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DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC MEETING ON FDA'S PROPOSED REGULATION
Monday, October 27, 1997 Cohen Building Auditorium
P A N E LFDA AAP
C O N T E N T SPAGE NO. William B. Schultz 4 PANEL 1: WHEN ARE STUDIES NEEDED?Sanford N. Cohen, M.D. 17 PANEL 2: COMMENTS ON TESTINGArthur J. Ammann, M.D. 51 PANEL 3: SPECIAL CHALLENGES TO TESTING CHILDRENEmmett Clemente, Ph.D. 105 PRESENTATIONS FROM THE AUDIENCEDr. Gregory Kearns 141
P R O C E E D I N G SMR. SCHULTZ: Good morning and thank you for coming. My name is Bill Schultz. I am the Deputy Commissioner for Policy at the Food and Drug Administration. This is the agency's public meeting on its proposed regulation that would require pharmaceutical manufacturers to assess the safety and efficacy of new drugs and biological products in children. This is a problem that is I think familiar to everyone in the room. Most drugs that pediatricians use today in children have never been tested in children and during the past several years, FDA has tried to address this problem in a number of ways. We have through the pediatric page in New Drug Applications and through conversations with drug manufacturers tried to encourage companies to do this sort of testing prior to the time drugs are approved. In 1994, we issued a rule that both required manufacturers to survey existing data and determine whether those data were sufficient for supplements that would be sufficient for pediatric indications, and while that requirement yielded some results, it clearly was insufficient. In addition, in 1994, we significantly simplified the testing required to get pediatric indications on drug labels, but we have recently gone back and looked at the situation, and it is clear to us that these efforts haven't solved the problem. Today, it is still true that about half of all new drugs that are approved by the agency, that are likely to be used in children, lack sufficient information to support their labeling for safe and effective pediatric use. So the proposed rule that the agency issued last summer, last August I believe, is intended to address this problem. The agency has indicated that this is a high priority for the agency. The rule was announced by the President and then Vice President. It is a high priority for the administration. But we also acknowledge that there are many difficult issues involved and many considerations that we need to take into account before we fine-tune the rule in a way that it works for the drug companies, for children, and in a way that the agency can implement it, and that is why we have taken the step of having this public hearing. We felt that the typical notice and comment route wouldn't get us the best information for this rule, and so we certainly appreciate the time that the panelists have put in, their willingness to come, and the willingness of everybody here to come and be part of this hearing. The proposed rule looks at this problem from two perspectives. The first one is new drugs, drugs that haven't been approved, but where companies have done the testing and have come to the FDA with a New Drug Application. Essentially, what the rule proposes to do is to create a presumption that new drugs should be tested in children, but then it would go on to say that that presumption can be overcome if the manufacturer demonstrates that the product is likely to be unsafe or ineffective in children, or that pediatric studies are impossible, highly impractical, or that reasonable efforts to develop pediatric formulations have failed. On the other hand, for drugs on the market, the rule would give the agency the authority in compelling circumstances to require pediatric studies for drugs that are widely used or that are used in very significant or life-threatening illnesses. Again, I want to emphasize that this is a proposal. We are in the middle of the public comment period which closes on November 13th. Everybody is invited to submit comments after this hearing up to that date, that time. Because of that, the agency won't give any indication of where it is. I mean we are still listening to comments, and so on, and I want to make it clear that in terms of this panel, everybody on my left, on your right, represents the Food and Drug Administration. We also have panelists from the American Academy of Pediatrics on your left. We will all be asking questions of the panelists who will be presenting to us, but nobody should take anything that anybody from the agency says as an indication one way or another, and certainly nothing that the other panels up here say would represent where the agency is. I would like to now introduce the panel sitting here. To my left is Dr. Paula Botstein, who is the Acting Director of the Office of Drug Evaluation III in our Center for Drug Evaluation and Research, and she has really taken the lead in the Center for Drug Evaluation on this issue of what the right standards are for pediatric studies on drugs. Next to her is Ann Witt, who is the counsel in the Office of Policy, and has taken the lead in developing the regulation. Elaine Esber is next to her, who holds the position in the Center for Biologics that is similar to the position that Dr. Botstein holds in the Center for Drugs, so she has the lead there. On my right is Dr. Robert Ward, who is the Chairman of the Committee on Drugs in the American Academy of Pediatrics. Next to him is Catherine Wilfert, who is the Chairman of the Committee on Pediatrics AIDS in the American Academy of Pediatrics. Next to her is Dr. Ralph Kauffman, the former Chairman of the Committee on Drugs in the American Academy of Pediatrics. I would now like to have Dr. Ward make a few opening remarks. DR. WARD: Thank you. I want to thank the FDA for its efforts to improve drug treatment for children through the August 15th rule that is intended to increase labeling of drugs for children. Many of us in this room have sought to address this need for several decades. Drs. Cathy Wilfert, Ralph Kauffman, and myself bring our special interest in pediatric drug therapy to this meeting through the support of the American Academy of Pediatrics to help address several important and difficult aspects of this rule. At the end of this public meeting, we hope to have assisted with the implementation of this rule through discussion and comments from families, clinicians, scientists, industry, and ethicists. Hopefully, these discussions will enhance the goal of improved therapeutics for children. We recognize that effective implementation must include practical approaches to the selection of drugs to study and to the design of studies, to strike a balance between the needs of children and the costs to industry. This can only be achieved through collaboration among the FDA and the pharmaceutical industry, pediatricians with expertise in pharmacology and the study of drugs in children, and the community of all pediatric specialists who are called upon to treat an enormous spectrum of childhood illnesses ranging from HIV to hypertension, and from RDS to OCD. It is a challenge to decide which drugs to study and when during development from the premature newborn to the adultlike adolescent. The decision of when during development to study specific drugs will have to be determined by the specific metabolic and clearance pathways for individual drugs usually determined from studies in adults. More basic science study of the developmental changes in organs and enzymes responsible for drug clearance, such as the cytochrome p450 enzymes, is needed to determine the ages of greatest change and degrees of immaturity for these enzymes and organs. These last few decades have seen significant advances in the speed of drug approval by the FDA, but limited success in stimulating labeling of drugs for children, at least labeling that identifies dosage guidelines for new pediatric populations. Labeling changes related to wording changes have been made, but these don't significantly improve the therapeutic situation for the pediatric patient. This rule has enormous potential to improve this situation. As indicated in the rule, it contains some very challenging issues that must be addressed. I find one issue quite puzzling. It is almost inconceivable that requiring studies of drugs in pediatric patients could be represented as unethical toward children. Leaving children either to suffer illnesses without drugs that may benefit them or to receive treatment with drugs that have not been studied in children represents the ultimate example of an unethical situation. The pharmaceutical industry, however, has become wary of studies in the sickest children, the very individuals who stand to benefit the most. Many of us practice in intensive care settings where we treat the sickest infants and children daily. We know the therapeutic needs of these patients. In Neonatology, we administer over 95 percent of our drugs off label because of the limited study of drugs in newborns. Now, through the strong efforts of the NICHD, there are centers with personnel, laboratories, and organizations ready to study and support such studies. Other centers not affiliated with the NICHD-sponsored PPRUs have also organized to support such studies, so the infrastructure to advance pediatric therapeutics is present and expanding. The pharmaceutical industry likely fears that they are going to be called upon to study dozens of drugs in children in whom there may be little use and thus little need for study. On the other hand, practicing pediatricians have concerns that potentially important drugs may be overlooked or receive unjustified waivers for study in the context of this rule. Perhaps both concerns are exaggerated. Yet, basing waivers on immature metabolic pathways for a drug, as proposed in the rule, would be wrong and inconsistent with current practice. This could prevent effective treatment of thousands of sick newborns where dosage modifications or therapeutic concentration monitoring could avoid toxicity. This is currently done for aminoglycosides, anticonvulsants, antiarrhythmias, digoxin, and, yes, even chloramphenicol at times. You will hear two quite different opinions about how to decide which drugs need study in pediatric patients. Each of these is going to need to be thoughtfully considered. Consistent with the 1962 Kefauver-Harris Amendment that supported comprehensive testing, one perspective advocates testing every drug in children if the disease occurs in children and the drug represents a therapeutic advantage over existing drugs. Exclusion of children under this perspective should only occur for diseases that do not occur in children, such as prostatic hyperplasia, menopause, or breast cancer. Excluding children is no more defensible than excluding an ethnic group or gender. If children are automatically excluded and industry and FDA decide when they should be included, pediatric patients may be minimally better off than they are now. From the other perspective, as a practicing neonatologist, used to having few drugs labeled for my patients, I think only a fraction of the drugs that are tested and available in adults will be needed for sick newborns. One example might be the group of histamine 2 blockers, when we finally passed from cimetidine with its cytochrome p450-inhibiting actions to ranitidine, this was a significant advancement. Newer H2 blockers after ranitidine, such as famotidine and nizatidine, do not seem to me to represent big enough therapeutic advantages to require study in premature infants of various gestational ages. Now that cimetidine has been largely abandoned in these patients. Every drug submitted will not represent enough of a therapeutic advance in pediatrics to warrant study, but clinicians and scientists can identify which therapeutic situations need to be addressed. These two divergent perspectives must be reconciled within this ruling. An approach that may alleviate or minimize industry and medical communities concerns is to establish an advisory panel to represent the concerns of each. It is simply not realistic to expect a group of physicians and scientists who are removed from the day-to-day practice of various areas of pediatric medicine to know which drugs are the most important ones to study. This is relevant to both the FDA and the Committee on Drugs from the AAP. We both have expertise in pharmacology and policy, but the rapid changes in clinical practice need input from those currently practicing in areas of concern. Because of size, an advisory panel would not be able to function efficiently if they included representation of every relevant pediatric specialty, but a panel could be required to obtain and use input from clinicians and experts in specific areas of pediatric medicine to determine what drugs really need study based on severity of the illness under treatment, the frequency of use, unique pharmacologic advantages of a drug, and the current knowledge base about that drug. In specific situations, each aspect of this assessment may represent an overriding reason to require study for some drug. Frequency of use alone will usually not be the most important reason to select a drug to study. Frequent use will, however, almost always be part of the reason, however, that a drug needs study. We do not underestimate the challenges that the pharmaceutical industry may face, such as the need for new formulations of drugs that are palatable. Every pediatrician and parent who has worn their child's dose on their jacket knows that palatability is important. Discussions with representatives of industry have emphasized how difficult it can be to develop appropriate formulations. Yet, some companies are having success with unique and often secret approaches to this chemistry. It may be a challenge, but we expect it to be surmountable most, if not all, of the time. I think pediatricians will be more understanding of this difficulty than many physicians based upon the daily feedback they receive from their patients and their families. Industry representatives, together with the FDA and a panel of experts, I think could best judge when the clinical need warrants more efforts to develop a difficult formulation and when it is time to abandon that effort. I look forward to a productive discussion of many of these issues. At the end of the day, we hope that all involved will have a clearer idea of how important the need for therapeutic studies is for children, their families, and pediatricians, a clearer understanding of the challenges involved in such studies, and a better idea of how these challenges can be addressed, so that children of all ages will benefit from these regulatory changes. Again, I am grateful to the FDA for their leadership in supporting improved therapeutics for children. May we all work together to make it happen. Thank you. MR. SCHULTZ: Let me just take a minute and tell everybody how the day is going to work and then I will call the first panel up. There will be three panels which will all give their presentations this morning. We are asking each panelist to speak for no more than five minutes. After the first panel makes their presentations, and after each one does, then there will be questions from this panel up here. There will be a break between the first and second panel. After the third panel, there will be a lunch break, and as I said, the afternoon is reserved for anyone in the audience who wishes to make a statement, and we would ask you to indicate that to us at the desk right outside within the first 15 minutes after the break. I also want to mention there is a lot to cover here, but we want to ask both the panels and the people presenting this afternoon to keep the focus on the proposed rule and all the considerations that underlie it. That means, for example, that issues, such as the legislation that is now being considered on the Hill, that would address this issue in a different way, granting exclusivity, is not really something we would be considering here, although obviously, the Hill will consider how the two things mesh together, but we want to focus here just on this proposed rule. Panel 1: When are Studied Needed?MR. SCHULTZ: What I would like to do now is ask the first panel to come up to the table. This panel will discuss the subject of when are studies needed, and we have asked them to look at a number of issues and let me just mention what those are. The definition of "widely used" in the proposed role and what should be the definition of a "substantial number" of pediatric patients. These are criteria for when studies would be required. The definition of "meaningful therapeutic benefit," the definition of "very significant or life-threatening illness," and the study requirements for drugs that are already on the market. The first panelist is Dr. Sanford Cohen. He is with the Children's Hospital of Michigan. Please begin when you are ready. DR. COHEN: Thank you, Commissioner Schultz. My name is Sanford Cohen, as you indicated, and I am Professor of Pediatrics at Wayne State University and at the Children's Hospital of Michigan in Detroit. I have been an advocate for the study of drugs in children for most of my professional career, certainly for more than 30 years. I have the pleasure currently of chairing the Network Steering Committee of the Pediatric Pharmacology Research Unit program, the PPRU so called, a position I have held since the inception of the program in 1993. This program is funded as a cooperative agreement by the Center for Research in Mothers and Children of the National Institute of Child Health and Human Development. The PPRU program exists to provide a focus for research into pediatric pharmacology issues and to train pediatric clinical pharmacologists, but its main objective is to study drugs in children, so that proper labeling can be developed to guide pediatric use. I am honored to have been invited to join such a distinguished list of participants at this hearing, and the topics to be covered here today, as has already been mentioned, are of vital importance to those of us who both provide care for infants and children, and who advocate for their protection and well-being. I believe that the question that heads our panel's portion of the arranged program, that is, when are studies needed, is only pertinent to be approached in that direction for the unique circumstances starting the process of achieving labeling for pharmacotherapeutic agents in the various ages and developmental stages of infancy and childhood. The process that will assure continuing attention to the needs of infants and children in this area should be explored, in my opinion, by asking the question differently, that is, when are studies not needed. Let me explain my position. In the present situation, it is most important that at least one or two agents of each class of drugs defined by their therapeutic effect, that is an important class for the treatment of specific symptoms or disease processes have appropriate labeling to inform and to guide those who provide care for infants and children as they implement therapeutic plans that involve such drugs. The situation that has left pediatricians and other practitioners to their own devices when ordering important therapies for their patients has existed for far too long. It really should not be tolerated any longer. The agency's policies and practices during this transition period should include a method to establish which drugs should be included in this phase of the program to label drugs for pediatric use and to implement studies that will permit such labeling to occur as soon as possible. I might add parenthetically that I am aware of the fact that the agency has embarked on such a plan and I wish to both congratulate it and to encourage it to continue. Of even more importance, in my opinion, however, is the need to establish policies and procedures to assure that all new agents and most new preparations are studied in infants and children while they are under development. It is therefore of vital import that the agency acknowledge that its regulatory authority requires it to insist that agents be tested as early in the developmental process as is practical. Exceptions to the requirement for such testing should be granted only sparingly. The burden of proof for the need for such an exception should be borne by the requester and exceptions should be granted only after the agency has consulted with a body composed of recognized experts who are free from conflicts of interest. It is only in this way that we can assure the parents and children of our country that the medical needs of pediatric patients will be attended to fully. I have no doubt that exceptions will have to be granted and it will be difficult at first to identify and to define the exceptional circumstances that will justify granting these exceptions. However, I also have no doubt that experience with such a system will permit administrative action to modify the procedures and to prevent inadvertent miscarriage from being created by the application of the rules. Our history in this area is replete with examples that should caution us to approach this issue in this manner rather than to begin with the premise that only selected agents will ever be studied for pediatric labeling. It would be wrong, in my view, to perpetuate the myth that such a system can take care of the needs of pediatric patients into the future. Will the approach I am suggesting be controversial? I am sure it will. Will it be difficult to pursue? Naturally, it will. However, my view is that we are obliged to ensure that appropriate pediatric studies are carried out in proper settings, with appropriate ethical and clinical protections. I believe that this is the opportunity to establish the framework for this to occur. Again, I would like to thank you for the opportunity to appear on this program. I will be pleased both to answer questions you may have and to discuss my views in more depth. Thank you. MR. SCHULTZ: Thank you very much, Dr. Cohen. The next presenter is Susan DeLaurentis, who is the co-founder of the Pediatric AIDS Foundation. MS. DeLAURENTIS: Thank you. Good morning. My name is Susan DeLaurentis and I a co-founder of the Pediatric AIDS Foundation, and I am pleased to be a part of this meeting. Elizabeth Glaser started this foundation to promote and support research and drug access for children with HIV, and I am happy that this meeting is taking place preparing to make sure that children are no longer automatically left behind in the progress of biomedical research. Children should not be an afterthought, but they are in pharmaceutical development. Despite encouragement, streamlining, and a range of appeals, drug manufacturers are still not voluntarily testing most drugs for children. The proposed regulation we are discussing today is not only necessary, but also long overdue. It is the presumption today that drugs are not tested in children unless there is a special reason to do so, and even then the testing may come years after approval in adults. This proposed rule is the chance to reverse that presumption. It should be the case from now on that drugs will be tested in children unless there is a special reason not to do so, and that the testing will be carried on simultaneously with adult testing unless there is a special reason not to do so. This is the most important point about this proposed rule. Expectations of drug development must change. This proposed regulation must end the routine exclusion of children from research progress and bring their well-being into the mainstream of pharmaceuticals. In order for this to be accomplished quickly, the FDA should adopt the rule in final form and resolve any questions by erring on the side of research. In reviewing the applicability of this regulation, the FDA should cast its net wide, making as many drugs subject to the reach of the requirement of children's studies as possible. To select whole classes of drugs or diseases as too expensive or too difficult to study is effectively saying that there are children who are not worth the trouble of saving. I cannot agree with that view. Some have argued that the proposed rule is too burdensome on industry. In response, I would first note that the requirements in the regulation can be waived all together if the FDA finds that pediatric studies are impossible or highly impractical. Having said that, I would then also say that this waiver should be used only in the most extreme circumstances. A small patient population should be accepted as an excuse for not doing research only when all reasonable efforts to recruit pediatric patients have failed. This is not a judgment that should be undertaken lightly. In the case of HIV-AIDS, for instance, I can imagine that companies might argue that the patient population available to be studied is too small, but I would remind all concerned that the failure to supply AIDS drugs to children has been at the heart of much of the public and political outcry against current policy. This should be your benchmark. If a waiver is sought that would excuse companies from doing research on a patient population that is the size of the pediatric HIV-positive population, then the waiver should be refused. I would go even further and argue that no group of sick children is too small to command research on drugs that are believed to be effective in adults. The license to introduce drugs into the American and thus the world market is worth a great deal. Is it too much for the nation to ask that drug companies return the favor by looking out for the interests of the youngest patients? Others have argued that the proposed regulation is too costly, a very disturbing argument. The response should be only too costly for what, for healing sick children? Surely, this cannot be the intended meaning of the argument, but if the argument is too costly for pharmaceutical manufacturers to bear, it is hardly credible. I have discussed cost more thoroughly in my written statement, but let me simply say now that the FDA estimates the maximum expected cost to be about $20 million annually. By any reckoning, the number of sick children who stay sick, the number who have unstudied side effects and adverse reactions, the number of needless hospitalizations, or the 8/10,000ths of 1 percent of the revenues of the top 10 pharmaceutical companies that this amounts to is an extremely small cost. In general, the proposed rule is necessary and the Foundation supports its immediate finalization and implementation, however, we believe that the tone and requests for guidance are far too tentative and imply a lack of the courage of the FDA's convictions. Suggesting that the very question of whether the rule should be adopted is uncertain, saying that the agency has tentatively concluded, asking for guidance on costs, all of these actions are out of place in a rule dealing with this subject matter. Inasmuch as the agency has been supported in this action by all children's groups, by medical experts, and indeed by the President, the agency should move forward in an aggressive and urgent manner. FDA requests guidance as to whether there are additional means of achieving the goal of research on drugs in children. Clearly, there are additional means to supplement this requirement, but there is no other means that should be considered in lieu of this requirement. All other avenues can also bolster this proposed rule. None will have the same effect of reversing the current presumption that children are an afterthought. Even as we are here now, the Congress is also working to address the same problem through additional means. In both House and Senate bills to reauthorize user fees, there are provisions to grant extended market exclusivity to companies that test their drugs for children. This regulation is a necessary companion to such legislation. It is also clear from statements of the chief sponsors of that legislation in both houses, Senator DeWine and Congressman Greenwood, that they too envision their legislation and this regulation as working in tandem. I know that drug company lobbyists are even now seeking a version of the legislation that will not be construed to ratify the existence of these regulations. They are openly jockeying between House and Senate language to find the one that will give them millions of dollars in exclusivity, but still leave them the ability to sue to stop these regulations. I hope that the drug company representatives who are here with us today will take back a message. All the lobbyists and lawyers and public relations firms you can hire will not protect the industry from the anger of parents whose children's health is at stake. In closing, let me return to the reasons that this meeting is occurring. From early elixirs to recent AIDS drugs, the problem has never been adequately solved. This proposed rule would make a giant step towards a solution. We must take this step. I don't want to enter into a debate about the costs or burdens to industry when a child's health is at stake. My children are worth every penny I could beg, borrow, or steal, and I believe that Americans all feel the same. I think it is up to those who would oppose this proposed rule to make their case to the American people that children are not worth this effort. Thank you. MR. SCHULTZ: Thank you very much, Ms. DeLaurentis. The next presenter is Dr. Thomas Hazinski of the Vanderbilt University Medical Center. DR. HAZINSKI: Thank you, Mr. Schultz. My name is Tom Hazinski. I am a professor and Vice Chairman of the Department of Pediatrics at Vanderbilt. I am also a children's lung specialist, which means I take care of a small part of the five million children in the United States who have asthma. We think there is probably another million out there who are coughing all night or missing school, and have not yet been diagnosed. So we take care of one of the most frequent childhood illnesses requiring drug therapy, and we also take care of some of the orphan disorders. In addition, my partners and I have participated in Phase I, II, III, or IV trials, about 20 of them in the last five years. In the interests of time, I just want to make four points and I would be happy to respond to questions. First, the question that the panel is dealing with right now, the definition of "widespread use" and "severity of illness," this is a very difficult area to make formal policy in. On the one hand, a disease may be very frequent and be deserving, on the other hands, the drugs may well be safe. By the same token, there are rare diseases which require urgent new drugs and urgent study in terms of pharmacokinetic safety and efficacy in small groups of children. The only answer I conceive to define the question of where studies are needed and when is, as Dr. Cohen stated, a pediatric advisory panel that could review, free of conflict of interest, in a timely fashion, when certain drugs need or need not be studied for pediatric applications. Second, I think that the Achilles heel of the current rule, as written, is the waiver system. It seems to me that a waiver can be granted too easily under the current regulations. The notion of impractical and biologically plausible extrapolation are very slippery concepts and again I think that just favors the notion of an advisory panel to weigh the merits of each individual molecular entity. Academic health centers and centers, such as Dr. Cohen's, are retrofitting or fitting themselves to be eager participants with industry to test these new biologicals and new drugs. There are clinical trials networks being formed. We have one at Vanderbilt which we would like to soon offer to industry to avail themselves of, so that issues of geographical impracticality or not enough patients can be resolved to our mutual satisfaction. My final point is that I believe that the FDA, the American Academy, and academic health centers, such as my own, have a real interest in training our physicians, both physicians in training in medical school and physicians in practice, to resist adopting prematurely formulations that have not been thoroughly tested. We are teaching our medical students and residents an evidence-based approach, and we need to immunize them better against the very skillful advertising and subliminal advertising and the parental and teacher pressures that they have to deal with on a daily basis. So I realize that no one is holding a gun to my head when I prescribe a medicine that has been poorly studied, but I also think that this rule, perhaps modified in the ways I have suggested, could go a long way to helping our children feel better. MR. SCHULTZ: Thank you, Dr. Hazinski. The final speaker on this panel is Dr. Anthony Temple. He is with McNeil Products Company. DR. TEMPLE: My name is Anthony Temple. I am Executive Director of Medical Affairs at McNeil Consumer Products Company. We are a nonprescription drug manufacturer. I also am a pediatrician with a background in clinical pharmacology and toxicology. I feel like I have a personal concern for children's health and I have been an advocate for standardizing approaches to pediatric dosing in the OTC environment for many years, which have yet to necessarily come to pass. Let me begin by stating my appreciation for being asked to participate in today's discussion. I particularly appreciate the opportunity because this gives us a chance to encourage careful scrutiny of policies and processes that could lead to better care for children. Among the many competing priorities for the time and resources of health care expenditures, academic and research interests, the Food and Drug Administration, pharmaceutical manufacturers, and clinicians and other health care practitioners, children need to given more attention. The proposed rule for regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients indicates that it is meant to be part of a comprehensive effort to increase the number of new drugs and biological products with clinically significant use in children that carry adequate labeling for that subpopulation. That is certainly a laudable effort. One issue is whether processes can be put in place and resources allocated to accomplish those processes and achieve the benefits of the proposed rule. As I understand the proposed rule, one of the key questions is when are studies needed of a new drug. To me, that question includes both the issue of whether a drug should be studied in children, and if so, at what point in the developmental process should it be studied in children. New drugs that are likely to be commonly used in children or that represent a meaningful therapeutic benefit over existing treatments are the stated targets of the proposal. The proposal indicates that an initial determination of whether studies are needed for a given drug is slated to be made at a time point early enough that at the end of the Phase II meeting or, at the earliest appropriate opportunity, the agency will notify manufacturers of the agency's best judgment at that time of the pediatric studies that will be required for the product and when the studies should be submitted. When the studies will be conducted will be an important issue. Therefore, one of the issues that this panel is to address really is when is it likely to be widely used in children, when is there meaningful therapeutic benefit over existing treatments, and what studies and when. It seems to me that most drugs are developed because they are expected to have a meaningful therapeutic benefit. When would this criteria not be invoked? With regard to "widely used," the agency has used some potential databases, but if most drugs already exceed the current suggested hurdle of 100,000 physician mentions for pediatric use per year, when would this criterion not be invoked, and how would this data be used for a drug not yet in the marketplace, in the first place? The definitions in the rule are not yet sufficiently clear to have a workable process. Additionally, the proposed rule is inherently fraught with complexity because of the complexity of the nature of pediatric therapeutics. As we go through this discussion, my sense is that we will find that there are no clear definitions that will satisfy the need for a simple way to accurately and fairly implement this proposed rule, because every case will be unique. I am also concerned about the resources of the Food and Drug Administration. Unless additional resources are provided, and unless additional help is available, the challenges to the agency to implement this proposed rule will be enormous. You will need much outside assistance. If it were me, I would postulate that the agency could only do this if they were to establish a substantive standing review committee of pediatric experts in various clinical specialties and with special pediatric clinical pharmacology expertise, with industry input and feedback, which could then have available to them the resources of the agency and then potentially answer the specifics of the questions that will be raised in an attempt to answer the potential for widespread use or meaningful therapeutic benefit for each individual circumstance. It seems to me a very complicated process, but absolutely necessary to be fair and appropriate. When we will talk about how to define these issues today, I think we will ultimately find that each unique case will require new thinking about whether and how and when to do pediatric studies. Even though it may be possible in some cases to decide by the end of Phase II that a drug is likely to be of benefit in children, the timing for those studies must be carefully weighed. It may be injudicious to start studies in children or perhaps even decide what kinds of studies should be conducted until there is sufficient data on effectiveness and safety in adults, which will invariably mean a great deal of flexibility will be required. So, from my perspective, implementation of this rule will require a mechanism to institutionalize within the agency a substantial influx and ongoing use of expertise in the pediatric community with industry feedback, great flexibility in its application, and perhaps adequate incentives to all who participate and who expend resources in this process. There is a similar need for drugs already in the market, but only the same type of collaborative effort, on a case-by-case basis, will be adequate. We need to do a better job at pediatric therapeutics. If there is a substantial commitment to this on the part of all of us, we can make a difference. If there is not, we will not. Simple implementation, perhaps too expeditious, of this rule may not accomplish that. We have to weigh it very carefully. Thank you. MR. SCHULTZ: Thank you very much. Let me start and ask Dr. Kauffman whether he has any questions. Discussion DR. KAUFFMAN: Dr. Temple, you alluded to, at the end of your comments, about how to handle drugs already on the market, but the other panelists did not address that real explicitly. I would like to hear some more discussion as to whether or not the regulation should deal with new drugs not yet marketed and drugs already on the market the same way, should they be separated out and handled differently, and if so, how. DR. TEMPLE: Gee, thanks, Ralph. DR. KAUFFMAN: You can share the burden with your panelists. DR. TEMPLE: I would be interested to hear other people's comments, too, but I don't think you can handle them exactly the same, but I do think that the issue -- my particular concern, as I have reviewed this, is that there is a tremendous amount of insight that has to be applied against each individual case. There is expertise in the pediatric community, there is expertise in the agency, and there is expertise in the industry. That has to somehow come together and to be applied against these issues. In fact, you might apply it a little differently with currently marketed products than you would about new products coming to market, but I think it is the same fundamental approach, that is, bring your group together to discuss the issues and really getting down to what the matter at hand is, rather than providing some arbitrary hurdles under which you might pass. MR. SCHULTZ: Does anyone else on the panel want to add to that? Dr. Cohen. DR. COHEN: I think, as I tried to indicate in my prepared statement, I think that it does need to be a two-tiered system and I am not here to pretend that at this meeting I could suggest to you the ideal system for either drugs already on the market or new ones. The only piece that I would disagree with Dr. Temple on is the apparent support for the concept of starting with a zero base and saying that one has to prove that something is needed. My view is that that is exactly wrong and it should be that one has to have the burden of proof on those who believe it is not needed when we are talking about new drugs. I can't quite understand the argument that we have to, without information about the use of drugs that is extensive for new drugs coming down the pipeline, that someone will be able to make an adequate decision that it is absolutely necessary to do studies which would otherwise not be required. I believe it is a far safer approach to say, and a much more logical, human approach to say, that we really do need to study these drugs except when a case can be made that the studies are not necessary. MR. SCHULTZ: Would you apply the same principle to drugs on the market or a different principle? DR. COHEN: No, sir. As I pointed out earlier, my view is that drugs already on the market need to be handled differently just to clear the decks and move forward. Drugs now on the market, in my view, perhaps could be handled by a consensus agreement of several drugs within each therapeutic class that need to be studied and the proper labels applied, so that we can put that behind us. That is a one-time fix. It is drugs on the market now. If this rule continues to be implemented, we will never confront that situation again. You will always be testing drugs in a forward-thinking manner. MS. DeLAURENTIS: I just want to make one comment. There is 5 million prescriptions written a year for the top 10 unstudied drugs for children that are already on the market, and I think that is a substantial reason to absolutely include drugs that are already on the market in this regulation. MR. SCHULTZ: Dr. Hazinski. DR. HAZINSKI: The 10 drugs listed in the Federal Register are gleaned from databases in 1994. It could be argued that 3 to 5 of those are for asthma, and the NHLBI, your sister agency or brother, or whatever, has already made some very strong evidence-based opinions about the value of Albuterol by inhalation, Intal, and Alupent elixir as to whether more studies are needed or whether we can go ahead and use these. So, some of this list could be cleared quite rapidly by taking advantage of the work of others, and the panel could deal with this in a relatively brief period of time. MR. SCHULTZ: Thank you. DR. WARD: Dr. Hazinski, are there some criteria that you might apply to some already marketed drugs that would not require them to be studied? DR. HAZINSKI: Well, I think there probably are, but I think that would require some collective wisdom of some people smarter than me, free of conflict of interest, and as free of incentives as possible. I think this notion of biologically plausible extrapolation is biologically plausible, but I don't think that should be used to overwhelm other concerns with respect to what we don't know. We don't know what we don't know in some of these situations. Sometimes the urgency of the situation may preclude those sorts of issues and bring a drug rapidly to the marketplace or not. MR. SCHULTZ: What did you have in mind, Dr. Ward? DR. WARD: For example, let me push you on Albuterol. Is there both adequate clinical experience and testing to support its labeling without additional study at this time? DR. HAZINSKI: Albuterol by inhalation figures very prominently in the acute and chronic management of asthma in the expert report issued by the NHLBI, first in 1990, and now just several months ago. By contrast, Albuterol by oral administration is of extremely limited benefit, never studied, fraught with hazards and probably could safely disappear tomorrow with no adverse effect on the asthmatic population. In fact, one would argue that they would be moved onward to much more effective therapy. I should also mention that drugs, new agents, leukotriene receptor blockers and leukotriene antagonists for the treatment of asthma, which have been fairly well studied in older people, are already being marketed to people like me for use in populations for which they have not been studied adequately. I realize those trials are underway and we look forward to those results, but we are already seeing patients referred to us on these medications who have not been given any benefit of currently well-accepted asthma management. So, the premature adoption of some of these agents by well-meaning, but insufficiently educated primary care providers causes a real problem. The question I always wonder is how did these drugs get to be prescribed in the first place, who is responsible for wide use, and at the end of the day, it is people like me that are responsible for that. MR. SCHULTZ: Dr. Wilfert, do you have questions? DR. WILFERT: It seems to me that each of the speakers have advocated not establishing a definition for waivers, but rather placing the authority in a standing committee answerable or within the framework of the structure of the FDA. Is that committee envisioned to review only those drugs, new drugs, which are not to be used in children, and to have as a second function, establishment of priorities for existing drugs which require pediatric approval? MS. DeLAURENTIS: I didn't mention the committee, but we have been talking about that privately, and we also thought it was a good idea, and I think that what you are suggesting there is what we would support, that it is a committee that would not only review the waiver situation, but would also talk about existing drugs. DR. TEMPLE: Let me just comment. I think Dr. Hazinski has just pointed out how important it is that you have to deal with these on a case-by-case basis, because he has talked about Albuterol, in some circumstances it would be appropriate to study, in others it would not, and I think that is what is fundamentally important about this process, that a group gets together to help make those decisions and provide that input. I definitely think it needs to be representation by all concerned, and I have heard a couple of groups say it needs to be people without any conflict of interest. I just don't know that that exists in the world, because I think academic researchers have a conflict of interest and that they want to do academic research, and I think that pharmaceutical manufacturers have a conflict of interest, and they want to manufacture pharmaceuticals. I think we all have a certain degree of this. I think what we need is to stop being too suspicious and try to find a way to satisfy the need of doing better for kids, and so I think it is a bigger group that needs to be involved. MR. SCHULTZ: Dr. Cohen. DR. COHEN: I would agree to take the concept of a lack of conflict of interest out of my statement as Dr. Temple suggests if he would agree to include the condition that all are pledged to take the high road. MR. SCHULTZ: That is always a condition. My grandmother always said you don't ask a barber if you need a haircut, but the barber could be included in the decisionmaking process. Dr. Wykoff is the Associate Commissioner for Operations at the FDA, and I think he has a question. DR. WYKOFF: Several of you mentioned the importance of a panel, an advisory board. At what point in the development of a product would it be taken to the panel? I mean when trials are completed in adults, when trials are ongoing in adults, before the Phase II trials begin? MS. DeLAURENTIS: I think it is complicated because of proprietary information on the part of the drug companies, and so I don't know that the drug companies would ever allow an outside, ad-hoc panel to review information early on to determine whether it was going to be appropriate for use in kids, and so I think that is immediately an obstacle that you have to think about. I think that the group, you know, in my view, I really believe that -- and I am not a doctor -- but I believe that the trials for kids should begin much earlier than at the end of Phase II. I think that there will be appropriate situations where trials could begin at the end of Phase I, and that that needs to be considered. So, I think the panel again it is going to be different situations for different drugs. DR. WYKOFF: It is possible for advisory committee members to become special government employees and to see confidential trade secret information, so that may not be a prohibition. MS. DeLAURENTIS: If that is not an obstacle, I think it would be important to be there as early on in the process as possible, and I know that the FDA has now, with the 1994 plan, put forth its -- you know, the idea now is that you sit down with the drug companies much earlier in the process and talk about their pediatric plans, and so for a committee to be involved in that would be important I think. DR. COHEN: Without trying to flog this issue too hard, let me point out that it is my view that the panel be called to consider the possibility of not studying a drug at the request of the manufacturer, and that the assumption is it will be studied unless such a request comes forward. DR. WYKOFF: If it is not that approach, then, the committee would have a tremendous workload, looking at every possible product that comes along. DR. COHEN: I would concur. I would also say again, as one who has been advocating for this position for a long time, that this sort of idealistic view is the one that we should start with, and that is that the approach really needs to be one that begins with the assumption that drugs will be studied and that only on exception it will make the workload lighter if we follow that suggestion. MR. SCHULTZ: Dr. Botstein. DR. BOTSTEIN: Several of you have talked about the need to look at drugs individually, case by case, to see whether studies in kids should be required. Can you give us some general guidance as to what kind of scope you are thinking of, should this be just for drugs for life-threatening diseases, for serious diseases, for hospitalized kids, for symptomatic treatment, or only for drugs that modify disease? Should it be for drugs that offer a meaningful therapeutic benefit, and if so, is that meaningful therapeutic benefit over nothing, or compared with drugs that are already labeled for kids, or what, or used in medical practice? MS. DeLAURENTIS: One of the things that we have talked about is that, for instance, with an HIV drug for a child, it may not have a meaningful therapeutic benefit over another drug, a protease inhibitor, for instance, but if you look at issues of resistance or issues of toxicity, it may be that that drug needs to be used in a child, and studied in a child. It is sort of you could call it a me-too drug, but it could save a child's life, and I think it is really hard to put a number on what is the number of children who are important enough to potentially save their lives. I don't know how you do that. I don't know that you say -- how could 50,000 kids be a number or 100,000 kids, or why isn't it 10, and if it's your child, don't you want that one child to be included in those studies. DR. HAZINSKI: One approach to get some sort of guidelines -- I am not smart enough to do that -- but one approach would be to take advantage of the resources of the Academy or pediatric research societies, or subspecialty societies, to ask them what drugs are they least comfortable with, what would it take to increase their level of comfort. You know, they are the end users, and that would be a way to do it. DR. COHEN: That would work for drugs already on the market. That would work for drugs already on the market, and I agree with you. DR. HAZINSKI: By extension, you know, what disorders are most needy of new approaches. DR. TEMPLE: Paula, I think your question is searching for what is a meaningful definition, which groups should we be looking at, which groups don't need to be looked at. I have thought about this a lot, because this was not an issue for me. I cannot come up with a rational way to solve this without it being an interactive discussion between the parties involved, and I think that it is going to be very difficult to get more specific than that. You know, when a manufacturer comes in with a drug that says it is likely to work here, and it is not likely to work there, there has to be discussion about that, and I think that is when you have to begin the discussion, and somebody has to win. I think it has to occur before you go out and make the decision. MR. SCHULTZ: Ms. Witt. MS. WITT: I have a question that is not specifically listed on your list of issues, but I think it is included within the scope of this panel. Dr. Cohen mentioned that he thought once this rule was implemented, we wouldn't have to worry about marketed drugs anymore, because all new drugs would be included. One aspect of this rule, as proposed, that might not work the way I think you are anticipating. As it is currently drafted, it applies to new molecular entities for their first approved use, and we specifically did not include subsequent indications, subsequent dosage forms, but we asked the question. We asked for comment on whether that was the appropriate line to draw, and I would be interested in what this panel thinks about that question, about whether we should have also included new indications and new dosage forms or some subset of them. DR. COHEN: You are right, of course, that I was addressing only the specifics of the initial indication for drugs on the market. I believe that when new indications come along, be they pediatric or not, that it would be important for the agency to have, as I believe it does have, regulatory responsibility for and assume the authority to require studies to establish that that indication is indeed an appropriate one to add to the label. I think therefore, and just following that, that the drug on the market, that comes along with a new indication, ought to be studied in children unless there is a reason not to study it for that new indication. I would treat it as though it was a new drug. DR. WARD: Could I just respond? There are several examples over the decades of new formulations that have been particularly toxic in pediatric patients, and so I think testing of those new formulations is really going to be essential, at least for safety, to help define when there is a population at risk and when that formulation contains something that we haven't anticipated to be a problem. MS. WITT: Dr. Temple, would you like to respond? DR. TEMPLE: Well, if it is a safety issue, the first indication, unless you are substantially changing the dose, meets that criteria, but it still may not meet the second criteria. I think there would probably be some cases where second indications, it might be useful to study in children, but I think you get at the heart of most issues with the first indication. MS. WITT: Thank you. MR. SCHULTZ: Dr. Esber, do you have questions? DR. ESBER: Yes, I do. Related to one of the questions, but a little extension beyond it, is the issue of severity of illness. The way the question has been posed, it has directed the questions to disease conditions which are severe, but the proposed rule also applies to biological drugs in its broadest sense, which includes in vivo diagnostics, as well as preventives, such as vaccines. I wonder if the panelists would comment on this committee structure or some of the other suggestions that have been made as it would apply to, let's say, an imaging agent for a cardiac problem in a child or imaging agent for a tumor diagnostic or other such in vivo diagnostics, as well as for vaccines. DR. COHEN: The only comment I would make -- and again it may be very simple minded, and too simple minded to have any weight -- but if you start with the premise that it is going to be used in children, it should be tested in children, your answer is evident it seems to me. That is why I believe the simple-minded approach, if I may suggest that that is what it is, is one that is useful for us to begin as a baseline premise, modified along the line as you must, but start with that premise in my view. MR. SCHULTZ: Does any other member of the panel here have questions? Would any member of the panel like to say anything additional? MS. DeLAURENTIS: I would just like to second what Dr. Cohen said, that it is about changing the presumption and changing the paradigm, that the past has always been about leaving children out and now moving into the future, what we need to do is say that drugs need to be tested in children unless there is a really good reason not to, and to start from there and move from there. It is hard for me to understand why anyone would not want to start from there, and worry about the health of America's children. DR. HAZINSKI: Just one observation. Dr. Cohen keeps using if it is going to be -- a comment -- if it is going to be used in children, it should be tested in children. The "if" is the question and I am not sure we have resolved that fully. DR. COHEN: I was addressing the specific question that Dr. Esber asked, and that has to do with diagnostics for pediatric conditions, and that defines that it is going to be used in children. My earlier comments, one specifically assumed that drugs will be used in children, and it is only those that can be established with a burden of proof on the requester that it won't be used in children that it could be excluded. MS. DeLAURENTIS: There are clearly drugs, as Dr. Ward said in his statement, that will not be used in children. Children don't get prostate cancer, they don't get breast cancer. Those are the drugs that clearly do not need to be tested in kids, but otherwise I think the burden of proof is on the pharmaceutical company to say that we don't think this drug will be used in children and they have to prove why it won't. DR. COHEN: I would add it is not only the manufacturer that might request the exception. It seems to me that others might come to the manufacturer and suggest that they think an exception should be granted. Don't ask me for an example. What I don't want to do is to indicate that I am taking a position that is putting a burden on industry alone. I am taking a position that I hope will be seen as protecting the welfare of children, and there are many ways of doing that. MR. SCHULTZ: I want to thank this panel. I found the discussion excellent. I think there were a number of new points made or new ideas that I know we will consider. I want to thank you. It is twenty after 10:00. We will take a break until 10:35, and at that time begin With Panel 2. [Recess.] Panel 2: Comments on TestingMR. SCHULTZ: We are going to start with Panel 2 now, which is going to discuss issues around testing drugs in pediatric populations including issues such as extrapolating through pharmacokinetic tests, from adults, defining dose ranging, what age ranges should be tested, issues around neonates, and issues about how many patients need to be tested. We will begin with Dr. Arthur Ammann, who is the President of the American Foundation for AIDS Research. DR. AMMANN: Thank you, Deputy Commissioner Schultz. I would like to begin by making some general comments and then moving to the specific issues. I personally believe that we are currently confronting a worsening crisis in pediatric drug development just because we have an enormous gap in the number of drugs that have not been adequately evaluated. To help people understand how unjust and tragic the current situation is, I will use an analogy. What if other laws that affected individuals of all ages were selectively applied to adults and omitted children from consideration? Let's take, for example, laws passed by Congress to ensure that buildings we all work in are safe from environmental toxins. What if we knew that there were several hundred toxins that everyone was exposed to on a daily basis and the agency responsible for making sure that those toxins were studied and removed said we will enforce our congressional mandate for all of the buildings that adults work in, but not for schools? We will allow a voluntary cleanup program for schools only. What if waivers were provided just for schools because there are fewer children or because it might cost more money to include schools? This is precisely what some of the issues are in the new FDA rule. It says that we will grant waivers for children alone. It says that if it will require extra work or additional money or additional time, then, the availability of safe and effective drugs for the sickest of our children in this country is least important. It says that if it is going to be a burden to the FDA or a burden to the pharmaceutical company, we are going to consider waivers. I need to make it clear it also says that the FDA will ignore the congressional intent and the authority it has already been given to make certain that all drugs are safe and effective for all individuals for their intended use. Let me address some of the specific issues. New FDA rules and voluntary methods have failed. We have heard that in the previous testimony. The inescapable conclusion is that the FDA has allowed the gap between drugs approved for adults and drugs approved for children to widen to the greatest number in the history of modern drug development. Formalization of deferrals and waivers will further threaten our sickest children, and let me now be specific. Here are some of the deferrals and waivers that are suggested. Deferral until information on adults is collected. No deferrals should be granted for serious and life-threatening diseases where there is no substantial difference between the disease and the anticipated effect of the drug in children or adults. To grant a deferral under these circumstances would substantially delay the availability of life-saving drugs for the pediatric population, and this cannot be rationalized scientifically, legally, or ethically. Deferral because collection of pediatric data might delay the availability of drugs for the adult population. Under no circumstance should drug availability be delayed for adults, however neither should the pediatric population be held hostage. It is already too easy for a pharmaceutical company to take advantage of the fact that the FDA has not delayed approval of a drug because pediatric data has not been submitted. There are other options available. The FDA could provide a limited approval, such as restriction of advertising or distribution without reimbursement until pediatric data is supplied. If pediatric data continues to be unavailable, the FDA should use its current authority to initiate legal proceedings. It is unfortunate that some members of the pharmaceutical industry are already attempting to incite the public against the pediatric community by suggesting that a requirement for pediatric data will slow the drug development for adults. I find this particularly offensive. It attempts to pit children who cannot speak, cannot vote, cannot lobby, against adults who can. Further, we know it is simply not true. Waivers. The product does not represent a meaningful therapeutic benefit over existing treatment. This has already been discussed. However, this waiver, if enacted, would selectively discriminate against children. Would a seventh anti-cancer drug or a tenth anti-asthma drug be considered a non-meaningful therapeutic benefit for children, but meaningful for adults? These are pharmacoeconomic decisions, and not decisions within the FDA's current authority. The pharmaceutical industry has itself determined that it will provide data for a drug even if the drug is not a meaningful advance. For example, three growth hormone products for children from three different manufacturers, all of whom provided safety data and efficacy data, are currently approved. Waivers because populations are too small or geographically dispersed. Such waivers should not be granted. No experimental drug should be administered to a child with a serious and life-threatening disease without the requirement that some safety data and pharmacokinetic data be obtained. Protocols can be designed to capture children in geographically dispersed areas, and further, many safety and pharmacokinetic studies are already performed using blood samples which must be shipped to distant laboratories. The drug was not likely to be used in a substantial number of pediatric patients. This is unacceptable. As best translated, if the pediatric market is too small, the pharmaceutical company should not be required to perform pediatric studies. The agency's role, and one of its most important roles, is to assure the safety and efficacy of drugs, and not to consider pharmacoeconomic claims for exemption. Further, to suggest that a waiver could be based on the number of prescriptions written also suggests, one, that the drug is already in use and being prescribed without adequate safety data, and it does not take into account how much information will be obtained and by whom; and three, does not take into account changes in the number of individuals with a disease or number of drugs available. Where the cost would justify a pediatric waiver. This should not be the basis of waiver. There have already been attempts to exaggerate the cost of pediatric studies by using cost data from pediatric AIDS clinical trial groups or cancer studies. These estimates include payment for many areas that are peripheral to actual drug safety and pharmacokinetics, such as payment of academic salaries, nurses, social workers, et cetera. Pharmaceutical companies are not constrained in adjusting their final drug costs based on the cost of pediatric studies, just as they are not constrained to adjust their final cost on required studies for adults. Reasonable efforts to develop a pediatric formulation have failed. This is a very important consideration because it is one of the considerations that has held up safety and efficacy studies, and dosing studies especially for infants. However, this should be the basis of a waiver. The reasonable effort waiver would be used primarily to argue cost and resource issues and would select against pediatric formulations for the newest therapeutics for serious and life-threatening diseases. Even if a waiver were granted under the latter circumstance, the pharmaceutical company should be required to allow other manufacturers with appropriate agreements to attempt to formulate the drug for pediatric use. The "we can't do it or won't do it and won't let anybody else do it" position continues to hold the pediatric population hostage. If a pharmaceutical company is economically or technically incapable of developing pediatric formulations, they should with appropriate agreements be required to provide the drug to requesting parties for pediatric formulation. If a pharmaceutical company is unwilling to release its drug formulation in a timely manner, they should not be permitted to maintain developmental rights. There is a suggestion that a waiver be granted because of undue burden or minimizing the burden, and this is used in reference to manufacturers in the FDA. This reviewer suggests that the undue burden as a consequence of lack of dosing and safety data has been inequitably placed on the sickest of American children. The FDA has not been granted the authority to ease the burden of performing drug and safety dosing studies if the drug is indicated or likely to be used in the pediatric population. Already marketed drugs. Waivers should not be granted for already marketed drugs if they are indicated for pediatric use. It is not appropriate to rank these drugs in relation to the severity of disease or other qualifications. Adverse events are not confined to drugs used only for serious and life-threatening diseases. Studies on different age groups. It is appropriate to consider whether dosing and safety studies should be required in all pediatric populations on a drug-by-drug basis in terms of the age groups to be evaluated because of differences in drug indication and physiology. Notwithstanding this, however, the FDA should not routinely determine that all drugs for serious and life-threatening diseases be sequentially evaluated first in older children and later in infants and last in newborns, or first in adults and then in children. In many instances, it is entirely appropriate and necessary that drugs be first evaluated in infants. Quantifying societal costs of adverse reactions or lack of approval. This is not a waiver, but is an attempt to get at what is the extent of the problem. It is difficult to get the data, but with HIV-AIDS, which has been more closely tracked than other pediatric diseases that are serious and life-threatening, it can be estimated that the two-year delay in the evaluation and approval of AZT in infants resulted in a delay in the initiation of AZT-G076 to reduce maternal infant transmission of HIV. The subsequent two-year delay in the availability of study results can be estimated to have resulted in 2,000 unnecessary infant deaths during that two-year period. Further, since there is more than a two-year delay in the approval of antiretroviral drugs for infants, and only five of 11 drugs are currently approved for infants infected with HIV, it is likely that as many as several thousand additional infants have unnecessarily rapidly progressed to AIDS or death as a result of the lack of availability of new and more potent antiretroviral drugs. In conclusion, I suggest the following potential remedies. In suggesting the remedies, the principle which presides is that the FDA already has the existing legislative and legal authority to require pediatric studies. Therefore, the FDA should use its existing legislative and legal authority to require pediatric studies for all drugs for serious and life-threatening conditions including new and already approved drugs. The drugs which require studies should be determined by the Secretary utilizing an advisory committee or committees of pediatric specialists who have knowledge in specific pediatric diseases and drug development, as well as child advocates. This has been almost a universal recommendation by all of the panel members. The concept of formally identifying waivers and deferrals should be eliminated from the proposed FDA rule. Waivers should not be granted on a pharmacoeconomic basis or on technical difficulties or on cost of formulations unless the pharmaceutical company is willing to provide all of the details of the scientific formulation efforts and costs, relinquish formulation and marketing rights with reasonable royalty agreements to private or governmental parties, so that they can develop pediatric formulation. Failure to provide pediatric data or formulations in a timely manner should be remedied by the Secretary by filing an injunction with a penalty which the court could order. Fees awarded to the FDA should be used solely for pediatric formulation in this area and dosing studies for generic drugs which require studies, which have generally not been addressed by this panel. MR. SCHULTZ: Dr. Ammann, could you please conclude. DR. AMMANN: There is another alternative and that is Congress could enact a pediatric drug user fee, which could be used to assist in developing the data that is necessary. In summary, the proposed new rule has a porosity which is unacceptable. It will worsen the inequities which already exist regarding the availability of safe and effective drugs for children, and continue to segregate children into a category for which drugs for serious and life-threatening conditions are not evaluated for safety and dosing. MR. SCHULTZ: Thank you. The next presenter is Ms. Wendy Goldberg, who is a patient and family representative. MS. GOLDBERG: Good morning. My name is Wendy Goldberg. The Academy of Pediatrics asked me last week if I would participate in this hearing. Despite about 26 hours a day of reading and researching on this subject for the last seven days, I have become neither a scientist nor a doctor. Not even close. I have learned that you have a very hard job. I guess I should begin by giving you some background. I have multiple sclerosis, and have had it for 16 years. I do not go to doctors, I do not take medication, and I would not participate myself in any clinical trials. I have five terrific children. The youngest, Abby, is six years old and has severe asthma. She takes nine medications every day and still has a hard time. We start the morning with a three-drug nebulized cocktail - Proventil, not approved for children under 12; Atrovent, also not approved for children under 12; Budesonide, not approved at all in the United States. We then move to Propulsid, not approved for children under 12; Accolate, not approved for children under 12; Flonase, not approved for children under 12. She finally has breakfast and then takes Medrol, not approved for children under 12. Well, you get the picture. Some of these medicines are not even available in a form I can give Abby. I need to cut two of them in half. One is scored, so I can break it. She is bigger now. When she needed quarters, that was really hard. The other is coated, and like a little stone. I got a gadget from my pharmacist that is supposed to cut it in half, but it doesn't work exactly right. Do I give her the big "half" or the small "half"? I usually give her the big piece in the morning on the theory that if something really bad happens, at least we will all be awake. This adds yet another level of anxiety to the day-to-day care of a sick child. I have read these proposed regulations more than eight times. I still don't quite understand them. I think they are about both new drugs and drugs currently on the market. Do all drugs need to be tested in children, or only those that may be helpful in treating children's diseases? Does the drug company or the FDA make that determination? What about drugs for diseases that occur only rarely in children? Is that what the waiver sections refer to? Are the studies to be done in parallel or only after adult trials have shown the drugs to be safe and effective? Does every test run on adults also have to be run on children? Or can the tests be just for dosage? How much longer will this delay making drugs available? I guess I also don't quite understand the results of the rule change in 1994. Has all that information been reviewed and put into the base of knowledge about drugs already on the market? If so, why isn't that information included on the packaging label? If not, why not? If not, should the rules be changed again so soon? Obviously, this is a complex and difficult issue, and I have more questions than answers. But I do know one thing - i use a lot of medicines on Abby that are not approved by the FDA for use on children in her age. I guess you all agree that testing is a big issue, but I feel as though I am testing drugs on my own child, every day, and it isn't even helping anyone else. How will I explain this to her when she gets older? How would you explain it to her? How would you explain it to your own children? How will she explain it to herself? If you asked me to try a new asthma drug on Abby, having shown it was safe and effective in adults, to learn the correct dosage and pharmacokinetics -- a new word for me -- and if my doctors recommended it, I think I'd say okay. I already have a sick child. I am already at the point where I say, "I will do anything to make her better." There is already a great unknown, and a great risk for me, for her, and for our family. Every day I am already worried. Every night when I hear her coughing, I am already worried. Every time I give her a piece of a tablet, I am already worried. I don't think you could scare me any more. If we could work together to gather information and understand the effect of these medicines, we would be making great progress. It seems to me that there is a lot of information out there, both in the store of general knowledge, the experience of doctors, and in journals about the use of these medications. Albuterol has been around for almost 20 years. Drug manufacturers, physicians, and the FDA must know by now the correct dosages for children. How can't you? There are other drugs for which the same is true. Abby has been taking some of these drugs her whole life. That is six years. For these medicines, there must be a well known and well understood standard of care. Why can't it be codified? Is that a fear of litigation weighed against the health and well-being of children, of my child? My anecdotal evidence should be helping others. I understand this is not the same as controlled testing and the general standard of scientific study. But I am talking about medicines that are already being used in pediatric patients, in some cases for decades. Let's be practical and use common sense. There are other issues as well as safety and efficacy. The time factor is a major issue. I understand it takes 12 to 15 years to fully develop a drug and make it generally available. That is an entire generation of children. What can we do to move the process along without compromising safety? Can they be fast tracked, like the new AIDS therapies? Cna you use more market incentives, like the Orphan Drug Act or the legislation now before Congress? In this new world of the global economy, what about global regulation? The Budesonide I get from Canada has labeling about safety and dosage for children down to three months old. Can't we cooperate and use some of this data in our own country and in our own regulatory process? I think, too, perhaps parents don't understand enough about drug testing. If there was a more clear and simple communication, there might be less reluctance to enroll in clinical trials. You are already looking to a group of parents willing to go to great lengths to help their children. In some cases, all that is needed is a few more forms or a little record-keeping or an extra doctor visit - a small price to pay for a chance at a healthier life. The expense issue also cannot be overlooked. If it takes $60 million or $500 million to bring a new drug to patients, we cannot impose rules that make this an even bigger burden. Again, a balance needs to be found between the expense of testing and the danger of moving too fast to save money. It seems to me that market incentives might help, using and expanding market exclusivity, or giving research and development tax credits. It also seems to me that there are too many lawsuits and the damage awards are way out of line. They don't cure children or make doctors and companies more careful. They just make things more expensive and make people afraid to help children, afraid to help Abby. In conclusion, I would say there should be more testing of all drugs for all ages of children, from neonates to adolescents. But I would say you should be able to do this while speeding up the time it takes to make new treatments available and without pushing the costs out of sight. It seems to me that the key is to be practical and use common sense. Maybe these applications need to be looked at individually. Maybe a blanket rule just does not work. Just as each disease and each drug is different, each application is different and should be looked at on its own context and on its own merit. Certainly, some broad parameters should be drawn, but trying to regulate for every possible situation risks making every situation impossible. I am willing to trust you, all of you, to use your experience and good judgment. Please get started now. Thank you. MR. SCHULTZ: Thank you very much. The next presenter is Dr. Gail McCarver, Associate Professor of Pediatrics and Pharmacology, Children's Hospital of Michigan. DR. McCARVER: Good morning, Commissioner Schultz, members of the panel, and guests. As stated, I am an Associate Professor of Pediatrics and Pharmacology at Wayne State University in Detroit, Michigan, and I am an attending neonatologist at the Children's Hospital of Michigan. My previous experience, however, includes several years as a general pediatrician in private practice and in training in clinical pharmacology within a Division of Internal Medicine. I have the pleasure of currently serving on the American Academy of Pediatrics Committee on Drugs, however, the comments I will be making this morning reflect my personal opinion and not those of any organization or institution with which I am affiliated. I will be addressing two issues - first, the extrapolation of adult safety and efficacy data to pediatric patients and the inclusion of neonates in labeling. For most drugs, adult pharmacokinetic and pharmacodynamic data should be generated and used in planning pediatric studies. However, extrapolation of adult data is unable to replace pediatric studies because morphology, physiology, disease process, and response to treatments differ in pediatric patients compared to adults, children may exhibit different efficacy requirements and may experience a different range of adverse drug reactions. These reactions are not necessarily predictable from the adult experience. Several historical examples, such as that of chloramphenicol, can be recounted. The application of adult data to pediatric therapeutics is complex and will require drug by drug consideration. The specific enzymatic pathway or pathways responsible in adults must be known, as well as to what degree that pathway is active in children of various ages. In addition, likely alternative pathways must be recognized and the ontogeny of these pathways defined. Data defining the ontogeny of drug-metabolizing enzymes must be from studies in children or in human tissue, because dramatic interspecies differences are well recognized. Importantly, if human data about the ontogeny of enzymes responsible for metabolism are not available, extrapolation from adults based on weight or body surface area is likely to be erroneous. To decide how to interpret adult data, the clinical importance of the observed differences in drug disposition must be estimated. In some cases, adult data will be highly relevant. For example, adult data about drugs that are metabolized by pathways that are known to exhibit genetic polymorphism are extremely important. For such drugs, information about efficacy and toxicity in adults, who are genetically poor metabolizers, will be highly relevant to pediatric therapeutics. For instance, if a drug is metabolized by n-acetyl transferase, newborns and young infants would be expected to behave like adults who are genetically slow acetylators. In conjunction with the information regarding metabolic capability, specific knowledge of the efficacy and toxicity of the active moiety and any toxic or active metabolites must be known. Further, the narrowness of the therapeutic window, as well as the seriousness of morbidity from either inadequate efficacy or drug-induced toxicity, are determinates of the margin of error that will be allowable in extrapolating adult data to pediatric patients. Regarding the inclusion of newborns and infants, several scientific points are worthy of note. The disposition of many drugs in newborn patients is significantly different from that of older children. Developmental changes in drug absorption, distribution, metabolism, and elimination occur during the first few months of life. Of these processes, the magnitude of the changes observed in drug metabolism appear to have the greatest impact on drug disposition. Most of the known changes in drug metabolism occur in the first two years of life, many within the first few months. These differences in drug metabolism may be quantitative in that an enzyme involved in a particular substrate's metabolism is not fully expressed in the newborn, and therefore the disposition of that drug is quantitatively reduced relative to that of an older child. Alternatively, differences in drug disposition may be qualitative, that is, the relative importance of a given pathway may be different in the newborn and young infant compared to the older child. Several historical examples of these differences and the important impact on efficacy and toxicity can be recounted. For example, impaired glucuronidation is believed to be responsible for decreased clearance of chloramphenicol that was associated with the deaths of infants from cardiovascular collapse. In other cases, impaired metabolism of excipients, such as benzoyl alcohol, have accounted for severe morbidity and death in newborn infants. In addition to the differences in drug disposition, developmental differences in pharmacodynamics have been clearly documented. For example, newborns appear to be more sensitive to neuromuscular blocking agents due to differences in receptor expression. In some cases, newborns are of less risk to adverse drug reactions, such as the nephrotoxicity seen with aminoglycosides. With other drugs, unexpected adverse drug reactions occur in neonates. These are not anticipated from the adult experience. An example of this is the cardiovascular collapse seen with verapamil use in newborns with SVT. Thus, just as children cannot be physiologically viewed as small adults, newborns cannot be viewed as miniature children. Why should children and specifically newborn infants be different from the remainder of society? I believe they merit the same quality of therapy and therefore they merit the same level of study. Others may argue that studies may not be ethical, but based on currently available knowledge, the failure to pursue or to inadequately pursue studies is clearly unethical. Involvement in research, of course, entails risk of harm to subjects, however, the risk to an individual child in a well-designed, carefully-monitored trial is far less than receiving a drug in the absence of data. The question of the probability and the magnitude of risk must be assessed in every proposed study. However, we have guidelines and the expertise to assure ethical conduct of studies, not only in pediatric patients, but in newborns. Significant strides have been made in the methodology necessary to conduct studies even in the smallest of patients. Based on the scientific evidence available, I believe global failure to pursue obtaining information in newborns is unjustified and unethical. In particular, drugs in two categories must be studied - drugs that represent a major therapeutic advance and drugs likely to be used in newborns because of their applicability to diseases that commonly occur in the newborn period. If for a specific drug, evidence documents that studies are not necessary, or in rare circumstances not feasible, then individual waivers for a specific drug may be considered, but this should be exceptional. In summary, I have presented two major points. First, in most cases, adult efficacy and toxicity data should be available prior to pediatric studies, but mere extrapolation of adult data will not be adequate for pediatric patients. Estimation of appropriate drug dosing in children from adult data will be complex and must be addressed on a drug-by-drug basis. Second, neonates represent the greatest disparity in drug disposition compared to adults, and on a scientific and an ethical basis, they must be included in drug studies. MR. SCHULTZ: Thank you very much. Our next presenter is Dr. Stephen Spielberg, who is the Executive Director of Clinical and Regulatory Development at Merck Research Laboratories. DR. SPIELBERG: Thank you, Commissioner Schultz. All of us who care about improving therapy for sick children come to this meeting optimistic that the FDA's initiatives to focus on pediatric pharmacology, wisely, flexibly and scientifically implemented, will produce improved efficient and safe drug development and labeling for children. Indeed, it is my belief that the 1994 final pediatric rule has already enabled us to make substantial progress. My response to the questions raised by the FDA about the 1997 proposed rule will draw on my experiences for 15 years in academic pediatric clinical pharmacology, caring for sick children, and studying new medications in pediatric patients, and more recently, five years in the pharmaceutical industry helping to develop new medicines for children. First, timing of studies. With the exception of life-threatening disease or unique pediatric medications, such as Surfactant, pediatric studies in general should not be initiated with a new chemical entity prior to the establishment of the adult dose, serum concentration profile, and a clear "go" decision for the drug development process. Adult pharmacokinetic data are necessary in order to plan rational pediatric pharmacokinetic studies. Only once it is clear that a given pharmacokinetic profile is associated with the desired therapeutic endpoint and an understanding of the safety of the compound has been determined in adults can one rationally and safely plan pediatric studies. This is particular critical if the goal is to apply the FDA's concept of using bridging pharmacokinetic studies along with extrapolation of efficacy based on similarity of disease pathogenesis and likely response to therapy. Furthermore, it is highly questionable to expose children to the risk and discomfort associated with pharmacokinetic studies prior to the ascertainment of the correct dose in adults, and even worse, to a compound which later is abandoned in Phase II, a very common event. Probably 50 percent of drugs in studies do not ultimately make it through the process, and if these drugs are indeed abandoned in Phase II in adult studies based on lack of efficacy, or unacceptable side effects, children are then exposed to new chemical entities with no benefit to them, nor to society as a whole. In many circumstances, it also may not be apparent at a given state of development whether or not a pediatric indication for a new class of drugs may be appropriate at this time or evolve subsequently. Thus, the timing for initiation needs to be flexible, but with great care not to expose pediatric patients needlessly by doing studies too early. However, and I suppose the primary principle here is that early and periodic discussion between the FDA and the sponsor should be encouraged at early stages of drug development in an open and flexible context in order to plan whether or not pediatric studies will occur and at what time. Formulation. Prior to initiation of trials, a formulation needs to be developed, possibly several different formulations for children of different ages. This can take several years, requiring stability, bioavailability, and palatability testing, and the 1997 rule I think underestimates some of the difficulties intrinsic in this development process. Three. Dose Selection. Dose selection under the 1994 FDA rule can be achieved by modeling pharmacokinetic characteristics associated with optimum efficacy and safety in adults, assuming the efficacy extrapolation principles put forth in the rule. This can actually provide for a very efficient approach to minimizing the number of children who need to be studied and, together with population pharmacokinetic sampling, minimizing the blood volumes that need to be obtained from each individual child, and in general, avoiding the need to do dose ranging studies. However, where disease extrapolation is less certain or the indications for children and adults are clearly different, different pharmacokinetic profiles may be associated with optimum therapy for those different diseases and thus dose ranging studies may have to be done. Several basic principles need to be emphasized. Studies in children are in patients, not in normal volunteers. They tend to be studies of fewer patients, using sparse blood sampling techniques, and thus are not as elegant as adult studies. But because they are done in clinical settings, they may actually reflect the real world better than the studies done in traditional normal volunteers. Nonetheless, the acceptability of study design in children must take into account the special requirements of these studies in small patients and be flexible with the final goal of getting the dose right with a minimum amount of patient exposure and discomfort. Age categories. Age for pharmacokinetic studies should be based on application of knowledge of the ontogeny of clearance pathways of the drug, not on arbitrary categories. Understanding specific pathways of clearance from in vitro drug metabolism studies, as suggested in the FDA guidelines for in vitro drug metabolism, and studies in adults should be applied to understanding and planning pediatric PK studies in children. For pharmacodynamic studies or clinical trials, validated endpoints and the ability to assess these endpoints by age should be the determinant of how the studies are done, again not arbitrary age categories. Some objective measures may be easier to assess over age than measures, for example, requiring patient participation, such as forced expiratory volume, in doing asthma studies. Here again, the 1994 rule may be helpful in our ability to extrapolate efficacy data from older children together with pharmacokinetic data across pediatric ages where efficacy may be more difficult to assess in younger children. Safety. Safety is an obvious critical feature of all clinical trials, but particularly among vulnerable populations, such as children. The design of safety studies will depend on the disease, duration of therapy, and ages of patients being studied. This can be everything from simple postmarketing surveillance or may in fact require ongoing controlled clinical safety trials looking for longitudinal effects of medicines. The newborn represents a unique pharmacokinetic and clinical trial challenge. The neonate is not a homogeneous population. Studies may need to be done in several different patient strata based on gestational age and weight. Rarely will extrapolation of adult efficacy data be possible, and the newborn thus has to be considered a unique population, not typically included as a standard age category under the current rule. However, consultation among the FDA, AAP Committee on Drugs, the PPRUs, together with Pharma, will be needed to come up with novel approaches to this critical population which is clearly in need of improved pharmacotherapy. A few final general points. There is a critical need for prioritization for labeling of already marketed compounds. The Academy of Pediatrics, PPRU, pediatric pharmacy groups, FDA, and after Mrs. Goldberg's talk, clearly patient and family groups need to be included in this dialogue to prioritize these compounds. Appropriate incentives to raise the priority of pediatric studies within and among companies, integration of legislative and regulatory approaches hold real promise for achieving this desired goal. Similarly, much of neonatal drug development and labeling of compounds currently off patent will require novel approaches, and again an active collaborative spirit among the AAP, PPRU, FDA, Pharma, and the generic industry. Finally, the FDA's approach to the use of pharmacokinetic studies, disease, and efficacy extrapolation, and flexible approach to study design based on scientific understanding of developmental pharmacology is clearly at the cutting edge internationally. Harmonization is desperately needed on an international basis, so that studies done in one population can, in fact, meet international labeling requirements. The goal here, however, is not to produce another set of documents with arbitrary age categories and yet other arbitrary approaches to doing studies and losing disease extrapolation. We really need to base things on what the FDA has already suggested. I believe that the agency is to be congratulated for their leadership in this regard, but we must attempt to achieve the same kind of an approach on a worldwide basis. Thank you. MR. SCHULTZ: Thank you very much. The final speaker on this panel is Dr. Alan Sinaiko, who is a professor at the University of Minnesota. DR. SINAIKO: Thank you. I appreciate the opportunity to participate in this panel on what I believe is an important issue for drug use in pediatrics. As you mentioned, I am a professor at the University of Minnesota in Pediatrics, and my specialty training has been in clinical pharmacology and nephrology. I participated in the original panel for nonprescription drugs that the FDA started I guess it was about five or six years ago now, and so I am well aware of some of the important problems and also the potential for labeling of pediatric usage of drugs, and I appreciate the complexity of what we are dealing with today, but I do think that the issue is not quite as complicated as we are being led to believe in certain areas. My remarks are going to be relatively brief and I will base them on some of my experience in looking at drugs in children, which I have been doing for about 20 years. My group has had major experience with cardiovascular drugs in children and, in particular, with antihypertensive drugs. Both of those are areas that are not classically drug testing areas, nevertheless, we have been able to conduct some studies with propranolol, with minoxidil, with captopril, and with nitrendipine, and as most of us know, all of those drugs with the exception of nitrendipine, which never quite made it to the market, were released primarily for use in adults, but drugs that became widely used in children, similar to many of the drugs that we see on the market today. I want you to know that we have been able to do crossover studies, we have done dose response studies, and we have done pharmacokinetic studies. We have enrolled teenagers, junior high school students, grade school students, preschool students, infants, newborns, and premature newborns, and we have been able to use virtually all these drugs in all of those populations. So, I don't believe that there is any question anymore whether studies in children of all ages are feasible or whether complete information about drug dosage in this age group can be obtained. As I look at the discussion issues for our panel, I think at least my perception is there are two key questions here. The first is should drugs be tested in all age groups, and can data from adults be extrapolated to children. Personally, I think it is crucial that drugs be looked at in all age groups in which they are going to be used, and as I suggested from my earlier remarks, I believe that drugs that go on the market almost always are used in children and are almost always used in all age groups. We have had some personal experience where a drug used in adults has given some very surprising results in young children and while we are all aware of the problems with drug dosing based on pharmacokinetics and problems with metabolism, I would ask us all to be cognizant of the differences in some physiology between different age children, and I think those are equally important to the issues that we are all aware of and pay attention to about pharmacokinetics and metabolism. Can information in adults be extrapolated to children? Well, I guess in some cases it can, but there are problems, and I again would call your attention to one of the very recent problems that everybody has become aware of with nifedipine, a very popular calcium channel blocker used as an antihypertensive in adults, and which recently has been noted to cause some problems with cardiovascular disease. In contrast, this continues to be an extremely important drug in children, one that I am not aware of has ever been shown to cause any similar problems, but which is very important to us in our therapy, and one can only imagine the impact it would have on us as pediatricians if the same restrictions applied. Finally, I would like to bring up an issue that I think is equally important here, and that is about the type of studies that will be performed. The studies that we have conducted over the years were initiated by us and through contacts with drug companies, so that they were investigator-initiated, scientific projects. I sense today that as the companies are becoming more aware of the need to look at studies in children, and as the FDA is getting more involved, and there are some overt and some subtle pressures put on the companies to do this, that the type of studies are changing. I would suggest to you that what we are beginning to see are what I would call studies directed at regulatory science rather than true medical and basic science, and I think that is a real problem. Studies of pharmacokinetics alone are not adequate for studying drugs in children. There are important other differences that we need to recognize, and I would hate to see that these studies restrict rather than maximize the potential for the development of new information, and I hope that this latter principle will be primary in guiding these new regulations. Thank you. MR. SCHULTZ: Thank you very much. We are going to start the questioning from the other end of this table with Dr. Esber. Discussion DR. ESBER: I appreciate everyone's comments. It has been very helpful. I wonder if I might start by reflecting on some of the comments made now, in particular, I guess Dr. Spielberg, with the comments made in the earlier panel regarding some suggestions on panels or committees, and so forth. Could you focus a little more on timing of when companies decide to do studies in children, how FDA could better interact or be more helpful, or be providing more guidance regarding sizes of population, timing, or across ages, as well as how we might or might not be able to use the concept of a committee or panel or outside experts, and dealing with the issue of confidentiality, and also focusing on the issue of formulation? I am sorry, it's a mouthful, but if you could integrate those, it would be helpful. DR. SPIELBERG: I think timing varies again greatly depending on the nature of the compound and on the indication, patient numbers, and the nature of the chemical and whether or not it is going to able to be formulated. I think probably the abiding principle, and I think probably one of the benefits of this kind of meeting and of the rule, is that it is putting pediatric issues on a higher burner, upfront, people are going to start thinking about it, and I think that is probably one of the major benefits that can accrue from this kind of interaction. Clearly, the agency, with the 1994 rule, has an ability to begin having periodic and early discussions with manufacturers about the potential for pediatric drug development, and some of the things that will go into this is, is it clear at this stage whether or not the drug really will have a pediatric indication, or in fact, is being developed for benign prostatic hypertrophy or something like this that clearly will not. That is one break point. Often, it is very unclear whether or not there will be a pediatric indication, and sometimes it will be very clear-cut, such as an antimicrobial that is going to likely be used in life-threatening bacterial or fungal infections. At that point, then, as the compound enters Phase I and we begin gaining adult information about it, and again with the principle of exposing populations, such as adults, prior to more vulnerable populations to gain as much information in a population where the studies are easier to do than in a population where the studies are more difficult to do, decide are we dealing with a life-threatening condition, should this be a priority situation where we are going to move very quickly, and then from the initial studies begin to understand how forgiving that compound is, how broad the therapeutic index is, how able we are going to be to begin planning the pediatric pharmacokinetic studies to assure maximum safety for the children who are going to participate in those studies, as well as to get maximum information in those patients. It is not infrequent, for example, if we take a dose that is 6 or 10 times the final adult dose, start doing our Phase II studies in that, that will be the wrong time to study the children because, in fact, we are going to cut back 6 or 10-fold in dose, and if we based on pharmacokinetic models on those elevated levels, we are going to end up with totally incorrect information in the children. So, again, it is going to be highly variable depending on the nature of the compound and the need of the compound. I suppose the critical path is for this early and periodic discussion. For older compounds already marketed, I think here again the issue of prioritization and having expert panels drawn from practicing pediatricians, the PPRUs, parent groups, and the FDA working together to set up both classes of compounds in need, as well as individual compounds. For new compounds, paying particular attention, as we discussed, in the newborn, those areas of therapeutic gap, so that where it is clear that the therapeutic area is being underserved, and a new class of compounds evolves, that that class of compounds is something that the agency might well want to go and talk earlier to a manufacturer rather than later. It doesn't necessarily mean that the program is going to go dashing along and that you are going to end up with labeling for kids at the same time as adults. It may, again depending on the compound and all the things we have talked about in terms of kinetics and dynamics, side effects, and formulation. But again the issue is to bring that to the burner first, early in the process, and then allow the process, as we always do in all aspects of drug development, be an ongoing dialogue between manufacturer and the agency. MR. SCHULTZ: Ms. Witt, do you have any questions? MS. WITT: Does anybody else on the panel want to address Dr. Esber? DR. McCARVER: I think in general what we are hearing repetitively is that the question is who decides when are pediatric studies or neonatal studies indicated, and when in the process is that decision to be made, and I think in talking with people, I certainly feel, and I think there is a consensus feeling, that we need pediatric studies and we need for the paradigm to be yes, they will be done. The question of who decides when they are not to be done should be based on a panel of experts who put their heads together and use a logical, rational approach to say this is unrealistic and unreasonable, so this drug will quality for an exception, but that again, the paradigm is the studies are to be done. The question of when is a decision to be made similarly must be made in a rational fashion. For some drugs, where the disease process is uniquely in children, we do not need to wait on adult studies to be done before we do pediatric studies. By the same token, I agree with Dr. Spielberg, it is reasonable to get adult data together before we begin the actual studies, however, we must anticipate doing pediatric studies during the planning phase. So, beginning the discussions in Phase I is appropriate with the expectation of reaching an early decision. DR. AMMANN: Perhaps the panel could clarify the difference between use and indication, or someone in FDA could clarify that because I think there is some confusion. Certain drugs are clearly indicated for children, and many pharmaceutical manufacturers have responded by immediately performing the studies that are necessary. In the AIDS arena again, 3TC nelfinavir, the data presented simultaneously with adults for approval. That is the ideal. However, there are many drugs which are already marketed which are used in children, but may not be clearly indicated, and yet it is widespread use, and I am having difficulty. My interpretation of FDA rules is that FDA is required to ensure the safety of drugs that are used in a particular population, whether or not we agree that they are indicated. A panel of experts may not feel it is indicated. MS. WITT: That is actually a very difficult and controversial question that you are touching upon. It is not perhaps as straightforward as we might like it to be. I think we might have an argument about whether we can require a drug company to study its product in every population in which it might be used whether or not the company has promoted the product for that use. The legal basis for the proposal that we have put forward argues that we do have that authority at least in some settings to require manufacturers to study their products in populations in which the drug is used, as well as for which it is labeled, but that is the subject of controversy. DR. AMMANN: One of the reasons I asked that is because there is somewhat of a paradox that struck me from initially reading the New York Times in August 10th, 1997, which says use of antidepressant medicine for young patients has soared. It lists under Prozac, in the 6 to 12 age range, that in 1996 alone, there were 200,000 new prescriptions. It also talks about Zoloft and Paxil. Last week when I picked up my New England Journal of Medicine, a very prominent advertisement for Prozac, advertises that it is now available in an oral liquid formulation. Above that statement is the safety and effectiveness in pediatric patients has not been established. It would appear to me that with that degree of prescription use, there should be a requirement that the studies be done. MR. SCHULTZ: That really is the issue raised by the proposed rule, and so that is one of the issues that we are here to talk about. DR. AMMANN: But it would be for new drugs and already marketed drugs. MR. SCHULTZ: The proposal has a proposal for both and it has different approaches for both. It is a proposal and we obviously don't have the answer, but we are here to hear the discussion. MS. WITT: Let me just clarify one thing. One of the bases on which we are moving forward is that at this point, we consider children not to be so much a separate use as a subpopulation for the indication that the manufacturer has claimed in the label, and would like to treat it similarly to how we treat gender. If a product were indicated for men, we would assume it was going to be used in women and wouldn't consider that a separate indication. There are separate pediatric indications for some drugs, but here we are talking about use in children for the same indication as adults. DR. SINAIKO: If I could comment, the issue about timing and formulation is always kind of an interesting one. I think we ought to kind of look at the clinical facts. The clinical facts are that most drugs that go on the market are used in children, and to talk about timing in terms of somehow or other delaying the testing of these drugs in children until they have been on the market, and until they are being used in adults, et cetera, seems to me to beg the issue of whether they ought to be tested in children before they are used in children, because as soon as a drug hits the market, it is used in children. The question of formulation also is problematic for me anyway. I understand that there are some difficulties with formulations of certain drugs and in preparing them in preparations that are you could say palatable to children or easily administered to children, but again, drugs that hit the market are used in children whether there are pediatric formulations or not. Somehow or other, the doctors and the parents figure out how to do this if the physicians believe that it is indicated and if the drug seems to be an effective agent. So, what we are dealing with here, I think, is beginning with a very simple question, and that is, should drugs be tested in children if there is any likelihood that they are going to be used in children, and once that question is answered, then, I think we get to the issues of what is the timing for it, do we need pediatric formulations, do they have to be used in adults before they are used in children, and things like that. I worry that we get caught up in the smokescreen of all these ancillary issues not really dealing with the basic issue, and I would just emphasize again the experience that we have had with using these cardiovascular drugs that we were told many times were dangerous, they ought not to be used, is that they can be tested in children, they can be tested adequately, and I don't want to take anything away from the industry here because the reason we were able to use those drugs, and the reason we had our protocols approved, is because there were some creative and forward-looking people in the industry who realized that this was important. I don't understand why it is not more uniform, but I think it is important to understand. At least I feel that people do want to do the right thing, so what you, as an agency, need to do is establish what needs to be done and let people deal with it, and it will be done. MR. SCHULTZ: Thank you. Ms. Witt, do you have any more questions? MS. WITT: In the interests of time, I will let the next person have it. MR. SCHULTZ: Dr. Botstein. DR. BOTSTEIN: No, I don't. MR. SCHULTZ: Dr. Wykoff. DR. WYKOFF: Dr. Ammann, you mentioned several waivers that are proposed that you did not agree with. Other than a disease not occurring at all in children, do you see any situations in which trials would not be done in kids? DR. AMMANN: The answer is yes, I think there are some situations in which trials would not be done in children. However, I think for the FDA to have a new rule which contains waivers is inappropriate. I think that as the panelists have said, that there needs to be individual consideration of what population to study, what age range to study, what drug, under what circumstance. DR. WYKOFF: If an advisory committee were set up, what guidance should be given to them before they started deliberating on waiver criteria? DR. AMMANN: Well, that is my other seven pages of testimony that I couldn't give, but I would be glad to -- Deputy Commissioner Schultz is smiling -- but I think there could be specific guidance given. I think it is absolutely critical that that committee consist of -- I know conflict of interest was talked about -- but there is no question that what needs to be brought to that table is representation by industry, pharmaceutical company, advocates, people who are experienced in drug development, because I think there are issues and we are moving into an area which is my concern, in which we are dealing with new molecular entities which are going to have very unique questions, while we have not yet dealt with the drugs that are already marketed. MR. SCHULTZ: I would like to emphasize that the comment period on this rule does remain open until November 13th, and we are anxious to receive comments from any of the panelists or any member of the audience. Maybe I will just read where they should be sent to. It is the Dockets Management Branch, the Food and Drug Administration, Dockets Management Branch, 12420 Parklawn Drive, Room 1-23, Rockville, MD 20857. The Docket Reference Number is 97N-0165. Dr. Ward. DR. WARD: I will pass. MR. SCHULTZ: Dr. Wilfert. DR. WILFERT: I would just like to point out that this panel and the preceding panel have indicated that there are drugs which are developed uniquely for a specific pediatric use, and there are drugs that are developed for life-threatening illnesses for which the development in children proceeds without an antecedent development in adults, and I think I heard no disagreement about that, but you may certainly comment. Secondly, the large area of drugs which are used both in adults and pediatrics, I guess I would like to ask Dr. Spielberg and ask others to comment if you would delineate the process since the paradigm is that drugs will be developed for use in children unless there is an acceptable reason that they would not be used. So, I would like to hear from you, Dr. Spielberg, your version of the process. DR. SPIELBERG: Again, the process that I think is reasonable is based on several considerations. Most of the rule, the 1997 rule that we are dealing with here today, deals with compounds where the indication is going to be the same in children and adults, where the extrapolation possibility exists for extrapolation of efficacy, and thus, based on pharmacokinetic studies in children of different ages, as well as safety considerations, and sometimes rather extended safety studies. One will be able to label that compound with the correct dose in children in as expeditious a time as possible. Now, there are again situations where depending on the nature of the compound, one can begin very early in the process. The things that would push one towards that are again life-threatening illness or unique pediatric indications. Unique pediatric indications, however, are going to require a rather different study design than that proposed in the 1997 rule, which is going to be indeed full efficacy studies for that indication in children. You cannot achieve efficacy information on the effect of Surfactant in RDS by studying adults, you must study children. It is pretty obvious. So that the controlled clinical trials are going to be done in those populations for which the drug is indicated. For other compounds where the disease is extrapolatable -- and this is a difficult thing and this also requires input obviously from pediatric subspecialty groups in terms of how able one is to, for example, extrapolate adult hypertension to pediatric hypertension, adult asthma to pediatric asthma -- we can, in fact, hasten and make the process more efficient by focusing on kinetic studies, taking the adult pharmacokinetic profile and an understanding of how forgiving that compound is from a safety point of view in adults, and move rather quickly into the pediatric population using pharmacokinetic studies as our bridge, sometimes with some limited efficacy data, sometimes and almost always with safety data in those populations. I think the ability to do that where the specialty groups agree that extrapolation is possible, allows us to be much more efficient and much more rapid in the process of getting pediatric labeling present on new chemical entities. However, if, for example, a drug for hypertension in the adult is going to be used in primary pulmonary hypertension in the newborn, we are actually going to end up having to do real efficacy studies in those patient populations, which again is going to require a somewhat different paradigm. So, the default and straightforward paradigm is similarity of disease, extrapolation based on pharmacokinetics, initiation of studies when one is confident what the dose is, what the safety profile looks like, and a formulation availability, go ahead and do it and get it done as quickly as possible, all the way on up to much more difficult studies where the disease entity and the indication is different in children and we are going to have to do the kind of studies that Dr. Sinaiko discusses, which are going to be both pharmacokinetic, pharmacodynamic, and clinical trials. So, again, it depends on the compound, it depends on the situation. DR. AMMANN: Just to amplify on what Dr. Spielberg has said, because he has raised an issue that has not been discussed in the panels, and that is, that the FDA has the authority to require the drugs, if the indication is the same. It does not have the authority, as I read FDA rules, to require studies of drugs for another indication in pediatrics. This is one of the reasons that many of us feel that we need both the FDA regulatory authority and the incentive component. I think we also have to, in our discussion, as these panels would meet, I would envision new pediatric indications coming about in which we could not require those studies, but certainly legislative incentives, which we already have in the Orphan Drug Act, and perhaps some additional ones, would tremendously benefit the pediatric community. MR. SCHULTZ: Dr. Kauffman. DR. KAUFFMAN: Dr. Spielberg, and I think Dr. McCarver, talked about the age groups that should be studied. A plea was made by several people that we shouldn't have rigidly defined age groupings, but drugs should be studied within the age ranges that there is an anticipated use. Is there a way within the regulations to define how this would come about -- let me ask it a different way. Are there particular ages at which you would anticipate the most important changes will occur which should be a priori targeted? DR. SPIELBERG: Some of the things that we have already talked about clearly are the neonate, where changes in clearance, changes in disposition entry into the central nervous system, displacement of bilirubin from protein binding, all of those features become very real issues. As we are getting more information -- again, this is a real plea that the NICHD-PPRUs thrive and survive into the future to get the information we need, on the ontogeny of the various drug metabolizing enzymes, for example, some end up undergoing significant down-regulation at the time of puberty, a child maintained on theophylline at 40 milligrams per kilogram per day is the requirement, may fall to 12 milligrams per kilogram per day with the onset of puberty. These kinds of shifts and break points need to be defined, and then, in turn, to improve efficiency and to get the job done most rapidly in terms of understanding pediatric dosing, is to apply that knowledge of the ontogeny of the pathways across age spectrum. One paradigm, for example, might be if you are dealing with a drug that really is going to change dramatically at puberty, do small numbers of children stratified by Tanner [ph] stages to get much more information than a larger number of children across a much longer age span with much more variability, so that you understand the impact of those physiologic changes in dosing. With respect to pharmacodynamics, again, that raises some additional issues, and I think there we have run into many situations where validated endpoints just don't exist in the populations of interest where we want to study the drug, which sometimes requires development of validated endpoints and the ability of kids of different ages to participate in those endpoints. Again, the example of asthma where two-year-olds really don't give us good replicated FEV-1s, whereas, the six-year-old child is really quite able to. Again, there, I think it is again critical that there is this discussion and dialogue going up and back. Whenever we design a protocol, we come to the agency with the protocol, the agency critiques it, we come back with responses. This is the process that should be going on within the pediatric venue, as well, where we come up with designs and ability to extrapolate, for example, if a six-year-old responds some way, and we can't do that same assay in a four-year-old, can we extrapolate based on the dose in that four-year-old. If we can get agreement there, we benefit everybody, and then we set up other ways of looking at safety. So, the issue again is ongoing dialogue, early and periodic, and using the knowledge gained from the PPRUs and other pediatric investigators, both to plan out the pharmacokinetic, as well as to plan out the pharmacodynamic studies. DR. McCARVER: Ralph, I will respond briefly to your question because, for the most part, I agree with what Dr. Spielberg had to say. What I hear you asking is what I believe is a shift in thinking or a shift in paradigm. In the past, we have thought of children in arbitrary age groups. Those arbitrary age groups have little or nothing to do with the reality of the ontogeny of drug disposition, and we have come to understand that in the last several years, and it is now time that we apply what we know. We have learned it is much more complex than we thought and therefore it must be individualized. That is clearly true in the area of pharmacokinetics, and in some cases has also been found to be true in pharmacodynamics. So, I think rather than being able to arbitrarily define age groups, we are going to have to look at the issues much more carefully. MR. SCHULTZ: Do you feel like we can establish the metabolic pathways in adults and then have enough data at this point to predict which age ranges, especially developmentally, to tests? DR. McCARVER: I think again it is going to require an individualized information base. For example, we know a fair amount about n-acetylation, we know about when it matures, 12 to 15 months, at least somewhere in that range. So, for a drug that is handled by that pathway, yes, we can make some very good guesses about what to expect. We are still generating data on many of the other pathways. For instance, we don't know when does 3A7 convert over to the more mature form. So, I think as we are learning more information, that information can be brought to bear. DR. SPIELBERG: This is also really the rationale for using in vitro drug metabolism and using knowledge gained in adults to validate that in vitro drug metabolism to plan out pediatric studies. I would posit in the long run that the use of that knowledge is going to make our studies in pediatrics more efficient and get the job done faster rather than empirically diving into kids except in those situations where we have to because we don't have an adult database to go with. MR. SCHULTZ: Did you want to add anything, Dr. Sinaiko? DR. SINAIKO: Just one brief comment, and that is that again I would like to just draw attention to some of the physiologic differences that I think are so important and, as has been mentioned, we are just beginning to learn about. I think that all of us grew up in an era where we thought that once you got through your first year of life, things were pretty stable until you went through puberty. Now we know that there are physiologic changes all along there, and we know that during puberty, there are some just amazing things happening. I happen to work in the area of insulin resistance, for instance, and there are enormous changes that take place during puberty. So, there are important reasons to look at the drugs and the actions of the drugs, not just the metabolism again. I know I have kind of been pushing on that, but I think that is an important concept that needs to go along with the rest of what we are talking about today. MR. SCHULTZ: Maybe I could ask each of the panelists what is really almost a yes or no question, whether they favor FDA going ahead with the regulation. There obviously are lots of discussions, if we do go ahead, about what form it should take and how it should be refined. But I would be curious to know from each of the panelists whether they think that this is the right time to go ahead. Maybe I could start with you, Dr. Sinaiko, and just come down the row this way. DR. SINAIKO: I think there should be regulations. As I said, I would like to see the regulations start from the standpoint that drugs need to be tested and that the industry has the obligation to request a waiver. DR. SPIELBERG: I think clearly putting pediatrics to the fore is valid at this point. There is no question about it. I think the 1994 rule, I think the FDA is actually underestimating the validity of that rule. I think it has a tremendous amount of strength both in terms of study design and in terms of its ultimate impact, remembering that the time lines for drug development, given that this came into play in 1995, and the programs sometimes take six to 10 years to develop, I think we are only going to see the impact down the line. I think there are some things that do need to be fixed in the rule. I think the input that everybody on the panel has had in terms of some of the specifics, I think ultimately we will end up in having a rule that will, in fact, enhance drug development. DR. McCARVER: I think we absolutely need a regulation. I think we have been too long to arrive at this process, and that continuing to operate the way we have in the past is just not acceptable. MS. GOLDBERG: I also agree that there should definitely be rules and regulations put forth as soon as you can about regulating drugs for children. DR. AMMANN: I believe that the problem is not in the rules, but in the enforcement of the rules. The current rules I believe are adequate to address most of the issues that we have discussed. They have not been enforced. We need the enforcement. The part of the new rule that is attractive is that it looks forward in terms of new molecular entities, it could add to the existing authority, but we have to look at rules that are inclusive rather than excluding and segregating, and the original FDA rule and the original intent of Congress was to be inclusive meaning that children were included, not excluded. MR. SCHULTZ: I want to thank this panel. This was an excellent discussion. I think we will find it very helpful. I would like to ask the third panel to come up to the table. Panel 3: Special Challenges to Testing ChildrenMR. SCHULTZ: We have organized Panel 3 to discuss what are really a hodgepodge of very important issues that we feel we will need to address in making decisions on the final rule, including issues about waivers and deferrals, issues involving whether formulation issues should be a basis for a waiver, the cost to the industry and the burden, and then finally, ethical issues. We will start with Dr. Clemente, who is the founder and Chairman of the Board of Ascent Pediatrics. DR. CLEMENTE: Thank you very much. Good morning. On behalf of Ascent Pediatrics, I thank the committee for this opportunity to participate in this discussion. I have two messages to convey to the committee. One, we fully support the proposed regulation addressing the need for clinical studies in children to determine safety, efficacy, and the appropriate dosing regimens; and two, there is a need for a more flexible regulatory pathway that addresses the real differences in conducting clinical studies in pediatric patients. While much of today's discussion will be on clinical testing, I will also address the development of pediatric formulations as an area where breakthroughs are needed. Ascent Pediatrics was founded in 1989, and we will be introducing products to the pediatric medical community next month. Our corporate focus is on improving pediatric medicines that will significantly enhance patient compliance. As a small company, we have chosen not to develop new molecular entities or new biological products. Instead, we have identified both technologies and products where we can help ensure that the right dose of the right medicine is actually taken by the child at the right time. Better medicines are of no value if they are not taken. This is particularly acute in pediatric patients where various dosage forms are inappropriate for children, where the taste and smell of the medication is objectionable, and where there may be an overall lack of recognition of why the medication is important. Specifically, Ascent takes currently available drugs and improves them for children by applying technologies that will reduce the dosing frequency, simplify the method of administration, improve the side effect profile, or improve the taste. Testing in children is different and it is also very demanding and expensive for a number of reasons, such as the limitation of qualified study sites, the identification of appropriate patients, parents reluctant to enroll their children in a clinical study. There are practical considerations, such as obtaining blood and urine samples, difficulty in obtaining outcome data as children may not be able to describe symptoms or side effects. With regard to the relative lack of approved pediatric medications, it is important for this committee to recognize the following. Barriers and inefficiencies surrounding clinical studies in children are just one part of the problem, and requiring pediatric clinical studies for more products is just one part of the solution. Some of the most serious problems and some of the best solutions lie with improvements in product development for pediatric medications. For example, creating a once-a-day formulation of a multidose product can be a significant advance in patient compliance, and this is an area where Ascent has considerable experience. Additionally, there is a stereotypical view that a spoonful of sugar helps the medicine go down. It would be nice if that were a successful strategy, but it just isn't. In fact, pediatric formulations are rarely easy to put together. For example, liquid formulations have different and possibly more complex stability and storage issues than tablets or capsules, but making a palatable solution or a suspension is critical for therapeutic compliance. The importance of taste in pediatric medicines was highlighted in a recent national survey conducted for Ascent Pediatrics by Yanklovich Partners. Among 500 parents of children 12 years or younger, nearly 75 percent blamed bad taste for their child's refusal to take the medicine. We must do a better job in providing children with medicines that are not only safe and efficacious, but are more palatable. With respect to the regulatory process, Ascent's pathway to obtain approval for improvements in existing drugs has been as demanding in many regards as the process for a new molecular entity. While FDA has become more responsive especially to smaller companies such as our own, it is still encumbered by its own rules and regulations and their process that lacks flexibility. We recognize the essence of a regulatory agency is to have a predictable set of rules, yet, the challenges the industry faces are often one of a kind or at least first of a kind, and often need an unconventional perspective and a more flexible response. In closing, I thank the Food and Drug Administration and the Academy of Pediatrics for convening this meeting today. Collectively, I think we are on the right track, but we believe that there are opportunities to improve the dialogue between the agency personnel and sponsors, centered on the need to achieve our common goal. In addition, for us to realize the full value of the Food and Drug Administration's commitment to greater flexibility and speed in the area of pediatric medications, we believe that the Food and Drug Administration's senior management needs to better communicate with the Review Division personnel its policy commitment in this area. Again, Ascent Pediatrics is appreciative of this opportunity to participate. I would welcome any questions the committee members have. Thank you. MR. SCHULTZ: Thank you very much. The next presenter is Dr. Charles McCarthy, who is a senior research fellow at the Kennedy Center for Bioethics, Georgetown University. DR. McCARTHY: Thank you, Commissioner Schultz. I am delighted to be here. I first want to make a general comment about ethics, that I may be the only card-carrying ethicist on any of the panels, but ethics is far too important to be left to professional ethics or ethicists, so it is really the concern of all of us, and I am happy to see that so far no panelist has shied away from making some ethical statements, and I think they all need to be carefully weighed. First, let me agree with a couple of generic kinds of statements. First, I think it is unethical to deny drug research to children and therefore I think the FDA, under its general mandate, has some obligation to go ahead and produce rules that govern the testing of drugs for children. Secondly, wise as many of my colleagues at NIH and FDA, former colleagues, are, I do not think you are likely the first time to get the rules exactly right. That is not an argument for not going ahead, it is an argument for building a review process into the system, so that perhaps after two or three years, you revisit the issue, revise the regulations in the light of experience, and I think you will make enormous progress that way. If the rules, as some HHS rules are allowed to stand, unchanged for 17, 18 years, then, any mistakes you write into them in the beginning will come to haunt you as the years go by. I do think you need to write or rewrite your section dealing with waivers. I think the reasons for waivers need to be narrowed. I think economic reasons should not be listed as those that obtain. Nevertheless, having redefined conditions for waivers, I still think that section will have to be interpreted by some sort of standing committee. There are different ways to do it. You all have experience with a whole variety of committees. Doing it in very much the way this hearing is being carried out would be one way where FDA officials listen to evidence provided by experts from the community and from the general public. I also think there is a serious lacuna in the approach, and that is to say that all of these studies that will be carried out must be approved by IRBs, and at the present time, the FDA has no special guidance or instructions for the IRBs in their review of the rules. The Department of Health and Human Services, in Section 45 CFR 46, Subpart C, has a lot of experience in implementing guidance rules for IRBs, and I think the FDA, rather than reinvent the wheel, could incorporate that by reference and thus fill a very important gap in an otherwise important step forward. I think two kinds of approaches need to be made, one for existing drugs and the other for proposed new drugs. With respect to existing drugs, I think it is very important that the approach, first of all, that the presumption be that there be an epidemiological study made of the use of the drug as it has been used in general practice. In that way, I think no new subjects would have to be recruited. I think a large number of these drugs could be then approved for use in children based on the experience of pediatricians and others who have collected this data, and the kind of data that is available from the case we heard of earlier, Mrs. Goldberg, I think, talking about her daughter Abby, that data could be collected and used for other similar kinds of cases and judgments made without recruiting new subjects. That will leave some residue of cases where the epidemiology is not entirely clear, and those cases indeed may need to be tested in well-designed clinical trials, but I think the first approach should presume to use historical data already developed. As far as new drugs are concerned, I think you need to be very careful about recruiting subjects. Particularly recent experience with washout studies in mental patients suggests that we must be very cautious about washout studies in children, that is to say, that the child should be taken off existing drugs that maybe were never tested in children, and the new drug tested against placebo. I think that could be very dangerous and I think, although I would be reluctant to say it should never be done, I think the presumption should always be against it and the burden of proof on those who want to do that kind of study. I think the presumption again -- and we have heard this particularly from the second panel -- the presumption is that the study should be done in adults first, then I believe in older children, perhaps in younger children, and finally in infants. There may again be reasons for exceptions to that general rule, and that is why I think a wide degree of flexibility is needed, but the presumption should always be that you proceed stepwise unless there are sound reasons to the contrary, and we have heard some examples already in the previous panel of reasons why, in some cases, that would not work. So, I don't want to make that a hard and fast rule, but surely it needs to be always the presumption, and it must be overturned by hard evidence. I think it is very important that somewhere, perhaps only in the preamble to the rule or perhaps in the rule itself, the understanding that there needs to be some sort of clinical equipoise, there needs to be some reason to believe that the drug is not effective in children or that the trial needs to be done because there is a dispute as to how effective the drug may in children, needs to be built into the study. You might borrow language from the emergency research rule that was published sometime last year by the FDA, and I think some very good statements are in that rule that could be adapted and incorporated in this rule. I think that concludes most of the comments I want to make. When I made reference to the IRB rules, they include such things as very careful rules about obtaining the permission of parents. They include some narrow cases where the assent of the child, if the child is old enough to understand, would need to be included. They have ascending levels of risk whereby the research would have to be categorized. All of that is beyond the time limits of this brief panel, but I don't want to leave those issues as if they should not be addressed. In fact, they are addressed in that parallel rule and I think it needs to be incorporated by reference, perhaps with some adaptation, but incorporated by reference into this rule, so that you have a comprehensive approach to research in children. Thank you very much. MR. SCHULTZ: Thank you. Our next speaker is Dr. Philip Walson, Division Head, Clinical Pharmacological/Toxicology, at Children's Hospital in Columbus, Ohio. DR. WALSON: Thank you, Commissioner. First, I wanted to point out that the American Academy of Pediatrics in February of '95 published guidelines for the ethical conduct of studies, which really deal with most of the special challenges to testing in children, and I think I won't add much to them with my comments which are personal, and not the Academy's. There are challenges to conducting trials, but these can be overcome. One of the problems we have is to convince people who do trials or who regulate trials that they can be done. That is probably the biggest barrier there is. Children deserve access to the benefits of drug development. Timing and design must be individualized, but waiver deferrals should be uncommon at most. Lack of pediatric trials has not prevented widespread pediatric use. Lack of available formulations has not stopped use either. Neither should these challenges prevent testing. Economic barriers, in fact, and not scientific, are practical problems that prevent most pediatric studies. They must be overcome. Drug use in children must be studied in children whether new or old, with or without a willing sponsor. Incentives may be needed, but it is unethical to shift risk of untested use on to children and practitioners. It is untenable to continue to use drugs in children without data because it is felt that testing is costly or risky to test. This is less ethical, although not an ethicist, in my opinion, and exposes children to more risk than does any adequately conducted clinical trial. Reasonably priced, ethical yet practical studies could be done more easily, however, and with more true informed consent if certain barriers which exist now are removed. The most important one is that we need some rationale included into inclusion and exclusion criteria. The sickest children, those with the most to gain, should be studied first, and not last, yet, except for cancer drugs, most pediatric drug trials begin with or are restricted to the least ill subjects. This makes it both more difficult to recruit subjects and less ethically defensible. It is unreasonable, for example, to study new life-saving drugs only in children with normal renal or hepatic function, those who, in fact, are unlikely to be life-threatened, because such patients are just the easiest to analyze or the least likely to have adverse effects. Other unnecessary criteria should be eliminated. For example, there is no scientific reason that patients treated with antibiotics for less than a day or who have received an antipyretic for 8 to 12 hours for a study should be excluded from antipyretic trials, but they are. This makes it more difficult and delays studies, and makes them more expensive. Some regulatory barriers need to be removed. Regulations are urgently needed, for example, to allow less restrictive study of pediatric formulations. I am referring to common sense, which is unfortunately not common. This is especially true for drugs that are already in widespread use including generic or low-priced drugs for which no sponsor exists. The FDA needs to appoint an unbiased group to decide what constitutes "a reasonable effort to develop a pediatric formulation" if the current wording goes forward, and whether lack of such a formulation will, in fact, prevent use. Finally, there are a whole bunch of disincentives to study participation including the negative guinea pig image of research which must be addressed. Everyone must understand that the current use of 80 percent of drugs or more in children is what is guinea pigs research. This kind of unregulated, unscientific research without benefit of true informed consent must be replaced by scientific well-done research. It is pediatric patients and not clinical trial subjects who are being used as guinea pigs. There are other reasons for this negative image and part of it is by allowing untrained or otherwise imperfect or less than optimal researchers to conduct research. We must develop ways to allow research to be done by people who are unbiased and well trained to do them right. The effects of publicity about nonexistent patients, faked data, and drug studies done without true informed consent, on legislative and public opinion illustrate how much damage may result when this is not the case. A final disincentive which should be removed is third party denial of payment for participation in research, legislation to require third party reimbursement for such participation should be enacted. These and many other barriers which I haven't had time to cover exist for testing in children, however, they can and must be overcome to correct the current untenable, unscientific research which is going on every day in children. Thank you. MR. SCHULTZ: Thank you. The final speaker is Dr. Hugh Tilson, who is a consultant of pharmacoeconomic and epidemiology at Glaxo Wellcome. DR. TILSON: Thank you very much, Mr. Chair. In the interest of full disclosure, I am Clinical Professor of Epidemiology and Health Policy at the University of North Carolina, and I provide consultation to Glaxo Wellcome and other companies in the pharmaceutical industry, and other regulatory authorities including the FDA. It is an honor to be here today, a great pleasure and a thrill for a public health physician to hear these issues being discussed as the public health issues that they are, and therefore I am particularly delighted to be able to speak. I should make it clear that while I was nominated to speak by the Pharmaceutical Research and Manufacturers of America, the industry association with whom I also provide consultation through my Glaxo Wellcome contact, my comments are my own. Let me be specific about a couple of observations. As the last speaker in a long morning, I shall not belabor points that have already been made although my prior comments and written comments I certainly spent more time on them than I will now, but I would like to observe a couple of things that have not been touched on and I will do that after I have had a chance just to reinforce and therefore to subscribe to a couple of points that have been made. First, it is clear that there is a convergence of goals here, isn't it? No one wants to deprive children of needed new medicines which can help to reduce their pain and suffering. Hearing from patients and their parents and their advocates is critical to remind us of that, and I am deeply grateful that you arranged that, Mr. Chair. The commitments between industry, researchers, and regulators likewise are congruent, aren't they? And that has been wonderful to witness. Everyone wants to be sure that the right thing is done, but the right thing is never easy and, as you observed in your initial comments particularly in this area, it is not. We were reminded that we need more, better drugs sooner, better understood for this and all subpopulations, and that is critical for us to remember, and we must remember in rulemaking that often we create barriers unnecessarily and need, as we move forward, to be sure that we don't do that, because the enemy is disease, and not the regulatable. The Institute of Medicine's Future of Public Health Report in 1996 reminded us that public health is about partnerships, new partnerships and creative partnerships. I congratulate you and my fellow panelists in moving forward and looking at a new way to get new voices into this important debate by bringing the American Academy of Pediatrics and pediatric research specialists, pharmacologists, patient advocates, and, yes, the industry, together to look at these issues perhaps in a newly constituted advisory mechanism. I don't think we have heard enough about that. I am not sure we will be able to hear enough about that today. It certainly seems to me to be the way forward and I applaud that, as well. We have heard that not all drugs are created equal, and certainly not all drugs need broad experience or should have broad experience in their early use. Our ethicist on the panel reminded us that there are sequential ways for us to learn, sequentially involving with their dignity and equitable access to research, the more vulnerable populations who deserve the protections that all of us enjoy plus others, and I thank him for that. Children are not just little adults, and we have heard from our clinical pharmacology colleagues that this is very complicated stuff, not the sort of thing that can be solved by a simple or simplistic approach to rulemaking, not that this is that, but perhaps it is more extreme than it needs to be to get this job done, where, in fact, what we need to do is reason together and therefore, finally, I have heard again and again congratulations to the FDA, and I add them for its 1994 rulemaking and introducing the kinds of dialogue that need to happen throughout the drug development process between industry and the government, introducing yet a third mechanism to be sure that when those parties do not agree on priorities, do not agree on strategies, do not agree on pediatric testing, then, they could be referred to a neutral forum. That then would address the problem of overburdening of our volunteer advisory panels, a serious one in my view. But you have heard all this already, let me just touch on a couple of quick additional items. First, we have heard several times about the issue of being a single world in a global environment. We need to learn from what is going on outside the United States, and we need to be sure that as we move ahead we reconcile our regulatory decisionmaking approaches with other countries of the world. Drugs are developed globally. Children of the world suffer similar diseases. They deserve similar access, and they deserve that we learn from the experiences abroad and incorporate into our rulemaking thinking abroad. I call to the attention of the panel something that you are already well aware of, and that is the recently issued guidance of clinical investigation of medicinal products by the CPMP in Europe just issued this year. Their definitions of age groups and sequences and appropriate testing are different from those in the proposed rule. I think we mustn't move forward without honoring out commitments to develop our regulations globally. It is a fundamental obligation and commitment that the Food and Drug Administration has embraced. I congratulate you for it and urge that you do it here. Finally, I am a physician/pharmacoepidemiologist, a public health doctor, and therefore I rejoice, Charles McCarthy, in your mentioning that there are many ways to learn truth. We need to rethink our paradigms here, don't we? When all you have is a hammer, then, the world looks a lot like a bunch of nails, but it is not true that the only way we can learn is through randomized trials, it is not true that we know everything at the time a drug is approved, it is not true that the label is the only way doctors learn. We heard from Wendy Goldberg eloquently that we must be better at learning from the experience out there. We must track better the use in pediatrics for drugs which are not specifically indicated in that age group, and we can do that postapproval with the cooperation and more energetic efforts of groups like the American Academy of Pediatrics, Med-Watch, and industry, and we haven't done that fully. And likewise, we must learn, as the Institute of Medicine, in its Future of Public Health Report urged that we do, that health care delivery has changed entirely in the last 10 years with the advent of large automated population-based computer databases. We now do have the opportunity to learn from the actual experience, and I think with that opportunity comes an obligation. So, Mr. Chair, in concluding, let me thank you very much for the opportunity to comment. I would be very happy to discuss the specifics of what might or might not be waived, but in my view, the issue is not that. It is how can we produce a mechanism which assures that we approach this very sophisticated and complicated area with the sophistication and dedication it deserves. Thank you. MR. SCHULTZ: Thank you, Dr. Tilson. Why don't we start with Dr. Wilfert. Discussion DR. WILFERT: I would like to just hear the panel speak to the issue of the pediatric formulation. I understand some of the difficulties, but we haven't addressed that generically. DR. WALSON: First, again getting back to the actual use, lack of formulations has not prevented the use of these products, whether by crushing tablets with ingenious or non-ingenious devices as Ms. Goldberg mentioned, or by extemporaneous production of formulations which is going on every day. Our pharmacy, for example, prepares 75 different drug formulations per day in our hospital. This is going on every day. This is a smokescreen. The lack of a formulation -- a formulation helps administer drugs to children -- but the lack of a formulation does not stop it, and it should not be allowed to be a waiver. In addition, at a minimum, the FDA should consider allowing manufacturers to put stability information -- which they have -- in labeling, so that they do not have to encourage the label, they do not have to indicate that it has been tested, but they do know what pH and what concentration something is stable or not, and they should be allowed to provide that information. The other thing is obviously children are not the only edentulous patients that can't take tablets. DR. WILFERT: Let me ask you a question which is obviously pointed. It is true that the lack of formulation does not prevent use. Is it not possible that making up formulations is potentially harmful and therefore the requirement to develop an appropriate formulation is necessary? DR. CLEMENTE: Yes, I think that the formulation question is a very important one, as we tried to point out in our opening remarks, that a formulation for a child is truly a daunting avenue to approach. It isn't a very simple, straightforward situation. Grinding up tablets -- and we all know that we have done this in the past -- and we all know that in pharmacies in hospitals that many times that is exactly what they have to go to because the medication, which may even be available in an appropriate dosage form for a child, the child will actually refuse to take. So, we know that that is an enormous problem. In terms of formulating products for children, we do know the ins and the outs of this, and I can assure the panel that this is very, very difficult situation. It can be done. There are wonderful technologies available, some of which are actually applied to formulations for the adult, which should be taken a look at for developing formulations for children. If you are going to take a formulation and you are going to test the product in a youngster, then, you must consider the age category because the children will differ. If you are taking a liquid, for example, which is objectionable tasting, it is an enormous task to make that into a palatable formulation. For the most part, when you have a drug which is an alkaloid, for example, in a solution, the child perceives it immediately. Now, most of the folks at this panel will say the compound tastes awful, therefore, it must be good for you, but a child will not take that approach. The child will most likely give it right back to you. So, what you really have to do is take cognizance of the technologies which are available, find those technologies and apply them. I bring to the panel's attention the fact that when you conduct clinical trials in children, the regulations are such that you really have to take the formulation that you have made and you have proven it to be stable, and take that formulation into the trial. That is really what you really have do with the present formulations, so let me explore something with you. It is very possible that the sponsor will not be in a position to take the best formulation available at the time of the clinical trials. So, here is an opportunity, and here is an opportunity for the agency to take a look at what has been developed and to make a judgment as to whether or not the final formulation has to go through the same type of studies as the initial formulations. For example, you could take a formulation and take a colorant out of the formula, and by our regulations as they now are constructed, we would be forced to run the clinical trials all over again, and all of the stability issues, and all of the technical chemistry and manufacturing control sections. What I am suggesting to the panel is that we get together, not as an adversarial group, but as a group that are working to provide good medication, whether it be a new molecular entity or an old drug that has been reformulated specifically for children, and test it in children, and get to the bottom of the goal, to develop those formulations for the child. MR. SCHULTZ: But here is the question. Is developing a formulation ever so difficult that that should be the basis for a waiver from the requirement to test the drug in children? DR. CLEMENTE: Let's take the extreme. If a formulation is impossible to make stable, for whatever reasons, then we have a particular problem - what is going to be the formulation that is going to be utilized for the child, will it have to be manufactured on an as-needed basis, what are we going to do about that situation. And I have no answer for you on that situation, but I can tell you this, that if a concerted effort is made to develop a stable, palatable formulation for a youngster, I would say to you that 90 percent of the time that is doable. It would be difficult, in many cases almost an impossible situation, and there may have to be an understanding with the regulatory agency that certain changes in the way in which we approach the approvability of such a formulation would be allowed. There are many cases, for example, where food additives, which are regulated as GRAS, generally recognized as safe, we can't use those materials in a product formulation in a pharmaceutical because of a regulation many times which is now in place. Let me give you an example of that. If a food additive has not been approved in a New Drug Application for a pharmaceutical product, the agency cannot approve a medication with that GRAS material in the formulation. It cannot. That is a regulation. So, these good folks can't even help us develop formulations which might be very useful for a pediatric population. Those are the things I am talking about that we have to address. It goes back to the previous panel's point about good common sense. MR. SCHULTZ: That is very helpful. Would anybody else on the panel like to comment on this issue? DR. TILSON: Only to add that you asked should this be a criterion or a waivable, I think the answer would be it would have to be one of the dimensions that a group considering these issues would have to take into consideration, not just formulation, but the overall question of feasibility. We heard other feasibility issues, access to patient populations, and size of patient populations, critical feasibility issues, barriers to development of drug that would have to be considered as one considered waiver. DR. WARD: Can we get any more specific as to what would equal a concerted effort or a good-faith effort I think as it was mentioned in the regulations, in trying to develop a formulation, is it number of trials, is it cost, is it length of time? DR. CLEMENTE: I wish I could answer that clearly. I don't have an answer for that. I think that if the sponsor in this particular case were to explain the reasons why the formulation were difficult or almost impossible to accomplish, and I think that there are very, very competent scientists within the agency who can address that situation, and I see no reason why a dialogue cannot or should not ensue between the sponsor and the agency's personnel to really come to a conclusions. DR. WALSON: I think it is also important to separate already marketed drugs from new drugs, because already marketed drugs for which formulations are being used, and in some cases actually stability and availability data exist, must be separated somehow. I would also urge, to turn it around, I would like to challenge the agency to tell me why, for formulations that have shown to be dangerous, if not lethal, in children -- and I will give the example of morphine -- are still allowed to be marketed without forcing the manufacturers to produce a safe dilution for children. MR. SCHULTZ: We will wait for the final rule to do that. DR. WARD: To Drs. Tilson and McCarthy, do you think the focus of the rule should be reversed, as some panelists have suggested this morning, that all drugs should be expected to be tested in children unless a specific exclusion is applicable particularly based on disease not occurring in the child? DR. McCARTHY: I would answer that in the affirmative, but I would add a qualification. Contrary to the opinion of at least some panelists who want very early initiation of studies in children, I would make sure that the studies are at least through Phase II in adults before you move to children, and I would like to see it in two or three phases - older children, then younger children, and finally infants. I would not make that an absolute rule. Obviously, there are situations where that could not or should not obtain, but as a generic kind of presumption yes, the studies should be done in adults and followed with studies in children and in the sequence that I suggested. DR. TILSON: Let me be sure I understand your question. Let me rephrase it. This is a good regulatory practice, this question, that is, is this the sort of situation -- we have before us a proposal which is the all or none. You presume that the drug will be developed in children, and the only way not to is by a process by which you apply for a waiver and perhaps discuss it. There is another extreme. That is, you assume that the drug would never be developed in children, and the only time you do it is when you decide to propose, and then there is the middle road, which I prefer as a person who developed regulations for many years, that is to say, that there would be criteria under which one would want to advance pediatric testing, development, and eventual labeling, but not all drugs would be susceptible to it. In other words, if you put together a complicated regulatory mechanism in which waivers must always be applied for, even when they are not appropriate at all, drugs being developed in adults, drugs where there is not a considerable burden of illness in children, drugs where it is not likely that there will be early pediatric uptake, then, you are in the same position that you are with any of the many things that you will need to learn following drug approval, that is, you put them into a priority sequence. But to have to require a waiver proposal, with all of the literature review and intensive homework of the proposer, all of the staff time and diversion of the reviewer, and perhaps even an excessive burden on a voluntary committee to adjudicate, it seems to me isn't good regulatory practice. I think you can have, as we do now, intelligent discussion at the reviewing division level about which drugs are and which drugs are not appropriate to move forward on. DR. McCARTHY: Could I add just an additional comment to that? I would disagree slightly in that I think the presumption ought to be that all drugs will be tested unless a waiver is granted, but I believe that is exactly the kind of rule that should be modified after two or three or four years of experience, where certain categories of drugs need not be tested. So, I would end up exactly in the position of my colleague, but I would start, as we did, for instance, in recombinant DNA, with very strict rules and then, as evidence presented itself, relax those rules appropriately in the light of our experience. So, I would do it in a stepwise process. DR. WALSON: Can I ask Dr. McCarthy a question? What about a drug that is being developed in an ethics sense, it is going to be developed for a known pediatric disease. When should formulation work start, after you are sure it is safe in adults or before? Should children wait? DR. McCARTHY: Assuming that there is some evidence of bioequivalence, so that the data in adults would at least give you some idea of the appropriate use of the drug in children, and so on. I would start this after Phase II, when you begin to get data on both safety and efficacy. DR. WALSON: I am sure I wasn't clear. Let's say a drug that is going to be used in children. You know it is going to be used in children. But what I heard you say is that you shouldn't start pediatric testing until you are sure it is safe in progressively younger children, and I am saying should children have to wait? DR. McCARTHY: I guess I am questioning the premise, because we already heard evidence that roughly 50 percent of the drugs, the new drugs tested, wash out eventually anyway, and we heard some arguments for not including children until there is some reason to believe it really will be used in children, and you are not likely to have that until at least after Phase II. DR. WALSON: But if you do that, 50 percent of the drugs that are needed for children will then have to wait as formulations get developed. DR. McCARTHY: I understand and I think there is a cost. The other side of the cost is the 50 percent of drugs that will be useless in children will be tested in them, and I think it is a wash. DR. WILFERT: I want to reiterate a distinction which I think we agreed to, and that is, that potentially fatal illnesses and illnesses which are unique to children are not in this current discussion about the stepwise development. Isn't that correct? DR. McCARTHY: And I would agree to that. DR. TILSON: Certainly, I would, too, Cathy, as you well know. May I comment, Mr. Chair -- MR. SCHULTZ: Yes. DR. TILSON: -- about Dr. McCarthy's comments about my comments. MR. SCHULTZ: But understand we don't have to decide this today. DR. TILSON: No, I understand that, but I think Dr. Ward asked about good regulatory practice. Another way forward here, as you well are aware because you have used it many times before, is to attempt the mechanism without the regulation. That is to say you have the authority now to put together an advisory committee and begin to deal with these difficult adjudicative issues. There are many that are matters of very complex pharmacologic, as well as ethical judgment, about how to proceed. Until we have a way forward, perhaps the question of all or none regulation is one that should be deferred. MR. SCHULTZ: Dr. Kauffman. DR. KAUFFMAN: I want to ask Dr. McCarthy a further question for clarification. Could you elucidate us on your assumptions for advocating the stepwise progression in studies, what are your implicit assumptions that lead you to that recommendation? DR. McCARTHY: The implicit assumption is simply that in a well-designed clinical trial, there is generally just about as much probability of doing harm as doing good. If we introduce a stepwise process, we can very likely reduce the harm to the most vulnerable segment of our population, while nevertheless going ahead and developing useful products for them. So, I think that is really what is underlying this, but obviously, there are exceptions to that general rule. We have heard of several. DR. KAUFFMAN: Are you assuming that there is a greater probability of harm to the toddler than there is to the adolescent? DR. McCARTHY: No, I am simply assuming that to do harm to children who cannot consent to participate in research, and to do harm to those who are not able to comprehend what is happening to them, seems to be in a different ethical category than to do harm, not intentionally, but to understand that there is a possibility of doing harm to those who understand the risks and are willing to participate. DR. KAUFFMAN: Thank you. MR. SCHULTZ: Dr. Ward. DR. WARD: That is all of my questions. MR. SCHULTZ: Dr. Wykoff. DR. WYKOFF: I will pass. MR. SCHULTZ: Dr. Botstein. DR. BOTSTEIN: The proposal talks about two groups of drugs, one, already marketed drugs, the other set of drugs is not yet marketed drugs, and the proposal limits the requirement to not yet marketed drugs that are new molecular entities, drugs that have never been marketed in any way in the United States before. Do you all agree with that, or should we also include in it a broader set of drugs, new indications for a drug, new route, new dosage forms, whatever? DR. TILSON: Since I think that the way forward here is to have a reasoned advisory strategy, Dr. Botstein, I think that that strategy needs to look at all of the pediatric uses, and not simply NCEs. This is something that the Academy of Pediatrics has long done, but not rulemaking in the area, simply recognizing that there will be new indications, and they may, in fact, be unique pediatric indications for marketed products. DR. WALSON: I don't know if you voted a vote, but I obviously think it should be all drugs. DR. McCARTHY: Yes, I would like to include the marketed drugs, but on the basis that I suggested, that I don't think most of them need to be the subject of carefully designed clinical trials. I think the level of evidence, of efficacy and perhaps safety, could be based on the experience that has already been gained in their use. Again, it would require some sort of panel or judgment as to which drugs fall out of those criteria and might require a clinical trial, but most of them I think could be evaluated in a much less expensive kind of process, and that I think is important if you can get good results without so much expenditure of money. DR. CLEMENTE: I would suggest that if a formulation is being utilized for the first time, in a disease state which has been shown to be useful in a child, and the pharmacokinetics of the medicament is well known and behaves similarly in the adult and in the pediatric population, that probably a pharmacokinetic trial would suffice. A bioequivalence trial should be able to link the drug to the pediatric population. On the other hand, if there is a new indication for a medicament, then, I would suggest that the scientific data be evaluated for a judgment as to whether or not a full clinical trial would not be more appropriate. I would further suggest that in the pediatric population, because it is so unique, that we also evaluate the types of clinical trials, when they are necessary, or even pharmacokinetic trials, when they are necessary. What I am getting to here is this. Perhaps we don't need all of the information that we normally proceed to approve a new molecular entity in an adult for a pediatric population, and I think that should be also considered, as well. MR. SCHULTZ: Ms. Witt. MS. WITT: I will pass. MR. SCHULTZ: Let me just ask this panel the last question that I asked the other panel, which is I would like to ask each of you whether you favor the FDA going ahead with the regulation with modifications or whether you think the FDA should not go ahead with the regulation. I start with Dr. Clemente. DR. CLEMENTE: As we said in the outset and in our statement, that we fully support this regulation. We do understand the complexity of it, and we do suggest that there may be modifications which might be appropriate. DR. McCARTHY: I would make essentially the same statement. I think you ought to go ahead. I think you ought to take into account some very important suggestions that have come out of the various panels today, and undoubtedly some that will come out of your public hearing to follow. But, yes, in general, I think weighing all that and coming up with a judicious outcome, I would encourage you to go forward. DR. WALSON: While I wish that the previous legislation, which I agree with Dr. Ammann already gives you more than enough legislation to handle this problem, it hasn't worked, and therefore I think you need new legislation, new requirements. DR. TILSON: I take the contrary view, that is, if the opportunity is there to make our existing statutory and regulatory framework work better, we ought to try that first. MR. SCHULTZ: Thank you. We thank everybody on this panel and the earlier panels. I want to say this is I think the most informative one of these public meetings that I have attended. We truly appreciate the tremendous effort that each of the panels have put into it. I know it is going to help us in considering the proposed rule. We are going to break now. It is five of 1:00. We will break for an hour and come back at five of 2:00. [Whereupon, at 12:55 p.m., the proceedings were recessed, to be resumed at 1:55 p.m. the same day.] A F T E R N O O N S E S S I O N [2:00 p.m.] MR. SCHULTZ: For those of you who are going to make presentations, what I want to do is ask everybody to come and sit at the table, and we will just do it that way. I want to ask people to limit their presentations to five minutes, so we will do eight presentations, and then if there are any questions from here, we will have time for that, and the intention would be to finish by 3 o'clock. Why don't we start from my left, your right, and if you would just state your name and your affiliation, then make your presentation, and then just pass the mike down the row. Presentations from the AudienceDR. KEARNS: Thank you, Commissioner Schultz. My name is Gregory Kearns. I am the Marion Merrill Dow Professor of Pediatric Pharmacology at the University of Missouri, Kansas City, chief of the section of Pediatric Clinical Pharmacology at Children's Mercy Hospital, and a member of the PPRU network. I would like to address a statement made, I think by Dr. Tilson, concerning whether or not we really needed to proceed with the new regulations. I heard him say that we were in a position that was middle of the road. Having spent many years in Arkansas, we never use the phrase "middle of the road." We use the phrase "straddling the fence." I can tell you from being there it is a very untenable, useless position to be in. Clearly, some action is warranted and by your own straw poll, which to my count was 8 yes out of 9 people asked whether we should proceed, 2 of those being representatives from industry, 4 from academia, 1 from a foundation, and one mother of a child, I think the imperative is clear, we have to proceed. The '94 pediatric rule clearly placed us on the road, but it is not enough to move us down the road. The '97 proposed regulations afford that opportunity, to move the whole state of affairs for making drugs better for children, to move us down the road in the right direction. Clearly, there is an immediate impact issue of these regulations. We all know that and I will not spend any time going through it, but there are some important delayed impact issues that bear mention, because the ramifications of this action won't be a here and now endeavor. It is going to change the face of pediatric pharmacology just as this historic meeting is evidence of that face changing. First, and most importantly, the new regulations will provide insurance, insurance of an increased position of children in our society and how they are cared for in terms of their medication needs. It will provide insurance to afford a cooperation and a collaboration between regulatory agencies in the country, between industry, the people who make and spend the money to do research on new drugs, and of people who practice, whether in academia or in the small town in the middle of Missouri, it is going to afford that avenue that is unparalleled in my view of what has happened in pediatric pharmacology in the last three decades. It is going to provide insurance to improve the safety of what we give our children. It is appropriate that we should focus our concern on the right dose, but what about the outcome, what happens when that child is 17 years old, out of the neonatal nursery, and attending the prom, or 22 years old and having their first child, what kind of insurance do we want about what we do today? It is going to afford insurance that will permit an ability to answer critical questions. We heard Drs. Spielberg and McCarver today, stress the importance of having a road map of ontogeny for critical drug metabolizing enzymes. Who is going to pay for the road map? Today, I don't know the answer to that question, but I know for certain that if these regulations go into force and we move down the road, that the momentum and the avenues in this country that always rise to the call will make the resources available to answer those critical questions. It is going to afford insurance, the ability to train a whole new generation of pediatric clinical pharmacologists. I can't say how pleased I am to be one of the young men in the group and to sit here with the old men who have paved the way. What are we going to do for the next generation? How will those people come about? Some of them are snickering, but really, how will they come about? Well, if we create a need by improving what we do for children, society will help us fill that need, and there will be enough people to carry it on. We are going to create the insurance associated with making science that is new for children, not just trying to adapt something, not trying to put a size 2 shoe in a size 12 shoe, which is what we have done with science. We need new science to do studies in children, and this will make that happen. It won't be an issue of hand-me-down science anymore. This is critical because, as we heard this morning, Abby Goldberg gets up every day and Abby and her mother are faced with the same questions. Abby is waiting for some change, and at the Children's Mercy Hospital, we have a little slogan that we are using in our fund-raising campaign, and it is kind of trite, but it is true. It says, "The children are waiting." Passing these regulations will end the wait. Thank you very much. MR. SCHULTZ: Thank you very much. MR. GRINDER: My name is Dave Grinder and I am currently President of the Pediatric Pharmacy Advocacy Group and editor in chief of the Journal of Pediatric Pharmacy Practice. Today, I represent the Pediatric Pharmacy Advocacy Group, or PPAG, and the American College of Clinical Pharmacy, Pediatrics Practice and Research Network, the ACCP-PedPRN. PPAG and ACCP applaud the FDA for advancing regulations requiring pediatric safety and effectiveness studies for new chemical entities. Too many times have some pediatric populations been considered therapeutic orphans with no access to new therapeutic agents because of the lack of information regarding dosing and administration and the lack of safety and effectiveness data. However, sometimes we feel the claim that children are not small adults may have been misinterpreted. Children do suffer from hypertension, cardiac arrhythmias, depression and other pathology normally expected to occur in adults. Pharmacotherapy for these conditions must be made available to children in a rational and well thought-out basis. The PPAG and ACCP support the following: 1. We recommend that a waiver for less than substantial use only be provided for anticipated or documented uses less than 10,000 patients per year. The proposed regulations would allow the FDA to grant a waiver for not yet marketed drugs if the drug was not going to be used in a substantial number of patients. At the annual meeting of the PPAG last week, our membership discussed what a substantial number of patients should mean. The consensus was far less than the 100,000 figure being considered by the FDA. Interestingly, there are only 30,000 children and young adults with cystic fibrosis in this country. There are a total of only 75,000 hospital admissions annually for sickle cell disease. There are only 24,000 infants born each year with respiratory distress syndrome. There are no more than 4,000 infants with bronchopulmonary dysplasia, and there are fewer than 21,000 children with hemophilia in this country. These disease states utilize a significant portion of resources with pediatric health care. It is clear that the developing consensus today is for a panel of experts to determine when it would be appropriate to grant a waiver for pediatric studies. This panel will consider the therapeutic benefit and various stages of human development against the risks identified in Phase I and Phase II adult studies. At some point, an estimate of the number of uses will guide the panel's decision. It is important that this guiding number be significantly lower than previously considered. Over one-half of the free-standing children's hospitals in this country, who are members of the Child Health Corporation of American, CHCA, participate in a shared clinical and financial database called the Pediatric Health Information System, or PHIS, which was developed and is maintained by CHCA. Line item charges are identified at each institution for every admission and provided to the PHIS database. This database can identify with a high degree of accuracy the number of uses or doses of a particular drug and within a specific diagnosis. The PHIS database can provide reasonable estimates of annual usage of medication in children. Recommendation No. 2. For drugs that are currently marketed, a manufacturer should be required to develop a pediatric dosage form. Without requirement to complete safety and effectiveness studies in pediatric patients, its significant use in pediatric patients can be documented. Appropriate bioavailability studies would need to be completed. The FDA has tentatively concluded that the pediatric study requirement would not apply to applications for supplements for new indications or dosage form or already marketed drugs. Currently, if a manufacturer wishes to develop a dosage form that makes it easier to use in children, meaning an oral solution or a suspension, the FDA may require appropriate safety and effectiveness studies in children. Recommendation No. 3. For every new chemical entity and currently marketed drug still under patent, with our without safety and effectiveness data in children, where no oral liquid dosage form is available, the manufacturer should be required to provide a formulation that effectively converts an oral solid or intravenous dosage form to an oral solution or suspension dosage form. This option would be available to manufacturers of products that do not meet the substantial use requirement or where reasonable attempts at developing an oral liquid dosage form has failed. We understand that significant resources are required to establish chemically and microbiologically stable oral liquid formulations suitable for marketing, however, throughout our practice we are required to invent or create extemporaneous preparations suitable for administration to pediatric patients from solid oral dosage forms. The stability and bioavailability of many of these formulations have not been studied. Manufacturers should be required to establish an extemporaneous formulation with chemical stability and microbiologic stability to allow a 60-day expiration date and demonstrate acceptable bioavailability. This formulation would need to use commercially available compounding products. The resources required of the manufacturer would be significantly less than that required for a product with a two- or three-year shelf life. The FDA could then publish a compilation of approved extemporaneous formulations for all relevant products. The publication could parallel the FDA's Orange Book or the data could be incorporated into the Orange Book. Recommendation No. 4. We recommend that a reporting mechanism be developed between the pediatric adverse drug reaction, or PADA, reporting program, and the FDA, so that a sense of the extent of adverse outcomes associated with naive use of a drug in pediatrics can be determined. The PPAG established the PADA reporting program two years ago. Twenty-eight children's hospitals participate in a shared database examining adverse drug reactions in pediatric patients. Within the database, the dose on a milligram per kilogram basis is captured for each adverse drug reaction, and the database can identify ADRs relative to variable dosing. Year to date, as of October 23, 1997, there have been 712 adverse drug reactions reported to the PADA program; 24 were classified as being a dose-related adverse drug reaction. Only 4 of those 24 ADRs involved drugs with pediatric dosing information in the official labeling. The other 20 ADRs occurred with drugs with no pediatric dosing information including bupivacaine, metoclopramide, benztropine, and clonidine. The PADA program has been developed to identify trends in ADR occurrences for the purpose of establishing strategies to prevent ADRs or minimize the severity of the ADR. MR. SCHULTZ: Mr. Grinder, could you try and conclude, please. MR. GRINDER: I have two more paragraphs. MR. SCHULTZ: Okay. MR. GRINDER: Well-defined side effects are included in the database and add value to the process of identifying potential intervention strategies. The purpose of the FDA's Med-Watch program is to identify adverse reactions not identified in clinical trials or in the literature. Rightly or wrongly, this is the perceived purpose of the Med-Watch program, which in itself is an extremely valuable service to the medical community, however, it may not be able to identify trends of commonly reported adverse drug reactions associated with variable dosing. I was hoping to go on to describe what the PPAG and ACCP-PedPRN is, but I will save your time and simply thank you for opportunity to express our recommendations regarding this very important proposed regulation. MR. SCHULTZ: Thank you very much. For the panel, there is a light in the middle of the table that will being flashing at five minutes. MR. WESTMORELAND: My name is Tim Westmoreland. I teach at the Georgetown University Law Center, and I also do Washington representation for the Pediatric AIDS Foundation. However, today, I would like to give a disclaimer, that the views I present are my own. They should not be construed to represent those of past, present, or maybe future employers. I am also discarding my prepared statement, which I will submit as a comment for the regulations to try to respond to some of the issues raised this morning. The first one I would like to discuss is the proposal enunciated by Dr. McCarthy, studying different ages in different steps starting with older children and going down to neonates. I believe that this is perhaps a guiding principle, but it should not be a rule. We have to consider studying the use of drugs in the context of the severity of illness first, not in the context of age first, and we must also study it in the context of probability of success of the treatment, not in the strict context of age only. I believe that the general risk standard that we should be using in looking at age should be the general risk standard we use for looking at most other factors here, the risks to the child of failing to study the treatment. Secondly, formulations. I believe however often there may be some formulation problems, it is all too often used as a smokescreen for companies who do not attempt to develop drugs for children. I would call to you not these scientific finding, but the logical conclusion that if formulations were genuinely the issue, we would expect to have many drugs approved down to, say, for instance, the age of 6, not stopping at the age of 12 or the age of 16. If drug companies were willing and anxious to do drug studies on children who can swallow pills, we should be seeing those drugs approved and tested to that level, but we do not. Formulation seems to me a convenient cry of wolf, which the industry has used too often. I would also point out, as the mother this morning pointed out in the break, that swallowing pills is not something that comes completely with set age groups, that her young child, who has to take those pills every morning, started swallowing pills at the age of 3, and that chronic illness may make it easier for children to come to understand how to swallow drugs. Next, I would like to discuss the distinctions that are being drawn between new drugs and already approved drugs, on-label or off-label drugs, initial indications and uses, and secondary indications and uses. While I recognize that there is a need for guidance in these areas, I would urge the agency to reconsider how they have drawn this guidance. Drawing distinctions in this rule is purely an artificial commercial and legal distinction. For kids, the rule should be if it makes a difference in safety or effectiveness. We should consider that only as the basis of whether we are considering old drugs or new drugs, on-label or off-label. The regulatory taxonomies that we need for clarification in other areas are irrelevant to the basic question we are looking at here. Next, I would like to discuss the recurrent theme that the '94 regulations are enough and that we should stop there. I think that the FDA proposed regulation's prologue lays out extensively why I believe that the '94 regulations have not had the effect that we had hoped for, but I would also call your attention to prepared testimony that was delivered in the House of Representatives by the Pharmaceutical Research and Manufacturers Association, in which they said that even with six months of additional exclusivity, commonly estimated to be worth $100 million, that the industry would not be able to achieve much success. It seems to me with that testimony in place, that you have every reason to believe that a voluntary effort on the '94 regulations is not going to be the solution we are all looking for. Next, I would like to discuss cost and convenience for the industry. It seems, as I have alluded to already, that this is a backwards consideration. It is the cost of the failure to study the drugs. The number of children who are sick, the number of hospitalizations we can avert, the adverse reactions, we should juxtapose that against the cost to industry and decide then whether the cost is worth undertaking. I know that many of my industry colleagues will now tell me that I am being sentimental and that not every kid can be worth that effort, and I need to do something other than snatch numbers from thin air. So, let me turn to an attempt that I have worked on, on many occasions with industry advocates in which they have attempted to value the worth of a child's life. Consider the Vaccine Injury Compensation program that pharmaceutical manufacturers have vigorously supported and in which a death caused by vaccine injury is flat-out cashed out at a liquidated value of $250,000 per child. I would encourage the agency, in determining the burden on industry, to consider if the agency supports that value, and that if, for instance, four children can be saved by studying this drug, that an additional million dollar expense on the industry is one that they have readily accepted as an alternative to facing jury awards. If 1,000 children can be potentially saved, then, $250 million is not too much to expect of the industry since it supports that in other areas, as well. Finally, I would like to say in closing that I think the legal authority is much stronger for this regulation than even the agency has described it to be. The standard of safety and efficacy in the statute itself contains no exception for some subpopulations. It says safe and effective, it does not say save and effective for adults only. It is a long-standing principle of statutory interpretation that the Congress knows how to draw distinctions if it wishes to, and if it has not drawn those distinctions, they should not be read into the statute. I do not believe that the Congress has ever given the FDA permission to approve drugs that have not been tested for all patients who will be consuming them. Even if I did believe that the language was unclear, the legislative history on this point is abundantly clear. All FDA statutory provisions have been adopted in recent years from the thirties on to this date in response to children's catastrophes, and every statement that is on the floor begins -- not every statement -- many statements that are on the floor begin with discussions of how this legislation was intended to protect children and mothers and children. The FDA has more than ample authority to issue this regulation, and I believe you should not be so timid in suggesting that it is up to discussion. You have many standard sources for legal authority under this provision. Thank you very much. MR. SCHULTZ: Thank you. Mr. Harvey. MR. HARVEY: Ditto. I am David Harvey, Executive Director of AIDS Policy Center for Children, Youth, and Families. We represent approximately 350 clinics across the U.S., serving 50,000 infected children, youth, women, men living with HIV and AIDS. Thank you for this opportunity. I, too, want to tailor my remarks to a couple of specific issues that developed this morning, but before I do that, I also want to acknowledge and thank the Office of the Vice President for their work on this issue, as well. They did a lot to call attention to these particular sets of issues. First, my organization wholeheartedly supports the adoption of this rule with some modifications to the waiver provision and perhaps an in-depth review by FDA after a year of implementation to assess how it is going. The first concern and fear I think that the families have that we serve is that the pharmaceutical industry will use creative strategies to get out from underneath this rule. So, therefore, we are recommending that we review how this goes in the future, at least that one year after implementation. Three additional issues. I want to drive home the point of public health safety in relation to these concerns. Think about it. Families living with AIDS, parents living with HIV and AIDS, right now can avail themselves of new AIDS drugs. In many situations, there is dramatic results. These parents are desperate to provide access to these drugs for their kids, and I have pushed pediatricians to prescribe them on an off-label basis and in some situations, have provided the drug on their own, under their own prescription to their kids. This raises a lot of safety and ethical issues. These parents are desperate for a cure. They are looking to the Federal Government and the FDA for action, swift action on this issue. On the issue of waivers, companies can apply for waivers generally in four areas. Our understanding of the current rule is that in the case of kids with AIDS, a company will not be able to apply for a waiver on the basis that it doesn't represent a meaningful therapeutic benefit, but I want to address a larger issue that goes beyond the pediatric AIDS community, which is the issue of substantial numbers. The 100,000 figure to us seems somewhat arbitrary in terms of prescriptions or uses among kids, and instead we would recommend that a series of criteria be adopted by this panel and that an absolute number not appear in the rule. There is probably some precedent for this in existing law and policy. One small example of this, which is an issue that a colleague, Tim Westmoreland, certainly knows about, is in Title IV, which has a provision that requires care providers to enroll a significant number of patients in clinical research programs. That was implemented by Health Resource Services Administration, not in terms of an absolute number, but in terms of criteria used to try to provide access to children to clinical trials. Finally, the point was made this morning that it may be hard to recruit or to seek involvement of families and children in clinical trials. We know from our experience that when there is a trusting partnership between providers, clinical researchers, and patients, and that services are provided in a one-stop shopping model in the communities where they live, families will participate in clinical research. Ask them and they will tell you that. Thank you. MR. SCHULTZ: Thank you. MR. GOLDSTEIN: My name is George Goldstein. I would like to begin by suggesting to my good friend, Greg Kearns, that we are all children in aging skin. I sat here all day and was reminded of two very disparate people. One was the late Harry Shirkey who 40 years ago coined the term "therapeutic orphans," and as Sandy Cohen remind me earlier today, it went from children and disease over to drugs. I also had the privilege of being an original member, subsequently Vice Chairman and Chairman of the Pharmaceutical Research and Manufacturers Association's Orphan Drug Commission throughout the decades of the eighties, and it is that experience that I would like to bring to you today. Incidently, that brings me to the second person that I remembered today, and that is that great philosopher Lawrence Peter Berra, known better as "Yogie," because I, too, had the deja vu all over again feeling - the same hearings, the same legislative history, a lot of meetings in lawyers' offices, FDA, and elsewhere, resulted in an Act that, as amended, is generally acknowledged in industry, in academia, and practice -- and I spent 15 years in the practice of pediatrics before coming to industry -- as an Act that has worked, and I would urge, much as Dr. McCarthy has urged, that there is language in prior regulation and legislation, the legislative and regulatory history of the Orphan Drug Act, as amended, that can be infinitely valuable in your efforts -- which, by the way, I applaud. The bottom line is look at the Orphan Drug legislation. I serve on the National Organization for Rare Disorders' Research Advisory Board. It works, and I think there are some useful things in there that could make whatever you do work even better. That is the take-home message. There are balances built into that legislation in terms of incentives, in terms of linking with the tax laws, in terms of research, which I strongly support, and incidently, I am Chairman-elect of the American Academy of Pediatrics section on Clinical Pharmacology, so it matters, and I do care. I am not obviously representing any of those bodies here today. This is purely personal. But look at the regulation and look at one more thing, and that one more thing -- and Hugh Tilson alluded to it -- every single transaction between a mother and child, on the one hand, and a physician, on the other, is an epidemiologic event. We have been less good than we could be in marshalling that vast body of information to provide information for the labeling and for the other things. Is this in any way to be construed as saying to you don't do more research? No, not at all. It is just another way of bringing information, which is what we are all here for. Finally, I will dare to touch on one subject that needs to be touched upon. I don't know how you are going to solve it, I wish I knew. That is the tort laws, the legal inhibitions, very practical and very topical. All you have to do is read the newspapers, that exists. If there are ways, and I don't know, but I believe in Samuel Johnson's dictum that there is no problem set by the mind of man that the mind of man cannot solve. We need to come up with a solution or beginning of a solution, that, too. All of these, taken in the aggregate, should result in what we all want to see happen - more, earlier research for the benefit of the children. Thank you. MR. SCHULTZ: Thank you. DR. MIZRAHI: Good afternoon. My name is Eli Mizrahi. I am the Chairman of the Professional Advisory Board of the Epilepsy Foundation of America, and I also serve on the Board of Directors of that organization. Also, I am Associate Professor of Neurology and Pediatrics at Baylor College of Medicine in Houston, and there I am the Director of the Clinical Research Center for Neonatal Seizures, which was established about six years ago as one of the three NIH-funded centers. In my capacity there at Baylor, I take care of newborns, infants, and children with epilepsy and conduct clinical research on specific aspect of this disorder. I am here, however, representing the Epilepsy Foundation of America. It is a national organization serving people affected by seizures and with epilepsy through research, education, advocacy, and service. We are non-profit. We have a network of 66 affiliate organizations and we are in about over 100 communities around the country. We represent 2 1/2 million people in the U.S. with epilepsy. That includes both adults and children, and my comments today, I want to emphasize that they really do represent a balanced view with our understanding of our mission of being advocates for both adults and children. Approximately one-third of the individuals that we represent are children. Seizures and epilepsy may occur at any age, but many consider epilepsy primarily as a pediatric disorder because of the prevalence in children and because many adults have experienced their first seizure or their onset of epilepsy in childhood. For some children epilepsy is relatively benign, but for others seizure control may be very difficult and currently available antiepileptic drugs may not be helpful in their current formulation or in their current circumstance, and if seizure control is achieved, it may be at the cost of significant adverse effects of the medications themselves. Seizures affect children's educational and social development, so it is vital to achieve control of the disorder as soon as possible after onset. About 50 percent of childhood epilepsy may not be controlled by currently available antiepileptic drugs and the degree of intractability can be, for the most part, determined by adolescence. Patients with medically intractable seizures may turn to alternative forms of therapy including surgery and, less frequently, the ketogenic diet. Recently, after a very long hiatus, the pharmaceutical industry and the FDA have responded to the need for new antiepileptic drugs, and in the past few years we have seen some new medications that have been approved for seizure control. However, for the most part, children have been left out of this process. The population which perhaps has the greatest need has been denied the potential benefits of these advances. Thus, we enthusiastically support the Food and Drug Administration plan to establish regulations requiring manufacturers to assess in children the safety and efficacy of new drugs and biologic processes. We will submit some written response to this process, but we would also like to make a few recommendations and comments, which I will do briefly. First, in the introduction to the proposed regulations, there is a list of the number of classes of drugs which have inadequate pediatric labeling. We simply ask that antiepileptic drugs also be placed in that category. We agree that regulations should establish and enforce the expectation that all drugs be tested in children. Among our major concerns with the proposal is the number and variety of conditions which may allow a partial or complete waiver of the regulations. Waivers based upon the idea that obtaining the information would delay marketing of the adult preparation could be applied to many applications, and we do not favor this. Let me emphasize again that we advocate for both adults and for children. In addition, waivers based upon the projected numbers of prescriptions written or upon the number of patients who may use the drug, may be too easily obtainable when applied to specific types of seizure disorders at different age groups. Some of the children with the most dire need perhaps may not fall into the category of being testable with waivers that can be applied. We ask also that you consider the burden of the disorder, as well as the number of children who experience the disorder, in considering issues relating to the requirement for testing. We ask that you maintain strict limits on the circumstances in which deferment of establishing pediatric data and formulations is allowed in order that the intent of the regulations not be easily circumvented. The proposed regulations describe a number of remedies if manufacturer's compliance is limited. In addition to those remedies, full disclosure may allow market forces and the forum of professional and public opinion to be felt. We ask that you consider that one method of doing this would be to have packaging information include a specific section on the status of the development of pediatric data. If data exists, it can be presented. If waivers or deferments have been requested and granted, let us know about it, and the reasons and the current status can be provided along with a timetable for full compliance. Finally, I would like to refer the panel to the proceedings of a workshop on the development of antiepileptic drugs for children, which was held in February of 1994, sponsored by the Epilepsy Branch of the National Institutes of Neurological Disorders and Stroke. Representatives from government, academia, consumers and the pharmaceutical industry participated. I was one of the participants, as well. The recommendations of the workshop are very pertinent of today's proceedings and I just want to mention one or two of them as I close. One of them, and the main one, was that antiepileptic drugs are needed for pediatric epilepsy, and trials for new antiepileptic drugs should include trials for children. Also, if a drug is shown to be effective for partial seizures in adults, this is sufficient to justify approval for use in partial seizures in children provided that safety and pharmacokinetic considerations are appropriate. We ask also that postmarketing surveillance for long-term developmental cognitive and other safety issues be developed for all new antiepileptic drugs. Finally, I did want to mention one last item, and that is that in the consideration of the development of panels which address specific questions relating to antiepileptic drugs or other drugs in children, we ask you to consider and to avail yourselves of the expertise within the major advocacy organizations that represent various children with very specific disorders. Thank you very much for your time. MR. SCHULTZ: Thank you. DR. OREN: I am Joseph Oren. I am a pediatrician and allergist. Currently, I am a consultant to the pharmaceutical industry after 26 years of working in industry. Prior to that, I practiced pediatrics and as a practitioner of pediatrics, I was very aware that I had to identify the optimal dose of most every drug that I was using de novo for each child that I treated. I felt at that time, and I have felt every since then, that the pharmaceutical industry essentially has abdicated the responsibility of identifying appropriate dose for children. In my 26 years in the pharmaceutical industry, I have done hundreds, perhaps thousands of clinical trials, many of these in children. It is not difficult to do. It is not hard to do studies in kids. The patients are available, the parents are willing, and the various tests that need to be done, if carefully designed studies are performed, the tests can be done. I am especially interested today in, first of all, thanking the FDA and the committee for the effort to produce this proposal, but secondly, to ask that in this proposal, you make a real concerted additional effort to recognize that any drug that is used in children should be studied in children. I do not think that there should be waivers unless there is an absolute necessity for the waiver. I also feel that the whole concept of excluding out of label uses is a terrible mistake. Out of label uses, if you want to be practical about this, is that almost every drug used in kids is being used out of label, and that we have very few drugs where we have appropriate labeling for children under 12, and hardly any with appropriate labeling for children under 6. We haven't done the job, and letting people say or avoid doing these studies because this is an out of label use, and the sponsor has not taken responsibility for asking for this labeling, I think is abdication on their part and abdication on the part of FDA. I think that FDA should require that studies be done whenever a drug is being used in kids to any significant degree. I think that the points that should be included in the recommendation for studies in children, the sponsor must be required to, at the very least, collect safety information on any use. The sponsor should make a clear-cut and strongly coordinated attempt with the input of the FDA to identify and define doses for different ages and sizes. Finally, the sponsor should make every effort, in a controlled way, to look at appropriate drug interactions. I thank you for your attention. MR. SCHULTZ: Thank you very much. DR. WILSON: I am John Wilson, Professor of Pediatrics, Chief of Clinical Pharmacology, at LSU Medical Center in Shreveport, Louisiana. I am also the principal investigator of one of the NIH PPRUs at that institution. Commissioner Schultz, panel, I welcome this opportunity to make four points on the rule. First, the rule background discusses a premise for action, that is, show harm results from off-label use in children. The regulations are clear for drug approval in all populations. Rationale for labeling is not contingent in adults or children on first showing harm results from a drug. Let us be clear on that. This proposition to first show harm is not to be dignified by rebuttal or requests for data to serve as a basis for the rule. Children are granted the same benefits and protections as adults for safe and effective drugs. No. 2. Allegations of increased costs for pediatric clinical trials. If there is significant cost -- and I doubt that the FDA estimate of $5 million per company, per year is significant cost -- then, let us consider that a relative but major absence of drug trials and labeling in children has indeed subsidized drug costs for adults for 30 years. Some argue that payback is overdue. From this viewpoint, cost alone is not sufficient reason to delay or deny pediatric labeling. No. 3. Is the rule timely or necessary? That question has been raised this morning. Pediatric drug labeling is now clearly before the public and Congress. There can be no retreat. The therapeutic orphan of 1968 has now been repeatedly validated by private and government persons. Too many drugs are used off-label in children. Society holds us accountable for corrective action. Delays sought by a request for further dialogue are, in my opinion, no longer acceptable. No. 4. What about generic off-patent drugs notably absent from mention in the rule? These constitute major off-label use for prescription and, as I have recently documented, for OTC drugs off-label use. Who will fund the trials for labeling? That is a major question for these drugs. I suggest funding by the original innovator, a consortium of generic companies actually and currently marketing the drug, or a federal agency, such as NICHD or FDA, and I am sure many on the panel could think of other sources of funding for this important problem. Finally, I thank the agency for its leadership role in behalf of children and beseech it to persevere in this noble effort through creation of an effective partnership with industry, trial site investigators, and expert advisory groups. Thank you. MR. SCHULTZ: Thank you very much. Discussion Dr. Kauffman, do you have questions? DR. KAUFFMAN: No. MR. SCHULTZ: Dr. Wykoff. DR. WYKOFF: Mr. Grinder, could you talk a little bit more about the extemporaneous dosage form? I didn't understand what your proposal was in that regard. MR. GRINDER: The proposal is to have manufacturers of yet to be marketed drugs provide an extemporaneous formulation of an oral solid dosage form, meaning rather than require the manufacturer to develop an oral solution or oral suspension, if substantial use in children is not expected, they can provide this formulation to the FDA, which can be published in the Orange Book. The formulation would have documented stability and microbiological stability for 30 or 60 days, and this formulation would become the standard formulation, then, that pharmacies throughout the country could use to prepare this product for that occasional pediatric use. DR. WYKOFF: Would that be easier and less costly than -- MR. GRINDER: I would think the requirements of the manufacturer to provide stability data for a 30-day product would be much less than for a product with a 2- or 3-year shelf life. This is a practice that we, as Dr. Ward mentioned earlier -- I am sorry, someone from Columbus -- stated earlier that we do this dozens of times each day with little or no data available. This process would formalize the database. DR. WYKOFF: Are you suggesting that it be done as a last resort? MR. GRINDER: If there is not substantial use in pediatrics expected, this would be a required option to developing a pediatric formulation. If substantial pediatric use were suspected or documented, then, the manufacturer would have to provide a pharmaceutically appropriate solution or suspension. MR. SCHULTZ: Dr. Esber. DR. ESBER: Dr. Goldstein, you had mentioned earlier in your presentation about the Orphan Drug Act and the advisory board that you sit on. There were a lot of comments earlier today about the possibility of seeking expert advice by the FDA for this rule, such as committees or other mechanisms. I wonder if you could go into a little more detail about this board, the Orphan Drug Board, and any potential aspects of it that could be useful in relationship to the comments this morning. MR. GOLDSTEIN: Not much, Dr. Esber, simply because the composition of the board has evolved in recent years, and it has been some months since we have had a meeting. I suggest that you call Abbie Meyers at -- I can give you the number -- and ask Abbie. I am sure she will be glad to help as indeed would I. DR. ESBER: I was just looking for information, such as the kinds of advice that that board provided, prioritization or recommendations. MR. GOLDSTEIN: Generally passing on applications for support of research initiatives and what was, by comparison, with NIH and industry, woefully small funds, but nonetheless, they went at the process appropriately, and I believe, in fact, it's a neurologist, Dr. Melvin Van Woert, who chaired the committee. But it would be the conventional grant review, rating kinds of things, and then trying to provide funds, also using the connections of the people on that group to solicit additional advice, additional input where possible, particularly from either manufacturers or people of means, additional funds. That is basically what it was there for, to try to do everything we could to enhance the effort with respect to orphan drugs. Incidently, that part this morning, I found a bit amusing because one of the original premises was that industry could not do a study in 50 children with epidermolysis bullosa. In fact, they could and they did as the long experience, now 14 years with the Orphan Drug Act, as amended, has conclusively proven. There is all sorts of material in the literature showing the effectiveness of that particular act and it's a marvelous example of government, FDA, and then kudos to Dr. Haffner, who has been single-handedly responsible for a great deal of good, industry, government, and the research community. So, it does work and the legislative history and regulatory history, as I noted earlier, is long and deep, and ought to be considered prior to finalization of whatever it is you do. DR. SPIELBERG: I would like to ask Dr. Oren and maybe Dr. Goldstein, or anyone else, whether you have any insights into why industry has not done more testing of pediatric uses, of drugs that are used in children? DR. OREN: I am very pleased to speak to that question. I feel very strongly that industry hasn't done it because they haven't been forced to do it. The need is there, the ability to do it, as I said, is there. The money actually is there, because, let's face it, the pediatric sales are incremental sales, and as long as they are earning money on the product, they certainly can afford to do the studies. I think that your overall view of children in our society is such that we haven't thought it to be really important, and I don't blame the drug companies. I think it's the whole society. I feel this current proposal is a very important step in the right direction, to say to the sponsors, look, we do expect it to be done, you can do it, and we will expect you to give us the data, and I think you are right on, I want you to keep on doing it and do it right. DR. MIZRAHI: I will just intervene for a second as I pass the microphone over. I think also there is an issue of liability and the concern that pharmaceutical companies may have in performing such studies. I personally have cleared out a number of rooms of pharmaceutical executives talking about testing drugs in neonates. That will really become a show-stopper if you start talking about that. One of the reasons really relates to what the consequences might be later on. Perhaps one of the issues might be considering aspects of indemnification that may somehow help along on this issue. MR. GOLDSTEIN: Firstly, I would like to take vigorous exception to Dr. Oren's rather gratuitous comment about industry not doing it unless it is forced to. The second point I would like to make is that there is a disproportionate number of pediatricians in the ranks of the pharmaceutical industry. In fact, the founding chairman of the American Academy of Pharmaceutical Physicians was a pediatrician. In fact, the chief scientific officer at the moment of the industry research organization is a pediatrician. Believe it or not, there are people, lots of them in the industry that want to do, and in fact do do, a great deal of research particularly in the pediatric area - allergy, infectious disease, and a whole host of other things. I have seen it and from time to time been in a position to review it, so forcing industry is, with all due respect, Dr. Oren, not true. Let me contain my comments there. MR. WESTMORELAND: Let me also respectfully take issue with the question of liability as a barrier here and litigation. Again, in my earlier incarnation I dealt extensively with the Vaccine Injury Compensation Act, a program that was in many ways initiated at the behest of the pharmaceutical manufacturers. In that effort, and in a follow-up effort on AIDS vaccines in a keystone process, the keystone center, the vaccine manufacturers to a person said that they did not have a problem with clinical trial liability, that they had questions about liability after a drug was approved, but the clinical trial liability was not something that they even sought federal assistance for. So, while I have heard industry representatives allege several times that liability during clinical trials is a substantial barrier to pediatric testing, each time I have asked them to go back and check with their counsel, I have not heard back again on that topic. I believe that it is an issue that is abstractly there, but I do not believe that it is the issue that motivates the companies not to do pediatric trials. MR. GOLDSTEIN: Let me make one additional comment. As in so many other situations that I have been through, the military and elsewhere, for some strange reason adults are sometime afraid of children. Children represent a mystery to them. I have seen surgeons quail before a two-year-old with a temperature of 101. So whether there is a mystique here that inhibits them from doing it, I don't know. The other thing is that as a result of clinical trials, I believe there is a very large degree -- and Dr. Westmoreland is correct -- because the incidence of legal actions coming out of clinical trials is exceedingly small, it is really not a factor. It is more a factor akin to what Dr. Spielberg said earlier today in which he pointed out that getting some adult data and getting some safety information and getting some pharmacokinetics and starting with the older children and working down provides a level of assurance and a level of safety that makes it proper, if you will, appropriate to go into the smaller groups. I am developing a vaccine now that has remarkable abilities in terms of its ability to provide immunity for a major disease with a fewer number of shots. I wanted to take it directly into the population that was the most risky, the ones that would not come back for a second shot or a third shot. I was told by the agency -- and I think not at all inappropriately -- get some healthy data first, get some data in healthy adult people, then, come back to us. No one, not pediatrician, no one in the industry, certainly not I, wants to conduct a clinical trial on the basis of inadequate information, and it is just the adequacy of that information that is at issue here. We are not going to go into children prematurely, it's as simple as that. No one wants to be responsible for a tragedy. Where that line is, is I think the subject of discussion here today. MR. WESTMORELAND: If I may amplify on that for a second, first, I would point out that in vaccine trials, you are dealing with an otherwise healthy population, so it is the population that you would most likely see litigation in if you were going to see litigation at all. Studies in sick children, which is what I am about to address, is less likely I think to produce litigation than dealing with otherwise healthy children who are in vaccine trials. The second thing I would say -- and I think it is just a clarification of the preceding speaker -- is that again the issue in my mind is what is the consequence of not developing the treatment, as well. No one wants to be responsible for a tragedy of treating a child with a minor illness with a very strong drug, but at the same time there are situations in which not to respond is more of a danger than responding I think. MR. GOLDSTEIN: I certainly agree with the premise that treating children with inadequate information to do so is wrong. I certainly agree that as much or more damage can be done with inadequate information than trying to get adequate information. I mean there is nothing unusual about that. I think there is a remarkable degree, frankly, of consensus here. It is a question of where that needle along a line from most to least fluctuates. MR. GRINDER: I would like to add one comment to my response to Dr. Wykoff's question, and that is, the FDA, in cooperation with the American Academy of Pediatrics, the PPRUs, PPAG, and the Pharmaceutical Research and Manufacturer Association, will examine pediatric formulation issues in a symposium currently being planned for the spring of 1998. Maybe at that symposium we can further this discussion. MR. SCHULTZ: Does anybody have anything else? All right. I would like to thank the American Academy of Pediatrics for co-hosting this discussion. They have always been one of my favorite organizations. I would also like to thank Lisa Barclay, Fay Fink, and Sherry Castle who organized the meeting. Again, thank you to all the panelists and this recent panel, as well as the audience. [Whereupon, at 3:10 p.m., the meeting was concluded.]
Date created: November 18, 1997; last update: July 7, 2005 |
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