
> in many of these countries, is failing fast and also chloroquine
> which, as you know, in most of the world, is no longer effective. So
> there were quite a lot of recrudescences in the patients who received
> these drugs.
>
> The comparator group in Malawi received more quinine than did the
> artesunate group so they had a better, if you like, consolidation
> treatment.
>
> \[Slide.\]
>
> What happened to those patients with the recrudescence infections?
> Most of them just had a fever and were found to have parasites again
> when they were retreated and about a third had other symptoms of
> nausea, vomiting and so forth. One patient was temporarily obtunded
> but recovered rapidly and there was no development of severe malaria
> and there were no deaths in the recrudescent infections.
>
> \[Slide.\]
>
> We have had a question as to how relevant are those studies compared
> to the ongoing, very large community-based studies. These studies
> which are, as I said, ongoing have as their entry criterion that the
> patient cannot take antimalarial drugs by mouth. But they are not
> associated\-- because they are community-based, we are actually
> testing how these drugs would be used in real life. They are not
> associated with immediate availability of diagnosis.
>
> But, generally, the populations appear to be comparable, similar rate
> of patients being obtunded, similar seizure rates. We would contend
> that these populations are comparable. But, obviously these patients
> had to be studied in hospital because we had to provide the data
> appropriately.
>
> \[Slide.\]
>
> So, in summary, the basis or the evidence that we would like to
> provide to you for efficacy of rectal artesunate is based on 310
> patients ranging from young children to adults in countries where
> there were very different background levels of drug resistance and
> background levels of intensity of transmission ranging from very low
> transmission in Southeast Asia to very high transmission in Ghana.
>
> The median parasitemia reduction at 24 hours is 99 percent. These
> drugs reliably cut the parasite biomass by a huge amount. All but four
> patients were able to take oral drugs within 24 hours.
>
> \[Slide.\]
>
> So, in conclusion, we believe that this is a highly effective
> treatment. It has a particular place, a particular application. It
> produces consistent results on the main determinate that it kills
> parasites quickly. That is associated with rapid clinical responses
> and these benefits are independent of the patient\'s age. They are
> independent of their geographic location and, therefore, the intensity
> of transmission and associated background immunity. They are
> independent of the patient\'s ethnic origin and they are independent
> of the prevailing levels of resistance to the other antimalarial
> drugs.
>
> Thank you.
>
> DR. RELLER: Thank you, Professor White, for that comprehensive review.
>
> Professor Peter Folb?
>
> PROFESSOR FOLB: Good morning, Mr. Chairman and members of the
> committee.
>
> \[Slide.\]
>
> The FDA in its executive document points out correctly that, under
> certain exceptional conditions of experimental design, the
> artemisinins, as a class, are neurotoxic. We deal with the issue of
> neurotoxicity in the following way; firstly, to draw your attention to
> the strictly limited indication for which we propose whereby the drug
> will be used once or, at the most, twice in the dose of 10 milligrams
> per kilogram body weight.
>
> We argue from a hierarchy of evidence starting with extensive clinical
> experience of the artemisinins in general and artesunate in particular
> including artesunate administered in the way that we propose,
> rectally, moving from the clinical to the experimental. We shall point
> out that, except under the most exceptional circumstances
> experimentally, artesunate, given orally is never neurotoxic not even
> to experiment animals and that no human toxicity, neurotoxicity, has
> been demonstrated with artesunate given in any formulation or any mode
> of administration.
>
> We shall also argue that artesunate, within the class artemisinins, is
> arguably the safest.
>
> \[Slide.\]
>
> This is the basis for the concern including that concern addressed by
> the Food and Drug Administration. From animals, mice, rats, rhesus
> monkey and dogs, there is both symptomatic and observational evidence
> on the one hand that, with very high doses given parenterally apathy,
> unsteadiness, collapse, even coma and death have been observed.
>
> Neuropathologically, specific lesions have been described of
> chromatolysis and necrosis of brain-stem nuclei in particular. These
> nuclei are identified especially as vestibular, cochlear, the olivary
> and the red nuclei in the brain stem. As pointed out, it is
> identifiable in several animal species. So it is reasonable to
> question whether there is a likelihood that this would apply also to
> humans.
>
> \[Slide.\]
>
> Here is an example of an isolated dead neuron in the brain stem in an
> experimental animal showing enlargement, hyperchromasia, swelling of
> the neuronal soma and pigmentosis of the nucleus. This is the
> characteristic lesion that has been identified by those experimental
> investigators who have described it.
>
> \[Slide.\]
>
> Moving, as I say, from the experimental to the clinical, I draw
> attention to the work done in the first instance on mice who have been
> studied in terms of abnormalities of balance and gait and survival. I
> wish to point out that dihydroartemisinins certainly are more potent
> and more potentially toxic antimalarial than artesunate. In human
> equivalent doses up to 342 milligrams per kilogram produced no
> functional or neuropathological injury.
>
> Artesunate, in a human equivalent dose of 683 milligrams per kilogram
> produced reversible abnormality of balance and gait in two of twenty
> animals in this particular experiment.
>
> Oral artemether, artesunate and dihydroartemisinin have not produced
> clinical or neuropathological evidence of toxicity in doses below 200
> milligrams per kilogram per day given for 28 days. Members of the
> committee will recognize that this is orders of magnitude greater than
> the proposed dose to be given to humans.
>
> \[Slide.\]
>
> In this work done by Nonprasert and Dr. White and others, I wish to
> highlight the evidence that oral artesunate has produced\--this is the
> only evidence of its kind\--oral artesunate has produced abnormal
> equilibrium given in table form in doses of 250 to 300 milligrams per
> kilogram per day for 28 days. These, of course, are exceptional doses
> compared with what we propose for humans.
>
> \[Slide.\]
>
> With regard to a study commissioned by the World Health Organization,
> a 7-day artesunate toxicity study in rat largely designed on the basis
> of work previously done which had suggested neurotoxicity, designed
> that way in terms of dose and observation, no neurotoxicity was
> demonstrated over this range of human equivalent doses. Besides the
> small number of animals that died in their cage and could not
> immediately be preserved for autopsy, the brain stems of all the
> remaining animals were studied and stained with hemotoxinin and eosine
> and toluidine blue, primary stains for determining neurotoxicity, and
> were examined by an eminent neuropathologist previously mentioned, Dr.
> Antony Dayan, in the United Kingdom.
>
> These stains showed no evidence of neurotoxicity.
>
> \[Slide.\]
>
> Repeat human artemisinin exposure has been looked at by a number of
> investigators including Kissinger, Van Vugt, and they have tested in
> their clinical investigation, clinical neurological
> investigation\--they have included audiometry, brain-stem-evoked
> potential and auditory-evoked response. This refers to patients in
> Viet Nam, 240 patients, compared with 108 matched controls.
>
> With artemisinin, a cumulative exposure of artemisinin, median
> cumulative exposure of 168 milligrams per kilogram. In Thailand, 79
> patients were compared with 79 matched controls with a mean cumulative
> exposure to artesunate of 39 milligrams per kilogram and no clinical
> or neurophysiological toxicity was identified in these patients.
>
> These tests clearly enable one to evaluate function from frontal
> cortex through to cochlear nucleus and acoustic nerve.
>
> \[Slide.\]
>
> The work of Price and others based on 1,971 subjects over the age of
> five years, 307 of whom received artemether, 1,664 artesunate in
> artesunate doses of 12 milligrams per kilogram given over three to
> seven days and investigated clinically carefully by heel-to-toe
> ataxia, fine-finger dexterity, hearing and assessment for nystagmus
> and balance, evaluated at these days from naught to 28 days after
> admission, showed no evidence clinically of deafness or permanent
> neurological disability.
>
> \[Slide.\]
>
> In a randomized, double-blind comparison of artemether and quinine in
> severe falciparum malaria in work reported by Dayan and Hien, full
> neurological assessment was done on 560 adults including audiometry
> and assessment of balance at discharge.
>
> Now, in these patients, there were 36 deaths following artemether
> treatment and 47 following quinine. The total artemisinin exposure was
> 4 to 44 milligrams per kilogram which allowed 21 patients who died to
> come rapidly to autopsy. Of these patients, fifteen who died and who
> were examined in rapid autopsy, fifteen had received quinine and six
> artemether and they were compared blind by neuropathologists including
> those in the United States. There was no evidence of drug-induced
> neurotoxicity whatever.
>
> \[Slide.\]
>
> We have referred, and will refer further, to Study 013 which is a
> safety update conducted at present in Bangladesh, Ghana, Tanzania,
> double-blinded, randomized and controlled, in which, of 3,366
> patients, there has been a 99.3 percent follow up. Sixteen patients in
> this follow up had neurological sequelae.
>
> \[Slide.\]
>
> These were identified on schedule follow up over the period seven to
> thirty days after treatment. Now, of these sixteen patients, four had
> confirmed meningitis and we attributed the neurological effects of the
> meningitis. Six of the sixteen were unconscious at the time of
> enrollment and we might argue that they largely would be accounted for
> by cerebral malaria.
>
> Four of the sixteen had focal neurological sequelae, quite
> uncharacteristic of the drug effect, and two of the sixteen, 0.05
> percent of the 3,366, are, we believe, possibly attributable to
> artesunate. They have not been followed up in the long term. One had
> unsteady gait. One had generalized weakness and we would not be able
> to say which of these patients fell in the comparator arm and which in
> the treatment.
>
> \[Slide.\]
>
> In the largest study of its kind in the comparison of artemether and
> quinine for deaths, if I may draw your attention to the overall
> result, artemether was on the borderline of being better in terms of
> preventing death than quinine at this level of significance, 0.08 in
> the comparison of 961 patients who had received artemether and 950 who
> had received quinine.
>
> There was lower mortality in the artemether group, as the graphic
> indicates, but of borderline significance. The question is whether
> this lower mortality would translate to a higher level of neurological
> abnormality.
>
> \[Slide.\]
>
> Here is the examination of the neurological sequelae. In the
> artemether group, there were 81 of 807, in the quinine group, 91 of
> 765. The inference is that, with improved survival with artemether,
> there was no greater incidence, on the contrary, of neurological
> abnormalities.
>
> \[Slide.\]
>
> In conclusion, the World Health Organization, in developing this drug,
> accepts that there is a prima facie case based on experimental
> evidence of the possibility of the artemisinins as a class being
> neurotoxic. We point out that artesunate never in clinical experience,
> regardless of the therapeutic regimens that have been used, has been
> neurotoxic in humans.
>
> An expanded use of artesunate would require reconsideration about
> potential neurotoxicity, but we propose that this is not an issue in
> the circumstances in which we are to be using the drug.
>
> The FDA may wish to consider with the applicant, the World Health
> Organization, the neurotoxicity potential in terms of labeling and
> that, of course, we would have no objection to.
>
> Thank you.
>
> DR. RELLER: Thank you, Professor Folb.
>
> Professor Fred Binka.
>
> DR. BINKA: Mr. Chairman, members of the advisory committee, the WHO
> has, in the past two presentations, presented its case on the efficacy
> and safety of rectal artesunate. But, in addition to that, WHO is
> committed to making sure that this drug is properly deployed if it is
> registered in a manner that would benefit the great number of people
> in endemic countries who need this drug most.
>
> In doing this, it has made a firm commitment to understand some of the
> crucial issues that need to be addressed in order to deploy these
> drugs and also has a commitment in trying to make sure that, if the
> drug is registered, it is properly implemented.
>
> It is currently conducting studies, phase 4 studies, in three
> countries, in Ghana, Tanzania and Bangladesh, to try to understand
> some of the crucial issues that are involved. These studies have been
> alluded to by my previous colleagues. These studies are currently in
> these three countries. They are double-blind, placebo-controlled
> trials and they are recruiting patients that we expect this drug to be
> used for.
>
> Most of these patients are patients who cannot take anything by mouth
> and have provided consent to be part of the trials. In these studies,
> the recruited patients are given a single dose of rectal artesunate,
> 100 milligram in children and 400 milligrams in adults.
>
> They are followed up in hospital and expected to have consolidated
> treatment for malaria based on the national treatment guidelines. They
> are followed up for seven to thirty days to measure some of the
> potential outcomes. In these outcomes, we are looking basically at
> survival and neurotoxicity.
>
> \[Slide.\]
>
> Professor Folb has already presented the issues on neurotoxicity and I
> am going to concentrate on the other major outcome which is mortality.
> The studies have recruited about 3,300 patients so far in the three
> countries, and the slide above shows the distribution in the three
> countries, approximately about 1,000 in Ghana and Tanzania and the
> remaining in Bangladesh.
>
> \[Slide.\]
>
> The characteristics of these patients partly have been shown to you
> but let me reemphasize who they represent, the target population for
> which this indication has been proposed. About 11 percent of these
> patients were unconscious at baseline at the time of recruitment and a
> proportion of these patients, almost 22 percent, have had repeated
> convulsions.
>
> I think Professor White has already alluded to the fact that, in these
> cases, these are community-based trials where enrollment is basically
> based on being not able to take things orally. 74 percent of these
> patients have demonstrated a positive slide for malaria.
>
> The follow up has been very remarkable. 99.3 percent of these patients
> have been followed up over the period from seven to thirty days prior
> to recruitment into the trial. So far, the study has recorded 99
> deaths.
>
> \[Slide.\]
>
> The distribution of these deaths is shown in the slide above. I think
> it is important to know that approximately half of the patients who
> died were unconscious at the time of recruitment into the study. Also,
> to demonstrate this indication and the need to work very hard in
> trying to make sure we have something to help these patients, 87
> percent of these patients died even before they reached hospital. A
> further 43 percent died in hospital. The rest, about 20 percent, died
> at home after leaving hospital.
>
> \[Slide.\]
>
> These studies are being closely monitored by the Data and Safety
> Monitoring Committee. Their plan was to recruit close to about 10,000
> patients. The analysis of review of this data in April of this year,
> the committee basically agreed that there was no reason for the study
> to be unblinded or the protocol to be modified.
>
> So these studies are ongoing and we hope that they will provide a
> large body mass of information on the safety of rectal artesunate.
>
> \[Slide.\]
>
> This is not the only commitment. The WHO is committed to a plan of
> implementation if this drug is registered. Basically, there are
> several crucial issues that need to be addressed. It is committed to a
> controlled, phased introduction and deployment of this drug in five
> countries to appropriately understand how we can reach those who need
> these drugs most.
>
> This controlled phased deployment will include extensive work in
> trying to train mothers, health workers and, in this case, in these
> settings, traditional healers to whom most of these cases ascend when
> they present with these conditions. These training programs and
> communication programs will ensure the correct use of this drug and
> also to make sure that patients are provided or are encouraged to have
> consolidated treatment after the emergency phase.
>
> WHO is also committed to establishing postmarket registration
> surveillance to continue to monitor the safety of this drug as it is
> implemented.
>
> I think these two phases show a commitment not to just register drug
> and just leave it on the shelves but to make sure that this drug,
> after it is registered, is properly used for the indication for which
> we are asking the committee to review the dossier.
>
> I will spend the last few minutes to remind you of the true situation
> in which these patients in which this drug will be used and the
> population for which we seek the registration.
>
> \[Slide.\]
>
> I think you have heard already about the burden, but let me remind you
> that these mothers who are sitting here with their kids, most of them
> might not see those kids live to age of five years in most
> malaria-endemic countries. So they are looking very bright and nice
> today, but the chances of losing these kids are very great.
>
> Not only that, even if they die, most of them, nobody will know that
> they are dead.
>
> \[Slide.\]
>
> Most of these children die at home. Over 90 percent of the cases with
> malaria die at home and very few are seen in health facilities, just
> under 8 percent. I think this is the challenge we face in trying to
> control this disease.
>
> \[Slide.\]
>
> Not only that, when these people are sick, all these children are
> sick, most of them will be sent to traditional healers for any kind of
> disease at all. If you see the brown slide here, in this pie, about 24
> percent of children are sent to traditional healers. But when it
> involves acute febrile illness, the percentage gets bigger. It is
> about 27 percent. It gets even bigger when we are talking about acute
> febrile illness with seizures where almost half of these kids will see
> a traditional healer for treatment.
>
> \[Slide.\]
>
> That is not the only problem. The major problem that these people face
> is that they really have a problem with geographical access to
> healthcare. Most people live several distances away from a health
> facility. In a district in Ghana, a huge part of the population live
> over 10 kilometers away from a health facility. We will say, \"Well,
> that is just 10 kilometers.\" But the problem is how do they get
> there.
>
> \[Slide.\]
>
> The best means of transport would be on a bicycle in most cases if
> they are fortunate. Unfortunately for them, if it is in the rainy
> season where malaria occurs most of the time, there might not be even
> roads.
>
> \[Slide.\]
>
> They might have a child who is having a serious condition like this
> and the whole place is flooded in the seasons where malaria is most
> common. So you can see the problems that these people have and the
> challenges that they face in trying to get care for their kids.
>
> \[Slide.\]
>
> I think I want to reemphasize the issue related to the fact that this
> is a disease that deteriorates rapidly. In a study in Bangladesh, 73
> percent of these children under six were found to deteriorate quickly
> to severe malaria and about 83 percent within 48 hours. So this is a
> disease that has really grave consequences if there is no immediate
> intervention.
>
> But if most of these people get to health facilities, what kind of
> infrastructure do you have?
>
> \[Slide.\]
>
> In my district, in northern Ghana, with a population of 160,000
> people, we have a district hospital and maybe there will be only one
> doctor, three health centers. You can see the mass of traditional
> healers, 240. So, obviously, these are the people who will provide the
> services.
>
> If you go to the facilities, those who get there form the bulk of the
> work that the health workers are tasked to try and deal with. Malaria
> is the major problem.
>
> \[Slide.\]
>
> Over half of these patients are outpatients with cases of malaria and
> half of the patients on the pediatric wards are certainly cases of
> severe malaria. I think this gives you a true picture of what is
> happening in these parts of the world.
>
> Having said that, I think, in the last couple of years, there has been
> a concerted effort to try to deal with the burden of malaria. It is
> really a joy to see that we are increasing the tools that we can have
> to treat this disease.
>
> \[Slide.\]
>
> In the last couple of years, the World Health Organization has
> endorsed full management of malaria as one of the key strategies to
> try and reduce the burden of malaria. There are several tools in
> trying to help the families in villages like this to address this
> problem. First, and the cardinal one, is prompt diagnosis and
> treatment. Invariably, we think mothers and people in the community
> can diagnose this disease early.
>
> There is also a big push to try and look at the preventive measures of
> malaria both in infancy and in pregnancy and also the use of
> insecticide-treated bed nets to protect against malaria.
>
> We look forward to including another tool which is rectal artesunate
> to prevent death in cases where we have severe malaria. If we are to
> do this effectively, we think there will be a big prize at the end of
> the day.
>
> \[Slide.\]
>
> Happy little children in endemic countries. Thank you very much.
>
> DR. GOMES: Mr. Chairman, members of the advisory committee, this
> concludes our presentation and we would be prepared to answer
> questions.
>
> DR. RELLER: Thank you, Dr. Gomes.
>
> Dr. Bell?
>
> DR. BELL: I want to commend the speakers for their very nice
> presentations and for the hard work that they are doing to address
> this terrible problem of malaria. My question is a rather basic one
> that has little to do with the scientific issues involved.
>
> Malaria is a terrible problem overseas. The artemisinins in all their
> forms, intravenous, oral, rectal are widely available overseas. In
> some respects, therefore, I find the discussion we are having this
> morning to be a little strange. The indication that is being sought
> for approval by FDA in the United States is a very limited one to
> address a problem that does not exist in the United States.
>
> We don\'t have babies who die of malaria before they can get to the
> hospital. What we do have are concerns about drug resistance that we
> would, perhaps, like to have this drug available to treat when they do
> get to medical care. We don\'t have to worry. We have facilities to
> give it intravenously but it would require, presumably, repeated
> dosing.
>
> I guess my question is the FDA has regulatory authority in the United
> States where this drug is not available. The FDA is being asked to
> approve the drug for single-dose rectal\--to address a problem that
> doesn\'t exist in the United States. I guess I am wondering why that
> is. There must be some very clear reason that FDA approval is being
> sought for this indication that would only be applicable outside the
> areas of FDA jurisdiction.
>
> Could you explain that please?
>
> DR. GOMES: I will provide an initial comment on behalf of WHO but then
> I would like Nick White, perhaps, to take the nearest microphone and
> comment in terms of the indication as it applies or would potentially
> apply within the United States.
>
> We are clearly here with a concern for a public-health issue that is
> global, not necessarily limited or of wider relevance within the
> United States. This is a group of compounds which, essentially, have
> not been taken to registration for the purpose between ten. So we took
> this submission of a dossier to the regulatory authorities that would
> have the highest level of review as a global health organization,
> ourselves.
>
> So our purpose here is actually for the infants and children that are
> in malaria-endemic countries but we do believe that this has an
> implication for the United States. I would like perhaps Nick White to
> comment on that in more detail.
>
> PROFESSOR WHITE: The currently recommended treatment for severe
> falciparum malaria in the United States is quinidine gluconate. That
> was introduced following studies that we did in Thailand because the
> previously available treatment, quinine, was provided from the Centers
> for Disease Control and there were undue delays in getting the quinine
> out to the various parts of the United States where people returned
> and presented with severe malaria.
>
> So quinidine became the treatment because essentially because of its
> availability. I will very briefly show you that.
>
> \[Slide.\]
>
> Quinidine is not a safe drug. It is very difficult to use. It has a
> very narrow therapeutic ratio. It requires intensive-care monitoring
> certainly which is available, as you quite rightly say. I think there
> are serious concerns over the dosage.
>
> \[Slide.\]
>
> This is the basis for your current recommendation, a study of fifteen
> patients, multicenter, multi-instance. It was a telephone-directed
> study from CDC. Only five of them received quinidine alone. Only two
> of those would have fulfilled WHO criteria for severe malaria. The
> other ten got quinidine plus exchange transfusion. The three deaths
> were associated with low blood concentrations.
>
> \[Slide.\]
>
> This was the original study we did in Thailand with a much higher
> dose, much higher blood concentrations.
>
> \[Slide.\]
>
> We don\'t actually know what the therapeutic range is for quinidine
> but, by extrapolation from quinine and the available evidence would
> suggest that the currently recommended dose is relatively low. But
> that is not my main point.
>
> \[Slide.\]
>
> My main point is that quinidine is increasingly unavailable. It is no
> longer widely used as an antiarrhythmic drug. Therefore, it is not
> stocked in pharmacies. Therefore, there are delays and that now
> approximates the indication we are talking about. I think that there
> is a genuine possibility, if you are admitted in, I don\'t know, in
> Nebraska or Nevada or somewhere like that, your hospital would not
> have quinidine and there would be a delay, a potential lethal delay,
> instituting treatment. So I think there would be a strong case for
> each pharmacy having in their refrigerator ten artesunate rectal
> formulations.
>
> DR. RAMIREZ: May I answer his question?
>
> DR. RELLER: Professor White, if you could stay close for a moment,
> there will be at least one more question.
>
> Dr. Ramirez?
>
> DR. RAMIREZ: Just to give you my point of view. Even though at the
> University of Louisville, in Kentucky, we have our Claver Clinic.
> During the years, I have seen, I would say, several families, all
> missionaries, that have been in the middle of Ghana, in the middle of
> Columbia, but mostly in Africa and I have been treating some of
> the\--usually the fathers with malaria.
>
> But they are in areas that they are 10 kilometers from the medical
> center. This may apply to some American children. When I came here,
> the only children that I can see that are going to be in the bush at
> 10 kilometers from healthcare are going to be children of
> missionaries.
>
> Sometimes, people look at the FDA to say, \"If it is approved by the
> FDA, I am going to give it to my family.\" If it is not approved, they
> have some questions. I don\'t see that any military is going to
> be\--because, wherever there is the military, there is medical care.
> But I can see children of missionaries.
>
> If you want to make a case, you want to see American children that may
> need this drug\--at least, if the FDA has any other considerations. I
> also had your questions before coming to this meeting. That was my
> only answer, if there was any other issue if we need to address.
>
> DR. RELLER: Dr. Patterson.
>
> DR. PATTERSON: Just to echo Dr. White\'s comments about I.V.
> quinidine, we recently had a case at our medical center of a returning
> traveler with severe malaria who had ventricular tachycardia, was put
> on amiodarone and really couldn\'t take I.V. quinidine and had to be
> treated with exchange transfusion. So it would have been much easier
> to give them rectal artesunate. So I think there are cases where we
> would use it in the United States.
>
> DR. RELLER: Dr. Bell, when the Epidemic Intelligence Service offices
> are dispatched to the far corners of the earth, Peace Corps workers,
> et cetera\--Dr. Albrecht mentioned this earlier\--what is currently in
> their kits for therapy until reaching appropriate medical care? I
> would like anyone who wants to comment on that and then I would pose
> the same question to Dr. White, what role, if any, might this be for
> those groups.
>
> DR. BELL: Perhaps Dr. Parise knows the question about the Peace Corps,
> the answer to that.
>
> DR. PARISE: What currently, as far as my understanding of the Peace
> Corps, they have is a drug for self-treatment. In most cases, that is
> Fansidar. In areas where there is Fansidar resistance, it would be
> malarone, I believe. But there is not any rectal or other\--I mean,
> that would be for people who can take oral. That would be for people
> who can take oral.
>
> PROFESSOR WHITE: So, did you say malarone?
>
> DR. PARISE: I believe. What we are recommending here at CDC is that,
> in the areas where there is too much Fasidar resistance like the
> Amazon, Southeast Asia and parts of East Africa is that people should
> take malarone as self-treatment. I believe Peace Corps is echoing
> that.
>
> DR. RELLER: We will let Professor White comment on this when we get
> all of those comments together. I ask, in particular, because of these
> issues, because of resistance to some of these agents that was pointed
> out earlier.
>
> Dr. Archer and then we will hear Professor White.
>
> DR. ARCHER: Actually, I have a question for Dr. Binka but maybe Dr.
> White can answer if you know the results of the study. In the
> operational studies that were conducted, so far, that are ongoing, one
> of the questions is the problem of misdiagnosis of malaria when, in
> fact, the patients that are severely ill have something else.
>
> How many patients who were unconscious who had severe malaria in the
> operational study had another infection like meningitis or typhoid? Do
> you know those data?
>
> DR. BINKA: There are four cases of meningitis out of the 3,000 that
> were confirmed.
>
> DR. ARCHER: Were those initially diagnosed as malaria or were they
> recognized as bacterial meningitis?
>
> DR. BINKA: The diagnosis was mainly for people getting the studies not
> on the basis of the diagnosis of malaria but the condition that they
> cannot take anything orally and they are febrile. So there it is not a
> diagnosis of malaria. It is a clinical diagnosis.
>
> DR. ARCHER: So you really couldn\'t confirm.
>
> DR. BINKA: Yes; in most of those situations, we don\'t confirm the
> diagnosis. We use the clinical diagnosis of malaria.
>
> DR. GOMES: Can I just clarify that point? All of the children of
> patients who would have been non per os, which is the basic criteria
> for entry into the study, and likely to be the way in which it happens
> in reality, would have had a blood smear taken. It is not read and
> cannot be read at the time they are recruited. They would, following
> treatment, have been referred to a hospital. At the hospital level, a
> diagnosis would be made as to the attributable cause of the illness
> and, in four of those patients, there would be meningitis.
>
> If your question is reaching to a broader issue which is what is the
> probability that patients exposed to the drug would have another
> underlying cause of the disease, this is a general issue. Fred can
> probably answer this very well, but in malaria-endemic areas where you
> would have very high inoculation rates, there would be two
> coinfections. One would be acute respiratory infections and the other
> would be malaria.
>
> Within the WHO, we had gone to a great deal of trouble to try to
> separate the two causes, both clinically and parasitologically. It is
> very difficult, even for a very trained pediatrician to separate the
> two courses. It is complicated by the fact that you may have acute
> respiratory infection but you will have parasites as well. But we are
> dealing essentially with the vast majority who would have malaria but
> may have another infection. They would be treated for malaria with
> this particular drug.
>
> Some of them, however, a small proportion, might have meningitis. The
> issue before us would be that we don\'t have an alternative for the
> children that do have malaria and have parasites and for whom
> parasites would be on board in any case. The likely prospect would be
> that if you give the drug, the patient would reach the hospital. If
> they hadn\'t responded, then the hospital would treat the patient such
> as in the case of the children that have meningitis. But the vast
> majority of the children would have malaria.
>
> DR. ARCHER: Just one follow up while you are at the microphone. A
> question on the cerebral malaria and the possibility that cerebral
> malaria might mask neurotoxicity of this drug in some of the studies,
> is that a possibility? Is there enough overlap that you might have
> missed some of the toxicity?
>
> PROFESSOR WHITE: It is very difficult to be absolutely categorical,
> but the neurotoxicity in the animals is irreversible. The studies of
> Professor Folb shown with artemether, I think, is the most
> illustrative because that is, by far, approximately six times more
> neurotoxic, intramuscular artemether. That is a very large database of
> evidence. Specifically, the studies we did in Viet Nam, which was a
> 600-patient study, about half of them receiving artemether, we looked
> very carefully for any of the tell-tale signs.
>
> Every patient on discharge had audiometry and a full neurological
> examination. There wasn\'t a hint of any of the aberrances that have
> seen in mice, rats, adults and monkeys. So I can\'t be absolutely
> categorical and say there isn\'t a transient effect, but it is not
> detectable.
>
> Also, if you look at the\--we do four hourly full neurological
> examinations in these patients. In the double-blinded study, there was
> absolutely no difference in the evolution of neurological
> symptomatology, signs and symptomatology, in target patients who
> received artemether and quinine, the only difference being slightly
> faster recovery in the patients who received artemether.
>
> So there is no suggestion. But I can\'t be absolutely categorical.
>
> DR. RELLER: What is known, if anything, about the interaction between
> those patients who have malaria and the neurotoxicity of these
> compounds? Are there any primate studies that address this of primate
> malaria with and without graded doses of artesunate?
>
> PROFESSOR WHITE: I know there is somebody in the audience who knows a
> lot more about this than I do but there are studies going on at the
> moment. But, to my knowledge, there are not good data to look at that
> interaction.
>
> DR. RELLER: Before taking other questions, I would like to return to
> several that were related to your views on the potential role of
> rectal artesunate for therapy in groups apart from the recognized
> primary beneficiary, namely children in impoverished and rural distant
> areas away from healthcare, but the potential ancillary use in
> selected other populations, be it workers abroad from various
> backgrounds and for various roles.
>
> PROFESSOR WHITE: I think that the artemisinin derivatives in whichever
> form you can get them are the drug to have if you are away from
> medical attention and you are ill because of the rapidity of action
> and the fact that you don\'t get vomiting and so on.
>
> Now, the specific role of rectal artesunate hasn\'t been assessed as a
> standby treatment, but the oral drugs are widely used as standby
> treatments. I think they do have a very important role particularly in
> that group of people who are becoming sick.
>
> If you can take malarone, for example, you have uncomplicated malaria,
> that\'s fine. There has never been a good population PK study with
> malarone, interestingly. The one that was done didn\'t address
> severity. But if we borrow from data with mefloquine, which would be
> the alternative, it is quite clear that you malabsorb mefloquine in
> proportion to your disease severity. I would have grave concerns with
> malarone, a lipophilic drug, in somebody who is developing severe
> malaria. I think the absorption of that would be unpredictable.
>
> It is an excellent antimalarial drug. It is effective against
> parasites throughout the world. But I would be concerned about taking
> that drug. So I think there is a specific benefit for these drugs in
> people who are becoming severely ill. While I am speaking, I don\'t
> think that that provides a resistance generator as some people have
> said. I think that the proportion of people involved is so small that
> it doesn\'t impinge on resistance.
>
> But this is speculative and it has not been formally assessed.
>
> DR. RELLER: Dr. Sumaya and then Dr. Cross.
>
> DR. SUMAYA: My question relates back to the issue on a population
> studied in the intended population for use. You had data, in some of
> the literature I was reading on this, on children but I was still
> unclear how many children under the age of five, for example, have
> been studied in the age brackets one, two, three, four and five. I\'m
> sure you have that data but it wasn\'t presented. I think it would be
> very useful to have that, not only for efficacy but certainly for
> safety.
>
> Secondly, related to that, outside of the U.S., presumably, in poor
> populations, transportation problems, rural areas, who is the intended
> prescriber? Who would be the intended prescriber of this rectal
> suppository? Would this be the traditional worker? Would this be, as
> you had a slide on home management, somebody within the family, or
> would it be in a more clinical setting?
>
> DR. GOMES: In relation to your first comment, we do have an age
> breakdown of the patients. One of the trials is in Bangladesh where
> the majority of people who are exposed to malaria happen to be adults.
> So a large proportion of what you saw in the 3,366, from just that
> study, would be adults.
>
> But, on the African continent, because of the studies in Tanzania and
> Ghana, we are finding that a significant proportion of the people who
> are recruited into these trials in the real-life situation tend to be
> under 24 months.
>
> The irony of the development of this drug is we wanted to be able to
> do the initial work in conditions in which we could manage the
> patients very carefully and, therefore, we obviously did all the
> phase-3 studies and the phase-2 studies in hospitals. The inclusion
> criteria were very broad. They were six months upwards. But, clearly,
> the patients that we saw in the hospital-based studies in terms of age
> don\'t represent what happens in the community in terms of age.
>
> I think it was Fred Binka that stated that many of the children die
> and you may never see them in the statistics. So, what we find in the
> community-based studies in this one that has been referred to is we
> see a much younger population than we ever see in hospitals. So,
> although we are not asking for registration for children below 24
> months because we have very few that we have studied and, therefore,
> have been submitted in the dossier, we are, therefore, asking for
> registration for children above 24 months.
>
> We have in place\--we have had to produce a smaller dosage form for
> children under 24 months and we have in place studies that would
> address this issue for the age, the pediatric age, under 24 months.
>
> But, since your question was phrased what proportion, I just want to
> tell you that, in reality, what happens is we get a much younger
> population that has never before been described.
>
> If you want further details on the age breakdown, we can provide them,
> but we would be able to provide them, perhaps, later.
>
> DR. RELLER: Dr. Cross?
>
> DR. CROSS: You showed us neurotoxicity data in mice and rats. I am
> just wondering whether any of those studies have included a different
> range of ages of those animals; for example, have you looked at the
> potential neurotoxicity in very young or newborn rodents or, as a
> measure of its potential, have you even looked at its potential effect
> on the developing nervous system in experimental animals?
>
> PROFESSOR WHITE: While Professor Folb is coming to the microphone, I
> will mention about the pregnancy experience. In Thailand, we don\'t
> have such multidrug-resistant parasites that we are forced to use
> these derivatives in pregnancy having no alternatives.
>
> If you can show that.
>
> \[Slide.\]
>
> We basically prospectively followed up all the children born to women
> who were exposed at any stage in their pregnancy to an artemisinin
> derivative with a standardized and validated full neurological
> assessment at birth and developmental milestones. The bottom line is
> we may not be able to find it in time, but there is absolutely no
> evidence of any difference between those children and the other
> children.
>
> I can say that in experiments that we did in mice, we did not
> specifically address young mice.
>
> PROFESSOR FOLB: We don\'t have the experimental data on very young
> rodents or other experimental animals. We are not in a position to
> answer that part of your question.
>
> \[Slide.\]
>
> We can draw on human experience, in particular the work of Dr.
> McGready and colleagues. Here is a study of pregnancy outcomes in
> women treated with artemisinin compared with those not treated with
> artemisinin, compared with the community in general. You will note
> that the incidence of spontaneous abortion, stillbirth, congenital
> abnormality, gestational age at delivery and low birth weight do not
> appear to be meaningfully different. That is the best source of
> information on which we can draw to give you some assurance about the
> safety of the unborn child.
>
> DR. RELLER: Dr. Ramirez?
>
> DR. RAMIREZ: Some questions regarding the drug, itself, because my
> interpretation seems to be that this will be the mother or the
> traditional healer giving this drug to a child. I imagine that you
> have to distribute this drug almost to all households to have the drug
> available. What do we know about the stability of the drug and what do
> we know about\--do we have an expiration time?
>
> Also, this concept of 10 milligrams per kilogram, and then you have to
> have suppositories for different milligrams, that this is going to be
> extremely difficult for a mother to figure out, at four years old. I
> don\'t know if you even know the weight or the kilograms.
>
> DR. GOMES: I realize that we have not completed our response because
> you had asked who, in fact, would be prescribing or making the drugs
> available. So it is a good point. Our approach, the onset, to it is
> that we have not formulated exactly how it would be delivered. In the
> conditions in which we are doing the work, it is what we refer to as
> Study 013 and the operational studies, these are given by field
> workers.
>
> This would be the basic indication for delivery of the drug, would be
> that the child cannot, or the patient cannot, take drugs by mouth.
> There are several ways in which they are assessed in terms of
> suspected malaria during the malaria season, and so forth. In those
> trials, we have an age group. The majority of patients, as I said,
> have essentially come below the age of five. In those cases, when we
> have only one suppository now that is for pediatric use which is 100
> milligram, the children that are recruited, we gave one suppository
> and it averages at 10 milligrams per kilogram if you are above 9 or 8
> kilograms and below the age of two years.
>
> So either if you have a weight or age, you can work within that group
> to get the dosing around 10 milligrams per kilogram. But we would like
> to become much more accurate, particularly for the younger child. So,
> as I refered to earlier, we would like to include a 50 milligram
> suppository that includes the age range from about three months to
> about a year old so that they have a much more targeted dose that is
> given to that age group.
>
> DR. RELLER: Do you have any issues to maintain this drug at room
> temperature\--
>
> DR. GOMES: Not so far. In terms of the stability, no. We have taken a
> great deal of advice from the review team of the Food and Drug
> Administration in terms of the packaging that we must make the drug
> available. Our intention is to have at least a two-year stability for
> the tropical conditions that we, of course, have in mind.
>
> So we have put the drug in that packaging for that period of time to
> be able to examine the conditions. We are talking about, of course,
> conditions that are not only hot but humid at the time the drug would
> be used.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: I had two points. The first one is that the artemisinins
> are arguably the only class of antimalarials we have for which there
> are not drug-resistant parasites recognized. I can\'t think of a
> better scenario for selecting drug-resistant parasites than to give a
> subtherapeutic dose of a single agent to people with immature immune
> responses who are teeming with parasites. To me, that is the ideal
> recipe for selecting resistant parasites.
>
> The second point is human nature being what it is, if one is treated
> for malaria and has symptomatic improvement, the incentive for getting
> in the boat and getting to the healthcare center is very much reduced.
> If people can\'t get there when the child is dying, they are certainly
> not going to get there when the child is better.
>
> So it would seem that this temporizing measure perhaps may provide
> time for people to get to the hospital but, perhaps, will prevent
> people from going to the hospital and may result in just repeated
> doses whenever the parasitemia rises above a threshold of concern.
>
> That scenario plays into both the issue of resistance and the issue of
> safety; that is to say, repeated subtherapeutic doses.
>
> PROFESSOR WHITE: I quite agree with you. You are quite right. This is
> the ideal way to induce resistance. Therefore, it is incumbent on us
> to try and do everything we can to educate people on the need to
> provide an adequate treatment. I think I will ask Fred to speak to
> that, but our approach is, as Fred explained, an integrated approach.
> But you are quite right. It is a major concern.
>
> DR. BINKA: I think you are quite right. This is a major concern to
> everybody but the direction now is to try and make sure that when
> drugs are developed, they are developed in such a way that we take
> into consideration those who are going to use them. There is an
> increasing push to try and make sure that we can package these drugs,
> like in the previous question, and make sure that the mothers can
> differentiate between the different weights and the amount of drug
> they have to give them.
>
> So, if they are packaged and labeled appropriately, showing whether a
> very young child or a middle-aged child, the mothers are able to read
> these pictures and are able to use this appropriately. This has been
> ongoing. In fact, currently, the regular antimalarial drugs that are
> prescribed in most of the countries, WHO is seriously advising
> countries to package these drugs in such a way that illiterate mothers
> can appropriately decide on the dose that is supposed to be given and
> to appropriately administer the drugs.
>
> So, yes; these are some of the issues why the plan is to have a phased
> implementation and to address some of these issues that are truly
> there. But I think this can be overcome.
>
> DR. RELLER: There will be much time for discussion this afternoon so,
> because we are at the time of our break, we will take brief questions
> from Dr. Patterson, Dr. Bell and then that\'s it for before the FDA
> presentation and our break.
>
> Dr. Patterson?
>
> DR. PATTERSON: The briefing document indicates that the drug is
> metabolized by the liver. In the clinical studies or in clinical
> experience, is there any evidence of hepatotoxicity and should the
> drug be adjusted in patients with liver disease?
>
> PROFESSOR WHITE: That is a good question. Artesunate is very readily
> hydrolyzed in neutral pH to the dihydroartemisinin which is the main
> biologically active metabolite. And then the main route of elimination
> of the dihydro appears to glucuronidation which is impaired in liver
> dysfunction.
>
> We have looked at\--we have got pharmacokinetic data which are not
> published and you have not before you and, therefore, I can\'t really
> comment, but I can tell you that there isn\'t a relationship between
> liver dysfunction, per se. But there is certainly a relationship
> between overall disease severity measured in terms of metabolic
> acidosis, renal impairment and so forth and reduced clearance.
>
> But the inter-individual variability actually is greater. So the
> intrinsic inter-individual variability in pharmacokinetics is greater
> in the disease effect on contraction volume and distribution and
> reduction and clearance.
>
> Finally, we haven\'t found any side effects so we haven\'t got any
> side effects to relate to anything.
>
> DR. RELLER: Dr. Bell?
>
> DR. BELL: I would like to ask the presenters if they could to expand
> their comments on the safety and efficacy of repeated dosing. Again, I
> am trying to think of the problems we face in the United States and
> how this drug is actually likely to be used.
>
> I attend, sometimes, on the pediatric infectious-disease service at
> Emory University. I take the point about the difficulties in acquiring
> quinine. In my experience, we do have a rare case of cerebral malaria
> but it is much more common to get a sick infant who is febrile, anemic
> and we don\'t know the drug-resistance profile of the parasite.
>
> I suspect the principal advantage here is going to be that there is
> very low resistance so far to the artemisinins and so it is likely
> that this drug will be given once, followed by clinical improvement.
> Then, the question is going to be, \"Then what?\" I suspect there will
> be almost irresistible pressures for repeated off-label dosing because
> you can\'t argue with success.
>
> You have clinical improvement. What is your experience with this in
> the field in terms of its safety and efficacy? When do you switch to
> what? I know this isn\'t the indication that is being sought but,
> realistically, this is the problem that we have in the United States
> and this is how it is likely to be used.
>
> So, could you talk a little bit more about the hazards to the extent
> of what is known about repeated dosing and how would you use this?
> What would you switch to and when?
>
> PROFESSOR WHITE: First the benefits and then the risks. I actually
> think that the benefit is the rapidity of action. That is so apparent
> to the consumers in endemic areas that there have been tremendous
> problems with fake drugs. So, basically, you get better a day quicker,
> go back to work, back to school, a day quicker than any other drug. So
> that, to me, is their great benefit.
>
> Certainly, the fact that you don\'t have to think about resistance is
> an advantage but I think, operationally, it is the rapidity of the
> action.
>
> What do you do next? This drug is to stop the person dying. They then
> have to have a full course of antimalarial treatment, whatever the
> national recommended program, whatever is available. What do we do? In
> Thailand, where we have multidrug-resistant malaria, we continue with
> oral artemisinin in combination with Mithracin. It is whatever you
> have available, but it must be a full course of treatment. Otherwise
> we are going to return to the scenario of selecting for resistance.
> Outside endemic areas, resistance selection is not an issue but, in
> practice, you give the full course of treatment.
>
> Repeated treatment, well, that is what people will get. That is what
> everybody has in endemic areas because of the frequency of infection.
> But, as Professor Folb has shown, we haven\'t been able to show any
> adverse effects associated with that, either in terms of toxicity or
> induction of resistance.
>
> DR. RELLER: Thanks to the WHO and the committee members for a rigorous
> discussion. We will return in fifteen minutes at twenty minutes before
> the hour of 11:00 to hear the FDA presentation.
>
> \[Break.\]
>
> DR. RELLER: Dr. Leonard Sacks will begin the FDA\'s presentation of
> rectal artesunate.
>
> **FDA Presentation**
>
> DR. SACKS: Good morning.
>
> \[Slide.\]
>
> I am Leonard Sacks. I am a medical officer in the Division of Special
> Pathogens. What I will be doing during the next half hour or so is
> reviewing the clinical efficacy of rectal artesunate as evidenced in
> this submission.
>
> \[Slide.\]
>
> Before progressing, I just want to acknowledge the excellent help from
> the rest of my colleagues in the review team and several other members
> of the Division who are not listed on the slide.
>
> \[Slide.\]
>
> I am going to spend a short time recapping some of the background
> information which, at this point, has been very adequately covered by
> the previous presenters.
>
> \[Slide.\]
>
> Just a word about the rationale for product development. I think it
> has been adequately addressed that malaria carries a very high
> mortality, especially in children. This is largely due to delays in
> effective therapy. Malaria patients are often unable to take orally
> and this may be the result of cerebral involvement. It may be the
> result of the fact that many of these patients are vomiting.
>
> Finally, parenteral therapy is not available in the bush.
>
> \[Slide.\]
>
> The goal of a the applicant, in this application, was to develop an
> effective antimalarial that can be administered rectally that serves
> as an emergency treatment until definitive therapy can be reached and,
> finally, that decreases malaria mortality and morbidity.
>
> \[Slide.\]
>
> The indication, as provided by the applicant\--I will read it out to
> you. We have covered it in previous slides. The indication is for the
> initial management of acute malaria in patients who cannot take
> medication by mouth and for whom parenteral treatment is not
> available. In the label, there is additional information suggesting
> that treatment with rectal artesunate must be supplemented and/or
> followed by effective oral or parenteral drug therapy for malaria as
> soon as possible.
>
> \[Slide.\]
>
> The product that was chosen to satisfy these objectives was rectal
> artesunate. The question is whether this is a suitable candidate. This
> is just a brief recap of some of the issues in favor and against the
> product. Artesunate is an artemisinin derivative. We know that
> artemisinin products are very potent antimalarials. They have been
> used with a lot of success in areas of drug-sensitive and
> drug-resistant P. falciparum malaria.
>
> The downside is that they have a short half life. They have been
> associated with recrudescences of infection and they carry the
> potential for some neurotoxicity.
>
> \[Slide.\]
>
> I want to digress briefly and just to make a few remarks about the
> clinical pharmacology of rectal artesunate. Artesunate, as we have
> heard earlier, is rapidly biometabolized to dihydroartemisinin.
> Dihydroartemisinin is also an active agent against P. falciparum.
>
> When we look at the pharmacokinetics of these products in healthy
> volunteers, given a single 400-milligram dose, the Tmax for both
> products is somewhere between 2.5 and 3.5 hours. The Cmax for the
> parent compound and for the principal metabolites is similar. Note
> that the elimination half-life is less than three hours for both of
> these moieties.
>
> \[Slide.\]
>
> In the course of the product development, the formulation that was
> used in the clinical trials and the formulation that is to be marketed
> were different.
>
> \[Slide.\]
>
> Attempts were made to establish the bioequivalence between the
> formulation in clinical trials and the formulation to be marketed. A
> bioequivalence study, Study 009 in the submission, was performed in
> healthy volunteers. This study failed to satisfy the regulatory
> requirements for bioequivalence.
>
> A couple of comments on the results of this study. First of all, the
> point estimates of the area under the curve and for the Cmax for the
> clinical-trials product and the to-be-marketed product were similar.
> But the problem was that the 90 percent confidence intervals around
> these point estimates were too wide for the regulatory requirements.
>
> This was partly ascribed to the fact that there was variability due to
> difficulties, technical difficulties, in the measurement of both
> artesunate and dihydro artemisinin in plasma. There was a wide range
> of inter- and intrasubject variability both in absorption,
> distribution, m metabolism and elimination. Finally, given all these
> variables, the study left adequate power to demonstrate tighter
> confidence intervals.
>
> To address these concerns, the applicant performed an equivalence
> study with clinical endpoints, Study 014 in the submission. This was
> performed in malaria patients. This study showed similar parasite
> clearance of 24 hours in patients treated with the product used in
> clinical trials and in patients treated with the product to be
> marketed.
>
> \[Slide.\]
>
> In taking all these issues into account, we addressed the totality of
> the data. We were aware and cognizant of the technical difficulties
> and the intrasubject variability in the measurement of bioequivalence
> study. We took into account the satisfactory clinical perforation of
> the to-be-marketed product in Study 014 and we viewed this in the
> context of its potential use for a life-threatening illness where
> really no alternative therapy is available in that particular setting.
>
> \[Slide.\]
>
> To return to our theme of efficacy, the applicant was faced with the
> challenge to develop appropriate clinical studies. The underlying
> scientific question was as follows: prior to a definitive treatment,
> is the emergency use of a single dose of rectal artesunate more
> effective than no treatment in reducing malaria morbidity and
> mortality.
>
> \[Slide.\]
>
> To address this question, there were several practical challenges. I
> am going to go through a couple of them. Firstly, given the high
> mortality from untreated malaria and the dangers of delaying effective
> therapy, treatment cannot be clinically withheld for the first 24
> hours if effective therapy is available.
>
> So, it was for these reasons that the clinical trials submitted in
> this NDA have employed active comparators. In the studies in this NDA,
> provisions are made for the rescue of patients showing an
> unsatisfactory clinical or parasitological response. We should bear in
> mind that, while these studies do not directly address the advantages
> of rectal artesunate over no treatment, they do give a relative idea
> of the efficacy versus the standard of care.
>
> I have added a point here about Study 013 which was mentioned earlier.
> This is a trial which is currently underway to investigate the product
> under conditions that more closely reflect the intended use. This
> trial has not been submitted to the FDA and will not be reviewed as
> part of this efficacy overview.
>
> \[Slide.\]
>
> There are other problems in modeling the projected use. I have listed
> them in two columns here. Firstly, in the clinical studies in this
> NDA, most of the participants in the trials lived in malaria-endemic
> areas and they had some degree of malaria immunity. We anticipate
> that, in projected use, this may be used in U.S. travelers, in U.S.
> military recruits, in Peace Corps participants as well as in residents
> of malaria-endemic areas. So there is likely to be a spectrum of
> malaria immunity in the projected use.
>
> In the clinical studies, the diagnosis was confirmed on smear before
> entry into any of the regimens whereas the diagnosis will not be
> confirmed before treatment in the field. There were entry criteria in
> the clinical studies which determined that patients coming into study
> were diagnosed with moderately severe malaria whereas we anticipate
> that all degrees of severity will be seen in the clinical setting.
>
> Patients were hospitalized in all the clinical trials and they will
> not be hospitalized in the clinical setting at least until they get to
> definitive care.
>
> \[Slide.\]
>
> Ancillary treatment was provided to all patients in the clinical
> studies as needed. This may have included fluids, glucose,
> anticonvulsants and antipyretics whereas clearly ancillary treatment
> in the field will not be available.
>
> Suppository retention was supervised in these studies whereas
> retention may be supervised in the field depending on the abilities
> and the cooperation of family members. Patients failing on
> parasitological grounds in these studies were rescued with other
> antimalarial therapy whereas no rescue would be available during
> emergency therapy in the field.
>
> Finally, definitive therapy was provided to all study participants at
> 24 hours whereas, in the field, we anticipate that access to
> definitive treatment will depend on the local infrastructure.
>
> \[Slide.\]
>
> There was also another question in the selection of suitable
> endpoints. The first problem is although the object is to reduce
> mortality, mortality is really not a realistic endpoint because deaths
> are very rare in patients with moderately severe malaria who are
> properly treated. So we have been left with a number of alternative
> endpoints to consider. I have listed the most important of these.
>
> Firstly, the response in the degree of parasitemia after drug therapy.
> Second of all, clinical responses to drug therapy. Finally, an overall
> evaluation of the success of the regimen in terms of recrudescence
> rates.
>
> \[Slide.\]
>
> I am going to move on now to review some of the studies of efficacy in
> NDA 21-242 in a little bit more detail.
>
> \[Slide.\]
>
> This is just a quick overview of the studies which were regarded as
> supportive of clinical efficacy. There were three studies which we
> designated pivotal studies, 005, 006 and 007. These were comparative,
> randomized and unblinded studies and they employed the projected dose
> of the drug for the first 24 hours given alone.
>
> There was a bioequivalence study which we have spoken of a little
> earlier, 014, which compared three formulations of rectal artesunate
> used in the projected dosing regimen.
>
> \[Slide.\]
>
> There were two other supportive studies which were primarily
> biopharmaceutical studies, or pharmacokinetics studies, 003 and 004.
> These were crossover dose-escalation studies comparing rectal and
> intravenous artesunate given sequentially over periods of twelve
> hours.
>
> Finally, there were a couple of additional studies which were
> previously published and reanalyzed by the sponsor, Studies 010, 011
> and 012. These studies employed twice the recommended dose and they
> did not, in our view, support the efficacy of the projected dose. I
> will not review these further.
>
> \[Slide.\]
>
> This is an overview of the three pivotal studies, the first performed
> in Thailand, 005, the second in Malawi, 006 and the third in South
> Africa, 007. As you can see, in the experimental arm, the regimen was
> the same in all three studies. All patients received a single dose, 10
> milligrams per kilogram, approximately, of rectal artesunate given
> alone for the first 24 hours of therapy.
>
> The comparator, in the case of the Thai study, was oral artesunate,
> again given as a single dose for the first 24 hours. In the Malawian
> and South African study, the comparator was three doses of quinine
> given parenterally over the first 24 hours.
>
> After the first 24 hours, a consolidation regimen was given, or
> definitive therapy, was given in each of the three studies. Notice
> that in the Thai study, the consolidation regimen incorporated several
> sequential doses of oral artesunate plus two doses of mefloquine. In
> the Malawian study, the follow-up therapy was a single oral dose of
> sulfadoxine/pyrimethamine. Parenteral quinine could be given if
> patients were not yet able to take orally, and the same effectively
> applied in the South African study where the consolidation therapy was
> oral sulfadoxine/pyrimethamine given as a single dose.
>
> \[Slide.\]
>
> In this next slide, I want to mention some comments on the study
> drugs. First of all, quinine, which, as you may remember, was the
> comparator used in the Malawian and the South African studies. Quinine
> is generally given as a course for seven days in the treatment of
> malaria. Most would regard 24 hours as inadequate on its own and
> almost certainly likely to result in recrudescences.
>
> Sulfadoxine/pyrimethamine, which was the consolidation therapy used in
> the South African and Malawian studies, is a long-acting agent. It is
> given as a single dose. But sulfadoxine/pyrimethamine resistance is
> high and exceeds 60 percent in many parts of Africa.
>
> \[Slide.\]
>
> As far as mefloquine goes, mefloquine is a long-acting agent, has a
> very long half-life. It may be given as a single dose and it has been
> used very effectively together with artemisinins for the treatment of
> drug-resistant malaria in areas of the world where this is prevalent.
>
> \[Slide.\]
>
> This is just a brief overview of the inclusion and exclusion criteria,
> to give you some idea of the population in the clinical studies. The
> noteworthy points here are that in the Thai and the Malawian studies,
> children were recruited. In the South African study, the recruited
> population were adults.
>
> In two of the studies, there was a requirement for a minimal eligible
> parasitemia with P. falciparum, greater than 4 percent, approximately,
> in the Thai studies, greater than 0.4 percent in the Malawian study.
> There was no such criterion in the South African study.
>
> There were some clinical criteria in two of these studies. In the
> South African and the Malawian study, patients had to be unable to eat
> or drink. As far as exclusion criteria go, for obvious practical
> reasons, diarrhea was an exclusion criteria. Previous antimalarials in
> the 24 hours before therapy were also an exclusion criterion.
>
> Attempts were made to exclude patients with severe or complicated
> malaria based on the presence of the factors I have listed here;
> acidosis, severe anemia, jaundice, bleeding, shock, decreased
> consciousness, et cetera.
>
> Patients were also excluded if they had excessive levels of
> parasitemia, either greater than 20 percent in the Thai study or
> greater than 10 percent in the South African and Malawian study. I
> just want to mention before going on to the next slide that the South
> African study also incorporated another arm which attempted to look at
> patients with severe and complicated malaria. In this particular arm,
> all the patients were to be given quinine together with or without
> concurrent artesunate.
>
> For this reason, the fact that all patients were treated with another
> effective antimalarial medication, we regarded this as not valid
> evidence of the efficacy of rectal artesunate alone, so I am not going
> to discuss that section of the study in any more detail other than to
> say that, among those complicated patients, there were three deaths
> that were probably due to malaria and they will be addressed later in
> the safety discussion presented a little bit later.
>
> \[Slide.\]
>
> The baseline characteristics of the study patients: first of all,
> study numbers. We see that there were 46 patients in the artesunate
> arm of the Thai study, 87 in the artesunate arm of the Malawian study.
> This was the biggest study. 27 in the South African. Comparator
> numbers were substantially smaller, 17 in the oral artesunate arm of
> the Thai study, 22 in the quinine arm of the Malawi study and eight in
> the quinine arm of the South African study.
>
> The mean age; children, again in the Thai study and the Malawian
> study, adults in the South African study, a slight preponderance of
> male patients across the board. Entry parasitemias, again, with P.
> falciparum in the artesunate arm. First of all, in the Thai study,
> entry parasitemias were the highest. These were the median counts,
> 245,000 in the artesunate arm, 376,000 in the comparator arm.
>
> I have to add that these were statistically significantly different,
> the median, or at least the parasitemia, in the comparator arm was
> higher. Slightly lower parasite counts on entry in the Malawian study,
> 183,000 to 230,000. These were not significantly different and even
> lower counts in the South African study of 51,000 and 58,000.
>
> I have included the platelet counts here just as an indication of the
> disease severity. Suffice it to say, there were no statistically
> significant differences between the arms in terms of the parasite in
> each of the three studies.
>
> \[Slide.\]
>
> I wanted to mention the criteria for rescue therapy within the first
> 24 hours. This was during the first 24 hours when rectal artesunate
> had been given alone. If the parasite density, after the first twelve
> hours of observation, had not fallen to below 60 percent of the
> baseline count, then patients were eligible, in some of the studies,
> for alternative antimalarial therapy.
>
> If there was frank clinical deterioration with development or features
> with severe malaria or repeated convulsions or coma, patients were
> also eligible for rescue therapy. Rescue therapy was not equitably
> applied. In the Thai study, rescue was available to both arms. In the
> Malawian study, rescue therapy was only available to the rectal arm
> and not to the quinine arm. In the South African study, some form of
> rescue therapy was available to both arms.
>
> \[Slide.\]
>
> The primary endpoint defined by the World Health Organization was the
> fractional remaining parasite count at 24 hours. There were
> difficulties with this endpoint in terms of the ability to incorporate
> data from patients who were rescued or had failed because, once they
> been rescued or once they had failed prior to the first 24 hours, some
> of the effect would have had to have been attributed to the rescue
> therapy.
>
> So, on this basis, we derived a couple of other endpoints which we
> thought would best represent the clinical efficacy of the product. The
> first was the 24-hour clinical success rate. This referred to all
> treated patients who were evaluated after 24 hours on study drug, who
> had not received rescue therapy or alternative antimalarial therapy
> and who neither died nor deteriorated clinically since the baseline
> evaluation.
>
> We then defined the 24-hour parasitological success rate as all
> 24-hour clinical successes, as referred to here, whose 24-hour
> parasite count was less than 10 percent of the baseline parasite
> count; effectively, those patients who had cleared 90 percent of their
> baseline parasitemia.
>
> Finally, as an indication of the overall efficacy of the regimen, we
> looked at the 28-day recrudescence stroke reinfection rate. This
> referred to any patient who received study drug and was found to have
> a recurrence of parasitemia between the time that there was stopped
> and Day 28.
>
> \[Slide.\]
>
> Just a synopsis of the important study-related events with an impact
> on the clinical results. Again, a recap of the number of patients
> enrolled. There were small numbers of exclusions in all three studies
> and these were based on technical difficulties, problems with a
> mistake in drug administration. As you see, there were five and three
> in the Thai arms, three and one in the Malawian arms and one in each
> of the South African arms.
>
> In terms of the patients rescued for failing to reach 60 percent at
> baseline parasitemia within twelve hours, in the Thai study, there
> were seven patients in the rectal-artesunate arm, four in the
> comparator arm. In the Malawian study, three patients were rescued in
> the artesunate arm and, just to remind you, there were no provisions
> for rescue in the comparator arm among these 22 patients.
>
> In the South African study, one patient rescued in the artesunate arm,
> two in the comparator arm. In terms of clinical deterioration, one
> patient was designated clinical deterioration in the Thai study
> rectal-artesunate arm, four in the rectal-artesunate arm in the
> Malawian study and none in the South African study.
>
> There was one death in all these three studies. The death occurred in
> the artesunate arm of the Thai study and it occurred in a
> three-year-old child who evidently was admitted ambulant to the study,
> was given rectal artesunate, showed a response in the parasitemic
> counts but was given rehydration, subsequently developed Type-O
> neutremia, mental deterioration. The death was ascribed to
> overhydration and not to malaria. That death will also be dealt with
> further in the safety study.
>
> There were a couple of other sundry failures for reasons of expulsion
> of suppositories. That really covers the study-related events.
>
> \[Slide.\]
>
> What this slide shows are the 24-hour clinical success rates for each
> of the three pivotal studies. What you see here are 76 and 71 percent
> success rates in the Thai study where both arms, remember, were
> treated with artesunate, rectally in the yellow bar, orally in the
> blue bar. 24-hour clinical success in the Malawian study was
> 91 percent in the rectal arm and 100 percent in the quinine arm. Bear
> in mind that there was no provision for rescue in this arm and, in
> fact, had rescue been implemented for patients failing to reach 60
> percent of the baseline parasitemia at twelve hours, the success rate
> in this arm would have been 14 percent.
>
> In the South African study, again, 96 percent clinical success rate,
> 24 hours in the artesunate arm, 75 percent in the quinine arm. Between
> all these arms, there were no statistically significant differences.
>
> When we look at the 24-hour parasitological success rates, we see the
> same figures for the Thai study where both arms were treated with
> artesunate rectal and oral. When we look at the Malawian study, there
> is a very impressive difference between the 24-hour parasitological
> results, 88 percent success rate according to the defined criteria for
> the rectal-artesunate arm and only 14 percent success rate in the
> Malawian arm. A similar picture in the South African study where, bear
> in mind, the numbers of patients were very much smaller. For example,
> there were only eight patients in the comparator arm here.
>
> The point really is that again this illustrates the very rapid decline
> in parasitemia that we can attribute to artesunate.
>
> \[Slide.\]
>
> The next slide shows the 28-day recrudescence rates for each of these
> studies. Now, this slide refers to blood smears that are positive
> within the follow-up period from the end of therapy to 28 days. For
> those of you who have a briefing package, you will notice that there
> is a difference in the figures for the South African recrudescence
> rate. That is because those reflected in the briefing document show
> the results of PCR analysis where this is restricted to
> smear-positivity. I will go into that in a little bit more detail.
>
> Suffice it to say that, in the Thai study where the consolidation
> regimen incorporated repeated doses of artesunate plus mefloquine,
> there were no recrudescences on blood smear. However, in the Malawian
> study, there was an enormous rate of recrudescence in both arms but
> significantly higher in the rectal-artesunate arm. Almost half the
> patients had a recrudescence of a positive smear within the 28 days of
> follow up. 23 percent of those treated with quinine in the initial 24
> hours had recurrence of positive smear. Very high recrudescence rates.
>
> Bear in mind that, in this study, a single dose of
> sulfadoxine/pyrimethamine was used as the consolidation therapy and
> also, I guess, one should be cognizant of the fact that high rates of
> sulfadoxine/pyrimethamine resistance are prevalent in Africa. So the
> geographic location may have some impact on this result.
>
> In the South African study, among the 27 patients in the artesunate
> arm, there was only one patient who had a smear-confirmed
> recrudescence or reinfection. There were none in the quinine arm.
>
> Just to complete the thought on patients with PCR-detected
> recrudescences, in this particular study, there were a couple of
> patients who presented during the follow-up period with clinical
> symptoms and PCRs were performed on these patients. There were two in
> each arm which were found to be PCR-positive. But these were not
> confirmed on smear owing to the fact that we really haven\'t
> established the validity of PCR diagnostics. In this setting, I have
> really confined the analysis to those who are smear-positive.
>
> \[Slide.\]
>
> What can we conclude from these three pivotal studies? First of all,
> at 24 hours, the clinical success rates for rectal artesunate are
> similar to those seen with oral artesunate or quinine. Secondly, at 24
> hours, the parasite clearance is significantly more rapid with rectal
> artesunate than with quinine.
>
> In terms of recrudescence, by Day 28, recrudescence rates are high
> when sulfadoxine/pyrimethamine was used as definitive therapy and
> recrudescence rates may be higher in artesunate-treated patients than
> in quinine-treated patients. Again, this may depend on the geographic
> location.
>
> \[Slide.\]
>
> What can we not conclude from the pivotal studies? First of all, we
> cannot conclude that we have adequately characterized the impact of
> rectal artesunate on malaria mortality. Secondly, we cannot conclude
> that the same result will be seen in the field where hospitalization,
> supportive therapy and laboratory diagnostics are unavailable.
>
> \[Slide.\]
>
> I want to raise a couple of other sources of data from some of the
> supportive studies. This is the equivalence study with clinical
> endpoints, Study 014, which aimed to compare the efficacy of the
> product used in the clinical studies with two formulations of the
> product to be marketed.
>
> \[Slide.\]
>
> The next slide shows the study regimens. In this study, all patients
> in the study were given a single rectal artesunate dose of 400
> milligrams, one of the three preparations. The follow-up treatment in
> this study was oral artesunate given daily for three days and two
> doses of mefloquine.
>
> \[Slide.\]
>
> The study populations; the study was performed in Thai hospitalized
> adult patients. The patients were diagnosed with uncomplicated
> moderately severe malaria and there were 23 patients in each of the
> three arms.
>
> \[Slide.\]
>
> The 24-hour clinical success rate in this study was 100 percent for
> all of the arms. None of the patients were given rescue therapy. In
> terms of the parasitological outcome in this study, this was the
> clinical product and these were the two products to be marketed. These
> were the admission parasitemias, somewhere between 30,000 and 47,000
> on admission.
>
> Within twelve hours, a rapid fall, which we see with most artemisinin
> products, somewhere between 3,000 and 13,000. By 24 hours, effectively
> the parasites were below 100 in all three arms. At 48 hours, they were
> virtually undetectable recognizing that, by this stage, consolidation
> therapy had already been given, so, again, showing a rapid decline for
> all three arms with effective elimination by 24 hours.
>
> \[Slide.\]
>
> In terms of recrudescence, or new infections in the study,
> unfortunately, this is data that we do not have. Data was not
> collected beyond seven days in these patients.
>
> \[Slide.\]
>
> So our conclusions on Study 014; this study showed equivalent efficacy
> of the three formulations in the 24-hour parasite clearance. The study
> also served to demonstrate the noncomparative efficacy of rectal
> artesunate given alone for the first 24 hours to 69 adult patients
> with moderately severe uncomplicated malaria.
>
> Among these 69 patients, none were judged by the study physicians to
> require rescue therapy or made an uneventful clinical and
> parasitological recovery. But, of course, the outcome beyond seven
> days in these patients in terms of recrudescence or new infection is
> not known.
>
> \[Slide.\]
>
> Just a brief comment on Studies 003 and 004. These were
> pharmacokinetic studies. They were crossover studies between rectal
> and intravenous artesunate given at two different dosing strength. The
> patient population; again, patients with moderately severe
> uncomplicated malaria. 003 was performed in hospitalized Thai adults.
> 004 was performed in hospitalized Ghanaian children.
>
> \[Slide.\]
>
> These were the treatment arms. As you can see, in intravenous therapy
> given for the first twelve hours followed by rectal artesunate, 10
> milligrams per kilogram in this arm. This was the reverse; rectal
> artesunate, 10 milligrams per kilogram followed, after twelve hours,
> by intravenous. In these two arms, intravenous followed by a
> double-dose of rectal and double dose of rectal followed by
> intravenous after twelve hours. Approximately twelve patients per arm.
> This arm was not represented in the Ghana study.
>
> \[Slide.\]
>
> Consolidation therapy in this study, in the Thai Study 003. Mefloquine
> was used at 36 and 48 hours. In the Ghana study, chloroquine was used
> over the first three days although a proportion of patients unable to
> tolerate chloroquine was given sulfadoxine/pyrimethamine.
>
> \[Slide.\]
>
> The next slide shows the inclusion criteria. The Thai study was
> conducted in adults. The Ghana study was conducted in children. Entry
> parasitemia; the minimum parasitemia for entry in the Thai study was
> high, was greater than 100,000 per microliter. In the Ghana study, it
> was substantially lower, greater than 10,000. Patients were non per
> os. Patients with severe or complicated malaria were excluded.
> Patients with diarrhea were excluded.
>
> \[Slide.\]
>
> The 24-hour clinical success rate was high in all the arms, twelve out
> of twelve in the intravenous followed by projected dose of rectal, 23
> out of 24 in the reverse. In the double-dose rectal, 22 out of 23, 22
> out of 24.
>
> I have just made a note that it was these two patients that were
> diagnosed with clinical deterioration whereas the failures in these
> two arms were for reasons of inability to retain the suppository or to
> receive intravenous therapy. So there were two clinical failures
> across the four arms of the studies.
>
> \[Slide.\]
>
> The parasitological success rates; more than 90 percent clearance at
> baseline parasitological at twelve and 24 hours. We looked at two
> endpoints here. The 90 percent clearance at twelve hours was low but,
> by 24 hours, a very large percentage of all treatment arms had
> achieved 90 percent clearance, eight out of twelve, 21 out of 23, 20
> out of 22 and 21 out of 23.
>
> \[Slide.\]
>
> In terms of recurrent parasitological during the two to three weeks
> following therapy, I have pooled the two studies and divided them
> according to the consolidation regimen they received. What this shows
> is that recrudescence rates were clearly highest in the patients who
> had chloroquine as consolidation therapy, 30 product of the 23
> patients. They were lowest in the patients who received mefloquine, 15
> percent, seven of the 48, and they were intermediate in the patients
> who received sulfadoxine/pyrimethamine, 22 percent.
>
> \[Slide.\]
>
> What did we learn from Studies 003 and 004? Well, first of all, there
> was no clinical advantage in using 20 milligrams per kilogram of
> rectal instead of 10 milligrams per kilogram of rectal. We saw a
> confirmation of the rapid reductions in parasitological with
> artesunate. The other thing to note is that, despite the twelve hourly
> regimen in these studies, recrudescence rates were still high.
>
> \[Slide.\]
>
> So, in summary, among the 229 evaluable patients with moderately
> severe malaria treated with 10 milligrams per kilogram of rectal
> artesunate over the first 24 hours, we saw one death which was
> probably due to fluid overload. The 24-hour clinical success rates
> were similar to comparator. The 24-hour parasitological success rates
> were superior to the comparator and the 28-day recrudescence rates
> ranged between 0 and 45 percent for the rectal-artesunate arms and
> from 0 to 25 percent for the comparator arms, bearing in mind that
> follow-up rates were rather low, and we will address this further.
>
> \[Slide.\]
>
> Some considerations which I wanted to raise were, first of all, delays
> in therapy are one of the most important contributors to malaria
> mortality. Given the potent effect on parasitemia and the good
> short-term clinical perforation of rectal artesunate, does this imply
> that it will reduce malaria mortality? Second of all, are there any
> potential hazards in the empirical use of rectal artesunate for
> emergency treatment?
>
> \[Slide.\]
>
> I just want to finish off by drawing your attention to some
> statistical issues. First of all, in the evaluation of these studies,
> there are difficulties in interpreting the parasitological responses
> based on the fact that patients were rescued before the 24-hour
> endpoint. Second of all, due to significant losses in follow up at
> later time points, the recrudescence rates that we calculated may be
> inaccurate.
>
> To help us out with these, I am going to turn over the podium to my
> colleague, the statistical reviewer on the review team, Ruthanna Davi.
> She will discuss the statistical implications of these problems.
>
> Thank you.
>
> MS. DAVI: Thank you, Dr. Sacks.
>
> \[Slide.\]
>
> As Dr. Sacks told you, I intend to discuss the interpretation of the
> parasite-count measurements in light of the rescue of subjects.
>
> \[Slide.\]
>
> Secondly, I would like to address the issue of the recrudescence rates
> that we are seeing in the artesunate arm in light of some of the
> missing data in lost-to-follow-up. Finally, I will present an
> exploratory analysis looking for any other risk factors that may be
> predictive of recrudescence.
>
> \[Slide.\]
>
> Let\'s start by looking at the parasite-count endpoint. You have seen,
> so far, that artesunate-treated subjects seem to experience a
> significant decrease in parasite counts from the 0 to 12-hour time
> point. I first want to motivate you to look at this endpoint rather
> than the clinical or parasitological success type endpoints that we
> have seen so far which are dichotomous endpoints giving a response of
> success or failure.
>
> The parasitological endpoint, however, is a numerical endpoint
> allowing a continuum of responses and therefore allowing statistically
> more chance of seeing a difference between treatment arms.
>
> In considering the parasite-count analyses, though, we have problems
> with the rescue subjects. To handle that, we will consider three
> cases. First, we will consider the case where we exclude subjects who
> were rescued. This is problematic, however, because this would exclude
> subjects who were doing poorly and the resulting analysis would,
> therefore, look at the success of the successes.
>
> The second possibility is that we could agree on some method for
> imputation of the data beyond the point at which subjects were
> rescued. Again, this is a biased analysis because we would be
> considering data that would was not actually observed.
>
> Finally, we could ignore the fact that subjects were rescued and look
> at their actual observed parasite counts, but this analysis would have
> the problem of attributing the efficacy of the rescue therapy to the
> randomly assigned treatment.
>
> The truth about this endpoint probably lies somewhere between these
> three analyses.
>
> \[Slide.\]
>
> I want to start with presenting Study 007 to you. You will notice I am
> doing these studies in reverse numerical order. That is not to confuse
> you. That is merely because there were a smaller number of subjects in
> Study 007 and it is advantageous to see the plots with a smaller
> number of subjects first.
>
> This is the South African study. What is displayed in the top plot is
> one line per subject illustrating the parasite count across time for
> artesunate-treated subjects. So, on the X axis, we have the time
> variable from zero, twelve to 24 hours. On the Y axis, the
> parasite-count response.
>
> Here you will see a rapid decline in parasitemia from zero to twelve
> hours and that continuing, then, from twelve to 24 hours. The plot
> below that is the similar plot for the quinine subjects. Again, there
> is a decline in parasitemia
>
> from zero to twelve hours but, perhaps, not so rapid as that observed
> in the artesunate group.
>
> If we add, now, the rescued subjects, plotting their observed parasite
> counts, ignoring the fact that they were rescued, we can see that it
> would not, in all likelihood, make a substantial impact on the
> analysis of that data being that there is only one rescued artesunate
> subject and two rescued quinine subjects. I intend to quantify that
> statement later in the presentation.
>
> Finally, I would like to show you one last presentation of the data
> and that is including the rescued subjects as what we refer to as last
> observation carried forward meaning that, at the point at which they
> were rescued, we took that observation and carried it forward through
> the rest of the trial.
>
> So, since they were rescued at twelve hours, their twelve-hour
> measurement was carried through to the 24-hour time point.
>
> \[Slide.\]
>
> If we continue, then, to Study 006, these plots are a little harder to
> look at because of the number of subjects, but the same trend is
> evident. This is a Malawi study and we see a rapid decrease in
> parasitemia in the artesunate group from the zero to twelve-hour time
> point and that continuing from twelve to 24 hours.
>
> There is, again, a decrease in the quinine group but not as rapid as
> that seen in the artesunate group. We quickly can illustrate the
> rescued subjects with their actual observed values. Again, remember
> subjects in the quinine group in this trial were not eligible for
> rescue so we make modifications only to the artesunate plot.
>
> Finally, I will show you the results including these subjects as last
> observation carried forward.
>
> \[Slide.\]
>
> We will now go on to the Thailand study where the comparator arm is
> oral artesunate. We observed the same rapid decrease in parasitemia
> from zero to twelve hours and continuing from twelve to 24 hours in
> both the rectal and the oral artesunate plots.
>
> We will illustrate now how the rescued subjects impact and this is
> with their actual observed values and finally with their last
> observation carried forward.
>
> \[Slide.\]
>
> At this point, I will show you the numerical results for what you have
> seen in the plots. These are median fractional remaining parasite
> counts at twelve and 24 hours. What we can see is that, in both Study
> 007 and 006, the median remaining fractional parasite count is
> statistically significantly lower for the rectal artesunate group than
> the quinine group. In Study 005 we observed no statistically
> significantly difference in that endpoint between oral and rectal
> artesunate.
>
> Again, this is the analysis excluding patients who were rescued.
>
> \[Slide.\]
>
> Let\'s move now to the analysis where we include rescue patients with
> their observed values. You will notice there are not substantial
> differences in the qualitative conclusions. The statistical
> significance of the results remain. There is a statistically
> significant result in favor of rectal artesunate in both Studies 007
> and 006 and no statistically significant difference between the oral
> and rectal artesunate in Study 005.
>
> \[Slide.\]
>
> Finally, just for completeness, let\'s consider the analysis where
> patients are\--we use their last observation carried forward. The
> results are much the same. The statistically significance remains with
> only minor changes in the magnitude of the difference.
>
> So I think, in conclusion, regarding the parasite count endpoint, you
> can feel comfortable that the data we are seeing is not an artifact of
> the rescued patients.
>
> \[Slide.\]
>
> Let\'s move now to an endpoint that is longer-term follow up, and that
> is recrudescence with artesunate. As Dr. Sacks told you, we did
> observe a fairly high recrudescence rate in one of the studies and
> that is the motivation for the presentation of this.
>
> Subjects\' malaria status was assessed at seven, 14 and 28 days
> post-treatment in all three of the pivotal studies. After a positive
> result for malaria was found, that subject was given additional
> malaria treatment. Therefore, we are considering cumulative failure
> rates in this analysis being that, after another treatment is given,
> the results can no longer be applied to the randomly assigned
> treatment.
>
> Part of the challenge in examining this endpoint is that the follow up
> of these patients was quite difficult. The missing values, as you will
> see, were quite rampant. Again, I am going to consider three cases.
> The first will be where we consider missing values as success; in
> other words, they did not have malaria.
>
> The second will be if we consider them failures; in other words, they
> were positive for malaria. The third case will be that we will ignore
> the missing values, not counting them in either the numerator or the
> denominator of the recrudescence rates.
>
> \[Slide.\]
>
> First, this is an overview of the recrudescence rates in each of the
> three studies. There were no, or very small, recrudescences observed
> in Studies 005 and 007 and, in contrast to that, Study 006 in Malawi,
> we observed a much higher recrudescence rate and much higher even in
> the rectal-artesunate arm than that which was observed in the quinine
> arm. This was our motivation for exploring the data in Study 006
> further.
>
> \[Slide.\]
>
> If we continue, then, the results for Study 006 are displayed in this
> table at each of the time points assessed. In this analysis, we are
> considering missing observations a success.
>
> At Day 7, we observed a 16 percent recrudescence rate in the rectal
> artesunate group and no recrudescences in the quinine group.
> Continuing to Day 14, there was a 29 percent recrudescence in the
> rectal artesunate group and a 9 percent recrudescence in the
> comparator group. Finally, by Day 28, the results you have already
> seen were evident, a 45 percent recrudescence in the rectal artesunate
> group and a 23 percent recrudescence in the quinine group.
>
> \[Slide.\]
>
> Let\'s move now to consider the missing observations of failure.
> Perhaps this is the least likely of the three cases that I will
> present to you. This analysis relies on the assumption that patients
> who did not return to their follow-up visit were positive for malaria.
> Here we see much higher recrudescence rates because of considering the
> missing data failures but we still see a discrepancy between the
> rectal-artesunate arm and the quinine arm in terms of the
> recrudescence rates.
>
> Continue, then, to the analysis where we ignore missing observations.
> This analysis makes the assumption that subjects who did not return
> for their follow-up visits would have similar recrudescence rates to
> those who did return for their follow-up visits.
>
> Again, we see an early discrepancy between the arms in terms of
> recrudescence rates. At Day 7, there was a 16 percent recrudescence
> rate in the rectal-artesunate arm and no recrudescence in the
> comparator arm. Day 14, there was a 29 percent recrudescence rate for
> rectal artesunate, 9 percent for the comparator and, finally, 45 and
> 23 percent at Day 28.
>
> \[Slide.\]
>
> Having said that, we took one more approach to the analysis of this
> endpoint and considered a time-to-event-type response where we looked
> at the time to recrudescence. This analysis afforded us the luxury of
> considering missing data as censored data. We found that there was a
> statistically significant result, that recrudescence appeared earlier
> and more frequent in the rectal artesunate group.
>
> In that same type of analysis, we aimed to identify other covariates
> that might be impacting recrudescence rates. In particular, we were
> trying to see if there might be some imbalance in the treatment groups
> in some other covariate that was impacting the recrudescence rates and
> could explain the possible treatment effect that we were seeing.
>
> We considered several demographic factors such as age and gender. We
> also considered numerous baseline disease-status endpoints such as
> baseline parasite count and baseline temperature. None of the
> endpoints we considered were found to be statistically significantly
> predictive of whether or not someone would recrudesce with the
> possible exception of the Blantyre coma score. However, the result was
> not statistically significant and this was an exploratory analysis of
> numerous variables.
>
> \[Slide.\]
>
> So, in summary, I would like to leave you with three thoughts. First,
> you can feel comfortable with the results of the parasite-count
> analysis because, regardless of how we handled the rescued patients,
> the results still were highly statistically significant in favor of
> rectal artesunate
>
> \[Slide.\]
>
> The second point is that we did see statistically significantly
> earlier and more often recrudescence in the rectal-artesunate arm than
> in the quinine arm in Study 006. Finally, an exploratory analysis of
> that data did not reveal any other covariates that were important in
> the prediction of whether or not a patient would recrudesce.
>
> At this point, I would like to introduce Dr. Johann-Liang who will
> address the safety review of rectal artesunate.
>
> DR. JOHANN-LIANG: Good morning. It is a pleasure to address such a
> distinguished and global panel this morning.
>
> \[Slide.\]
>
> My task is to present the integrated safety assessment by the FDA of
> NDA 21-242, rectal artesunate.
>
> \[Slide.\]
>
> Once again, the proposed indication is single, 10 milligrams per
> kilogram dose of artesunate, rectal capsules, in the initial
> management of acute malaria in patients who cannot take medication by
> mouth and for whom parenteral treatment is not available.
>
> \[Slide.\]
>
> As we go through this talk, please keep in mind the implications of
> the indication that is being proposed. These are, use in the field,
> use as empiric therapy. Patients with other severe febrile illnesses
> such as meningitis, pneumonia, bacteriemia, et cetera, will be
> exposed, use in patients with severe disease who are at least unable
> to take PO and use in mainly very young children.
>
> \[Slide.\]
>
> Three sets of information relevant to the safety evaluation of rectal
> artesunate was submitted to this NDA by the applicant. They are the
> WHO-sponsored studies consisting of thirteen study data and reports,
> the safety review of published and unpublished safety information on
> studies of artesunate derivatives and a summary of the data on
> artesunate injection presented to the Chinese regulatory authorities
> in 1989.
>
> This was reviewed for the sake of completeness but will not be part of
> this talk. I will go through an overview of these two safety
> submissions. I would also like to touch upon the issue, the important
> issue, of neurotoxicity.
>
> \[Slide.\]
>
> Let\'s start with the overview of the WHO-sponsored studies.
>
> \[Slide.\]
>
> The WHO-sponsored studies consist of a total of 501 patients, 435 with
> malaria and 319 of that 435 in clinical studies. I have broken out for
> you here the types of trials and the numbers of patients by disease
> severity populating those studies. So there were two bioavailability
> and two bioequivalency studies and then the six clinical studies,
> three in adults and three in pediatric, of which Studies 5, 6 and 7
> were the three pivotal clinical studies that were presented to you in
> the efficacy evaluation.
>
> There were 66 healthy volunteers, 344 moderately severe disease
> patients and 91 severe malaria patients making up this application.
> There were 166 children in total in this safety database all of whom
> had moderately severe disease. I want to point out that only eight
> patients out of this 166 were less than two years of age and only five
> in this group of severe malaria patients were from the clinical
> studies.
>
> \[Slide.\]
>
> This table accounts for all the patients enrolled into the six
> WHO-sponsored clinical studies separated out by numbers in the adult
> and children. All six clinical studies were open-labeled. This table
> illustrates the lack of comparative control data in this application.
>
> For adults, there were 153 patients, 148 with moderately severe
> disease and five with severe disease. Comparative statements are not
> possible for adults because, in the comparator group, there were only
> 14 patients and they were all categorized as having severe disease,
> all receiving I.V. quinine.
>
> Comparative statements may be possible for the children which
> consisted of about 166 patients all categorized as moderately severe
> disease in the rectal-artesunate arm as compared to the comparator arm
> where there were 39 patients all, again, with moderately severe
> disease, 17 who received P.O. artesunate and 22 I.V. quinine.
>
> \[Slide.\]
>
> Looking at the comparative adverse-event counts in children, the
> overall adverse events was 20 percent for the rectal-artesunate group
> versus 26 percent for the comparators. Looking at the adverse events
> by systems, the most common complaint was gastrointestinal consisting
> of nausea, vomiting, abdominal pain. The rates were similar in both
> groups.
>
> Next, the CNS adverse events consisted of headaches, impaired
> consciousness and convulsions and the rates were again similar between
> the two groups. Also, to point out, the impaired consciousness or
> convulsion complaints was not attributed to the drug.
>
> \[Slide.\]
>
> Due to the noncomparative nature of the data in this application, plus
> the fact that patients received subsequent antimalarials shortly after
> the rectal artesunate and the difficulty in sorting out what is
> disease effect versus drug effect, definitive conclusions are hard to
> make about adverse events in the safety datasets.
>
> Moving on to deaths on study, in total there were seven deaths across
> the thirteen studies. There was that one pediatric death that Dr.
> Sacks had pointed out earlier. This was a three-year-old boy who
> received a rectal-artesunate dose of 11.5 milligrams per kilogram
> times 1. The site investigators and the WHO attributed the cause of
> death to iatrogenic water intoxication.
>
> While in agreement with this conclusion as a plausible etiology, I
> want to point out that this little boy\'s dihdryoartemisinin, the
> serum levels at two hours and post hours were quite high, remembering
> that this boy died right after this four-hour time point.
>
> I want to also show you the reference mean and the standard deviation
> for a similar age group taken from the Ghana children. So, what
> contribution, if any, did the high DHA level make in the demise of
> this child? I don\'t think we have that answer.
>
> The three adult deaths in the clinical studies, and these are three
> deaths coming from the South African study, Study No. 007, were all in
> patients with severe malaria. The one death was an artesunate arm and
> the two other deaths were in the I.V. quinine arm. The WHO concluded
> these deaths were due to underlying malarial disease and we are in
> agreement with that.
>
> The three additional studies are coming from the reanalysis studies,
> Studies 010, 011 and 012. Actually, these three deaths were all from
> Study 010 and patients all had severe malaria.
>
> The thing to point out about these deaths is that all three deaths
> occurred at a time point when these patients were cleared of their
> parasitemia. So the cause of death in these three patients were not
> determined.
>
> \[Slide.\]
>
> Laboratory monitoring was limited in the clinical studies of the
> WHO-sponsored program. Only one study, Study No. 003, had
> comprehensive labs recorded including CBC chemistry and LFTs. In the
> 250 patients with malaria who had hematocrits monitored, overall,
> there was a transient decrease at twelve to 24 hours with rise to
> baseline by Day 7 and normalization by Day 28.
>
> Four the 48 patients monitored for liver-function changes in Study
> 003, there were three patients whose amino transferase levels rose to
> three times upper limit of normal after starting with normal baseline
> levels peaking at Day 7 to 14. It is possible that this lab
> abnormality may be drug effect.
>
> Again, only one study, Study No. 003, had EKG monitoring and no
> significant abnormalities were noted.
>
> \[Slide.\]
>
> The majority of patients in PK and clinical studies received one
> rectal-artesunate dose of 10 milligrams per kilogram with a range from
> 6.8 to 22.2. In the reanalysis studies, repeated rectal dosing over
> three to four days with mean doses between 25 to 32 milligrams per
> kilogram total dose occurred. So the maximum dose exposure for adults
> was 45.7 milligrams per kilogram total dose given over four days in
> eight divided doses.
>
> The maximum exposure for children was 21.4 milligrams per kilogram.
> This was the exposure of seven days where one rectal dose was followed
> by multiple oral dosing. It occurred in Study No. 005.
>
> \[Slide.\]
>
> Some specifics to point out about special populations in this safety
> data. Only eight of the 166 children, again, were less than two years
> of age. Only six of the 153 adults in the clinical studies or 269
> adults with malaria in total were older than 50 years of age. Neither
> renal nor hepatic-insufficient patients were specifically studied.
> Pregnant patients were also not included in these studies. However,
> looking at what information is available from preclinical evidence or
> in the literature, the overall impression from the preclinical
> evidence is consistent findings of impaired fetal survival but no
> evidence of teratogenicity in the babies born following first
> trimester exposure to artemisinins in the animal studies.
>
> From the clinical studies in the literature, there is no evidence of
> fetal injury or impairment of maternal health over and above the
> effects on reproductive health or malaria, itself.
>
> \[Slide.\]
>
> So, then, in summary, about the WHO-sponsored studies, this was a very
> small safety database. Studies were all open-labeled with multiple
> drugs and mainly noncomparative. It is hard to differentiate safety
> issues between disease and drug effect. Furthermore, safety assessment
> was not available for special populations, in particular the very
> young children.
>
> The dose exposure was mainly one rectal dose around the 10 milligrams
> per kilogram dose. Overall, no unusual or serious pattern of adverse
> events was identified but, again, minimal numbers were available for
> comparison. Overall, no unusual or serious laboratory abnormalities
> were reported but, again, monitoring was sparse.
>
> The deaths on study were few but not all had clear etiology.
>
> \[Slide.\]
>
> Let\'s turn our attention now to a different set of safety submission.
> I would like to present an overview of the applicant\'s submission
> safety review of the published and unpublished clinical studies on
> artemisinin derivatives. Once again, highlighting as I go along, some
> issues that particularly relate to the implication of the proposed
> indications of the proposed indication.
>
> Please also note that this safety submission did not contain any
> source data for the FDA to review. This was really a summary report by
> the applicant of the clinical experience to date with this class of
> compounds.
>
> \[Slide.\]
>
> 151 published and eighteen unpublished studies were reviewed by the
> WHO and safety information was available on 130 studies consisting of
> 13,639 patients. I have broken out for you how the applicant broke out
> the data of different study types. The numbers are quite impressive
> when you look at the comparative and randomized trials. There were
> 7,848 patients in this safety information.
>
> However, with the implications of the proposed indication in mind, I
> want to draw your attention to the fact that when these same patients
> are recategorized by the level of disease severity, we get the
> following picture.
>
> \[Slide.\]
>
> On the left side is a pie figure showing artemisinin derivatives taken
> together. It is around 13,000 patients. The majority of patients
> included in this safety information were patients with uncomplicated
> malaria here in the yellow. The patients with moderate or severe
> malaria, the red and the little blue here, was really 16 percent, a
> much smaller percentage of the whole safety information.
>
> A similar picture applies even when just the patients treated with
> artesunate, around 6,000 patients, are pieced out. The number of
> patients with moderate and severe malaria, again in the red and this
> sliver in blue, is a much smaller percentage when compared to the
> uncomplicated malaria patients.
>
> \[Slide.\]
>
> The applicant makes several conclusions regarding adverse events from
> their safety review. For comparative studies, the safety review states
> that the most common adverse event in the order of less than 1
> percent, were mild GI events like nausea, vomiting, diarrhea and
> abdominal pain.
>
> For severe malaria patients, the applicant concluded that fewer
> incidents of hypoglycemia, skin reactions, tinnitus, dizziness,
> occurred as compared to quinine. For uncomplicated malaria patients,
> the conclusion was that less pruritus than chloroquine, less nausea,
> dizziness, tinnitus than quinine and less vomiting than mefloquine.
>
> Again, it is important to keep in mind that this pooling of adverse
> events across many studies is quite problematic, especially in light
> of the fact that there were no source data reviewed either by the
> applicant or by the FDA.
>
> \[Slide.\]
>
> Laboratory abnormalities noted by the applicant in the order of 1
> percent included neutropenia, reticular cytopenia, eosinophilia,
> anemia, transaminitis, culture-negative pyuria, hemoglobinuria and a
> few cases of elevated bilirubin. EKG abnormalities in the order of 1
> percent included bradycardia, prolongation of QT interval and a few
> cases of first-degree AV block, atrial extrasystoles and T-wave
> abnormalities.
>
> \[Slide.\]
>
> The vast majority of studies included in the safety review did not
> have neurological assessments. Of the available information, dizziness
> appears to be the most common adverse event. The paper by Price, et
> al., is the article that the applicant refers to largely for the
> clinical neurologic safety of artemisinin derivatives.
>
> In keeping with what the implications of the indication that is being
> sought here, I want to point out that, in this particular clinical
> experience, patients with uncomplicated malaria were assessed. In the
> author\'s own words in the paper, neurological examination could be
> performed reliably only in patients greater than five years of age.
>
> Dr. Folb, in his earlier presentation, also pointed out two other
> papers in the more recent literature by Kissinger and Van Vugt from
> Viet Nam and Thailand. When you look at the age brackets and the
> neurological assessments that were done in those patients as well, I
> think there were only two patients for each of the papers that had
> children that were less than actually five years of age.
>
> The human histopathology experience in all the safety information
> really is just six patients treated with artemether from Hien, et al.,
> in Viet Nam. Here, the slides were looked at at autopsy and no
> neuronal necrosis was seen but chromatolysis was frequently seen.
>
> \[Slide.\]
>
> So, in summarizing the second safety submission, we agree with the
> applicant that this was a comprehensive effort to examine the
> available safety information on artemisinin derivatives. Relatively
> few side effects were noted overall and mainly mind and transient. No
> patterns of adverse events were seen.
>
> For comparative studies, the safety review did not find that patients
> receiving artemisinin derivatives had an increase in adverse events
> over comparators. In fact, the safety review concluded that
> artemisinin derivatives showed a better tolerability profile over
> comparators that are available.
>
> Moreover, there was a lack of clinical evidence to suggest an
> association between the artemisian derivatives and increased
> neurotoxic adverse events, neurotoxic sequelae or death.
>
> \[Slide.\]
>
> What are some of the problems with the safety review? There are the
> obvious methodological deficiencies of pooling all different types of
> studies together, particularly in this case when the safety parameters
> examined may be a result of either drug or disease effect and the
> uncertainties of pooling adverse events across studies become
> magnified.
>
> As I have pointed out, although the number of patients in the
> collective safety information appears to be large, the relevant
> assessments in relevant populations are not as large.
>
> One other issue that is worth mentioning is the issue of the quality
> of the active ingredient. The application has pointed out that apart
> from two WHO-sponsored studies, the rest of the safety data derived
> from studies which used artemisinin active ingredients not produced to
> good manufacturing practices and that this supports how remarkable the
> safety of artesunate is.
>
> I would submit that this issue could be looked at in a different
> light. It is possible that the many years of actual-use safety that we
> have is based on drugs that contain subpotent content of active
> ingredient. Moreover, there is at least one article, if not more, in
> the literature that discusses the relative abundant use of counterfeit
> drugs which contains really no active ingredient.
>
> \[Slide.\]
>
> I would like to focus now on the important safety issue of
> neurotoxicity and spend a few minutes discussing what we do know at
> this point and what we do not know at this point.
>
> As you have heard neurotoxicity is considered a class effect of
> artemisian derivatives in animals. Dose-related patterns of
> neuropathologies starting with chromatolysis, the necrosis of specific
> neurons in the brain stem of rats, monkeys, dogs and mice have been
> described with artemisinin, artemether, arteether and the principal
> metabolite dihydroartemisinin.
>
> \[Slide.\]
>
> The conclusion from the WHO sponsor expert consultation by Professor
> Dayan, et al., stated that only limited information was available for
> artesunate but no neuronal necrosis was seen at 420 milligrams per
> kilogram IM or 200 milligrams per kilogram per day PO over five to
> seven days.
>
> The applicant concluded in their briefing document that, for
> artesunate, a total of 210 to 300 milligrams per kilogram by I.V. or
> PO did not result in neurotoxicity. They further concluded that this
> is 21-fold to 30-fold greater than the proposed human dose and, thus,
> a wide margin of safety.
>
> If we accept this dose of 212 to 300 milligrams per kilogram as the
> best available approximation for no adverse-effect level for
> artesunate, the body-surface-area convergent from the animal model to
> human equivalent dose would be 35 to 50 milligrams per kilogram which
> is only 3-fold to 5-fold greater than the proposed dose, giving us a
> small safety margin.
>
> \[Slide.\]
>
> If we take a more conservative approach to the available preclinical
> evidence, the safety margin gets even more narrow. For artemether and
> arteether, Professor Dayan\'s expert review of the neuropathology
> materials concluded that the NOAEL for neurotoxicity in rats was 45 to
> 75 milligrams per kilogram.
>
> This dose by body-surface-area conversion would translate to a human
> equivalent dose of 7.5 to 12.5 milligrams per kilogram parenterally.
> For artesunate, looking down the right side of this schema, the
> seven-day rat in the study in the WHO Committee Toxicology Program was
> not specifically targeted enough for the determination of
> neurotoxicity NOAEL.
>
> Furthermore, there were unexplained death in one of 16 animals on Day
> 4 on the 75 milligrams per kilogram dose and two of 16 on Day 3 of 150
> milligrams per kilogram dose. So, for the overall NOAEL, the human
> equivalent dose calculated from adjusting for body-surface area from
> this rat model is 12 and 25 milligrams per kilogram if we use the dose
> at which the unexplained deaths occurred.
>
> This human equivalent dose is right around the proposed 10 milligrams
> per kilogram rectal dose not giving us any margin of safety.
>
> \[Slide.\]
>
> Having said all that for the preclinical evidence, what about
> neurotoxicity and clinical experience in humans? The WHO-sponsored
> studies contain neurological assessments in the three pivotal studies,
> Studies 5, 6 and 7, which gives 164 rectal-artesunate recipients out
> of the total safety database of 435 patients with malaria.
>
> However, these data were problematic due to the many missing data,
> especially in young patients who could not be reliably assessed.
> Nevertheless, no pattern of neurologic abnormalities were identified.
> In the literature on the actual-usage experience regarding
> neurological safety, the applicant has stated that there is a large
> body of safety experience with artesunate.
>
> Again, I point out to you that the actual safety information in
> patients with severe disease, especially the very young with severe
> disease who actually underwent systematic neurological assessment, is
> a very small percentage of the actual usage experience.
>
> What about the highest doses used in humans? From the literature in
> adults, it was the 45.7 milligrams per kilogram given over three to
> four days in eight divided doses. For children, the highest dose found
> in the literature was 57 milligrams per kilogram given over three days
> in daily divided doses.
>
> I just want to tell you that, for both of these experiences, the
> numbers are very small again, both less than 30 patients.
>
> \[Slide.\]
>
> In trying to put together our current collective knowledge about
> neurotoxicity, what do we know of the artemisinin compounds? We know
> that the neurotoxic lesion occurs in dose-dependent fashion in animal
> models and that the most neurotoxic substance from this group of
> compounds appears to be the major metabolite, the DHA.
>
> So why are neurotoxic lesions seen more with the lipid-soluble
> artemether and arteether than the water-soluble artesunate when,
> actually, artesunate is converted to DHA the most. This is probably
> because the lipid-soluble agents artemether and arteether are
> eliminated more slowly than water-soluble compounds like artesunate
> and thus producing much longer periods of DHA activity.
>
> Hence, the critical factor leading to neurotoxicity appears to be
> sustained levels of DHA rather than peak levels.
>
> \[Slide.\]
>
> With that in mind, what about what we do not yet know and thus causes
> us concern regarding neurotoxicity. The safety margin from preclinical
> to clinical has not been determined yet for artesunate and may not be
> as wide. So, for now, one rectal dose of 10 milligrams per kilogram
> probably is okay but it is unclear with higher and repeated dosing.
>
> We know that artesunate elimination is faster for I.V. over PO over
> rectal. So, with repeated dosing, could rectal formulation also act as
> a depot-type of compound like artemether and arteether causing
> sustained levels. Rats and dogs show damage to the olfactory and
> auditory nuclei whereas monkeys more to the vestibular nuclei.
>
> What nuclei in humans? We don\'t yet know. We could be doing the wrong
> types of neurological assessments. Also, in the animal neurotoxicology
> studies, it has been all done in non-disease models. In humans with
> malarial disease, using artemisinins, could the tissue distribution of
> DHA to parasitized cells act as buffers routing the DHA away from CSF
> and vulnerable neurons.
>
> If this is a theoretical possibility, then could the empiric use in
> febrile children which includes children without malarial disease
> potentially result in high enough sustained levels of DHA in the CNS
> to cause toxicity?
>
> \[Slide.\]
>
> So, finally, starting to summarize our view of the integrated safety,
> I want to once again touch upon the gap in populations. In the NDA
> application which constitutes the WHO-sponsored studies, the studies
> were all done with hospitalized patients, all with proven malaria and
> mainly in patients with moderately severe disease and mainly in adults
> and older children.
>
> The implications of the actual usage in the proposed indication would
> impact a very different population, those in the field with severe
> disease unable to take PO and mainly very young children receiving
> rectal artesunate as empiric therapy. This is a population we have
> very little information on, even in the large body of clinical
> experience, to draw upon for safety evaluation.
>
> Could we make this link at this time?
>
> \[Slide.\]
>
> In the end, what we have to make is the benefit and risk balance
> assessment. The applicant has stated that artesunate has a highly
> favorable safety profile and that the number of adverse events are
> small and no consistent pattern of toxicity has been identified.
>
> I have tried to highlight for you some of the uncertainties about
> safety, particularly the as-of-yet-unknown safety margin of
> neurotoxicity especially in the very young children and the
> as-of-yet-unknown safety parameters of the population implicated in
> the proposed indication.
>
> \[Slide.\]
>
> Given all that, we are mindful of the impact of the disease malaria
> due to the individual human suffering and to global public health.
> Based upon our collective current knowledge, the proposed rectal dose
> of 10 milligrams per kilogram for one dose we feel is within the
> safety limits.
>
> However, uncertainties and concerns expand if higher doses or repeated
> dosing becomes an issue.
>
> I thank you for your attention.
>
> DR. RELLER: Dr. Albrecht?
>
> DR. ALBRECHT: Thank you. As the last speaker of the morning, I intend
> to keep my remarks quite brief. While my slides are coming up, I just
> wanted to comment that I think now, having heard the presentations
> from this morning, you are familiar with the indication that the WHO
> is requesting.
>
> \[Slide.\]
>
> It is for the use of a single dose rectal-artesunate capsule in
> initial management of malaria.
>
> \[Slide.\]
>
> Having heard the presentations by the speakers, I think I would like
> to refer to some of the comments I made in the opening remarks and say
> we have now identified for you some of the difference in the
> populations that were studied.
>
> \[Slide.\]
>
> The patients that would receive this drug in the actual-use setting of
> the rural community compared to the patients who received these
> products in the hospital setting with available medical
> infrastructure.
>
> \[Slide.\]
>
> The differences in the age representations. The certainty in the
> diagnosis in the study populations with some uncertainties possible in
> the actual-use patients as well as issues on timing of drug
> administration.
>
> \[Slide.\]
>
> I think we have now heard about the endpoints of the studies. There is
> convincing evidence of parasite-count reduction at 24 hours. The
> question is does that serve as an effective surrogate for clinical
> success and perhaps, as importantly, is that an appropriate surrogate
> for the desired endpoint of mortality reduction in these patients.
>
> We have also seen the statistical difference in recrudescence,
> particularly in the Malawi studies at 28 days. What is the clinical
> significance of this finding and, importantly, what impact might this
> have on the emergence of resistance to the artemisinins?
>
> \[Slide.\]
>
> So I think what we would like you to think about is what is the impact
> of these differences, what is the significance and the possible
> limitations, how much of the available data can, in fact, be
> generalized to the proposed target populations and how much probably
> needs additional investigation or, perhaps, studies.
>
> Thank you.
>
> DR. RELLER: Thank you, Dr. Albrecht. We will look forward to
> continuing our discussion before the questions are posed later in the
> afternoon.
>
> It is eight minutes after 12:00 by my watch. Let\'s reconvene at 1:10
> just over an hour from now. We will begin with the Open Public Hearing
> and a presentation from Swissmedic.
>
> \[Whereupon, at 12:08 p.m., the proceedings were recessed to be
> resumed at 1:10 p.m.\]
>
> A F T E R N O O N P R O C E E D I N G S
>
> \[1:15 p.m.\]
>
> DR. RELLER: Welcome back to today\'s committee meeting. We will begin
> the afternoon session with the Open Public Hearing. Our scheduled
> speaker is Dr. Kemmler from Swissmedic, the regulatory group for
> Switzerland.
>
> Dr. Kemmler.
>
> **Open Public Hearing**
>
> DR. KEMMLER: Mr. Chairman, members of the advisory committee, ladies
> and gentlemen. First, I want to thank you that I have the opportunity
> to speak here to you.
>
> \[Slide.\]
>
> As you know, the artesunate rectal capsules are for this indication
> which has been mentioned several times now. This application is
> somewhat unusual in several ways because, first, the applicant is
> unusual, the WHO. Second, it is a little bit unusual that an
> application has been submitted to three regulatory agencies
> simultaneously, the FDA, the MCA from the United Kingdom and to
> Swissmedic, the Swiss regulatory authority.
>
> There are several other unusual issues which I will refer to in the
> next minutes and which give us some headaches for the decision.
>
> \[Slide.\]
>
> First, I want to show you what we have done in Swissmedic up to now or
> the time line which we adhered to. We received the submission in
> April, 2000. We had our first discussion in our advisory committee in
> November, 2000 and sent our first comments to the WHO in December,
> 2000.
>
> That was also a little bit an unusual procedure because we agreed to
> make some kind of rolling review. Also, we knew at the time in April
> that the documentation would not be complete. We agreed to receive
> additional material and we got it in March and August, September of
> 2001 and the last one just last month.
>
> We also obtained advice from external experts, from Swiss external
> experts, in tropical medicine, first in December, 2000 and the last
> one in January this year. We had, apart from the comments we sent to
> the WHO, discussions with the WHO and the last one was in December,
> last year.
>
> \[Slide.\]
>
> The main issues after our clinical evaluation which we have to
> consider are very basic. To obtain an approval, a drug must provide
> more benefit than harm when used and there has to be a little bit of a
> distinction. Of course, it has to provide more benefit than harm when
> used as intended but, in addition, it should also have a positive
> benefit-risk relation when it is used in the actual setting; here, in
> this case, in the bush or in the field.
>
> So we are aware of the fact, all of us are aware of the fact, that
> some extrapolation is always necessary. This extrapolation can
> normally be based on some recent experience.
>
> \[Slide.\]
>
> This is the normal cascade of the benefit/risk evaluations or the
> benefit/risk extrapolations. We assess the benefit/risk in the
> clinical trial, make some extrapolation to the target population and
> see the benefit/risk in the intended use. Then we have some experience
> on difference of intended versus actual use and can guess what the
> benefit/risk and actual use will be.
>
> \[Slide.\]
>
> So the usual situation is that from the clinical trial to the intended
> use that the clinical-trial population and administration
> circumstances are not too different from the intended use. Then we
> have a quite good experience on the unlabeled use to be expected which
> I don\'t know if you are aware of that. It is sometimes rather
> important, maybe up to approximately 50 percent unlabeled use. But, in
> most cases, the indications of this unlabeled use are at least near
> the labeled use.
>
> \[Slide.\]
>
> For rectal artesunate, the situation is a little bit different. We
> have, from the Studies 005, 007 and 007, which are considered as
> pivotal studies, only a relatively small line of evidence to the
> intended use because the clinical-trial population and administration
> circumstances are very different from the intended use as you have
> heard already in the last presentation about the safety of rectal
> artesunate.
>
> In addition, we have, in this case, very little experience on the
> unlabeled use to be expected. So this is clearly a little bit more
> problematic than the usual situation.
>
> \[Slide.\]
>
> In addition, we have one further problem which makes things even more
> complicated. We have the pivotal studies of with Formulation 2 and
> intended use is with Formulation 3 and the actual use, of course, will
> also be with Formulation 3. The bioequivalence between these galenical
> formulations is not shown up to now.
>
> \[Slide.\]
>
> This is the situation already mentioned several times, Study 013 will
> drop in. At least I hope so.
>
> \[Slide.\]
>
> Study 013 is, at least as far as we know up to now, somewhere between
> the intended use and the actual use, maybe not directly between the
> two but somewhere in this field which comes near to the intended or
> the actual use.
>
> \[Slide.\]
>
> If we already knew what Study 013 could show us, then we would have
> also have one problem less because Study 013 is done with the
> Formulation 3 and bioequivalence would no longer be an issue. So, what
> do we know, or what is Study 013? It has been mentioned a little bit.
> I want just to repeat that.
>
> \[Slide.\]
>
> It is a placebo-controlled, randomized, double-blind study and the
> projected enrollment was 10,000 patients of approximately, at least,
> the target population. This study, in contrast to the studies which
> have been submitted up to now, has very clear efficacy-related
> endpoints.
>
> One caveat of this study was it should be halted by the independent
> monitoring committee if proved beyond reasonable doubt that rectal
> artesunate is indicated or contraindicated.
>
> \[Slide.\]
>
> This study is still ongoing and blinded and we know some data already
> through the 120-day safety update. Another 3,366 patients have been
> enrolled as of March 22, 2002. 56 percent of the patients in the
> African studies are age below twelve months. That relates, as has
> already been mentioned, to an intended use in children beginning with
> 24-months old.
>
> We have 74 percent positive smears but, as also has already been
> mentioned, these 74 percent positive smears do not exclusively mean
> that all of these patients have fever from malaria but it could also
> be that they have a positive smear and the actual problem of their
> fever and their non per os status was another one. But, most probably,
> at least more than half of the patients had malaria.
>
> 99 of these 3,356 patients have died. This is 2.9 percent, 4 percent
> of them children and 1 percent adults. We have at least four cases of
> bacterial meningitis as was also mentioned already. But this fact we
> have to keep in mind that it was a very low number of patients which
> have been investigated if they have bacterial meningitis, but
> laboratory analyses have been done.
>
> \[Slide.\]
>
> The monitoring committee did not stop the trial after 3,366 patients,
> after the second interim analysis which the monitoring committee had
> the unblinded data available which are not available to us, to the
> regulatory authorities, and not available to the WHO.
>
> At least they did conclude that the study can go on. So the questions
> which arise then are is the advantage of using rectal artesunate as
> important as the results of the study which have been already
> submitted would suggest. After 3,300 patients, it is not clear whether
> rectal artesunate provides a real benefit or poses a special risk.
>
> The second question relating to the 56 percent of patients in the
> African studies with an age below twelve months and also to other
> issues is it inappropriate and possibly counter productive use, even
> in this clinical-trial situation so widespread that a possible
> beneficial effect of artesunate is diluted.
>
> If the use in young children is so high even in this trial, is there
> any point in restricting treatment to those aged twelve months and
> over. This relates clearly also to safety issues because those
> children obviously will receive much higher doses on a milligrams per
> kilogram body weight basis than the patients we have had in the
> clinical trials, 005, 006, 007 and the other ones.
>
> \[Slide.\]
>
> Our current considerations are that we don\'t have any major concerns
> about toxicity if used as intended. If a single dose is given, even if
> it is given to an eight or six-month-old child, we don\'t have too
> many concerns because all we know up to now, the therapeutic margin is
> high.
>
> But, of course, we have to have to keep in mind that, most probably,
> at least outside of the clinical-trial situation as it is in Study
> 013, for example if we assume that a mother has rectal artesunate
> available for an adult with 400 milligrams and her little baby gets
> sick and she thinks that it may be malaria, given the situation we
> have already in Study 013, can we assume that she will not give the
> 400 milligrams to her baby, if it has helped especially, and the child
> becomes feverish again or the artesunate was not indicated because it
> has a fever of another origin, will she, perhaps, then use such a
> capsule again.
>
> These are the things we don\'t know and are clearly the risks which
> are accompanied by this possibility of giving the rectal artesunate.
>
> One other consideration; the bioequivalence of the clinical-trial
> formulation and the market formulation is not shown. But this, of
> course, is also an issue because of the relatively broad margin of
> rectal artesunate that it may be that this is less important even if
> we don\'t have Study 013 available. At least in the oral dosage, the
> maximum effect is already reached with 1.6 milligrams per kilogram and
> we can assume that at least even a single dose with 20 milligrams is
> not possible for the difference between the two galenical formulations
>
> Even at doses, 20 milligrams was tolerated, so it may be that this is
> less important given the overall picture of this application.
>
> \[Slide.\]
>
> Where we really do have concerns is about the benefit/risk relation in
> the actual use. I want to cite what our critics from the FDA have
> written in the briefing document. Patients in the field might get a
> false sense of security after rectal treatment and fail to present for
> definitive treatment or therapy and may use another capsule and still
> another.
>
> This is especially difficult or, perhaps, a difficult situation if you
> consider that the diagnosis of malaria will, in a substantial part of
> the population, not be correct and they will be treated with
> artesunate for another febrile illness.
>
> Perhaps it is even a little bit more complicated than in Study 013
> because these are highly endemic countries where you have a high
> prevalence of malaria. But this may be a little bit different in other
> areas where the malaria makes only about 10 or 20 or 50 percent of all
> children which will be treated.
>
> So we have still the question which we have had already two years ago
> in our first assessment and the results, so far as we know up to now,
> of Study 013 only add a few more question marks to this question.
>
> \[Slide.\]
>
> What it not be wiser to wait for the results of Study 013 before
> taking a decision?
>
> Thank you very much.
>
> DR. RELLER: Are there any questions for Dr. Kemmler?
>
> Dr. Kemmler, would you be willing to answer some queries from the
> committee?
>
> Dr. Glodé?
>
> DR. GLODE: I just had two clarifications questions about the study
> design. I just wanted to confirm that the placebo is a true placebo.
> It is not a comparator; it is just a rectal suppository containing no
> active ingredient?
>
> DR. KEMMLER: Yes; this is a placebo-controlled study.
>
> DR. Glodé: My second question was is the study design to be
> essentially done under what would be considered to be sort of
> real-life considerations so that distance and time to getting to a
> hospital is kind of what we would be thinking about in the actual use
> of this, do you know, in those locations?
>
> DR. KEMMLER: I didn\'t totally understand the question. This is a
> real-life situation. This is given\--at least near a real-life
> situation. But, certainly, the representative of the WHO could answer
> that much clearer. As far as we understood, it is provided from a
> healthcare worker in the villages and then the child is transported to
> a healthcare facility.
>
> DR. GLODE: With distance and time delays being sort of about what one
> might anticipate if this were used widely.
>
> DR. KEMMLER: Yes.
>
> DR. GLODE: Thank you.
>
> DR. RELLER: Dr. Leggett.
>
> DR. LEGGETT: A point of clarification. On the bottom slide on Page 4,
> you state about your conclusions; is the inappropriate and possibly
> counterproductive use even in this trial so widespread that a possible
> beneficial effect of artesunate is diluted. Are you referring to the
> widespread use of counterfeit artesunate or are you talking about the
> misdiagnosis and, therefore, malaria only representing 20 percent of
> febrile illnesses or something of that\--
>
> DR. KEMMLER: I assume that the product which is distributed in this
> study is the real drug and is not a counterfeit. I mean the unlabeled
> use, the use outside the indication which has been applied for.
>
> DR. LEGGETT: So you are talking about the problem of diagnosis of
> malaria.
>
> DR. KEMMLER: Yes.
>
> DR. RELLER: Any other questions specifically for Dr. Kemmler? Dr.
> Bell?
>
> DR. BELL: You probably said this and I apologize because I missed it,
> but artesunate given in the study, is it the single dose or is it
> repeated dose?
>
> DR. KEMMLER: Single dose.
>
> DR. ARCHER: Assuming that the study goes to completion and all 10,000
> patients are enrolled, how long would you predict that it would take
> to finish the study, on the basis of how long it has taken so far?
>
> DR. KEMMLER: You should ask a representative of the WHO.
>
> DR. RELLER: With the questions specifically for Dr. Kemmler, I was
> going to\--any others? I think if someone from Dr. Gomes, others from
> the WHO, realizing this is an ongoing blinded study, No. 013, could
> you share with the committee what the design is and what the endpoints
> being monitored are and what the expected time table is.
>
> DR. O\'FALLON: Can I ask one more question? How is the drug being
> distributed \"in the bush?\" Who gets it? That isn\'t clear to me.
>
> DR. RELLER: This is what I hope we will hear with the study design.
>
> DR. O\'FALLON: That is another thing I want to hear addressed.
>
> DR. RELLER: Dr. Binka?
>
> DR. BINKA: Thank you, Mr. Chairman. I will start with the last
> question first. The drug is being distributed within the communities
> by field workers that are recruited and working with the study. This
> provides the distribution of the drug and encourages the mothers to
> apply the drug. So the mothers insert the drug and it is supervised to
> make sure that the children do not expel the rectal artesunate.
>
> So it is both a learning process for the mothers to be able to do
> that. This has been distributed within the community in the different
> settings. There has been quite some innovation in the way this is
> done.
>
> In Ghana, the distribution sometimes takes place at places where you
> have herbals. They refer these cases to the field workers. The field
> workers are working in close collaboration with the herbalist to whom
> people principally tend to refer these cases. So we are recruiting the
> patients from where we expect to find them. So that is the first one.
>
> \[Slide.\]
>
> The second one is to do with the design. As I alluded earlier on, this
> is a double-blind controlled trial. The study was designed in such a
> way that we were expecting to have approximately 10,000 patients as
> alluded in the previous presentation, but with an estimate of a
> mortality prevalence of about 5 percent.
>
> You can see from what we have shown so far in the recruitment of 3,300
> patients the mortality rate is about 3 percent.
>
> \[Slide.\]
>
> So, if you work out those figures already, we would expect that, to
> achieve the same level of difference that we expect, the original
> thinking was to have a reduction from 5 percent to 3 percent.
>
> That will quickly increase the numbers of patients that need to be
> recruited to be able to demonstrate a similar effect; I\'m sure almost
> fourfold. So we have to keep that in mind because this is just looking
> at mortality as the major endpoint.
>
> So we really have a problem with the low mortality rates that we are
> demonstrating now. That study will need to be largely expanded or to
> take a much longer time to be able to demonstrate the survival
> benefit.
>
> I just wish to remind us that this study, in the way it was designed,
> was basically trying to look at some of the personal issues. I have
> just alluded to some of them, working with people who actually see
> these patients and see how we can work with them and to find the
> results and to look at a real-life situation and address the issues of
> survival and also of toxicity.
>
> I am not sure this study will add greatly to some of the endpoints
> that were discussed today. We agree with the FDA in their submission
> that a selection of endpoints, especially mortality, is not really
> appropriate in this setting and that the most likely alternative
> endpoints are looking at its effect on both response to parasitemia
> and also the clinical responses that we are measuring in this case.
> The mortality endpoint would be very, very difficult to demonstrate.
>
> Study 013 will not provide additional information on these two
> endpoints. In some cases, we are not even taking initial blood slides
> so that we cannot compare the two.
>
> Briefly, just to look at the indication for which we requested, that
> this drug should be used, then Study 013 definitely will not be adding
> additional information to what we have already presented.
>
> DR. RELLER: Dr. Ebert?
>
> DR. EBERT: Just to confirm what you said a minute ago, are you saying
> that\--you said 74 percent of the patients were parasitemic so those
> samples are not always taken prior to therapy?
>
> DR. BINKA: No. The bulk of most of these studies, I mean the bulk of
> the patients that were recruited initially were having a blood film
> and then given treatment, and they are referred to the clinical
> facility for the final treatment. We have been trying to increase the
> numbers recently. At least in one location, some of the patients
> didn\'t have initial blood slides.
>
> DR. RELLER: Dr. Archer?
>
> DR. ARCHER: You basically said that, the mortality rate being 3
> percent instead of 5 percent, that your 10,000 patient endpoint is no
> longer appropriate, that you would have to go to two or three times
> that many patients? Is that what you are saying?
>
> DR. BINKA: What I am saying is that the initial thinking was that this
> mortality rate would be about 5 percent and the intention was possibly
> to reduce this to 2 percent. We were aware that this was an estimate
> and that the Data and Safety Monitoring Committee would review this
> very closely because nobody really knew what the estimates were.
>
> Currently, from the number of patients that we recruited, you can see
> the mortality rate is about 3 percent. Obviously, if we needed to
> demonstrate the same level of effect, then we need to increase the
> study much more, three or four times.
>
> DR. RELLER: Dr. Folb?
>
> PROFESSOR FOLB: We need to deal with two points of possible confusion
> in the last presentation, one relating to the discussion that has just
> happened. Study 013 will not address further the evidence of efficacy
> that we have presented and on which we are in agreement with the Food
> and Drug Administration.
>
> Study 013 is designed with two principal objectives. A primary
> objective is to show that in the field this drug, the efficacy of
> which has been demonstrated, will translate to a reduction in
> mortality. Our papers and our datasheet do not suggest yet that there
> will be a reduction in mortality as a result of this intervention.
>
> So we do not want the confusion that Study 013 simply adds to the body
> of evidence that we have brought before the FDA and this committee.
>
> The second point I wish to make relates to the question of
> bioequivalence.
>
> \[Slide.\]
>
> I would like to share this slide which was referred to by the Food and
> Drug Administration. Our understanding is that we are no longer at
> issue with the Food and Drug Administration regarding bioequivalence,
> that we are in agreement. We had a formulation that needed to be
> upgraded for general application once this medicine is approved.
>
> Now, that is, we had to show that Formulation F2 is equivalent in
> activity to Formulation F3. At the start, I must say that the
> artesunate content, the active principal content and the excipients,
> are identical. This is not at issue. But the content is different.
>
> We had the possibility of doing one of three things; the first was
> comparative dissolution. Clearly, that would not have impressed
> ourselves and certainly not yourselves. The second was to make a
> comparison of pharmacokinetics. We have already shown, and the Food
> and Drug Administration has drawn your attention to the fact that, for
> reasons that extend from the way this drug is assayed, the assay
> accuracy that is available to us, and the inherent variability amongst
> humans, pharmacokinetic comparison could not satisfactorily be made.
>
> We predicted that at the outset and we confirmed it. We would need to
> do thousands, if not tens of thousands, of pharmacokinetic studies to
> show equivalence. We never proposed that that would be our evidence.
>
> Pharmacoequivalence was demonstrated by us, we submit, by looking at
> therapeutic equivalence of the two formulations. This study confirms
> it. In effect, regardless of the formulation, F2 or F3, we achieved,
> in this study, 99.7 percent parasite clearance. With the two
> formulations, they were identical in effect, parasite clearance of the
> two formulations when compared with patients with moderately severe
> malaria. That is the very patients who were the target of our study.
>
> Mr. Chairman, and members of the committee, since this is likely to be
> the last time that I will have the opportunity of addressing you, I
> want to remind ourselves, the committee, that what we are hoping to
> achieve is what we have in common agreement with the Food and Drug
> Administration; that is, firstly, that intervention with this
> particular rectal artesunate in the dose that we propose
> substantially, reliably, predictably and virtually invariably reduces
> the parasite count over 24 hours to a point where it is either not
> detectable or is detectable by an order of magnitude less.
>
> We have shown the evidence and we have argued the logic behind the
> idea that such parasite response and such clinical response that
> attends it, as we have demonstrated, translates to meaningful clinical
> advantage. We could do hundreds, tens of hundreds, thousands of
> additional studies. But I do not believe, and I understand the FDA
> have not proposed otherwise\--I do not believe that that will add to
> the picture that we have put before you of efficacy for this
> particular indication and in this particular dose.
>
> With regard to toxicity, we appeal that the committee comes to the
> agreement, the joint agreement between the Food and Drug
> Administration and ourselves and even the Swiss authority that, in
> this dose, there is acceptable safety including neurotoxicity.
>
> Thank you.
>
> DR. RELLER: Dr. Archer?
>
> DR. ARCHER: I am still seriously confused.
>
> PROFESSOR FOLB: Sorry.
>
> DR. ARCHER: If Study 013 shows that there is no difference in
> mortality between placebo and rectal artesunate, doesn\'t that defeat
> the purpose for giving rectal artesunate?
>
> PROFESSOR FOLB: It means that we will not be able to make the claim
> that clinical advantage demonstrated translates in the field to
> reduction in mortality. It, in no sense\--
>
> DR. ARCHER: But isn\'t that the only reason you are doing this is to
> decrease mortality?
>
> PROFESSOR FOLB: No. Our reason for doing it is to intervene, to enable
> to the patient to get to hospital. We infer, and we hope\--
>
> DR. ARCHER: Without dying.
>
> PROFESSOR FOLB: Without dying.
>
> DR. ARCHER: That\'s mortality.
>
> PROFESSOR FOLB: That\'s mortality. We want the patient to get to
> hospital, in a situation where there is no treatment available at the
> moment
>
> DR. RELLER: Dr. Glodé?
>
> DR. GLODE: Could I ask, in Study 013, if, in a subset of patients, you
> are planning to look at secondary endpoints of clinical response and
> reduction of parasitemia because the valuable information, I think, to
> be gained that is not present now is the 56 percent of patients less
> than twelve months of age.
>
> So I don\'t think we currently have the information on reduction of
> parasitemia and clinical response in that particular young age group
> that would be relevant; is that correct?
>
> PROFESSOR FOLB: We agree. We agree that our evidence does not answer
> your question about children under the age of two. The answer to your
> question about secondary objectives is that we have, indeed, one
> secondary objective and that is the safety, in particular the
> neurotoxicity. So this is a large simple study aimed, as quickly as
> possible, to come to the additional point that we would hope to prove
> that implementation in this way translates to reduction in mortality.
>
> If we were not to demonstrate that, it in now way compromises the
> clinical evidence that we have put before you.
>
> DR. RELLER: Dr. Patterson.
>
> DR. PATTERSON: Could I ask Dr. Binka about Study 013. Do you think
> that maybe one of the reasons the mortality is lower than expected in
> the study is because there is a Hawthorne effect from the education of
> the field workers and the community in general about malaria and the
> importance of getting to the hospital?
>
> DR. BINKA: Yes; I would agree with that. This is a disease that we all
> understand kills. The way that we have designed it is not the really
> optimal way to design it. We are mindful of the fact that this disease
> kills. There is a lot of support for both those who are in the placebo
> group and the treatment group to get to the facility to get treatment.
>
> Obviously, that creates a problem to try and\--whatever estimate we
> are finding now is a clear underestimate of what we really would find
> if we were to design this in such a way that we maximize the design
> effect.
>
> DR. RELLER: Dr. Bell and then Dr. Archer again.
>
> DR. BELL: He has a quick follow up.
>
> DR. RELLER: Gordon, go ahead.
>
> DR. ARCHER: I just have a question. If this drug is approved at this
> time, would it compromise Study Trial 003 at all? That is, would
> rectal artesunate become so widely available that you couldn\'t do the
> study?
>
> PROFESSOR FOLB: Rectal artesunate, if approved, is a product of the
> World Health Organization. We have made public advertisement and
> received a number of responses from countries where the implementation
> and further implementation, contingent on the results of Study 013,
> will be done in collaboration with governments, regulatory
> authorities, communities.
>
> So we have planned\--and we are not compromising on this\--we have
> planned very strict release.
>
> DR. RELLER: Dr. Bell?
>
> DR. BELL: I want to come back again to the reasons that we would need
> this drug in the United States. I am a little confused. There are
> obviously decisions that have been made here about what type of
> indication to seek, to this agency and so on. But, again, we don\'t
> have people dying before they can get to hospital of malaria in the
> United States.
>
> What we do have is the specter of multidrug-resistant malaria imported
> from overseas for which this would, at least for some strains such as
> now found in Southeast Asia, be potentially a lifesaving drugs because
> these strains are resistant to the other approved drugs that we have
> in the United States.
>
> I am a little confused why resistance has not figured more prominently
> in this discussion as a reason for approval of the drug. Even
> overseas, the logistics of conducting the necessary trials were more
> formidable than this one. But could somebody address the use of this
> drug for treatment of multidrug-resistant malaria that would
> presumably require multiple doses?
>
> What experience is there in Thailand? Perhaps, Dr. White\--we know
> that multidrug resistance is increasing in Latin America and Africa.
> My view is that the reason we would like to have this drug in the
> armamentarium in the United States, whether in this preparation of
> some other, is because of the specter of cases of imported resistant
> malaria.
>
> Could somebody talk about the drug resistance issues.
>
> PROFESSOR WHITE: Firstly, there are two parts to your question. One
> was the question of delay. I don\'t know whether things have changed
> but when the mortality of U.S. servicemen in the Viet Nam conflict for
> malaria was compared to those who were treated in Viet Nam and those
> who had malaria when they came back, I understand the mortality was
> significantly higher in the United States. This was attributed to late
> diagnosis.
>
> So there is a delay, whether that delay is one of referral or
> diagnosis, and the result is that a higher proportion of patients
> present with severe malaria.
>
> In Thailand, as in much of Southeast Asia\--as in the adjacent
> countries, the standard recommended treatment for multidrug-resistant
> falciparum malaria is a combination of oral artesunate\--for
> uncomplicated disease is oral artesunate given for three days together
> with a split dose of mefloquine. And you don\'t have oral artesunate
> yet.
>
> DR. BELL: We don\'t have any artesunate. If a person from your area of
> Thailand were to show up in a hospital in Atlanta, we would have
> trouble because we don\'t have any artesunate here. I think that is
> the issue that needs to be brought up as well.
>
> PROFESSOR WHITE: To be fair, proguanil is effective against those
> multidrug-resistant parasites. I would like to say it wasn\'t and,
> therefore, you would have to use it.
>
> DR. RELLER: There are two times for ample discussion on not only more
> about resistance but any other relevant issue after Dr. Goldberger\'s
> charge to the committee. For proper procedure, we thank Professor
> White for his comments that were just made.
>
> Dr. Kemmler spoke on behalf of Swissmedic at the Open Public Hearing.
> Are there any other members who wish to speak in the forum of the Open
> Public Hearing, not sponsor, not committee members, but from the
> public.
>
> If not, the Open Public Hearing is closed. We will move to Dr. Mark
> Goldberger\'s charge to the committee and then Dr. Rotstein and
> others, we will open the discussion for any topic of relevance to the
> charge given us. Then there will be full and open discussion of all
> the relevant participants, a break, more discussion and then the vote
> on the questions posed to us.
>
> Mark?
>
> **Charge to the Committee**
>
> DR. GOLDBERGER: What I will do is go through the questions, make some
> comments and try to emphasize some points that we particularly would
> like you to include as you discuss these questions and issues.
>
> For the first question, the applicant has demonstrated the activity of
> artesunate by showing a decline in parasitemia over 24 hours\--it is
> just important to emphasize that we have no disagreement whatsoever to
> the fact that that has, in fact, been shown\--and a 24-hour clinical
> outcome\--we have no disagreement either with that.\--similar to that
> seen with comparator drugs of hospitalized patients with moderately
> severe malaria.
>
> Are these results sufficient to support the approval of artesunate as
> initial therapy in patients without other therapeutic alternatives. We
> have slightly modified the wording of the proposed indication from the
> WHO to, I think, reflect, at least from our perspective what, in fact,
> the actual indication would likely be.
>
> In your discussion, please include the usefulness of parasitemia as a
> measure of efficacy. One thing to keep in mind is we believe that, if
> this drug were to be approved, it would be approved under the FDA\'s
> accelerated approval regulations which allow the use of surrogate
> endpoint.
>
> Surrogate endpoints in the past have included mycobacteremia, CD4
> count, viral load and this would yet be another example. Beyond the
> issue of accelerated approval requiring you to show a benefit over
> therapies that currently exist, one would also need to have some
> evidence, or at least a suggestion, that the surrogate is likely to
> correlate with a longer-term, more durable benefit.
>
> So one thing is we would like you to at least make some comment about
> what you think about parasitemia as a surrogate. We would also like
> you to talk about the importance of recrudescence rates at Day 28 and
> issues of understand therapy. I think that one of the things, when we
> look at a surrogate, we look at issues of what is the longer-term
> endpoint.
>
> At a minimum, we think the longer-term endpoint, for instance, might
> be the status at Day 28; that is, whether the person has, in fact,
> been cured. That also raises the issue of how to integrate artesunate
> into more definitive therapy.
>
> Some issues have been raised about increased rates of recrudescence.
> We don\'t know if those are geographic, if those are specific to
> certain treatment regimens, et cetera. These issues are potentially
> important in providing advice in product labeling to physicians who
> might be using the product as to how treatment should, for instance,
> be continued.
>
> There is also the issue that has been touched upon several times of
> whether mortality is the definitive endpoint. That may certainly also
> be the case. There have been some issues about whether a mortality
> difference can be shown. I think that is something you may want to
> comment on as well as to whether that needs to be required or whether
> showing ultimately that the Day 28 recrudescence rates can be made
> similar would be sufficient.
>
> We will come back to the issue of how that might be shown in
> subsequent studies in a couple of minutes.
>
> Finally, the issue of the differences in the study population and the
> intended-use population. There has been, obviously, already a lot of
> discussion about the point. From a purely U.S. perspective, it might
> appear that use within the United States, how the drug might, in fact,
> be used, might not, in fact, be that dissimilar to the way the drug
> was, in fact, studied in hospitalized patients.
>
> People from the United States who go abroad, missionaries, Peace Corps
> workers, et cetera, obviously we be somewhat different than the way
> the drug was, in fact, studied to date in the studies that have been
> submitted to us. Obviously, there has been considerable discussion
> about the issue of how the data that has been presented to date, how
> that population compares to the actual intended-use population that
> might occur in other countries, for instance.
>
> I think that, at one level, it probably is important for you to think
> about your level of comfort as to the real intended-use population, in
> fact as stated by the WHO, and how comfortable you are that that
> represents a genuine population that has some degree of unmet need.
> You have heard a lot of discussion about Study 013. Study 013 may be
> one approach to looking at such a population but, as has been said,
> even Study 013 may not really duplicate what happens in even more
> remote settings.
>
> If your answer to the above question is no, then we would like you to
> indicate what additional information would be required to demonstrate
> sufficient evidence of efficacy.
>
> For the second question, is the safety information and safety profile
> of artesunate sufficient to support the approval of artesunate for use
> as initial therapy in patients without other therapeutic alternatives.
> In your discussion, please include the differences in the clinical
> trial and the intended patient populations, addressing the potential
> risks and benefits in the empirical use of the product for emergency
> therapy.
>
> Again, it is important to include, as has already been discussed, that
> patients without malaria will almost surely receive drug and there is
> a question as to whether patients who get the drug might be more
> likely to then not seek additional medical care if they, in fact, have
> malaria. Whether that you believe is, on balance, a significant issue
> to overcome potential benefits of the drug in terms of reducing
> parasitemia.
>
> If the answer to the above question is no, please indicate what
> additional information would be required. If the answers to Questions
> 1 and 2 are yes, please indicate if there any caveats or restrictions
> that should be included in product labeling. These can include the
> populations who should or should not receive the drug, issues about
> how many doses should be administered, issues about how definitive
> therapy might be used, any other considerations you think are
> relevant.
>
> Again, this information obviously would be important for any U.S.
> physicians prescribing the drug. It would also, we think, potentially
> be quite helpful to foreign regulators, foreign countries, perhaps
> nongovernmental organizations, et cetera, who may have involvement
> with present or future development of this product.
>
> Finally, the last question; if this product were approved under our
> Subpart H regulations\--that is, the accelerated approval regulations
> of which I spoke a few moments ago\--what additional studies would be
> required in the post-approval period?
>
> The accelerated approval regulations give us the authority to require
> additional studies be completed or performed. Unlike the normal phase
> IV postmarketing studies which are agreements reached between FDA and
> a sponsor but which FDA has no means to compel the sponsor to actually
> do.
>
> Examples of such things could be completing Study 013, providing the
> results, doing some studies with different types of definitive
> treatment regimens to understand whether there are interactions,
> pharmacodynamic or otherwise, between artesunate and other treatment
> regimens, pharmacologic, toxicologic studies or other things that you
> think are relevant to better understanding the product.
>
> We think that a number of issues potentially have already been raised
> and we think providing that type of advice would be quite helpful if,
> in fact, you advise that the drug be approved so that we can ensure
> that, over time, we have satisfactory information about the product.
>
> Thank you.
>
> **Discussion**
>
> DR. RELLER: The discussion is open and includes questions to anyone
> with potential answers.
>
> DR. ARCHER: I have a question about the questions, the charge to the
> committee. Are we just talking about single-dose, 10 milligrams per
> kilogram, artesunate? It seems to me the discussion has also included
> the availability of the preparation, itself, in all kinds of doses and
> dosage forms. Are we to limit ourselves only to\--
>
> DR. GOLDBERGER: The WHO is proposing to make two dosage forms
> available, an adult suppository and a pediatric suppository. Those
> are, in fact, therefore the subject of the discussion today. The fact
> is that these products, or at least different forms, have been
> available for some time as over-the-counter products, for instance, in
> both, I believe, Africa and Asia, is obviously an issue but not
> clearly an issue for discussion except, perhaps, as how this might
> relate to that in terms of resistance, et cetera.
>
> I think it is a legitimate issue if you wish to think about what the
> likelihood is of multiple-dose use, how much of a problem that is.
> That would potentially be germane to the discussion.
>
> But the WHO is coming forth with a proposal for artesunate for the
> suppository dosing form only in two different strengths. So that
> should be the substance of your discussion.
>
> DR. RELLER: As important as oral formulations may be, we have heard no
> data on their efficacy or safety directly.
>
> The discussion is open now. Dr. Rotstein had his hand up even before
> the discussion opened, so we will fairly turn to him first and then
> Dr. Cross and the other hands that were up.
>
> At the beginning of the meeting, we had introductions around the
> table. We did not have an opportunity for you to introduce yourself,
> so please do so now, your name and affiliation, for the record.
>
> DR. ROTSTEIN: Coleman Rotstein, MacMaster University, Hamilton,
> Ontario, Canada.
>
> DR. RELLER: Thanks.
>
> DR. ROTSTEIN: I do have a comment and then I want to try to answer one
> of the questions. The comment I have is what we are seeing around the
> table is really tremendous uneasiness with this compound. We see how
> it is being used elsewhere and then we see how it may be used, whether
> it be in the United States or whether it be in Switzerland, in two
> different types of situations.
>
> I think it is being used in young kids overseas and it is being used
> readily\--here in North America, it may be used, or, for that matter
> in Europe, it may be used totally differently. We are not exactly sure
> if it is applicable to our situation. There is uneasiness about the
> table about that, so I think we have to acknowledge that and approach
> our discussion with that sort of jaundiced view, will it be used
> appropriately here in North America.
>
> A comment about some of the questions. Usually parasitemia is really
> relevant in severe malaria and we don\'t know if this is going to work
> in severe malaria where we have more than 5 percent parasitemia. We
> have comments about moderate to severe and we know that there is a
> reduction in the parasitemia but will it really work in severe
> malaria. Some of the people we are going to see here, because of the
> delay in diagnosis that we have heard about, may actually be severe
> malaria with more than 5 percent parasitemia and we are unsure if it
> will work there.
>
> So I am unclear about that at this moment.
>
> DR. RELLER: Thank you.
>
> Dr. Cross?
>
> DR. CROSS: I think part of the issue is how will this supply of this
> drug be managed if approved. It is my understanding that the World
> Health Organization will be contracting the production of this drug to
> subcontractors. However, the control of the marketing, if you will, of
> this drug will be in the hands of the WHO as opposed to some
> independent subcontractor being responsible for the marketing and
> supply of the drug.
>
> I am just wondering whether, in fact, the WHO can confirm how the
> supply of drug will be made available and under whose aegis is it
> distributed. Is it only with the imprimatur of the WHO or will some
> other organization or manufacturer also make this available perhaps
> independently of their approval.
>
> DR. RELLER: Dr. Gomes or others, could you address this?
>
> DR. GOMES: I can address the second of the two points but, perhaps,
> Professor White will refer to the first point. The intention of the
> WHO is to control the way in which this drug will be made available
> within the malaria-endemic countries. At present, what we have done is
> commissioned all of the work\--that is the development of the active
> ingredient, the formulation into the suppository formulation\--and we
> have agreements with what is often referred to as the final tool
> manufacturer, the group that would be packaging the drug.
>
> If this drug is approved by the FDA, we would want to work with the
> company with whom we have worked\--it is a small, Danish company with
> whom we have worked for fourteen years in making multidrug therapy for
> leprosy. We have a long-standing relationship with this company. We
> would want to continue with this company to be able to control the
> manner in which the drug is made available which would be within
> countries through WHO.
>
> DR. RELLER: I can\'t remember who was first up here. There were three
> hands at once. Let\'s just go down the line. Dr. Parise?
>
> DR. PARISE: I have sort of a related question. It may be to the FDA.
> The rectal formulation today, how would that affect the ability in the
> United States, say, for an IV formulation of this later? Would that
> have to also be covered under the agreement with WHO? Would other
> companies be able to develop that?
>
> DR. GOLDBERGER: That should have no impact. I don\'t believe that that
> would have an impact. Certainly not for treatment of malaria which is
> a very different indication. I am not even sure that it would have an
> impact for the identical incidence such as this because\--I would have
> to go back and look at the details of orphan-drug exclusivity but,
> practically speaking, clearly this is a different indication than
> treatment of malaria and, in fact, it is a different indication even
> than prevention of malaria.
>
> So I don\'t think, actually, it would have a major impact except for
> another, perhaps, suppository dosing form for a similar situation.
> That seems, frankly, to be pretty unlikely.
>
> PROFESSOR WHITE: I wanted to talk to Dr. Rotstein\'s question, if that
> is possible. Dr. Rotstein was uneasy. I wanted to try and make him
> easy. You said would it work in severe malaria.
>
> \[Slide.\]
>
> This is the slide that Professor Folb showed. This is cumulatively by
> far and away the largest treatment experience in severe malaria. It is
> the individual patient overview from 1,900 patients, half of whom
> received artemether.
>
> In the prospectively defined group of adults in Southeast Asia,
> artemether was associated with a significant reduction in mortality.
> Although the overview of all patients the p was 0.08, in the
> prospectively defined subgroup of adults from Southeast Asia, it was
> significantly better.
>
> \[Slide.\]
>
> Artemether has a much inferior pharmacokinetic profile to either
> rectal artesunate or parenteral artesunate. So we would maintain
> strongly that this drug would work in severe malaria. If the
> ingredient gets into the blood, then it would work.
>
> DR. ARCHER: I have two questions that you may be able to answer. In
> the briefing document, there is some in vitro data about antagonism
> between these drugs and other antimalarials. I wonder if there is any
> clinical evidence of that.
>
> And then, secondly\--if you can remember the second question\--the
> recrudescence problem; would it be safe to assume that recrudescence
> is related to the shorter half-life of this drug compared to quinine,
> for instance?
>
> PROFESSOR WHITE: Yes. There are a lot of papers published in synergy
> and antagonism of antimalarial drugs. They usually refer to slight
> bowings of the isobologram. There is no evidence at all from the a
> clinical impact of these. In fact, the only clinically important
> synergy that occurs with antimalarial drugs is the synergy between the
> antifolates and the sulfalomides, which sulfadoxine/pyrimethamine
> exploits. But there is no evidence for either faster
> parasite-clearance time when you have a synergistic drug or a slower
> parasite-clearance time when you have an apparently antagonistic drug.
> To be quite frank, the degree of synergy and antagonism is very mild.
>
> Thank you very much for the second one because we have rehearsed, that
> is the question of recrudescences.
>
> \[Slide.\]
>
> I would like to congratulate the statistician because I thought it was
> a very beautiful analysis and it illustrates a very clear scientific
> point. The short answer is yes, but may I take a few minutes to say
> why?
>
> Here is the paradigm. What happens is that if you give a single dose
> of drug, of artemisinin, you will have a very profound effect on the
> parasitemia. But it is such a short half-life drug that, if you don\'t
> give any more, then you don\'t have any further reduction. You have to
> keep maintaining that. You have to maintain the presence of the drug
> until all the parasites have been eliminated from the body.
>
> With a slowly eliminated drug, of course, the plasma concentrations
> persist and you have antimalarial effect persists. But, for a rapidly
> eliminated drug, it has to be present until all the parasites have
> gone which means seven days in an autoimmune individual.
>
> So this illustrates the point that the longer you give the drug, and
> this applies to both the artemisian derivatives and quinine, which is
> still a rapidly eliminated drug but much slower. That is of relevance.
> That explains beautifully, I think, the Malawi findings.
>
> So, the longer you give the drug, the greater the opportunity you have
> of suppressing parasitemia to cure and the longer it takes if you
> don\'t cure the patient for recrudescence.
>
> \[Slide.\]
>
> So if we remember these worrying\--or at least they worried you\--the
> results from Malawi and we had a much higher recrudescence rate in the
> children who received this single dose of artesunate, followed, then,
> by, effectively, an ineffective drug, sulfadoxine/pyrimethamine.
>
> So the treatment response relied very much on the first drug,
> artesunate versus quinine. Now, the mean dose of quinine is four
> doses. Quinine has a terminal elimination half-life in malaria of
> about sixteen hours. So we would estimate that you would have
> antimalarial activity in the blood for at least 48 hours after the
> last dose of quinine.
>
> \[Slide.\]
>
> Now, quinine actually kills more slowly but it is present for an extra
> cycle. So the net result is better and, in some cases, where you have
> good background immunity\--these were semiimmune children\--you will
> cure. If you do have recrudescence, it will occur later on.
>
> So what we were seeing with the Malawi studies is a better
> contribution from a less effective drug simply because it is present
> for longer in the blood. So the true comparator would have been to
> give artesunate for the same number of cycles. Artesunate only
> affected one cycle. Quinine affected two or possibly three cycles.
>
> Finally, you showed very beautifully how the difference was most
> evident at seven and 14 days. By Day 28, in Malawi, which is a
> high-transmission setting, had a lot of reinfections confounding the
> issue. So you had a combination by Day 28\--of course, there was no
> genotyping done in that study to distinguish it\--of reinfections
> which would have been equally distributed amongst the two groups, plus
> recrudescences which were more in the artesunate group because only a
> single dose was given.
>
> DR. RELLER: Dr. Bell?
>
> DR. BELL: I have two questions, also. One is I would like to be sure I
> understand clearly what is known about the safety of repeated dosing
> of artesunate in any form, rectal followed by oral. Is it just that
> there is limited information to assess that it is safe or not or is it
> that we actually have reason to believe that it is harmful. That is
> one question.
>
> I know that is not the indication that is being sought, but Study 005
> in Thailand was repeated dose of artesunate although the subsequent
> doses were oral. Just in general, repeated dosing.
>
> PROFESSOR WHITE: Humans and then animals. In man, we use artesunate.
> Artesunate is standard treatment now in the multidrug-resistant areas.
> It is given either\--preferably in a combination with another
> antimalarial drug over three days or, in the case of reduction
> infections, it is given for seven days. People have multiple courses.
>
> Professor Folb showed you in those studies where patients were
> selected for having had multiple courses and matched with controls
> from the same community who had not had artesunate. There was no
> evidence, either clinically, audiometrically or, in terms of
> auditory-evoked potentials, there were no detectable abnormalities.
>
> The animal data that we have presented for artesunate shows that you
> need absolutely enormous doses to produce anything given by any route
>
> \[Slide.\]
>
> In fact, I think you brought it out very nicely in your presentations
> on toxicity that, basically, the problem appears, which was discovered
> initially by Dr. Berne and his colleagues, is related to artemether or
> artemether given intramuscularly because these provide a sustained
> concentration throughout the 24-hour dose interval.
>
> Whereas, give the same drug orally, which has a much more rapid
> absorption and elimination and is much less neurotoxic, if you want to
> make the oral drug neurotoxic, you can do so by providing a
> plasma-concentration profile that approximates the intramuscular
> injection by giving it constantly with food.
>
> So, if you coat food pellets with artemether, it becomes neurotoxic
> because the animal is eating it all the time and has a constant
> exposure. But, for artesunate given in any way, considerably, about
> six times, less neurotoxic.
>
> I don\'t know if that answers what you\--
>
> DR. BELL: I guess what I think I am concluding is that, although there
> is some reason to be concerned about neurotoxicity and we would like
> to have more evidence to assess how common this is, based on the
> evidence we have, at least in people, it is not a significant problem.
>
> PROFESSOR WHITE: We just simply haven\'t been able to find any. We
> don\'t know how else to look. We thought that auditory-evoked
> potentials would be about the best way to bring out any abnormality.
> There is not a single documented case of plausible neurotoxicity in
> man.
>
> DR. BELL: I have another question, but if somebody else wants to\--
>
> PROFESSOR WHITE: In fact, I will just say that they are just
> remarkably safe antimalarial drugs when you compare them with all the
> others.
>
> DR. BELL: I will pose my other question and then the Chair could
> decide if it should be postponed. I am a little confused when the
> discussion goes around to how this drug will be used in actual
> practice overseas. The FDA\'s responsibility is for how it will be
> used here. I am not sure how much it is relevant to FDA approval for
> use in this country, how it will be used in the field overseas. To me,
> that is more of a WHO issue and the local governments there.
>
> But I would like to ask WHO, because I am not sure I quite got an
> answer this morning, how important is FDA\'s approval for WHO\'s plans
> for malaria control overseas for FDA\'s approval of this indication in
> the United States. Maybe more specifically, what will be WHO\'s future
> course of action in terms of distributing this drug if FDA approves it
> for use in the U.S. or not?
>
> DR. RELLER: Dr. Folb?
>
> PROFESSOR FOLB: Our original purpose in approaching the Food and Drug
> Administration was to achieve the highest possible level that we could
> think of of review of our proposal. The Food and Drug Administration
> has a record and a commitment to public health that goes beyond the
> United States of America.
>
> It was to that that we appealed and to which the Food and Drug
> Administration responded. It was important to us, but I do want to
> make it clear that we do not have in our minds that this drug, as
> proposed by ourselves, will be used differently in the United States
> or by United States citizens outside the United States to that which
> we propose in developing countries.
>
> We believe that it needs to be used well and precisely and with the
> same kind of information support and package. That is inherent in our
> plans and we are quite committed to it. All the countries we work with
> know that.
>
> What was the reason for the importance of the Food and Drug
> Administration approval of this application. Firstly, it is clear that
> that will unlock, for any number of countries, the regulatory process
> in their countries. The importance of the Food and Drug Administration
> is important. This will enable us rapidly and appropriately to move to
> a public-health need that goes beyond the United States.
>
> Secondly, we have worked and will continue to work very closely in
> this regard with UNICEF, the United Nations Children\'s Fund, and with
> the World Bank and other United Nations organizations. It is
> remarkably important to them that the Food and Drug Administration
> should concur with our view that this is effective, safe and of good
> quality.
>
> That has been our purpose in coming to the Food and Drug
> Administration, or rather those have been our purposes.
>
> DR. RELLER: Dr. O\'Fallon had a question earlier.
>
> DR. O\'FALLON: I thought we were going to do toxicity later, but we
> keep getting back and forth, so now we are there. What is bothering me
> a great deal is the lack of information about toxicity profile in
> children.
>
> We are being told that in Study 013 roughly half, like slightly over
> half, of the people enrolled in that study are under the age of five
> and we have, just really basically, a handful of children in these
> other studies that have any kind of neurotoxicity evaluation according
> to the information that was put out for us, eight in one study, for
> example.
>
> I believe that the new regulations for the FDA, when it comes to
> putting in an indication or labeling indications, there is much more
> information needed in the very young children. But it isn\'t just
> enough to be treating them like this and looking for mortality.
>
> I think we really do need to see some information, some real toxicity
> data, about these children and how they are reacting to this drug
> since they are going to be the prime target, apparently, for this
> treatment.
>
> DR. RELLER: Dr. Sumaya, Wald and Poretz.
>
> DR. ARCHER: No one answered that question. Are they monitoring
> neurotoxicity in that study in these young children, in Study 013? Is
> anybody looking at neurotoxicity?
>
> DR. RELLER: It was on the list but the details of how it is being
> looked for, we could use further exposition.
>
> DR. SUMAYA: My concern is as those of Dr. O\'Fallon. She mentioned
> more toxicity. I am very unclear in my bias is completely insufficient
> data on the efficacy of the drug as it is being proposed in young
> children again. Being a prime target, I would want to know where the
> WHO stands on do they feel they have sufficient data at this point
> and, if not, what is going to be done about that, in young children.
>
> DR. ARCHER: Just as another comment related to this, in that Study
> 013, the children are getting 100 milligrams, not a milligrams per
> kilogram dose as I saw the slide. So, in small kids, that is going to
> be more than 10 milligrams per kilogram. So the toxicity might be
> greater; is that correct?
>
> DR. RELLER: Dr. Gomes and then Professor White will address these
> questions. We have got several waiting in the wings. Go ahead.
>
> DR. GOMES: To answer the question on the follow up in relation to
> neurotoxicity, specifically in Study 013 and in general, as Professor
> Binka would have indicated earlier, this is an ongoing study with an
> intended recruitment of about 10,000 patients initially on the
> expectation that there would be about 5 percent mortality.
>
> \[Slide.\]
>
> The current recruitment is much greater than the safety update we
> showed you earlier for 3,366 patients. The main endpoints are whether
> or not there is a survival benefit and whether or not there are
> serious neurological sequelae.
>
> Every single child is monitored between 7 and 30 days for the second
> or the first endpoint. So every single child would be seen with a
> case-record form to see whether there are new behavioral changes with
> a series of events that are predictable from the preclinical studies.
>
> In one of those study areas that is Ghana where more than 1,000
> patients have already been recruited and where a lot of the
> patients\--in fact, I think it was Dr. Kemmler that indicated that
> half of the patients are in children under the age of 24
> months\--there is a very specific study which is full neurological
> monitoring of those children.
>
> All of the children would be followed up by a clinician and fully
> examined for potential neurotoxic effects. So we are as serious as one
> can possibly be in attempting to follow up every human being that has
> been exposed to this drug in a proper and coherent and systematic way
> so that we can understand, ourselves, what, if any, are the safety
> considerations associated with this drug.
>
> This will continue until that trial is terminated.
>
> PROFESSOR WHITE: Regarding children and neurotoxicity, the artesunate
> in combination with mefloquine has been the standard treatment for
> falciparum malaria in the community in which we work on the
> northwestern border of Thailand. It is about 120,000 people. It has
> been used since 1994. It is used in all ages and in all the studies
> which we have had before you, there is no relationship at all between
> age and parasite-clearance measures.
>
> So there is no suggestion that parasite clearance, or parasite
> reduction, starts to slow down when you get younger. The two studies
> that Professor Folb presented to you were case-controlled studies
> where, as I explained, cases who had had multiple exposures were
> compared with controls.
>
> At the time they were studied, they had had multiple episodes of
> exposure. Now, both these were conducted in low-transmission areas,
> one in Viet Nam and one in Thailand. Now, the first exposures were
> often when they were very young. It would be possible to go back to
> those data and identify, I think, precisely at what age they were
> exposed. But, by the time you have had four or five courses, you are
> often five-years old. That is when the study was done
>
> So you have it logged at five-year olds. But, actually, the exposures
> were much younger.
>
> DR. RELLER: Dr. Wald.
>
> DR. WALD: It just strikes me as a little bit unusual that the FDA did
> not either have the opportunity or take the opportunity to review the
> raw data on any of these studies. Is that unusual and will there be an
> opportunity to do so and would that be something that we would want to
> happen?
>
> DR. GOLDBERGER: The raw data in which of the studies?
>
> DR. WALD: In general, when industry presents data, the FDA reviews the
> raw data.
>
> DR. GOLDBERGER: We reviewed the raw data from multiple clinical trials
> that the applicant submitted. I think Dr. Sacks and Dr. Johann-Liang
> went through a whole bunch of studies, as many as thirteen studies,
> all of which the raw data was reviewed from.
>
> In addition, the applicant presented, in essence, I believe, a summary
> of the literature to support additional safety. That is not something
> that they necessarily would have to produce the raw data. They may
> not, in fact, have access to it so that I think, as, in particular,
> Dr. Johann-Liang spoke about that issue, I think she made the point
> very clearly that we, in fact, did not have the opportunity to review
> the raw data.
>
> That would be entirely dependent on the applicant being able to submit
> that information. In general, unless an application is
> literature-based, which occasionally occurs, and in which sometimes
> the raw data is made available, the best that one does with the
> additional information from the literature is that it represents some
> level of support to the actual clinical trials that were conducted and
> whose data was submitted in detail.
>
> So I think that, in this case, there was a large safety review. I
> think that, realistically, the best that can be done with it is the
> issue that it may represent some level of support beyond the
> controlled clinical trials that were reviewed in more detail.
>
> This issue is slightly more confused by the fact that, as was
> mentioned, with regards, again, to the safety analysis, there is a
> question about the differential degrees of potency of preparations
> that were used in these different studies. That, of course, can lead
> to problems in drawing conclusions even if you had access to a certain
> amount of the raw data about what one could conclude about safety.
>
> That is the best answer we could give you. The application came with
> what would be described as probably the lower limit of what one would
> normally expect in terms of actual safety data from controlled
> clinical trials that were submitted in detail; in other words, in
> terms of the number of patients that one might expect and then
> supported by this additional information.
>
> But they had somewhere close to 500 patients. That is probably about
> the lower limit of what we would normally expect to see. Again, it is
> important to keep in mind that how one looks at all this depends
> ultimately on the seriousness of the underlying disease, the expected
> benefit from the product and the availability of alternatives.
>
> That was a point I made during the charge to the committee. At some
> level, in making your determinations, you have to decide on your level
> of comfort with the construct that WHO has put before you of a group
> of patients, a substantial group of patients, out in very remote
> situations who, at a high risk of acquiring malaria which may manifest
> itself with fairly significant clinical manifestations, who do not
> have access to parenteral therapy and who are not able to take oral,
> and that there is this population who would benefit from a dose of
> therapy that would allow them to get to a place where they could get
> more definitive therapy and that the benefits of the therapy would not
> be outweighed, either by patients not deciding to continue to some
> other health center or by the fact that some of these patients won\'t
> have malaria.
>
> At some level, you need to be comfortable with that construct, I
> believe, is sort of part of your deliberations.
>
> DR. RELLER: Dr. Poretz.
>
> DR. PORETZ: Aside from these studies, I know in some countries this
> drug and similar drugs are commercially available. I have had patients
> who come to my office with these medications. I have no experience
> with it myself. Certainly, through the years, as these drugs have been
> available, there must be Americans and other individuals who have had
> access to these drugs.
>
> Did they abuse it? Did they take a dose when they were sick, when they
> were in the Peace Corps somewhere in the bush and felt so well that
> they didn\'t seek further medical care? Did they take another dose?
> Surely, this has to be experience of our own population, of our own
> people, who have had access to their drugs. Does anyone know?
>
> DR. PARISE: I have talked to some of these people on the phone. They
> usually have not take a rectal formulation. My experience in talking
> to various physicians or patients it the it varies how many doses they
> take. I have the impression that they usually take as many as they
> were given, often five-days\' worth or so. But that is just a general
> impression.
>
> DR. RELLER: Dr. Ramirez?
>
> DR. RAMIREZ: I have several issues regarding resistance because, in
> this committee, we always discuss the antimicrobial but we also
> discuss how the antimicrobial is going to be used. We mentioned that
> antimicrobial, for a single patient, may be a lifesaving antimicrobial
> but, from the public health, may develop a serious problem if this
> antimicrobial develop a resistance for a particular organism.
>
> I still concerned with the possibility of the misuse of the drug and
> the development of resistance. It was mentioned during the
> presentation this morning that, in several African countries, 90
> percent of these children die at home with fevers, seizures, and they
> die at home.
>
> I wonder if having one dose of this medication, we are going to have
> still 90 percent that are going to die at home with one drug of the
> medication. Why is it going to make the mother travel the ten
> kilometers to see a doctor, having suppository or not having a
> suppository? This, to me, is a big issue because otherwise you are
> going to have a mother with a suppository and I can see a mother
> giving a suppository, the patient was in a coma, today is awake.
>
> Tomorrow, the mother is going to use this suppository for whatever,
> for headaches, for any form of fever because the suppository works. It
> was already mentioned here that if we want to develop resistance,
> overuse of the medication, use of the medication basically without the
> right indication, use of a low dose of the medication when the patient
> has the right indication.
>
> Besides this, I would like to ask the FDA if when we discuss here
> drugs, even when we discussed recently aseptic drugs that was for
> severe asepsis, we are concerned if physicians were going to use the
> drug in patients with sepsis that was not severe sepsis. There was
> this idea that this drug should be only for some specialists to use.
>
> I still have a difficult time to approve a drug that is going to be
> given by a mother. Or, I am twenty-years old. I am working in the bush
> or working and I put my suppository\--I don\'t have any more fever. I
> feel better. Why I am going to travel 10 kilometers?
>
> It is difficult for me not to separate how the drug is going to be
> used in real life with the approval of the drug. If we are assuming
> that this drug is active against even the resistant organisms, then
> are we setting the standard for developing resistance to this family
> of drugs because of misuse of the medication?
>
> Should we be concerned with these issues when we are discussing
> approval? I can say, well, the drug is effective. The drug is not
> toxic. But I may still not want to approve the drug.
>
> Do I set any standard to myself that tomorrow the company is going to
> come here, is going to say, \"I have these great antibiotics that work
> for all these respiratory infections and it is going to be given in
> the pharmacy without prescription.\" I would have a problem with this.
>
> And I don\'t say that the drug is good and I don\'t say that the drug
> can be used. And I don\'t say that it is perfect for this situation
> where the drug has been looked at for these countries in Africa. I
> totally agree with this approach, but, do we set a standard of
> approval with the actual use that is going to be developed? I see
> development of resistance coming.
>
> DR. GOLDBERGER: It sounds like some other people want to comment on
> this as well. As a general rule, we certainly think it is appropriate
> for the committee to comment on how a drug might be used in practice
> if they believe that that is going to be much different than how the
> drug was studied because that sometimes raises different risk/benefit
> issues.
>
> The issue here is, perhaps, a little more subtle and that is as you
> have talked about it, whether a patient will travel 10 kilometers, the
> mother giving the dose, et cetera. That, actually, really applies to
> the use in other countries really apart from how it might be used in
> the U.S. and probably how it might be used even by and large in U.S.
> citizens outside the country.
>
> So, on one hand, as someone asked earlier or commented earlier, there
> is the issue of should you just be limited in terms of thinking how
> the drug is going to be used for the U.S. indication, et cetera. I
> think that, strictly speaking, you could certainly limit your
> deliberations to that.
>
> However, as was mentioned a few minutes ago by Dr. Folb, there is a
> belief or an expectation that decision that is made by the FDA will
> impact upon the availability and use of the product potentially in
> many other countries. Therefore, although you are certainly not
> required to do so, I think, if you choose, it is reasonable to take
> into account some of the concerns that might exist about the use in
> other countries recognizing that your decision is likely to have an
> impact on that.
>
> We are not required to do that, but it is certainly something that you
> could consider and, in the past, advisory committees in various
> situations have elected to look at issues more broadly than
> specifically the FDA, itself, might.
>
> DR. RAMIREZ: Then, with this thought process that if you have to take
> an early disease to prevent mortality, why not approve an oral to give
> to mothers and they can give an oral medication for these 24 hours,
> and we can approve the rectal and the oral and whatever. It is going
> to be one medication after another for the mother to have in the
> cabinet as soon as they live 10 kilometers from the hospital.
>
> I have a problem to add this as a need because I also agree with Dr.
> Bell. Are we approving a drug for five patients that we may have in
> one year? As he mentioned, probably that everybody that goes from the
> United States to any one of these places taking the prophylaxis is not
> going to need the rectal suppository at any point.
>
> It is a challenge. It is a different type of meeting than our standard
> meeting.
>
> DR. RELLER: Thank you.
>
> Dr. Ebert, Patterson, Leggett and Parise.
>
> DR. EBERT: This is actually a very related question for Dr.
> Goldberger, trying to narrow down, perhaps, or maybe broaden the
> questions that are posed to us. I noticed in all the phrasing of all
> the questions the term \"initial therapy\" is used, or initial therapy
> when there are not other therapeutic alternatives.
>
> Should we, as a group, conclude from that that you mean as a single
> dose for initial therapy are is there also the potential that if this
> is a patient who is at a very remote location that there might be a
> possibility of two days of therapy, three days of therapy, if that
> patient doesn\'t have access to other care or are we restricted to a
> single dose.
>
> DR. GOLDBERGER: You should include that issue in your deliberations.
> You will notice, for instance, Question 3, in fact, deals with the
> issue, for instance, are there any caveats or restrictions if you
> believe the drug ought to be approved.
>
> One may be that it needs to be limited to, for instance, a single
> dose. That is our understanding of how the drug would, in fact,
> ideally be used. One thing that you may wish to get clarification from
> the WHO is the approaches, for instance, for the situations where they
> will be providing drug as to how they will try to ensure that it is
> used as it is intended to be used.
>
> With regards to U.S. use, I think that the normal approaches are, in
> fact, to, at a minimum, include information in product labeling about
> how the drug ought to be used. How effective that sometimes is is
> limited although, in truth, for internal U.S. use, not for travelers
> leaving the country, the likelihood of substantial abuse of this drug,
> given the amount of cases of malaria and the cases that it would used
> in are probably fairly sick people, the risks of substantial abuse are
> fairly low.
>
> Issues about how the drug might be employed for people leaving the
> country to travel to remote areas, Peace Corps, missionaries, are a
> little more complex. Obviously, having clear information and labeling
> about this would, at a minimum, be very important in terms of dealing
> with that.
>
> DR. PATTERSON: Just with regard to the issue of self-treatment that
> you were discussing, we already have recommendations for
> self-treatment for U.S. travelers, Peace Corps workers, for this
> disease because of the rapidity with which it kills and because of
> where the disease occurs which is in the field where you don\'t have
> access to medical care.
>
> It just seems to me that what we are considering is facilitating this
> recommendation to the communities in developing countries where the
> mother would be administering the medicine instead of the self. But I
> also wondered a question for WHO is that, with regard to issue of the
> concern for resistance and recrudescence, has there been a
> consideration for when this drug is distributed as a single dose,
> distributing with it a dose pack for continuation of follow-up therapy
> of whatever the standard of care is in the community? Could it be
> distributed as a multidose pack?
>
> DR. GOMES: The current sense that you have in relation to the
> follow-up treatment is one that we share. We, as Professor Binka would
> have indicated to you, are wanting to have a phase of controlled
> deployment one of which will be potentially using the drug or making
> it available with the follow-up treatment.
>
> There is a risk and a benefit associated with that. On the one hand,
> you want to encourage proper use. You essentially provide an
> antimalarial that can have a substantial effect and you want to refer
> people to a point at which you have definitive treatment.
>
> So you don\'t want to encourage a position in which that referral
> process does not occur. By making available the follow-up treatment,
> and we would have found, and you would have seen from that data, a
> substantial proportion of children return, or patients return, to per
> os status within 24 hours.
>
> Clearly, the need for going to a hospital declines the longer it
> takes. So it is this balance that we have in our minds in attempting
> to want to ensure that people actually get to a hospital for referral
> treatment and yet accommodating reality to the extent that we know
> that many people, if they return to per os status, won\'t actually go
> that far.
>
> It is this balance that we need to get a better understanding of in
> the next controlled phase and ensure that we get and optimize the use
> of the drug as much as possible, firstly restricting its use to the
> narrow indication and, secondly, providing the follow-up treatment
> where there really is no alternative to that.
>
> Peter, did you want to make an additional comment?
>
> PROFESSOR FOLB: I think WHO should deal with the question as to
> whether this is self-prescribed or to be prescribed by mothers. That
> is, indeed, a decision that would be taken by the regulatory authority
> of the national government of each country and they will differ
> between countries.
>
> It would be in the decision of the different countries. Our proposal
> to the Food and Drug Administration and for the United States is that
> this should be a scheduled medicine to be prescribed by a physician.
>
> DR. PARISE: I wanted to make a couple of comments. First, as far as
> the drug-pressure and drug-resistance issue, it is my impression that,
> as combination therapy, if sources become available and there is a way
> to pay for this drug, as that moves out in Africa and other places, my
> guess is the drug pressure caused by this indication is not going to
> be that much compared to how much use there may be of other forms like
> oral artesunate in combination with other drugs.
>
> I thought that the FDA raised quite a few safety concerns that concern
> me. My feeling is that, if the results of Study 013 were available, I
> think that would be an important consideration because that would
> switch the risk/benefit quite a bit, I think.
>
> As far as use in the U.S., I think, if this is approved, there will
> be\--I am almost certain there will be off-label use, there will be
> multiple dosing. We want to have some good mechanism to be able to get
> a handle on how safe that is.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: I guess I had two points, one with respect to resistance.
> The lessons from cancer and from HIV and from malaria, itself, have
> taught that multidrug intervention helps to protect against the
> emergence of resistance. If this strategy is to go in early, why not
> go in early with two agents instead of one. I wonder what the thinking
> is on that from the WHO.
>
> The second question is whether there are any data at all relating to
> this indication from non-immune patients.
>
> DR. RELLER: Professor White?
>
> PROFESSOR WHITE: We do agree that multidrug treatment is the way
> forward in malaria. The consolidation treatment, as it is termed here,
> would not be with an artemisinin derivative alone. It would ideally be
> with a combination. Of course, it depends on what is approved in the
> individual countries.
>
> I assume that we are not worried about resistance developing outside
> the endemic areas. So the idea would be that there would be a
> consolidation treatment with, ideally, an artemisinin-based
> combination so the parasites would not be exposed to artemisinin
> alone.
>
> DR. SHAPIRO: Why not ensure that by including two drugs in the
> suppository?
>
> PROFESSOR WHITE: By putting both in the same suppository?
>
> DR. SHAPIRO: Yes.
>
> PROFESSOR WHITE: It is an interesting approach. It is that the rectal
> route hasn\'t been particularly easy for the other antimalarial drugs.
> There is a rectal formulation of chloroquine, but chloroquine is no
> longer very useful.
>
> There is some evidence, and some studies, with quinine. But quinine is
> quite irritant. So I think there might be a difficulty choosing which
> drug. So our approach at the moment is to try very much to ensure that
> the follow-up treatment is adequate and that treatment will be ideally
> the combination preparation.
>
> DR. RELLER: Study 013 had what seemed to me to be impressive
> proportion of patients with confirmed malaria, 76 percent. Given,
> particularly in younger children, the difficult clinical distinction
> early on and a nearly impossible dilemma, I would think\--this is not
> chicken pox\--but for a parent to recognize malaria versus some
> mimicker at eighteen months.
>
> So I have a question about what is the effect of, used ideally, a
> single stopgap, potentially life-saving, measure of single-dose rectal
> artesunate on the ability, if is done what all would to see
> happen\--that is, get to healthcare\--what does it do to the objective
> diagnosis which is so much easier for malaria than it is for the
> mimickers.
>
> I mean, there is more capacity to diagnose malaria in impoverished
> places than there are the other things that can also be lethal, like
> the four known patients with bacterial meningitis and who knows in the
> vast number who die at home before even entering into Study 013 or any
> other study.
>
> So what is the effect of a single dose of rectal artesunate on the
> ability to make a diagnosis when somebody reaches healthcare?
>
> PROFESSOR WHITE: That is a good question. I forgot the second part of
> Dr. Shapiro\'s question and that is simply answered because the
> patients in Thailand are relatively nonhuman. They have the EIR. There
> is now about 0.3 and there is very little background immunity,
> particularly in the under-10. So I think that population would be
> equivalent to an expatriate population.
>
> It is a very good point that you raise. The advantage of these drugs
> in producing rapid parasite clearance is potentially a disadvantage in
> that, then, the parasitemia may go below the level of detection by
> microscopy.
>
> But, fortunately, there may be an answer to that and that is we hope
> increasingly that malaria diagnosis will also be possible by dip stick
> which is apparently about 50 cents. So the dip sticks, which are based
> on HRP2, remain positive for considerably longer than the parasitemia
> because of the very slow clearance of HRP2.
>
> So, in Viet Nam, where there is a lot of community use of artesunate,
> we are seeing patients admitted late with negative parasitemias, the
> dip sticks remain strongly positive. Of course, that depends on
> dip-stick availability, but there is as general move to try and
> improve the distribution to rural areas of dipstick diagnosis.
>
> DR. RELLER: Another question that I had, while you are at the podium,
> is a couple of people have mentioned, from diverse backgrounds, about
> comments on questioning the appropriateness of mortality as an
> endpoint.
>
> In your persuasive presentation, you emphasized the rapid road to
> death when the parasitemia reached, with the amplification, more than
> logrithmically. If the principal use of the single rectal dose of
> artesunate is to keep people alive long enough to get a potentially
> definitive diagnosis, or at least definitive treatment based on a
> clinical algorithm of some sort, why is it so difficult, and why is it
> even inappropriate in the only placebo-controlled trial that we have
> heard about, Study 013, to demonstrate what, at the outset of the
> presentation, was principal reason for considering approval of the
> drug?
>
> PROFESSOR WHITE: Do you mean why has it been so difficult to prove
> that this drug saves lives?
>
> DR. RELLER: Yes. There is a little bit of sort of an impossible
> dilemma here. In fact, there are two, to me, major concerns from a
> big-picture perspective. One is that where this is likely to have the
> greatest effect in saving human lives is in very young children, under
> two, the very group for which we have next-to-nil data, eight
> patients.
>
> Appropriately, there is no intention in the request, in labeling, to
> use it under age two because the data are not there; correct? But, in
> fact, knowing what the clinical epidemiologic realities are, this is
> potentially, whether it is off-label or after Study 013 where it may
> have the greatest effectiveness, indeed there is some evidence to
> suggest that that may be the case in that 56 percent of the patients
> enrolled in Study 013 are under age two years, as I recall, if I have
> got my numbers straight.
>
> The second sort of global concern was that what is presented, whatever
> its merits, is quite different from the actual intended use that was
> emphasized in the presentation by Dr. Kemmler.
>
> Now, given that, Study 013 sort of moved closer to intended use but
> still was pretty controlled; that is, field workers, village\--I mean,
> some\--and, as a consequence, it was stated that the reason that the
> mortality was not as great as what one would have expected in actual
> use, is because this was a semi-supervised, if not actual in-hospital
> treatment, at least supervised therapy.
>
> It wasn\'t just putting out an educational effort to mothers, many of
> whom have not had the advantage of much education. In other words, the
> mortality is down but the flip side is that the opportunity to assess
> more rigorously safety is there. So you sort of have a dilemma.
>
> If you put it in the real world where it is going to have the greatest
> use, we have got the greatest concerns about safety because it is
> almost like making it an over-the-counter drug except that it is not
> sold, it is distributed.
>
> So one has this dilemma of greatest effect, greatest evidence for
> efficacy, would be placebo-controlled with an unequivocal endpoint and
> what at real purpose is to save children to enable definitive
> treatment.
>
> So why have people raised the question of\--not that you would go on
> and children would die unnecessarily, but that you would stop as soon
> as there was a definitive answer that, in fact, it did save lives
> which is the whole intent of your presentation in the first place.
>
> Is that clear enough?
>
> PROFESSOR WHITE: Yes. We have a response to that and then a plan for
> the future. So the response to that is that, as you quite rightly say,
> you inevitably perturb the system by studying it. We could not
> ethically start studies in a life-threatening disease in patients who
> had a high mortality. So that is why the studies are presented in an
> intermediate risk group rather than in severe malaria.
>
> Study 013 has had 99 deaths. The Data and Safety Monitoring Committee
> want to go on to their three standard deviations between the two
> groups. That is what they say and that is what they have done in
> other\--for example, ISIS 2, the pivotal myocardial-infarction
> intervention\--and that to provide absolutely unequivocal evidence.
>
> With 99 deaths, we know there is some way to go. There may be a huge
> effect. But I think it is probably premature to say that at this
> stage.
>
> So it may not be too difficult to show this difference. It is in their
> hands and it is not in ours.
>
> DR. RELLER: Do you think in the context of Study 013 that, from your
> scientific clinical perspective, that, for the purpose intended in
> this study that mortality is a legitimate endpoint?.
>
> PROFESSOR WHITE: I think it is legitimate endpoint but this is not a
> phase IV study. We are testing an approach of which the rectal
> artesunate is a component. If we don\'t show a difference, it may not
> mean that rectal artesunate isn\'t a life-saving drug. It may just
> mean that that approach needs modifying.
>
> So we are testing an approach in a situation where healthcare is
> imperfect. Of course, if you are present in a place where healthcare
> is imperfect, it is very difficult not to intervene and make
> healthcare better. So it has been very difficult to approach this very
> delicate subject which you phrase quite clearly.
>
> It is a very difficult path. We have progressed towards, to try and to
> provide you with the data that would be convincing.
>
> DR. RELLER: Just a follow up because it is, I think, an important and
> crucial\--I mean, it is a delicate issue. The approach, perhaps, being
> flawed if it doesn\'t show but it doesn\'t mean that it wouldn\'t or
> couldn\'t show. Do you mean that, then, the challenge would be to try
> to\--if you believe, and I think everyone here does believe, that
> parasitemia is given\--I mean, it is not a single-dose knockout but it
> is a severe blow to the organism; that is, the malaria parasite to
> experience the metabolic derivatives of artesunate.
>
> But the challenge would be to move the treatment back even further
> than the context of Study 013 to get at those 90 percent, 80 percent,
> 70 percent of children, the under-fives, who are dying at home before
> they get to a village healthcare worker or anybody else. Is that what
> you are saying?
>
> PROFESSOR WHITE: Yes. My own opinion, for what it is worth, is that
> the benefit would be inversely proportionate to the level of
> healthcare. The worse the situation, the greater the benefit.
>
> DR. RELLER: It is a sort of pushing back where you get that full
> benefit with the potential, then, for what\--but then, the greater the
> benefit, then the more risk you are willing to, in terms of potential
> toxicity, to sustain to achieve that difference in mortality is what
> you are saying.
>
> PROFESSOR WHITE: Yes, although I would say that it is remarkably
> nontoxic.
>
> DR. RELLER: What I mean is that there is that balance. But it
> becomes\--what is already small may be vanishingly small pretty early
> in the process of moving back toward the level required for greatest
> efficacy, or greatest likelihood of being able to definitively show
> the efficacy as judged by mortality differences\--not that you need it
> to show efficacy, but to show efficacy with that clinical endpoint.
>
> Yes; Dr. O\'Fallon?
>
> DR. O\'FALLON: You bring up a question about\--I keep having trouble
> with this. How do you foresee using this drug? You keep talking about
> pushing it back. Right now, it is going into places where there are
> trained medical people to help with the distribution and
> administration, in essence, and education of the mothers that would be
> giving this drug.
>
> If we were to approve it, recommend approval, how would it be used in
> these nations? I come from a small-town area, myself. Some places
> don\'t have a pharmacy anymore even in the United States. How is it
> going to be distributed to the people further back than are involved
> in Study 013.
>
> How are they going to be trained? If a child in some tiny little area,
> there are just a few people living there, gets sick, how is the mother
> going to get hold of the drug? How will they go for it? What kind of
> training? That is the issue that I am concerned about.
>
> DR. GOMES: Just to repeat what Professor Folb said earlier, at least
> in the case of the United States, we would be making an application
> for a prescription-only drug. The scheduling in the different
> countries would really depend upon what the regulatory authorities for
> each of those nations decide.
>
> However, there will be certain countries, perhaps Ghana would be one
> of them, that would want to push it back to the point at which you get
> the greatest benefit and as early as possible.
>
> I would like to hand over to Professor Binka.
>
> DR. BINKA: Thank you. I think, generally, for the control of malaria,
> we all agree that there is a need to push back the treatment further
> to the home. In most of these countries, there is clearly recognition
> that we need to incorporate what currently called the private sector
> in all this process.
>
> So there is training going on for most people and we are making sure
> that, as far as we can, there are people who are trained and
> supervised to be able to help provide care. In fact, if you read
> recently in the last Malaria Day on April 25, I think in
> Uganda\--Uganda is about to put together about 80,000 people who have
> been trained and located in places to help.
>
> In my own country, in Ghana, currently there is a major move to move
> community-health nurses into villages where they live, are trained and
> they provide care. So, gradually, that recognition is there and is a
> massive effort to try and support this process.
>
> So when I showed the last slide, I was indicating that this is part of
> several interventions, part of which includes both the preventive
> measures and also the treatment. I think this will not just be left to
> the hands of people who are not trained but the level of training will
> vary from each country\--I mean the person that is trained.
>
> We cannot have pharmacists trained all over in Ghana, for example. But
> we can have another level of health worker that is trained to be able
> to help the mothers to administer this drug.
>
> DR. RELLER: Dr. Sumaya and then Dr. Wald.
>
> DR. SUMAYA: My question is will the approval or disapproval or
> recommendation from this committee to the FDA, from the FDA\'s
> standpoint, approval or disapproval of your request affect or
> influence whatever happens with this drug in other parts of the world,
> distribution, access, investigations?
>
> PROFESSOR FOLB: I have indicated that if FDA approval will probably
> profoundly affect the decisions of other authorities. That is always
> true for FDA decisions regarding medicines that are considered in
> other countries.
>
> But that question introduces trouble to our proposal because our
> proposal clearly\--our proposal and our request clearly\--is that the
> judgment should be made in terms of the evidence that we have provided
> for efficacy against safety, the risk/benefit between the two and the
> quality of the product that we have produced.
>
> So I feel that, as important as that question is, as profound as the
> influence will be of the FDA, that the decision be made on its merits.
>
> DR. RELLER: Dr. Wald and then Dr. Ramirez.
>
> DR. WALD: I have two questions. How different are the patients that
> are being entered into Study 013 in overall severity as the patients
> in the pivotal studies, 005, 006. The second question is are there not
> sufficient safety data already generated from Study 013 to reassure us
> if more than 3,000 patients have been entered, 56 percent were less
> than one year of age, are there not already a lot of safety data that
> might be reassuring?
>
> DR. GOMES: My colleague will be putting up a slide that was, I think,
> part of the original presentation of Professor White in terms of the
> representativeness of the population that we are likely to see in
> reality that is Study 013 and the population that we saw, we examined,
> in the pivotal trial.
>
> \[Slide.\]
>
> Essentially, all of the studies, apart from one in Thailand where
> there had been previous data that showed there was high risk of
> mortality in patients who were hyperparasitemic. All of the patients
> in the other studies were non per os which is the same inclusion
> criteria for Study 013, the same degree of consciousness, more or less
> the same history of seizures.
>
> The difference here is that, in the hospital-based studies, the
> inclusion criteria for entry into the trial was positive parasitemia.
> That inclusion criteria, in reality, is clinical presentation,
> inability to take drugs by mouth and suspicion\--normally it is
> associated with malaria season in different countries\--that the
> likely reason for this clinical condition would be malaria.
>
> As I said earlier, the likelihood of the clinical condition being
> malaria, very often you have an overlap in presentation, particularly
> with acute respiratory infections. So no further or better diagnosis,
> you will have patients with acute respiratory infections who are
> essentially parasitemic as well.
>
> So you would not be able, in a certain proportion of cases, be able to
> separate the two. In a large proportion of the cases, 74 percent,
> essentially, this would have been the primary cause of the illness.
>
> There was a second question.
>
> DR. WALD: That is why I think it is confusing that we can\'t show any
> difference in mortality that, on the one hand, the pivotal studies, we
> are loathe to use a placebo and we use a comparator drug because we
> say we can\'t risk placebo. In this field, the mortality is decreasing
> and so we are not going to be able to show a difference in 10,000
> cases. We are estimating that we are going to need a sample size that
> is two or three times greater than that. So it still leaves me a
> little bit confused if the overall severity of these patients is so
> similar.
>
> The second question was about are there sufficient safety data at this
> point from Study 013 to reassure us?
>
> DR. GOMES: This essentially would be safety data from Study 013.
>
> \[Slide.\]
>
> All patients, 3,366 would have been examined between seven and thirty
> days for the second major endpoint of that study which is severe
> neurological sequelae. You have been taken through the presentation of
> those patients of which two out of the 16 patients could possibly be
> sequelae that are attributable to artesunate.
>
> Your question, the way you phrased it, also referred to a very young
> age group. We are not applying for a label that would be under two
> years. We have very few patients in our pivotal trials, nine in total,
> that were under two.
>
> We plan, and we have submitted a pediatric plan, to recruit four
> hospital-based trials, a significant number of patients where we can
> examine the efficacy, clinical efficacy\--and this is not a mortality
> trial\--in this young age group.
>
> \[Slide.\]
>
> But, in order to study this population well, we would have to include
> patients only with that age group and we would have had to have
> produced a dosage form that can be taken by that age group. So this
> has limited our ability and we essentially plan to start that study as
> soon as possible.
>
> So this is a dedicated study that would be looking at patients between
> three months to 24 months in this young age group. We would be looking
> at moderately severe malaria.
>
> DR. RELLER: Thank you. It is exactly 3:30. We will take a brief break,
> come back refreshed for follow-up discussion and voting on schedule.
> We will be back at 3:45, please.
>
> \[Break.\]
>
> **Continued Discussion and Voting**
>
> DR. RELLER: I should like to call this afternoon\'s portion of the
> meeting to order. I am certain that our brief break enabled generation
> of additional questions to continue the discussion before voting on
> the questions put to the committee by Dr. Goldberger and colleagues.
>
> Any additional clarifications of information presented before the
> voting, additional questions or comments from the committee members?
>
> Dr. O\'Fallon?
>
> DR. O\'FALLON: It was pointed out to me during the break, actually
> there is quite a lot of information available about the neurotoxicity
> in children that has already come off of that infamous Study 013.
>
> It is in our packet but I didn\'t recognize it when I read it, myself.
> Perhaps the WHO guy would like to explain it a little bit better so
> that we knew a little bit better about what was going on.
>
> DR. GOMES: Study 013, this was slightly repeating the discussion that
> I would have had earlier with Dr. O\'Fallon, recruits patients that
> would be the intended population, patients who have suspected malaria,
> who would not be able to take drugs by mouth and who would,
> essentially, be referred to a hospital or healthcare center for
> definitive treatment.
>
> The protocol is essentially to randomized patients to either receiving
> a placebo or an active that is a suppository with either 100
> milligrams or 400 milligrams of artesunate. All patients in this study
> are automatically followed for two endpoints; one is whether they
> survive or do not and the second endpoint is whether they have serious
> neurological sequelae.
>
> There is a case-record form during the follow-up period between seven
> to thirty days where every single patient, if that is alive, is
> examined by the health worker who does the follow up and is assessed
> for different behavioral\--have you had new problems in walking and
> talking, in speech, in playing.
>
> Essentially, it is a form that evaluates each child or each patient
> that would have been exposed to the drug for potential neurotoxicity.
> If there is any one of the items that has been marked yes\--that is,
> there is a new difficulty or behavioral problem, each and every one of
> those patients is then followed up by a clinician and has a full
> clinical evaluation by a clinician.
>
> In one of the study sites, this goes even further. There would be a
> very detailed neurological examination of those patients. The study
> began in different countries, at different points. It is about
> eighteen months into recruitment. Our approach was to begin very
> slowly so that we could do it\--it would work perfectly; that is, we
> wanted to be able to be sure that, in a community-based study, we
> could effectively monitor every child or every patient between seven
> to thirty days.
>
> It is a very unusual thing in communities to be able to actually get
> 100 percent, or as close to 100 percent, follow up in the kinds of
> conditions that we are talking about. We wanted to have as little
> lost-to-follow-up so that there was no bias in the results at the end
> of the day.
>
> So we have moved in a phased direction to include patients in our
> target population. We now have sufficient confidence about eighteen
> months into the study that we can, in fact, recruit properly, that
> there is adequate follow up. We gave a safety update to the Food and
> Drug Administration. This would have been at the end of March where
> the DSMC evaluated the data and said there was no reason to terminate
> the trial, we should move forward.
>
> Between March and today, we have doubled the recruitment. It is almost
> a geometric progression because once you get confident in doing this
> kind of study where, initially, we would have wanted to make sure that
> every single child was monitored and the hospital had adequate drug in
> the hospital.
>
> Of course, these things affect the endpoint, mortality. Now, we
> broaden it into places which are much closer to the bush where we give
> the drug. This is much further from a hospital. Patients take longer
> to get into the hospital and likely the effect will be seen as we
> expand the study.
>
> I gather this was not clear either from the documentation or the
> description in the briefing document and I just wanted to make sure
> that you had this information because it was pointed out to me it
> wasn\'t there.
>
> DR. RELLER: Despite the Study 013 being closer to the reality of the
> potential population for treatment, still, it has all ages,
> differences in background immunity. Quite honestly, is it designed to
> show the endpoint or, as Professor White alluded to in the earlier
> discussion, if it doesn\'t show differences in mortality or much
> larger numbers are necessary, that wouldn\'t negate the possibility of
> showing that difference with the appropriate population.
>
> So, are we putting too much emphasis, potentially, on Study 013 for
> showing the very thing that your briefing document emphasized is the
> goal of the appropriate use of this formulation?
>
> Related to that, and I realize we don\'t have the code broken yet, but
> is part of that design to capture in actuality what the time is by
> patient and age group and outcome of time from receiving rectal
> artesunate to the time of getting definitive therapy, recognizing that
> no one has the intention of a single dose of rectal artesunate being
> sufficient for the appropriate therapy of malaria?
>
> DR. GOMES: You have brought up two issues; one concerns the design of
> the protocol and the secondary endpoints that allow one to measure
> whether or not in the subgroup analysis if one doesn\'t see an overall
> effect, one would see, let us say, an effect in patients that are
> further from the hospital than those who might be closer.
>
> That kind of secondary endpoint varies between studies but certainly
> it is there in the majority of cases; that is, parasitemia would be
> measured at\--there would be different endpoints, one of which would
> be time to return to per os status and distance, what time it took to
> reach definitive treatment.
>
> The second point that you brought up, to which Professor White
> referred to, is the emphasis on Study 013. Our indication, the way
> that we have phrased it, is for the initial management of acute
> malaria in patients who are unable to take oral drugs and cannot reach
> parenteral treatment, we are making a claim that we have shown benefit
> parasitological that has converted into return to per os status for
> patients who cannot take drugs by mouth and who normally would be at
> risk of death, an unknown unquantifiable risk of death, but, if they
> had progressed further, would have certainly have died in the absence
> of treatment.
>
> We are making the argument that the way we have phrased that
> indication is that we have shown a clinical benefit. We have not yet
> shown a survival benefit and we do not make a claim in the indication
> that we do so.
>
> So what we are asking for approval is on the benefit that we have
> shown in the pivotal studies bearing in mind the safety that we have
> also shown and keeping in mind the fact that, for these patients,
> there would be no alternative.
>
> We have put in place, corresponding with the regulations of the FDA,
> what we originally referred to as phase IV trials and now are
> referring to as Study 013, trials which we believe would convert the
> clinical benefit that we have shown, returning to per os status,
> returning to a clinically stable position, so that the patient can
> take definitive treatment, that we want to confirm whether or not that
> actually converts into a survival benefit in real-life conditions.
>
> Our argument is that you do not need to wait for the results or the
> continuation of that study although we would be wanting to present you
> with those results. In as much as you would want to know whether or
> not there would be a survival benefit, the WHO would wish to know
> whether or not there is a survival benefit because it affects policy.
> We would want to be able to, should we confirm that benefit, to
> convert to labeling to stating that there would be a potentially
> life-saving benefit with this drug.
>
> But we are not claiming that at present and we would only want to do
> that should Study 013 show that benefit was there. We have tried, in
> every way we can, to show that the patient population that we have
> seen in the pivotal trials, although they were done in hospitals, was
> as close as you can get to the patient population at baseline that we
> actually see in Study 013 so that they are clinically not substantive
> different.
>
> We are making an argument, the case, that if we had done more
> hospital-based studies, it would not change the picture substantially,
> that what we see with rectal artesunate compared with quinine is what
> you see in any form of artesunate given compared with quinine and that
> adding patient numbers to the hospital patient population will not
> change.
>
> So, in my view, the emphasis on Study 013 would be to establish
> whether or not it confirms the survival benefit would not change the
> indication that we are seeking but it might change the indication at a
> later point. Its value, I think, in this connection would be that it
> has a substantially much larger number of patients for which there is
> secure safety data in relation to this indication.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: Can I follow up on that presentation by asking what
> happens if Studies 013 and 014 don\'t show a reduction in mortality?
> We then have an approved intervention that affects the laboratory
> results and clinical results but not survival.
>
> DR. RELLER: Comment?
>
> DR. GOMES: If it did not show survival benefit, we would not want to
> persuade you to change the indication; that is to say, we would
> essentially live with the indication we have at present. We are
> essentially saying that we would be, then, limiting ourselves to the
> clinical benefit that we are seeking now and not a survival benefit. I
> am making the distinction.
>
> We have shown a return of the patient to a clinically stable position
> on the current evidence.
>
> DR. SHAPIRO: But one interpretation of a lack of impact on mortality
> is that you have protracted or, perhaps, eliminated the visit for
> definitive treatment and so, to pursue and continue using a drug for
> the indications that you seek currently might be counter productive.
>
> DR. GOMES: I am not quite sure I understand the question. Would you be
> able to repeat it?
>
> DR. SHAPIRO: Yes. One of my concerns is that intervening\--the
> mother\'s intervention with rectal artesunate will achieve some
> clinical response and will either delay or prevent the mother taking
> the child for definitive treatment. If the intervention in Studies 013
> and 014, which are looking at mortality, don\'t show a difference or,
> perhaps, even show a difference in the wrong way, one possible reason
> for that is that you have taken away the incentive for the mother and
> child to go for definitive treatment.
>
> So, to persist with the use of the drug in this indication in the face
> of either adverse or nonexisting mortality benefit, I can\'t quite
> understand.
>
> DR. GOMES: I would interpret it in a slightly different way although I
> would like Fred to come up. I may have misunderstood the question, but
> there are two points I wish to make.
>
> Firstly, this trial is in progress and we are informed by the Data
> Safety Monitoring Committee that we should continue, that there is no
> evidence one way or the other for a termination of the trial from
> which I understand that there is no evidence one way or another and,
> therefore, I don\'t think that anyone can conclude that we have not
> shown a difference definitively. We are still dealing with a trial in
> progress.
>
> The second issue, and it might just be an interpretation, if, let us
> say, that we do not show a difference at the end of the day, it would
> not necessarily mean that people would not have taken definitive
> treatment. I am not quite sure I understand the second point but,
> perhaps, Fred\--
>
> DR. BINKA: I think the second point you raised is quite important and
> that is the reason why this study is in place, because we will be able
> to answer that question that you have raised, will this drug lead
> to\--if mothers do not go to seek additional treatment from one short
> treatment from rectal artesunate, what will be the consequences of
> that.
>
> I think that is what is the strongest drive to have a
> placebo-controlled trial in this phase of the trial because we really
> didn\'t have to a placebo-controlled trial. So that question will be
> answered. I think the likelihood is much lower.
>
> DR. SHAPIRO: But the fact that you are seeking approval prior to the
> availability of those results\--Study 013, as I understand it, could
> show three things; rectal artesunate reduces mortality, rectal
> artesunate is no different from placebo in affecting mortality, rectal
> artesunate is worse than placebo in affecting mortality.
>
> Those are three possible outcomes from that study and we don\'t know
> which of the three it will be. At the moment, it seems not to be the
> worst-case scenario. Otherwise we wouldn\'t be in limbo.
>
> But if approval is rendered at this point while Study 013 is still
> outstanding, the possibility exists that we will learn something,
> either that rectal artesunate does not improve mortality or, arguably,
> that it makes mortality worse. And we will have on the market an
> approved drug with uncertain data about mortality.
>
> DR. BINKA: That is a good point. I think this is where we need to
> restate our case. I think the most important thing is that we are not
> trying to put in the drug one rectal capsule to reduce mortality. I
> think you should look at the other benefits that we get from bringing
> children who are getting seriously ill into a situation where they
> can\'t take oral drugs.
>
> If you see the huge advantage they will get in terms of hospital
> admissions, in terms of being able to treat these people appropriately
> even in the conditions in which they are, then that makes a lot of
> difference in the benefit.
>
> Most of these kids that we are directing this drug to are those ones
> that are getting into the severe case. If you were to succeed in doing
> that, in preventing of the progression mild disease into severe
> disease, this would be a real major contribution towards reducing the
> burden. I think that is the case that we are putting across now, that
> even if this doesn\'t show survival benefit, it definitely provides
> lots of benefit to the control of this disease in terms of making sure
> that patients don\'t produce severe disease and that we are able to
> treat them appropriately.
>
> DR. RELLER: I had asked earlier about the time to definitive therapy
> because, within the no differences, it may be that there are fewer
> deaths owing to malaria but more deaths owing to something else
> depending on what the distribution of the background illnesses are.
>
> But the other possibility is that, on balance, the delays in getting
> definitive therapy are sufficiently short that it is not possible to
> show a difference either in\--realizing that study is not complete, do
> we have some idea of what the ranges are in the population being
> studied? It may not be a population that is\--the populations may not
> be distant enough to be able to demonstrate a difference because the
> delays to therapy\--because this is something outside the hospital,
> community-based, but maybe not far enough away to be able to\--any
> comments on that? It is just an additional complication within the
> basic concern that Dr. Shapiro has raised.
>
> DR. BINKA: I think Dr. Gomes alluded to extension of this project. In
> the initial phase, when we started recruiting patients, we had to do
> it in such a way we could learn how to do this properly. Currently,
> lots of the patients that are being recruited are being recruited from
> quite a few more places that would allow us to address this question.
>
> I think that the Data Safety Monitoring Committees request that this
> should not be unblinded should not necessarily mean that this is not
> showing any benefit. I think the need for the study to be stopped or
> to be unblinded, you don\'t only have to show a benefit but you have
> to show it within a reasonable doubt.
>
> Maybe that is a part of the confusion. Nobody is saying that this
> study might not show the difference. But, at the time that the data
> was reviewed, there was truly no reason to unblind the study. Maybe
> that should correct it. I think the way it is designed it will answer
> the question.
>
> DR. RELLER: Dr. Ebert and then Dr. Sacks and Ramirez.
>
> DR. EBERT: This is potentially a two-part question. At what point are
> the children enrolled in the study? Are they enrolled when they
> present to the physician for follow-up care or at an earlier time.
>
> DR. BINKA: Currently, once the mothers find that the children cannot
> take things orally and they are sick, we have field workers that live
> in communities that are recruiting these patients. So they are not
> necessarily reporting to the facilities but they are being recruiting
> in those distant places where there is no care. That is where the
> studies have been carried out.
>
> DR. EBERT: So there is not a risk of a mother administering the dose
> and then not presenting and not being enrolled in the study so that
> you could have more than 50 percent of the patients who might have
> received placebo.
>
> DR. BINKA: No. This is a well-controlled study. We have shown the
> follow up to 99 percent. I think that is what is happening now.
>
> DR. SACKS: I just wanted to perhaps communicate my own discomfort with
> making too much of a judgment on the results of Study 013 which, a),
> we don\'t have and b), we do not really know the details of the
> protocol.
>
> In the course of the review, we requested copies of the protocol at
> least to understand what was being done. To me, the study does carry
> potential difficulties which I think we should be aware of before we
> can conclude that it either may or may not show a mortality benefit.
>
> In particular, I think, in my mind, it is important to stress the drug
> effect in order to see the mortality benefit. For example, if patients
> who are getting the placebo prior to definitive therapy only receive
> placebo for four hours and end up getting their definitive therapy at
> that point, the difference between the two arms will really not be
> visible in terms of morality benefit.
>
> Second of all, the study population, although it bears some similarity
> to that shown in clinical trials is different in a substantial way and
> that is the clinical trials admitted patients with a certain minimum
> level of parasitemia whereas the study population is likely to dilute
> that considerably because we don\'t know what the entry parasitemia is
> in this patients.
>
> We don\'t know what the level of immunity is. We don\'t know what the
> level is of other illnesses in patients who have immunity with
> background parasitemias so I think before knowing a little bit more
> detail about the actual structure of the protocol and before knowing
> more detail about the nature of the results, it is difficult to
> conclude whether the results show a mortality benefit, no mortality
> benefit or are unable to demonstrate a mortality benefit.
>
> DR. RELLER: Dr. Parise?
>
> DR. PARISE: I am sorry to go back to Study 013 but is there an ability
> in that study to look at the safety of kids who may have gotten
> multiple doses and do you have any data on that if there isn\'t the
> ability to look at that?
>
> DR. GOMES: Can I clarify that you mean multiple initial doses?
>
> DR. PARISE: No; I mean may have been treated several times.
>
> DR. GOMES: We do have data on all of the people that are recruited
> into the study. All patients just get one dose, as you know,
> initially. But, in the study that we have in Tanzania where it would
> be something like 1,400 patients so far, about ten in total would have
> had an attack more than once.
>
> DR. RAMIREZ: I just wanted to make a comment that even though, in real
> life in some of these countries, you may have to go one step farther.
> For the Americans that are going to be in this countries, the design
> of this study, the study that we don\'t have the answers yet, is
> probably more real life because you are going to have a mother that is
> going to be very committed, is going to be educated, is going to know
> that this is one suppository that you want to run to see the
> physician, either one hour, two hours, or ten hours.
>
> This is a study that, even though they are influencing now the mothers
> with education, this, to me, is a more real-life study how people are
> going to be using this drug.
>
> If we don\'t show that there is benefit in mortality, then, in my
> mind, when I start looking risk/benefit, I will have to say to this
> mother, well, you take this pill and what happens; you decrease the
> number of parasites? I would like to see something else because we
> still don\'t have enough on the safety in these children.
>
> Even if it is two cases of neurological deficit, we still don\'t know
> how many are there. Then it is going to be a balance as you have this
> risk for neurological deficit and what is the benefit. The benefit is
> that you are going to be sick two extra days or three extra\--I would
> rather take being sick for a couple more days.
>
> I am looking at the second question here. I still don\'t have probably
> enough information to answer the second question.
>
> DR. RELLER: Dr. Parise?
>
> DR. PARISE: I still think one of my concerns is that, in African
> children, they will get multiple treatments. You know, we don\'t know
> a lot about that. Granted, there are about 320 patients in Southeast
> Asia but not African kids. Is there any data on that? I am assuming no
> because we haven\'t heard about it and is there any plan to get any of
> that? It may even be in postmarketing. I don\'t know what the plan is
> but I think that is a concern.
>
> DR. GOMES: Can I try and understand your question? Is it related to
> this repeated treatment?
>
> DR. PARISE: Yes. Kids of Africa, as you know, get malaria many times.
> Many times, they will be able to take an oral medication but sometimes
> they won\'t. So they will get multiple doses of this potentially.
>
> DR. GOMES: Every single patient that is recruited, we essentially
> monitor. That is why we would know that about ten of the total would
> have had a repeated attack. Perhaps I should also say, while you were
> talking about postmarketing surveillance, we are in the process, in
> Study 013 of, of course, understanding what goes on in communities in
> relation to a presentation of disease that we have never done
> community-based studies about before.
>
> So this kind of work is done for the first time. But in our plans, and
> the plans are already in effect, we plan to not just make the drug
> available in any quantity to anyone but to be able to record in the
> same way that we have recorded in the current study, every single
> patient who does get exposed to the drug. So we would have not only
> repeated the understanding of safety and efficacy for repeated
> exposures in special populations, young children, pregnant women.
> Essentially, this forms part of a broader postmarketing survival that
> we consider or take very seriously and are committed to.
>
> DR. RELLER: Dr. Bell.
>
> DR. BELL: I also have questions about the safety of multiple dosing.
> Let me just ask, in Africa, say, if a child is unable to take oral
> medications and isn\'t near a place where they have intravenous
> medications, what happens to them? Do they die? Do they progress to
> cerebral malaria and by the time they get IV medications, they have
> had possible neurologic damage due to that?
>
> Is the question about safety of multiple dosing the difference between
> a theoretical unknown versus a highly likely adverse outcome?
>
> DR. RELLER: Dr. Binka?
>
> DR. BINKA: If children developing severe malaria cannot take things
> orally and cannot get injectables, yes, they go on to develop severe
> malaria and they die. They do die. Lots of them die for not getting
> treatment. I think that is the real emergency that we have now that
> there is a need to find something that can have that emergency
> situation.
>
> DR. RELLER: The time is soon approaching. Any other questions or
> comments from the committee members or any additional comments the
> sponsor wishes to make before we address the questions?
>
> Dr. Wald?
>
> DR. WALD: Just under ordinary circumstances, when a child is not that
> advanced and they can take oral medicine, who does dispense it? I am
> revealing my ignorance. I have no idea about the healthcare system? So
> you have a remote village and a child who probably has malaria but he
> is not the sick yet. Who dispenses the medication?
>
> DR. RELLER: They have to get to someone who has the medication. That
> may be a health center dispensary.
>
> DR. GOMES: I\'m afraid I didn\'t hear the question very well.
>
> DR. WALD: Under ordinary circumstances, when a child develops early
> malaria and seeks medication, where is it dispensed? Where do they go?
>
> DR. BINKA: Currently, the majority of oral medication is dispensed by
> healthcare workers. A large population of private-sector workers who
> provide services to most of the population. That is what I said
> earlier on, that there is a major move to make sure that these people
> are part of the formal health system and training has been provided to
> make sure that the services that are provided are better. But,
> generally, healthcare workers provide the drugs.
>
> DR. RELLER: Dr. Folb.
>
> PROFESSOR FOLB: Mr. Chairman, you have invited a concluding comment
> from the sponsor.
>
> DR. RELLER: Please.
>
> PROFESSOR FOLB: Dr. Shapiro raises a possibility that in more
> realistic practice than we have shown, the benefit that we claim may
> not, indeed, be seen. On the contrary, mothers may decide not the to
> follow through with what is advocated for this treatment.
>
> Our concluding comment must be that this efficacy must be seen in
> terms of this indication and the claim for efficacy must be seen in
> terms of what we advocate. We advocate that the mother takes her child
> to a clinic for substantive curative follow-up treatment as is the
> policy, as may be the policy, in the health center in the country
> concerned.
>
> Our indication is critically dependent on that happening. Now, it may
> be in your minds that this won\'t happen in many developing countries.
> If it is in your minds that that is the case, I hope that my
> colleagues have said sufficient to contest that.
>
> We have shown in work done so far, and it is our determination to work
> with governments to achieve this, that this medicine, as currently
> advocated, will be taken together with the advice that we propose. The
> medicine, plus the advice, which is the obvious and only advice that
> we can give to it, will achieve what we have shown repeatedly and
> consistently.
>
> Thank you.
>
> DR. RELLER: Dr. Goldberger?
>
> DR. GOLDBERGER: This applies to a couple of different comments that
> people have made. As we mentioned earlier, should this product be
> approved, it will be approved under accelerated approval using the
> parasitemia as a surrogate marker. Although there hasn\'t been a huge
> amount of discussion about it, my sense is that people feel that the
> parasitemia is of some value in looking at least at activity of the
> drug.
>
> The accelerated approval regulations do require that some ultimately
> clinical endpoint, a more definitive endpoint, be demonstrated to
> validate the benefit of the surrogate. That might turn out to be what
> happens by Day 28 although the regimen, as proposed by the
> applicant\--at least a single dose to tide people over\--is not
> necessarily going to translate to any advantage at Day 28.
>
> That may raise a little bit of question, therefore, as to what the
> parasitemia means. Should Study 013 not, for instance, show a
> mortality benefit, then that also raises a question about what the
> value is of the parasite.
>
> However, as has been pointed out, including by Dr. Sacks, we are not
> completely sure about the details of Study 013 to conclude that it is
> the best vehicle to do that. But the point I want to make is that we
> would have an expectation that if parasitemia is used as an endpoint
> that some other clinical benefit beyond simply reducing parasitemia
> would accrue to patients who receive the drug, whether it is a
> mortality benefit, whether it is less sequelae or some other things,
> that there would be a benefit to patients beyond simply reducing the
> parasitemia.
>
> That would be an expectation that we would have to work with WHO to
> ensure that there were studies available that could show that. I mean,
> I have to say that we are reasonably comfortable although if anybody
> else has any comments about parasitemia, this would be a good time to
> bring them up.
>
> That would be a useful surrogate but we would expect something beyond
> that and I have given a couple of examples. Should you recommend
> approval, for instance, for this product, Question No. 4 deals in a
> little more detail with making recommendations about the kinds of
> studies you would like to see to further understand this drug.
>
> DR. RELLER: If I might summarize succinctly, the decrease in
> parasitemia is a necessary but not sufficient criterion for a good
> clinical outcome in patients with severe malaria as reviewed earlier
> by Professor White. The key is getting, in the most severe patients,
> the\--well, in all patients\--the elimination of parasites altogether
> at the earliest opportunity and, in some patients, the additional
> supportive therapy, be it glucose, fluids, that are necessary for
> clinical success.
>
> So let\'s get to the questions.
>
> DR. BELL: I just have a question for Dr. Goldberger. If I am reading
> this right, the comparators, at least in Studies 006 and 007, are
> quinine given parenterally. Is there some reason that this cannot be
> viewed as a noninferiority trial of a rectal preparation versus a
> parenteral preparation bearing in mind that the indication is for
> situations where parenteral therapy is not available? Does that take
> care of the clinical outcome at 24 hours?
>
> DR. GOLDBERGER: I think the problem is in the treatment of malaria is
> a clinical outcome at 24 hours a sufficient clinical endpoint to be
> satisfied versus actual cure of patient which will occur with the
> subsequent therapy that is given to them.
>
> I think that there is some concern that the 24-hour status, although
> an extremely useful measure of drug activity, doesn\'t represent a
> definitive clinical endpoint.
>
> DR. BELL: But the indication is for one dose given once and nobody
> anticipates that that effect lasts for weeks?
>
> DR. GOLDBERGER: But we are using\--in other words, the approach we
> would be using to approve this would require that early benefit mean
> something else to the patients because I am not sure that, otherwise,
> that early benefit represents an established endpoint that people
> would feel comfortable would normally be the way you would evaluate a
> drug for malaria.
>
> I think because of the nature of the indication they are seeking, how
> they are approaching it, the expectation is that this early effect
> translates into something more. Otherwise, what does this early effect
> mean?
>
> DR. BELL: I am still confused because it is the consolidation
> treatment that takes over that is what you judge the final\--how can
> you ask this drug to do better than\--how can you really evaluate this
> drug beyond 24 hours when, after that, it is a consolidation treatment
> that takes over?
>
> DR. GOLDBERGER: Because the argument that has been, I think, raised at
> different points during the day is that the real purpose of the drug,
> of course, is not to use it in a hospital setting and then to see what
> happens at Day 24. But the patients who get it who have no other
> alternative will accrue some overall longer-term benefit. One argument
> has been mortality, whether there are benefits in sequelae, et cetera.
> That hasn\'t really been talked about although that is possible.
>
> Unless people are willing to say that a 24-hour endpoint in malaria is
> sufficient, then it is not clear what the drug necessarily is adding
> versus no therapy. That is, I guess, what we are saying, what would it
> then be adding versus not giving any therapy.
>
> DR. BELL: But the trial is against quinine. The trial is not against
> placebo; right?
>
> DR. GOLDBERGER: In other words, I don\'t think we would evaluate
> quinine as a treatment on malaria based on where a patient was at 24
> hours, at least not in terms of giving it an indication. That would
> require making a decision that that was a useful indication of its
> own.
>
> In other words, what has been requested here ultimately is the initial
> use of this in patients who don\'t have another alternative with the
> statement either implied or expressly stated in the protocol and
> during the meeting that benefit would accrue to patients.
>
> Otherwise, the indication would stand on its own, simply that, at 24
> hours, the patient had lower parasite counts without any regard to
> what happened to them. I don\'t know that that clinically makes sense.
>
> DR. BELL: Let me just ask one more question because I actually think
> this is pretty important. The sponsors are not applying for approval
> for a new malaria treatment. If I understand right, they are applying
> for approval of a drug to let a critically ill patient survive the
> first 24 hours until they can get parenteral therapy.
>
> They have demonstrated\--is this correct\--that a), there is
> parasitemia decrease and also there is noninferiority compared with
> parenteral therapy at least in terms of clinical response at the end
> of the first 24 hours which is all they are seeking approval for.
>
> DR. GOLDBERGER: The more strongly you believe that that, in fact, will
> translate into a benefit for the patient\--i.e., as you said, I think
> to prevent mortality until they can get definitive therapy. That
> implies that what you are trying to do ultimately is influence
> mortality.
>
> The more you believe that this model, that there are these patients
> who do not have alternatives, that the rapid reduction in parasitemia
> will translate into a benefit, perhaps the less you need to worry
> about how much evidence down the road there is of an actual clinical
> benefit.
>
> That is something that there hasn\'t been a whole lot of discussion at
> the meeting although I must say, from listening to many of the
> committee members, it seems as though most committee members had an
> interest in seeing something along the lines of some benefit in
> mortality or other benefit to the patient beyond what was shown in the
> in-hospital studies. I don\'t know whether it is worth asking people
> for that opinion.
>
> DR. BELL: I just think that there are lots of intervening issues that
> come between 24-hour clinical status and eventual outcome as has been
> alluded to, study-design issues. I just am less certain what that
> means. Perhaps, that is noninferiority also.
>
> I don\'t know. But I guess I am just wondering how fair it is to ask
> for the sponsors to demonstrate essentially improvement in ultimate
> mortality when maybe they don\'t have the right study to do that and
> if it is really the first 24 hours that we should be looking at.
>
> DR. GOLDBERGER: For instance, if it is not the right study, then that
> can be addressed by considering is there a study that could be done
> that would be better able to show it. It is more of a problem if you
> truly believe it would be impossible to show such a difference. Then
> you would have to think, well, why, exactly, would you being doing
> this? Why, exactly, would you be giving the drug when down the road a
> few days, a few weeks, it will make absolutely no difference to
> patients.
>
> Part of this from an analytic point of view is the difference often
> between an intent-to-treat analysis and an evaluable-patient analysis
> in terms of who you are looking at to see an effect. I mean, that is
> kind of tied up a little bit when we actually look at Study 013.
>
> I don\'t know if that helped, really, that exchange helped any members
> of the committee. It is not clear to me whether it did or not.
>
> DR. RELLER: We will see from the voting.
>
> Just to review the guidelines. All of the current members of the
> committee are authorized to vote on the questions posed. In addition,
> Dr. Parise and Dr. Shapiro are voting members of the committee today.
>
> Question 1; are these results, namely, decline in parasitemia at 24
> hours and 24-hour clinical outcome in moderately severe malaria as
> presented\--are these results sufficient to support approval of rectal
> artesunate for use as initial therapy in patients without other
> therapeutic alternatives?
>
> Dr. Parise? We will start at the right and move around. Yes or no?
>
> DR. PARISE: Yes.
>
> DR. RELLER: Dr. Archer?
>
> DR. ARCHER: Do you want us to address the other things at this point
> or just to answer yes or no?
>
> DR. RELLER: Yes or no. The caveats\--clearly, it is under Subpart H.
> There are conditions and what those conditions are\--if this should
> have no level of approval, you vote no. There is a place for it. I
> think the way these questions are phrased, you would vote yes. And
> then what else you would want before the labeling and all the other
> issues.
>
> DR. ARCHER: I would say yes but I am not yet convinced that
> parasitemia is an appropriate surrogate for whatever endpoint is being
> looked at. I don\'t think there is enough data.
>
> For instance, if we were looking at a bacterial infection, the rate at
> which a bacterium is cleared from the CSF or the blood doesn\'t
> necessarily correlate with outcome. So the rate of parasitemia drop is
> not necessarily a measure of outcome. We just don\'t have enough data.
>
> Mortality was the only other one that was given. If we had neurologic
> sequelae or return to active whatever function, or any other kind of
> surrogate that went along with that, I think that might be helpful. So
> that is my only caveat.
>
> DR. RELLER: So it is fair enough that you can\--the major limitations,
> if it is a qualified yes. Dr. Goldberger, is that okay? We want the
> true sense of how things are.
>
> DR. GOLDBERGER: If people wish to amplify their comments like that,
> that is certainly helpful. Questions 3 and 4, should Questions 1 and 2
> be yes, offer the opportunity to provide advice about any statements
> in the labeling and, equally importantly, the kind of additional data
> and studies that members would like to see.
>
> DR. RELLER: In a way, it is is it effective for doing something and
> then what else do you need and is it for that purpose as intended, the
> labeling requested. Is it safe enough to get that labeling? What other
> studies were required, mandatory for use beyond the restrictions of
> the label?
>
> Is that a fair summary?
>
> Dr. Leggett?
>
> DR. LEGGETT: If I understand it correctly, we are not being asked, at
> this time, as we usually are, to expound ad nauseam about why we are
> saying yes or no. You just want a yes or no, in which case, I will
> just say yes.
>
> DR. RELLER: Dr. Glodé?
>
> DR. GLODE: I will also say yes.
>
> DR. RELLER: Dr. Bell?
>
> DR. BELL: Yes.
>
> DR. RELLER: Yes, with limitations that we will get into later.
>
> DR. PATTERSON: Yes.
>
> DR. SUMAYA: Yes.
>
> DR. WALD: I would say yes also but I want to just ask a question.
> Suppose we impose these restrictions and, ultimately, we don\'t find
> that there is any other benefit besides a reduction in parasitemia?
> How will that ultimately affect the labeling of the drug? Really, what
> I am asking is is this really tantamount to approval no matter what
> else happens and, therefore, imposing these restrictions is not really
> meaningful?
>
> DR. RELLER: That would not be my intent, but this we will get to in 3
> and 4.
>
> DR. GOLDBERGER: To answer a little bit of your question, the
> accelerated approval regulations, in addition to utilization of a
> surrogate marker, also allow, in truth, for accelerated withdrawal of
> a product if the confirmatory trials don\'t show any other benefit.
>
> One thing that, of course, would be helpful as you talk in, for
> instance, Question 4, would be to talk about the kinds of things that
> would make you feel comfortable that the drug was demonstrating a
> benefit more durable than parasitemia unless you feel, as Dr. Bell
> very articulately argued, that the benefit that they have shown to
> date may in and of itself be sufficient.
>
> If people feel that, you don\'t have to say that now. You can reserve
> that for a discussion in Question 4.
>
> DR. RELLER: Dr. Ebert?
>
> DR. EBERT: Yes, subject to caveats and restrictions to be discussed
> later.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: A reserved yes.
>
> DR. RELLER: Dr. Ramirez?
>
> DR. RAMIREZ: I would like to make a comment. This committee, we have
> just recently discussed the idea of looking at surrogate markers
> mostly in patients with multiresistant organisms. How are we going to
> be able to test new antibiotics in clinical trials of patients, when
> don\'t have enough patients, are very difficult to evaluate.
>
> I think that even though there is some reluctance, we will have to,
> sooner or later, figure out that the prospective double-blind study
> looking at clinical outcome at 30 days is not possible in every
> setting.
>
> The same that we do for antibiotics. What can we ask for an
> antibiotic? Just to kill the bacteria. There is nothing else that an
> antibiotic can be doing. I think that what can we ask for an
> antiparasitic, for an antimalarial drug? Just to kill the parasite.
>
> I will say that this surrogate marker is appropriate. Now, the problem
> here is that we ask\--we want to see what happens at 24 hours. It is
> not that the drug doesn\'t work. It is that we didn\'t give time for
> the drug to work because we showed, or we were told, that you give
> time, you give one week, you kill all the parasites.
>
> Then I agree with Dr. Bell. At 24 hours, no drug is going to be able
> to kill all the parasites. That, to me, is an adequate surrogate
> marker to say that if you are using an antimalarial drug and you start
> killing the parasite, and you see a two-log decrease in 24 hours, it
> has very good antiparasitic activity. Then my answer is yes.
>
> DR. RELLER: Dr. O\'Fallon?
>
> DR. O\'FALLON: My answer is yes. I keep remembering that this is a new
> formulation. There is no such formulation in any of the other
> antimalarial drugs as I remember. So this was developed to meet a need
> of a population that right now doesn\'t have a therapy of a known
> effectiveness.
>
> So I think that that is an issue that needs to be kept in mind as
> well. I am, of course, worried about the age problems. But in terms of
> I think that they have shown that it at least knocks the parasites, or
> to a great extent.
>
> DR. RELLER: Dr. Cross?
>
> DR. CROSS: My answer is yes.
>
> DR. RELLER: Question 2; is the safety information and safety profile
> of rectal artesunate sufficient to support approval for use as initial
> therapy in patients without other therapeutic alternatives. In your
> discussion, please include the differences in clinical trial, intended
> patient populations, risk/benefits, empirical use for emergency
> therapy.
>
> We are to give a yes or no on this. Again, in 3 and 4 in the
> discussion, it will be important to articulate those things that we
> would feel would be important to be done including the restrictiveness
> of the labeling. Dr. Goldberger has opened the emphasis for if we
> think other things we be required for maintaining availability to
> articulate those.
>
> Let\'s go the reverse direction this time. Dr. Cross, is this drug, as
> requested in its indication, sufficiently safe to be used that way?
>
> DR. CROSS: My answer is yes. I say it because they asked only for a
> single dose which is shown to be, in a fair number of patients,
> nontoxic. It was also pointed out to us that there is a difference
> between the demonstrated class neurotoxicity and the data specifically
> related to this preparation.
>
> So, so far, we haven\'t seen any data to say that this specific
> preparation is any more toxic. So I would say, based on that, I think
> the answer would be yes.
>
> DR. RELLER: The request is rectal route, over 24 months of age, single
> use.
>
> DR. CROSS: Yes.
>
> DR. RELLER: Correct? Dr. O\'Fallon?
>
> DR. O\'FALLON: Yes. I think that the toxicity data, at least as we
> have seen it, are okay. Again, but not in children.
>
> DR. RELLER: Dr. Ramirez?
>
> DR. RAMIREZ: Did I miss the two years because the proposed indication
> here says initial treatment when no alternative is available. But we
> don\'t discuss the age of the patient and we don\'t discuss\--I don\'t
> see the 24 months.
>
> DR. O\'FALLON: It was in what we saw originally but I don\'t see it
> either.
>
> DR. RELLER: I am operating on the assumption that what we are talking
> about is also what the sponsor requested which is the usual\--I mean,
> if we do not think the safety support that was requested, that is one
> issue. If we want to go beyond what was requested, I guess we could do
> that, but there was\--
>
> DR. RAMIREZ: I read in the proposed indication in the document. It
> said initial management of acute malaria in patients who cannot take
> medication by mouth and parenteral treatment is not available.
>
> If I look at this indication, it is different from what you just
> mentioned because you removed all the patients that I would say no.
>
> DR. RELLER: Dr. Goldberger, help me. I realize that all of the details
> are not in this question, but the sponsor clearly requested what they
> had data for and there were only eight patients in the pivotal studies
> that were under eight years of age.
>
> DR. GOLDBERGER: The indication that you have seen is what the sponsor
> proposed. In their proposed package insert, they provide information
> on dose and administration for adults and for children basically from
> the age of two up or from a weight of 9 kilograms up. They indicate
> that there is not adequate information on children less than two years
> of age.
>
> So that is what basically the proposed package insert would say, at
> least at this time.
>
> DR. RAMIREZ: But if I read this proposed indication and the question
> is safety demonstrated for this proposed indication, my answer is no
> because this drug is going to be mostly used according with the
> clinical data in patients that are less than 24 months, less than 24
> months of age, and this proposal is for all patients initial
> treatment.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: There seems to be a discrepancy between the proposed
> labeling and what we are seeing in the ongoing Study 013 which is to
> say that more than half the patients are in this group that we are
> saying is not on the labeling. So I am a bit confused about what
> exactly is being sought here.
>
> If it is true that most of the deaths in malaria occur in the very
> young children, this is the population we most want to treat.
> Conversely, it is the population in whom we have the least, if any,
> safety data.
>
> DR. GOLDBERGER: Unfortunately, you saw the information that we
> presented in terms of safety data from a bunch of studies which
> included 166 children. However, only eight of those children were less
> than two years of age.
>
> As you noted, there is a much better enrollment of younger children in
> the ongoing Study 013. However, as a practical matter, essentially no
> information has been submitted to us about Study 013 other than about
> two or three pages of summary data. So we are not, certainly, in a
> position to, in any way, utilize Study 013 other than as a little bit
> of supportive data much as literature articles might be to just
> strengthen a little bit of the overall safety impression but certainly
> not to make a major change in our understanding of what we know about
> the safety of children, for instance, under the age of two.
>
> DR. SHAPIRO: I understand Study 013 is not even designed to acquire
> that except in the sense of neurotoxicity. So we won\'t learn anything
> about hepatotoxicity or any other form of toxicity that might occur.
>
> I think the thing that I am wrestling with is that whereas it seems
> the request is for two and up, indeed, the ongoing use is
> substantially for less than two. So I am not clear about this request.
> If the request really is for use in less than two, then I don\'t think
> we have the data for it.
>
> DR. GOLDBERGER: I think what is requested is clear. The request, in
> fact, basically the WHO at present does not provide information about
> how to use the drug in less than age two and basically states there is
> insufficient data.
>
> You, yourselves, have seen the amount of data that exists for children
> under the age of two at this time and it is certainly a limited amount
> of data. It then depends, in part, how comfortable you might be about
> a), an extrapolation of what we know in older children in terms of
> safety, b), the potential benefit from the dose of drug in these young
> children.
>
> I think that those two issues are obviously important in terms of your
> thinking about that. Finally, whether or not absent being able to use
> the drug under the age of two or feeling that off-label use under the
> age of two might not be appropriate, how much of a concern that would
> be given the lack of alternatives for this patient population.
>
> DR. RELLER: I phrased the question as I did so that we wouldn\'t be in
> an ambiguous situation. Maybe we would do a quick re-run and cut to
> the point. Alan, is it a yes above two or all comers?
>
> DR. CROSS: Are we clear that we are following what is in our document
> or what was requested in terms of the label showing recommendations
> for greater than 24 months?
>
> DR. RELLER: I phrased it one way, but if you answer it as I just
> mentioned, then we have got it taken care of. So you could say safety
> has been demonstrated without regard to age, or safety has been
> demonstrated to your satisfaction on the 10th of July, 02, of over
> two. Or neither.
>
> DR. CROSS: Clearly safety hasn\'t been demonstrated with regard to any
> age group since, as was pointed out, we have very little data on the
> less than 24 months. But I have seen sufficient data on those who were
> greater than 24 months that I would feel comfortable.
>
> DR. RELLER: Dr. O\'Fallon?
>
> DR. O\'FALLON: I agree.
>
> DR. RELLER: Dr. Ramirez?
>
> DR. RAMIREZ: I agree. Less than two years, we need data. More than two
> years, it is probably enough.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: I am not sure I am remembering the numbers. I thought it
> was just a handful that were children that were studied here,
> regardless of whether it was\--wasn\'t it just a dozen or so of any
> kind?
>
> DR. GOLDBERGER: 166 children, only eight of whom were under the age of
> two.
>
> DR. BELL: How many were under the age of five?
>
> DR. JOHANN-LIANG: About 80.
>
> DR. RELLER: Dr. Shapiro?
>
> DR. SHAPIRO: If the cutoff at two is an explicit component, yes.
>
> DR. RELLER: Dr. Ebert?
>
> DR. EBERT: Rectal administration, single dose, greater than two years
> old, yes.
>
> DR. RELLER: Dr. Wald?
>
> DR. WALD: Yes.
>
> DR. SUMAYA: Yes; over two.
>
> DR. PATTERSON: Yes; greater than two.
>
> DR. RELLER: Yes, as requested; over two.
>
> DR. BELL: Yes; over two and I am placing a strong weight on the phrase
> here \"without other therapeutic alternatives,\" because I am actually
> not all that comfortable with just 80 under five either. But if there
> really are no other therapeutic alternatives, then I would say yes.
>
> DR. RELLER: Dr. Glodé?
>
> DR. GLODE: I am going to say a very reluctant yes for part of the same
> reasons Dr. Bell mentioned. If this was a new vaccine before this
> committee or a new antibiotic and there were 80 children studies with
> essentially very few of those having any biochemical studies for
> hepatotoxicity, neutropenia, et cetera, I don\'t even think we would
> be discussing it.
>
> It is not. It is a rectal formulation of another drug for which there
> is at least historical safety information and there are no other
> alternatives. But it is a very reluctant yes with n equals 80 children
> under five and essentially almost no biochemical studies.
>
> DR. RELLER: Dr. Leggett.
>
> DR. LEGGETT: Yes; as in the product recommendation.
>
> DR. ARCHER: Yes; as amended.
>
> DR. RELLER: Dr. Parise?
>
> DR. PARISE: Yes, but because I have to leave in five minutes for a
> plane, let me say what I think should be added for No. 4.
>
> DR. RELLER: Please.
>
> DR. PARISE: Which is a review by FDA at some point of the safety data
> collected in Study 013, some kind of more information on repeat
> dosing; that is, people who get dosed for multiple episodes of
> clinical malaria, and probably also for a bigger database to look at
> the biochemical issue, the lab tests.
>
> DR. RELLER: So those are the votes. To set the stage for the
> discussion of 3, and, in part, 4, with the reserved yeses, I voted as
> I did because I think that there are patients for whom parenteral
> therapy is not available in remote areas who may be given the gift of
> time to get definitive therapy is this is used appropriately, and that
> is a big public-health challenge.
>
> At the same time, for its continued availability or approval in the
> first place under the regulatory process for accelerated approval, I
> think its persistent requires evidence, clinical evidence, including
> mortality or other substantive documented objective neurologic
> preservation or something along those lines, something beyond a
> laboratory assessment, however necessary it is, that it is not
> sufficient.
>
> So let\'s go around the table and say what would you like to see, Dr.
> Archer, in terms of additional studies, additional data, caveats or
> restrictions in labeling, et cetera? I think that it is logical to do
> 3 and 4 together. What else do you want to see that is required of the
> sponsor either in labeling or studies or follow up, et cetera?
>
> DR. ARCHER: Let\'s see. I think as far as labeling goes, the obvious
> things that have been mentioned. I think the labeling needs to define
> what was actually studied, namely no severe malaria, no kids under the
> age of two, are two that I can remember, and all of those things that
> were studied needs to be restricted to use in those folks in the
> labeling because nothing else was yet studied. I guess the labeling
> can change when Study 013 is finished if there is more data.
>
> As far as other things to do, obviously, toxicity in children under
> the age of two is a no-brainer. I think better studies to correlate
> parasitemia with outcome. Other outcome measures besides mortality
> should be looked at, whatever they may be, just to strengthen the
> validity of using parasitemia as a surrogate. I think that would be
> important.
>
> That is really all I have.
>
> DR. RELLER: Dr. Leggett?
>
> DR. LEGGETT: One thing I would like to point out is part of the
> problem appears to me is the lack of data as brought out by the
> multiple questions all day long. I would just urge the sponsors, when
> they come with the follow-up studies of which I am sure there are
> going to need to be some, that they provide us with more specific data
> to make us more comfortable with the choices we are making.
>
> One of the things that I would say is that, in terms of the labeling,
> as Gordon said, it should be sort of limited to a single dose in
> combination with appropriate consolidative therapy, da-da-da-da-da,
> something like that.
>
> In terms of other things, obviously more data, either a complete Study
> 013 or a subset of those folks who are at higher risk of death,
> whether that is coma, whatever that is identified, so that we can
> maybe get by with a smaller n but a higher degree of severity so that
> we can get the data that we really want to know, and in use in
> hospital with kids less than 24 months, if that needs to be the way it
> is done, so that we can get the other biochemical and all the other
> data that we need to get.
>
> So, other than that, it would just be a repeat of everything else
> everybody said.
>
> DR. RELLER: Dr. Glodé?
>
> DR. GLODE: I would just encourage, since it sounds like this drug
> needs to be used in children less than two, that, in addition to the
> neurotoxicity by an exam and a questionnaire, that at least in a
> subset of those children, some biochemical studies, basic screening
> biochemical studies, be done to increase the safety profile for a
> later indication to expand to younger children.
>
> DR. BELL: I think we need more safety information particularly in
> children under two and particularly those given repeated courses. It
> has been said before. I also think it would be helpful to have more
> clinical efficacy information but I would offer the thought that this
> might be considered a noninferiority study compared with parenteral
> treatment and that clinical outcomes\--there is equivalent clinical
> outcome at 24 hours.
>
> Perhaps that is too soon to really make a definitive assessment of
> noninferiority but, perhaps, a few weeks down the line\--I guess what
> I am saying is we don\'t necessarily have to show improvement in
> mortality over placebo. We could show noninferiority compared with
> parenteral treatment which, presumably, historically has been
> demonstrated superior to placebo and maybe that might suffice.
>
> DR. RELLER: I voted yes because I think that, used appropriately, both
> on the efficacy and safety, that it was important at this juncture in
> the drug\'s development and deployment to have a\--the alternative of
> \"no\" is implying that the drug is neither effective nor safe which I
> think is the wrong message. To the extent that we say \"yes\" with a
> very restricted labeling exactly as was requested, no more but not
> less than that the data currently allow, would help accelerate the
> gathering of the definitive information that would be required to
> properly position and deploy the drug.
>
> That was the basis for my qualified yes on both counts. I think that,
> unless, the additional numbers of children and safety is demonstrated
> and that there is clinical benefit that is objective, that can be
> documented with additional studies, that the opportunity to study, so
> to speak, should be as rapidly withdrawn as it might be approved.
>
> Dr. Patterson?
>
> DR. PATTERSON: With regard to No. 3, I would like to see something
> similar to what is on Page 2 of the FDA briefing document for the
> Warning and Precautions and perhaps to even emphasize under the
> Precautions not only referral and evaluation for full curative course
> but also that repeated initial dosing is not recommended.
>
> Also, something with regard to the dosage, the optimal dosage in liver
> disease has not been well studied particularly in patients with severe
> liver disease. Two, with regard to No. 4, the things that have already
> been referred to with regard to hepatotoxicity\--I know that is not
> planned in Study 013. Perhaps there could be a subset, 13A or
> something, or to look at it in Study 015 to at least look at a subset
> of patients with the effect of LFT as placebo versus artesunate.
>
> Also recrudescence. Finally, as a part of the follow-up, to hear what
> the implementation plan is for the education and distribution, both
> the field workers and the community, regarding referral and
> consolidation therapy.
>
> DR. SUMAYA: I am agreeing with practically everything my colleagues
> have stated. I would mainly reinforce the need to indicate clearly
> that this is initial therapy and it must be followed with more
> consolidated definitive therapy as part of a bigger package.
>
> Secondly, again taking comments just made, I think it would be very
> useful, particularly for the WHO, to look, carefully evaluate
> critically with scientific scrutiny how effective the use is of the
> community health workers in both access to the patient and their
> families of this drug and appropriate utilization.
>
> It may be useful, although maybe there are some data that wasn\'t
> presented, on what is the frequency of other illnesses that may be
> considered malaria and so therapy is initiated, but it is not acute
> malaria and is some other illness, and trying to get a better feel for
> the background noise, not only just to get an incidence or a
> prevalence of that but is it leading to other types of sequelae or
> problems in those individuals.
>
> DR. WALD: I think to endorse the use of this single-dose rectal
> therapy we should be able to demonstrate in the placebo study or at
> least some subset of patients that those who receive the rectal dose
> get better sooner and more often of both, that there is a difference
> in mortality or, again, some very objective outcome and that more
> safety data be generated both in those above and below age two.
>
> DR. EBERT: I agree with the comments from the previous committee
> members. I feel that if it is not already available that we need to
> come up with a consensus for an objective scoring, if you will, for
> mild, moderate versus severe cases of malaria so that we can try to
> determine outcome in those various groups.
>
> Pursuant to the accelerated approval, I think we need to have some
> additional data that shows that there is a clinical benefit, whether
> that could be done by completing Study 013 and stratifying by severity
> or other measures, or by doing an additional study, potentially
> either, again, a placebo-controlled study, if necessary, or I am not
> sure whether the FDA is able to accept historical control data but
> potentially something that would show a benefit of this early
> administration.
>
> DR. SHAPIRO: I haven\'t very much innovative to say. I think the issue
> of safety clearly needs to be addressed, particularly in those less
> than two. I would very much prefer to see carefully collected data on
> a rather small number of young children rather than incomplete data on
> a large number of children.
>
> I think the issue of the two-year break point has been rather pivotal
> in our thinking here. I think that should be reflected and up front
> and, for example, on the front cover of this book and not within the
> contents of the book.
>
> I wonder aloud what this decision with the two-year and older
> indication means for Study 013, half of whose enrollees are less than
> two.
>
> The other thing that I agree with is that we should have a mortality
> study. This is really the bottom line. We are trying to save lives
> here. The beauty of the mortality endpoint is that it collects not
> only efficacy but also safety data. It is possible that mortality is
> affected by both factors. I think a very carefully controlled
> mortality study is in order.
>
> DR. RAMIREZ: I think that the types of studies that we all want to see
> in the future is not going to be given by the data from Study 013
> because the sponsor was having different objectives. I was sitting
> here in the last minute and thinking that if I were to\--what I would
> like to see in a study, in a clinical study.
>
> Probably, we need to\--as was mentioned here, time to healthcare
> facility is going to be an important\--first of all, it has got to be
> placebo-controlled and double-blind. We need to control for time to
> healthcare facility and, ideally, we need to have from the same area
> 50 percent because in one area, people are living at twelve hours of
> the hospital. If 50 percent of these are going to get placebo, 50
> percent are going to get the drug, and then, at the end of the study
> we are going to know that once you have 50 percent, when we do the
> median time to hospital care, it is going to be the same time.
>
> Also the problem is that we need to have baseline data time zero and
> then we need to have time 24 hours, some data, because if we wait
> until the patient arrives to the hospital and we look at parasitemia
> there, still we don\'t know what happened, what was the drop between
> placebo and the drug.
>
> If we wait until the patient arrives to the hospital to see what is
> the severity of disease, we still don\'t know if we include severity
> or not. This has to be done by the healthcare person that goes to the
> area where the family is. Somehow, we need to have a simplified Apache
> score for malaria, five points, seven points, something like that. It
> has to be very simple that a nurse who is going to give the rectal
> suppository at twelve hours, we have to figure out some score because,
> otherwise, how are we going to know if, when the patient arrived to
> the hospital, that really the drug is decreasing severity. We will not
> be able to know.
>
> And, at 24 hours, we need to see parasitemia. We need to see severity
> of disease with some formal objective score, and we need to see
> mortality at this 24 hours comparing with time to healthcare facility
> and looking at mortality and severity, adjusted for severity of
> disease. Then we see placebo versus the drug.
>
> Then we need to see at 28 days what happened with the patient because
> there is where we have the neurological sequelae that may be a benefit
> of the drug for early treatment because, again, if you unplug the
> capillaries of the brain eight hours earlier, you may have less
> neurological sequelae than we see with some studies, the early
> oxygenation.
>
> We need to see the 28 days because this may be beneficial. But all
> this will require to me a well-planned prospective study. It is not
> going to be able to have a large study and it is not going to be the
> Study 013.
>
> DR. RELLER: Thank you.
>
> Dr. O\'Fallon?
>
> DR. O\'FALLON: Let me just say with some amusement that we could
> probably do survival-curve analyses on those different treatment
> groups rather than try to do it at such and such a time, just find out
> how long they lived and do survival analysis comparison.
>
> I agree with most of what everybody else has said, so I am not going
> to argue there. But I think my concern, if we are giving advice to
> somebody and I don\'t know who this is, I think we really do need to
> see the data analyzed by age groups.
>
> We haven\'t. The data have all just been blopped in together. I think
> it would help us a lot even now to see the data analyzed by age
> groups.
>
> Another issue that really concerns me is the\--I think some of the
> people were trying to get at it was some people are repeat\--this
> isn\'t their first bout of malaria. Perhaps, in order to understand
> what we are seeing in any of these studies, we need to know how often
> they have had malaria. So there is an immunity issue. I have been
> nervous or uneasy about the data from the adults because it seems to
> me that those adults are the survivors.
>
> They are the ones who have survived previous bouts of malaria. So they
> are, in some senses, more immune. They have some sort of immunity. So
> I don\'t know how much they tell us about what is likely to happen in
> the more naive patients who are presumably the younger ones.
>
> So I just think that there are some issues here in order to interpret
> even what we see that might be very useful. I understand they are
> telling me that Peto is, if not the chair of the DMC, he is the
> statistician on the DMC for this study. This is like bringing coals to
> Newcastle.
>
> But I think that the rest of the world would really like to see this
> data analyzed by some of these issues to see how this proposed therapy
> works for the ones who are the most vulnerable.
>
> DR. RELLER: Thank you.
>
> Dr. Cross?
>
> DR. CROSS: The information today was presented to us as part of an
> approach; that is to say, the single dose of the study drug is not
> being viewed alone but it is being presented as part of a total
> approach. Therefore, I think that we also have to have some studies
> further addressing the recrudescence rate.
>
> For example, if you look at the pivotal studies 005, 006 and 007, it
> turns out that the recrudescence rate with the artesunate is actually
> fairly low in Thailand and South Africa but it is very high in Malawi.
> Some of the initial presentations in our documentation, it was not
> clear whether the 28-day recrudescence was the sum total of the
> artesunate plus the consolidation therapy and, if so, are there
> differences in those combinations that we really have to pay attention
> to, or is the explanation for what is happening in Malawi what Dr.
> Binka said, and that is there is a very high rate of infectivity of
> the mosquitoes and what we may be seeing, therefore, are new cases of
> malaria occurring in a very short time.
>
> I think at least one way to address this is to have a better
> characterization of the malarial parasites that are obtained at
> recrudescence; that is, are these the same or different parasites. We
> have to have some common definition of how we go about this.
>
> Are we looking at this through PCR only, or PCR and smear, both? I
> think that has to be defined. So, in short, I think that the 28-day
> recrudescence rate really is an opportunity for us to get further
> information that really hasn\'t been addressed. As I said, we need
> more data on the actual parasites themselves, how common is the
> recrudescence in Southeast Asia, for example, versus Africa.
>
> Then, finally, I think the World Health Organization has to have some
> plan implemented, perhaps not in the short term, but how will they
> monitor drug resistance. All of us this morning expressed some concern
> about that. I think that, as this is put in the field, we have to have
> some way of capturing that information early.
>
> DR. RELLER: Thank you.
>
> Before concluding, two comments. First, I apologize to Dr. Sumaya who
> is like in the rear-view mirror in my blind spot here, so I don\'t
> think I specifically asked him when the votes took place. I will try
> to do better tomorrow.
>
> As regards tomorrow, we have a very full agenda. We have guests,
> consultants from overseas who have to return there. So we must stay on
> schedule. Consequently, I would like to ask all of the committee
> members who will be participating tomorrow to please arrive by 8:20.
> We will start sharply at 8:30 and I shall seek to be ruthless in
> adherence to the time table so that we can complete all of the
> discussions that will be required for reasonable decisions.
>
> Thank you, sponsor, FDA, committee members, for the rigorous
> discussions. The meeting is adjourned.
>
> \[Whereupon, at 5:20 p.m., the meeting was recessed, to be resumed at
> 8:30 a.m., Thursday, July 11, 2002.\]
>
> \- \--