Statement of the American Society for Clinical Pharmacology and Therapeutics on the Drug Regulation Reform Act of 1978 (H.R.11611)*
The following analysis of H.R. 11611 was prepared by F. Gilbert McMahon, President of the American Society for Clinical Pharmacology and Therapeutics, and by the Society's Drug Regulatory Committee under the chairmanship of William M. Wardell, M.D., Ph.D. It was presented by Dr. Wardell and by Arthur H. Hayes, Jr., M.D. Dr. McMahon is a Professor of Medicine and Head of the Therapeutics Section of the Department of Medicine, Tulane University School of Medicine. Dr. Wardell is an Associate Professor of Pharmacology and Toxicology and Assistant Professor of Medicine, University of Rochester Medical Center. Dr. Hayes is Professor of Medicine and Pharmacology, and Chief, Division of Clinical Pharmacology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania. The membership of our Society consists of 1100 clinical pharmacologists. Nearly 60% are from academia (including every medical school in the United States) and private medical practice, while most of the other members are in industry and government; two thirds of our members have hospital staff appointments. We do not speak for or represent any special interests-rather we speak for that group of scientists and physicians whose special expertise and concern are for the better understanding and use of those therapies we already have for the *Submitted to the Subcommittee on Health and the Environment of the House Committee on Interstate and Foreign Commerce June 22, 1978. (Presented on June 27. 1978.)
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sick, and for the development and rational use of better and safer treatments. In a very real sense then, we speak for the consumer-for our patients, particularly those unfortunate enough to have diseases for which today's therapies are inadequate. Like others mindful of consumers' needs, we are concerned with the safety of old and new therapeutic agents. However, we are in a better position than most to perceive the overwhelming impact that most diseases have on patients, the inadequacy of existing therapies, the compelling need for better therapies and better ways of using existing ones, and the mechanisms by which these needs can be met. The following aspects of the Society's membership are of special relevance to our evaluation of the Drug Regulation Reform Act of 1978. As research clinical pharmacologists we have special expertise in the methodology and standards for evaluating drug efficacy and toxicity. As clinical investigators, we are the clinician-scientists with special knowledge of the state-of-the art of clinical investigation; weand the studies we perform-would be directly affected by several provisions of the bill. As practicing physicians who specialize and consult at medical centers, we deal particularly with the problem patient-the unfortunate person who has particularly rare or severe disease, or who has unusual treatment needs or responses to therapy. In this capacity , we are involved in applying the frontiers of medical knowledge about drugs to human disease, and we have special concerns for the critical differ-
0009-9236/78/0324-0374$00.80/0 © 1978 The C. V. Mosby Co.
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ence between what is adequate for the "average" patient and w hat is needed for the patient who is in unusual trouble with his disease. As teachers of clinical pharmacology and therapeutics, we deal with how the principles of pharmacology can best be applied to the treatment of disease in real life in order to make the most effective use of existing drugs; we do this at the medical schoollevel, at the postgraduate house staff or fellowship level, and in continuing medical education for doctors in practice. We are aware of the statements be fore the Senate Health Subcommittee of those who have testified to date. Because the bill is so large in its scope, we will confine our analysis to those copies in the bill on which we have special expertise and which we feel either have not been adequately dealt with previously or which, because of their importance, deserve additional emphasis. Our comments are made primarily with a view to the bill 's effects, directly or indirectl y, on the well-being of the patient. Measures in the bill designed to facilitate the development of new therapies
We strongly support the statements in Section 101 of the bi II that refer to the need to encourage research and drug discovery and to optimize the freedom of scientific enquiry towards these objectives. However, few, if any, of the bill's provisions, will move us in this direction, and many of its effects will make the proeess of drug discovery more difficult. We see the following problems and areas for improvement in three of the ways in which the bill attempts to facilitate drug research and development.
"Unloading the front-end" by means of the New Drug Innovation Investigation provisions (Sections 125-127). The amount by which the proposed Drug Innovation Investigation conditions would facilitate the process has been substantially overestimated. In his March 17 testimony be fore the Senate Health Subcommittee, Secretary Califano stated that under the current law "the drug firm submits for detailed FDA review a drug development plan and protocol, as if the drug were certain to be the subject of extensive investigation" (page 22 of
Testimony on H.R. 1/6//
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transcript). Commissioner Kennedy at the same hearings stated that "by separating out this innovative process and not making companies plan research protocols that stretch over the entire investigational stage of drug development, we think we will save resources very significantly and allow them to be concentrated in other parts of the process, thereby reducing the time taken by the whole thing" (pages 81-82 of transcript). In fact, at present when a sponsor files an IND, he does not have to submit more than the first protocol plus a brief general statement of his plans for the remainder of the c1inical investigation phase; new protocols are submitted as they are developed, without a further waiting phase. Because of this overstatement of the requirements of the present system, we believe that the Drug Innovation Investigation provisions of the bill will not substantially facilitate development at the early stage. This should be borne in mind when attempting to estimate the overall impact of the Act on the process of therapeutic discovery.
Recommendations. I. Since there is general agreement on the need to unburden or facilitate drug development at its earlier stages, a detailed analysis of the Drug Innovation Investigation provision should be made to speIl out exactly what improvements it is expected to achieve. 2. Since the safety record of the present Phase land 11 studies is excellent, and since such studies are conducted by experts and in limited numbers of patients, we recommend that FDA be permitted to delegate responsibility for monitoring and reporting functions to the cIinical investigators and sponsor/monitors under the supervision of Iocal peer review committees. That is, once the initial notification of precIinical data and the proposed c1inical program is made to FDA, the exact conduct and details of the program, incIuding the protocol, should be handled at a local level, and the results reported to FDA.
The criteria for proof of evidence of efficacy. The 1962 law' s "substantial evidence" wording, and in particular the way this has come to be interpreted in the regulations, and in the way the regulations are implemented by
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FDA by means of administrative decisions, is increasingly divergent from medical reality and from the needs of sick patients. The greatest problem in the regulatory process is excessive demands by FDA for more data on efficacy at a time when there is no reasonable doubt that a drug is in fact effective. This problem is largely one of regulation and administrative practice, and is for the most part not due to legislation, but could be overcome by some specific legislative direction. We would therefore point out that the proposed criteria defining "significant evidence" [Section 110(b)(2)], i.e., that require "valid and meaningful scientific investigations ... conducted by experts ... [and acceptab1e after evaluation] by experts" ... offer some muchneeded legislative help. This is not (apart from the wording) an entirely new concept, having already been used for example in the approval of L-dopa in 1970. Such" significant evidence" is all that should reasonably be required for the approval of any drug-not just breakthrough drugs. To ask for more is to go beyond-and often against-the medical needs of patients and their physicians, and in many cases beyond the state of the art of clinical pharmacology. After significant evidence of efficacy (and adequate evidence of safety) exists, the decisions about whether a drug is to be prescribed for any particular patient should be left to the physicians and their patients. (As the bill recognizes, even a substantially effective drug will not necessaril y work for e very patient. For the same reasons, a drug with significant-or lessevidence of efficacy as determined in populations may be extremely effective for individual patients, and these persons should not be denied the opportunity of obtaining help from it.) We realize that complex benefit/risk tradeoffs are involved here, but these ultimately have to be made in the sphere of the individual patient and his physician; there is a limit to how far the treatment of individual patients can be prescribed legislatively without impairing the health of some. Recommendations. We strongly recommend eithe r (1) that the "significant evidence" definition, and the spirit in which it is being used, be adopted to replace the existing "substantial
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evidence" criterion wherever it now appears; or alternatively, (2) that the Secretary be given the needed fiexibility to evaluate the evidence by using legislative wording similar to the following words of Section SI3(C)(3) A and B of the Medical Device Amendments of 1976. "(3 )(A) Except as authorized by subparagraph (8), the effectiveness of a device is, for purposes of this section and sections 514 and 515, to be determined, in accordance with regulations promulgated by the Secretary, on the basis of well-controlled investigations, including clinical investigations where appropriate, by experts qualified by training and experience to evaluate the effectiveness of the device, from wh ich investigations it can fairly and responsibly be concluded by qualified experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device. "(8) If the Secretary determines that there exists valid scientific evidence (other than evidence derived from investigations described in subparagraph (A»"(i) which is sufficient to determine the effectiveness of a device, and "(ii) from which it can fairly and responsibly be concluded by qualified experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device, then, for purposes of this section and sections 514 and 515, the Secretary may authorize the effectiveness of the device to be determined on the basi s of such evidence."
Controls restricting drug distribution and prescribing. While controls over distribution and prescribing may offer some help with drugs of unusual benefit but high toxicity, the language of the bill could be construed to apply to most new drugs. This would give rise to difficulties in implementation and could be detrimental to patient care. lt should be recognized that such control systems have, to date, been feasible mainly in small countries that do not contribute to drug innovation and that have a national system of socialized medicine through which controls can be readily imposed. No large western drugdeveloping country has controls of the extent proposed in this bill. In the U.S., such controls would be particularly difficult to implement because of the structure of medical practice, and furthermore the issue of controls cannot be separated from the drug innovative process. For example, tight controls could reduce the size of
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the market in the U .S. to the point where it became uneconomic for a U.S. discoverer to build a plant to make the drug, thus effectively preventing its marketing here, or restricting the marketing to only those drugs that have already been marketed abroad. We urge that restricted prescribing of drugs be rarely called for, and that invoking such a contingency should be limited to those extraordinary instances in which such limited approval is the only alternative to FDA rejection. The bill does not adequately recognize the fact that patients' responses to drugs differ enormously. One of the major things that we as physicians and clinical pharmacologists have to deal with when we administer drugs in medical practice is this tremendous interindividual variability. The "normal" dose of some drugs may vary as much as 4,000% depending on the drug, the patient's particular handling of the drug (e.g., due to genetic factors or age), and the disease situation. This makes it impossible to treat each patient according to rigidly defined rules and regulations concerning dose and route of administration. The distinguished cardiologist Paul Dudley White estimated from his extensive experience that at least half of his patients displayed some unusual, unanticipated response to drugs. This means that the drug labeling must never be seen as a recipe for treating patients in cookbook fashion, but should instead encourage the physician to use his judgment and experience in accordance with the established principles of clinical pharmacology and therapeutics. By freezing the drug's labeling and by using it to control medical practice, patients with rare characteristics and with severe disease will be denied optimal treatment. Elderly patients and the very young are other groups who would be particularly disadvantaged by such Iegislatively mandated cookbook medicine.
Recommendation for earlier access to advisory committees. Because of the reluctance in the past of some of FDA' s reviewing officers to make and keep to decisions, we recommend that a mechanism be made available to invoke the participation of the Scientific Advisory Committee at the outset of the Drug Development Investigation, permitting sponsors and
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monitors access as deemed necessary on controversial issues to help establish guidelines for the DDI studies, to help identify breakthrough drugs, and to make recommendations on licensure to the Commissioner. Effects on clinical research into new therapies in the U. S.
Effects on clinical investigators. The scientific community accepts the concept of stringent peer review. However, the information-disclosure requirements in the new bill open up clinical studies, and clinical investigators, to the legal adversary process in the scrutiny of clinical trials. Given the unsuitability of this process for arriving at scientific truth, and the ad hominem approach that tends to become part of such adversarial proceedings, clinical investigators will become wary of participating in drug studies. The bill provides investigator disqualification provisions that are needlessly arbitrary and insensitive. Scientific reputations deserve more protection and due process than this bill provides. Under its provisions, cl inic al investigators will become increasingly reluctant to undertake research in the United States, with resultant damage to the status of clinical pharmacology in this country. Compounding of the effects of existing regulations. The increase in regulations under the existing law is already having profound effects on the willingness of clinical investigators to perform studies in the United States. Early clinical research has been moving abroad rapidly since 1970. The new Bioresearch Monitoring Program, whatever its desirability, vastly increases the responsibilities and decreases the willingness of clinical investigators such as ourselves to participate in clinical investigations. Inevitably the result will be a further scarcity of clinical investigators in the U . S. and an acceleration of the move abroad of clinical studies. Moreover, FDA's requirements under the Bioresearch Monitoring Regulations will be difficult to meet abroad. They will have the effeet of thwarting other FDA regulations (promulgated in 1975) that recognized the need to assure the admissability of foreign data. The
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Bioresearch Monitoring Regulations will therefore worsen the delay in the availability of drugs in the U.S. and the need to repeat c1inical studies here on drugs whose efficacy and safety are already weIl established abroad. Thus, there are substantial legal and ethical objections to the effects that existing legislation will have, and related provisions in the new bill will compound the deleterious effects of these. We therefore recommend careful evaluation of the cost-effectiveness of existing and proposed regulations, considering in particular the existing Bioresearch Monitoring Regulations together with those parts of the new bill that bear on the same or related issues; the aim should be to sc rap those that serve little or no useful purpose despite great cost and diversion of resources.
Disclosure of information. Research data. There is to be an opening up of hitherto confidential data files at a very early stage and in a way that will deprive innovative firms of the financial benefits of research expenditures. There is little scientific knowledge about a new drug desired by the public or academic scientists that cannot be obtained from an adequate summary that is released at the time the application for marketing approval is being considered. Such a summary, and its adequacy, could best be prepared and judged by a nongovernmental advisory committee, whose existence could be mandated by law. To revise drastically the current system, substantially disregarding the incentives to private enterprise, will penalize the creative firms the most and will be detrimental to patients. Furthermore, the bill' s proposed timetable for the very early release of raw data, and the proposal for public hearings, introduces gratuitous opportunities for the capricious and malicious use-and misuse-of evidence about a drug under the spotlight of national media attention, thus prec1uding the balanced review that is possible under the present system. In this manner a useful drug could be condemned irrevocably by special interest groups, to the detriment of those patients who could otherwise benefit from it. The effect of all this will be to make the United States the last place in the world where a firm will choose to introduce-or
C/in. Pharmacol. Ther. September 1978
even to undertake c1inical investigation of-a new product. As a result, there will be a further worsening of the drug lag, an acceleration of the current /light of American research investment, jobs and expertise abroad, and obvious adverse effects on the already unfavorable U.S. balance of trade. Wealthy Americans will continue to be able to go abroad for proved therapies that are delayed in reaching the U.S., while the poor will be even more adversely affected by any such measures that further delay the introduction of effective new treatments to the U.S. Patient package inserts. We agree with the concept of increasing information for patients, but would warn that the methodology for devising and using these in a way that will provide benefit, without harming a significant proportion of patients, has hardly begun to be devised. Recommendation: A patient package insert should be inc1uded only when the actual document has been thoroughly tested and, as a result of such tests, has been shown to have benefits that outweigh its hazards. FDA guidelinesfor clinical research. Clinical research guidelines are signposts that show how yesterday's drugs were developed. The effect of such guidelines will be to raise the standards of research at the lower end but to constrain innovation at its creative edge, where /lexibility is most needed. Moreover, we have serious concerns about the use of guidelines in view of the FDA policy that alternate designs "must be shown [to be] as appropriate as, or more appropriate than those in the guidelines." In summary, we predict that the bill' s new controls over c1inical investigation, taken cumulatively with the burgeoning regulations under the existing law, will seriously hamper c1inical investigation in the United States, to the patients' detriment. Other effects on drug innovation and on the drug regulatory process
Review points and time frames. The new proposal has even more points at which research is to be evaluated, and longer times for response, than at present. It is unrealistic to believe that these can be met, so the effect will
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inevitably be to slow the evaluation process. Postmarketing surveillance. While we support the concept of an improved postmarketing surveillance for both benefit and harm, the present proposals give the FDA too broad a mandate in requiring it and are being made before the outlines of feasible methodology are known. Since postmarketing surveillance is being increasingly used voluntarily by FDA and the industry, and since both the Joint Commission on Prescription Drug Use and the large FDA/ETIP methodology studies are already under way, we suggest waiting until the reports of the latter two groups are in before passing legislation on this issue-Iegislation that is otherwise bound to be scientifically outdated before it is passed. Consumer and expert representation on advisory committees. The bill proposes more consumer representation on FDA's advisory committees. We would fully support this if it meant genuine representation of the real consumers, i.e., those patients with a special interest in the disease category under consideration. We therefore strongly recommend that such consumer advocates be chosen from a list nominated by private disease-oriented foundations related to the specific drugs under consideration. Further with respect to advisory committees, the present conflict-of-interest interpretations actually have the effect of exciuding some who are the most skilIed experts on the subject in question. We would urge altering the current qualifications and disqualifications for membership on FDA advisory committees so as to ensure that such committees will be more optimally constituted of experts than they can be at present. Due process concerns
The bill seeks to put broad new powers into the hands of the Secretary of HEW, the FDA commissioner and his staff. Due process is a respected principle in American jurisprudence, but it is not served when officials are given powers that at times allow them to be detective, prosecuting attorney, judge, jury, and appeal court all rolled up into one. We feel there is cause for concern about due process in some of the bill' s provisions.
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Effects on the teaching of clinical pharmacology and therapeutics
Sound teaching in clinical pharmacology and therapeutics depends on a close relationship with research at the frontiers of both basic and ciinical pharmacology. The flight of ciinical pharmacological research from the D.S. will inevitably weaken the science of clinical pharmacology in this country, and thus lower the standard of teaching. Furthermore, the constraints on distribution and on prescribing for nonapproved uses, and the effect of these on the practice of medicine, will inevitably be reflected in the standards of teaching. This is not a beneficial effect of regulations. The questions of relative efficacy and safety
The bill provides for the Secretary to consider questions of relative efficacy and safety in determining whether a new drug should be admitted to the market. While relative efficacy and safety are key factors that are, and should be, routinely determined by physicians in the treatment of individual patients, we feel that access to the market is not the point at which this criterion can be effectively employed. There are several technical reasons for this. I. A drug's full effects are sei dom known at the time that it is submitted for admission to the market. Recognition of this fact is implicit in the bill' s desire to improve postmarketing surveillance (with which, as stated above, the Society agrees in principle but has reservations about the manner of implementation). Of particular importance is the fact that a drug's full utility may be discovered only years after marketing-sometimes in clinical areas where the drug was not initially even suspected of having efficacy. For example, the effects of ß-blockers in lowering blood pressure (they have become the most useful new anti hypertensive drug ciass discovered in the last decade) and in preventing secondary myocardial infarction mortality were not predictable at the time of marketing; discovery of these uses depended on the observations of astute ciinicians who already had the drug available for another use. Similarly, certain platelet-inhibiting drugsinitially introduced for unrelated conditions as
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widely divergent as pain and the treatment of gout-have recently been shown to have efficacy in the prevention of strokes and he art attacks. Such serendipitous clinical discovery of new uses for drugs is actually one of the major pathways of therapeutic progress and is increasing in importance. For this we need to have many drugs available with a wide range of molecular structures and mechanisms of action. By raising substantial hurdles at the premarketing stage, the comparative efficacy requirement would have an immediate dampening effect on the number of drugs available for serendipitous discoveries . 2. The second problem with imposing hurdIes of relative efficacy and safety on access to the market is that the scientific criteria-and even more so the regulatory criteria-are at present undefined. Often, patients can be found who respond to a new drug when they had not responded to an older one. How many such patients would have to be identified be fore the Secretary determined that this constituted superior efficacy: One patient? One thousand patients? One million patients? If the Secretary sets his cutoff (as he would have to) at some arbitrary level (e. g., 10% of the potential patient population), what happens to the therapeutic needs of those patients for whom the new drug is more effective but who constitute too small a minority to surmount the arbitrary regulatory threshold for conferring recognition of superior efficacy? Moreover, if the pattern of toxicity of the new drug is entirely different, on what grounds can the Secretary make the benefit-risk judgements the bill sets up? 3. The methodology for determining comparative safety and efficacy on a large scale is technically difficult. It requires complex experimental designs and analyses (which for some of these applications have not yet been developed) and large numbers of patients closely evaluated for subtle clinical effects. This means very costly clinical studies-even by comparison with today's large costs, which are for relatively unsophisticated designs. It is therefore highly likely that, if a relative efficacy requirement is imposed as a condition of marketing, drugs will drop by the wayside simply
Clin. Pharmacol. Ther. September /978
because the law's requirements go beyond our society's available technology and resources. By contrast, the relative clinical usefulness of such drugs for individual patients can be (and already is) deterrnined de facto in the course of ordinary clinical practice. If a range of more or less similar drugs exists for a given condition, it is simply routine practice for the patient, together with his physician, to find out which drug works best for hirn; for most drugs, this is the only appropriate point at which relative efficacy can be determined. The proposed national center for clinical pharmacology
We applaud the goals of increased support of general research and training in this field, but question the necessity for a new institution. (For example, most ofthe additional research needed to approve new drugs will not be feasible in a single center.) The NIH is already doing clinical pharmacology in many categorical disease areas, and the goals of this section could be achieved by increased funding through existing NIH institutes. If a clinical pharmacology institute is the only way to get adequate funding for academic and professional clinical pharmacology, we support it, and in that case we would strongly prefer to see it as an institute within NIH, not within FDA. The goal should be to assure continuing support for a discipline that will grow in importance in the years to come, not to create a politburo to oversee all drug research and usage. Evaluation of the effects of the Act
Section 202 embodies a most important and desirable aim, which we strongly endorse. However, 7 years after enactment is much too short a time to evaluate the effects of the Act, and a one-time evaluation is inadequate. For example, it took 8 years before the final regulations were published defining the "adequate and well-controlled clinical investigations" needed to implement the 1962 amendments' "substantial evidence" clause; and today, after an additional 8 years, the requirements for proof of efficacy are continuing to evolve and to rise
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stead ily as more regulations, guidelines, and administrative decisions are constantly being made. Given, in addition, the 6-year average time for investigation and approval of new drugs, the full effects of the changes that have already ftowed from the 1962 law cannot be measured until 1984- 22 years after those amendments were enacted. We recommend, therefore, that there should be: (J) A serious attempt to predict the bill' s impacts on all the factors mentioned before any bill is enacted (2) An ongoing attempt to measure any Act's impact after it is enacted, for as long as the Act remains in force (3) A positive statement requiring correction of those effects of the Act that are shown by the evaluation to have a deleterious impact on the health of patients (4) independence of the evaluative process from the Department of HEW. Conclusions
There are a number of other features in the bill that we support in addition to its opening
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statement of the need for therapeutic progress and its closing statement of the need to measure the law's effects. These include a less restrictive attitude than the present one toward exporting unapproved drugs, the elimination of personal gifts to physicians, steps to ensure the privacy of prescription data, and a more realistic definition of drug "safety." However, the present bill, although weil intentioned, is a ftawed document which we feel will not achieve significant amelioration of the serious deficiencies in drug development and regulation that were obviously in the minds of those who drafted the legislation. We make our recommendations with the primary thought of what this bill could do to the sick patient. We make them from our perspective of the present state of the art and the sciences of medicine, clinical pharmacology and therapeutics, bearing in mind the patient's dual needs: optimal treatment with existing therapies and-even more important-access to better therapies in the near future.
The following analysis of H.R. 11611 was prepared by F. Gilbert McMahon, President of the American Society for Clinical Pharmacology and Therapeutics, and by the Society's Drug Regulatory Committee under the chairmanship of William M. Wardell, M.D., Ph.D. It was presented by Dr. Wardell and by Arthur H. Hayes, Jr., M.D. Dr. McMahon is a Professor of Medicine and Head of the Therapeutics Section of the Department of Medicine, Tulane University School of Medicine. Dr. Wardell is an Associate Professor of Pharmacology and Toxicology and Assistant Professor of Medicine, University of Rochester Medical Center. Dr. Hayes is Professor of Medicine and Pharmacology, and Chief, Division of Clinical Pharmacology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania. The membership of our Society consists of 1100 clinical pharmacologists. Nearly 60% are from academia (including every medical school in the United States) and private medical practice, while most of the other members are in industry and government; two thirds of our members have hospital staff appointments. We do not speak for or represent any special interests-rather we speak for that group of scientists and physicians whose special expertise and concern are for the better understanding and use of those therapies we already have for the *Submitted to the Subcommittee on Health and the Environment of the House Committee on Interstate and Foreign Commerce June 22, 1978. (Presented on June 27. 1978.)
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sick, and for the development and rational use of better and safer treatments. In a very real sense then, we speak for the consumer-for our patients, particularly those unfortunate enough to have diseases for which today's therapies are inadequate. Like others mindful of consumers' needs, we are concerned with the safety of old and new therapeutic agents. However, we are in a better position than most to perceive the overwhelming impact that most diseases have on patients, the inadequacy of existing therapies, the compelling need for better therapies and better ways of using existing ones, and the mechanisms by which these needs can be met. The following aspects of the Society's membership are of special relevance to our evaluation of the Drug Regulation Reform Act of 1978. As research clinical pharmacologists we have special expertise in the methodology and standards for evaluating drug efficacy and toxicity. As clinical investigators, we are the clinician-scientists with special knowledge of the state-of-the art of clinical investigation; weand the studies we perform-would be directly affected by several provisions of the bill. As practicing physicians who specialize and consult at medical centers, we deal particularly with the problem patient-the unfortunate person who has particularly rare or severe disease, or who has unusual treatment needs or responses to therapy. In this capacity , we are involved in applying the frontiers of medical knowledge about drugs to human disease, and we have special concerns for the critical differ-
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ence between what is adequate for the "average" patient and w hat is needed for the patient who is in unusual trouble with his disease. As teachers of clinical pharmacology and therapeutics, we deal with how the principles of pharmacology can best be applied to the treatment of disease in real life in order to make the most effective use of existing drugs; we do this at the medical schoollevel, at the postgraduate house staff or fellowship level, and in continuing medical education for doctors in practice. We are aware of the statements be fore the Senate Health Subcommittee of those who have testified to date. Because the bill is so large in its scope, we will confine our analysis to those copies in the bill on which we have special expertise and which we feel either have not been adequately dealt with previously or which, because of their importance, deserve additional emphasis. Our comments are made primarily with a view to the bill 's effects, directly or indirectl y, on the well-being of the patient. Measures in the bill designed to facilitate the development of new therapies
We strongly support the statements in Section 101 of the bi II that refer to the need to encourage research and drug discovery and to optimize the freedom of scientific enquiry towards these objectives. However, few, if any, of the bill's provisions, will move us in this direction, and many of its effects will make the proeess of drug discovery more difficult. We see the following problems and areas for improvement in three of the ways in which the bill attempts to facilitate drug research and development.
"Unloading the front-end" by means of the New Drug Innovation Investigation provisions (Sections 125-127). The amount by which the proposed Drug Innovation Investigation conditions would facilitate the process has been substantially overestimated. In his March 17 testimony be fore the Senate Health Subcommittee, Secretary Califano stated that under the current law "the drug firm submits for detailed FDA review a drug development plan and protocol, as if the drug were certain to be the subject of extensive investigation" (page 22 of
Testimony on H.R. 1/6//
375
transcript). Commissioner Kennedy at the same hearings stated that "by separating out this innovative process and not making companies plan research protocols that stretch over the entire investigational stage of drug development, we think we will save resources very significantly and allow them to be concentrated in other parts of the process, thereby reducing the time taken by the whole thing" (pages 81-82 of transcript). In fact, at present when a sponsor files an IND, he does not have to submit more than the first protocol plus a brief general statement of his plans for the remainder of the c1inical investigation phase; new protocols are submitted as they are developed, without a further waiting phase. Because of this overstatement of the requirements of the present system, we believe that the Drug Innovation Investigation provisions of the bill will not substantially facilitate development at the early stage. This should be borne in mind when attempting to estimate the overall impact of the Act on the process of therapeutic discovery.
Recommendations. I. Since there is general agreement on the need to unburden or facilitate drug development at its earlier stages, a detailed analysis of the Drug Innovation Investigation provision should be made to speIl out exactly what improvements it is expected to achieve. 2. Since the safety record of the present Phase land 11 studies is excellent, and since such studies are conducted by experts and in limited numbers of patients, we recommend that FDA be permitted to delegate responsibility for monitoring and reporting functions to the cIinical investigators and sponsor/monitors under the supervision of Iocal peer review committees. That is, once the initial notification of precIinical data and the proposed c1inical program is made to FDA, the exact conduct and details of the program, incIuding the protocol, should be handled at a local level, and the results reported to FDA.
The criteria for proof of evidence of efficacy. The 1962 law' s "substantial evidence" wording, and in particular the way this has come to be interpreted in the regulations, and in the way the regulations are implemented by
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FDA by means of administrative decisions, is increasingly divergent from medical reality and from the needs of sick patients. The greatest problem in the regulatory process is excessive demands by FDA for more data on efficacy at a time when there is no reasonable doubt that a drug is in fact effective. This problem is largely one of regulation and administrative practice, and is for the most part not due to legislation, but could be overcome by some specific legislative direction. We would therefore point out that the proposed criteria defining "significant evidence" [Section 110(b)(2)], i.e., that require "valid and meaningful scientific investigations ... conducted by experts ... [and acceptab1e after evaluation] by experts" ... offer some muchneeded legislative help. This is not (apart from the wording) an entirely new concept, having already been used for example in the approval of L-dopa in 1970. Such" significant evidence" is all that should reasonably be required for the approval of any drug-not just breakthrough drugs. To ask for more is to go beyond-and often against-the medical needs of patients and their physicians, and in many cases beyond the state of the art of clinical pharmacology. After significant evidence of efficacy (and adequate evidence of safety) exists, the decisions about whether a drug is to be prescribed for any particular patient should be left to the physicians and their patients. (As the bill recognizes, even a substantially effective drug will not necessaril y work for e very patient. For the same reasons, a drug with significant-or lessevidence of efficacy as determined in populations may be extremely effective for individual patients, and these persons should not be denied the opportunity of obtaining help from it.) We realize that complex benefit/risk tradeoffs are involved here, but these ultimately have to be made in the sphere of the individual patient and his physician; there is a limit to how far the treatment of individual patients can be prescribed legislatively without impairing the health of some. Recommendations. We strongly recommend eithe r (1) that the "significant evidence" definition, and the spirit in which it is being used, be adopted to replace the existing "substantial
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evidence" criterion wherever it now appears; or alternatively, (2) that the Secretary be given the needed fiexibility to evaluate the evidence by using legislative wording similar to the following words of Section SI3(C)(3) A and B of the Medical Device Amendments of 1976. "(3 )(A) Except as authorized by subparagraph (8), the effectiveness of a device is, for purposes of this section and sections 514 and 515, to be determined, in accordance with regulations promulgated by the Secretary, on the basis of well-controlled investigations, including clinical investigations where appropriate, by experts qualified by training and experience to evaluate the effectiveness of the device, from wh ich investigations it can fairly and responsibly be concluded by qualified experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device. "(8) If the Secretary determines that there exists valid scientific evidence (other than evidence derived from investigations described in subparagraph (A»"(i) which is sufficient to determine the effectiveness of a device, and "(ii) from which it can fairly and responsibly be concluded by qualified experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device, then, for purposes of this section and sections 514 and 515, the Secretary may authorize the effectiveness of the device to be determined on the basi s of such evidence."
Controls restricting drug distribution and prescribing. While controls over distribution and prescribing may offer some help with drugs of unusual benefit but high toxicity, the language of the bill could be construed to apply to most new drugs. This would give rise to difficulties in implementation and could be detrimental to patient care. lt should be recognized that such control systems have, to date, been feasible mainly in small countries that do not contribute to drug innovation and that have a national system of socialized medicine through which controls can be readily imposed. No large western drugdeveloping country has controls of the extent proposed in this bill. In the U.S., such controls would be particularly difficult to implement because of the structure of medical practice, and furthermore the issue of controls cannot be separated from the drug innovative process. For example, tight controls could reduce the size of
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the market in the U .S. to the point where it became uneconomic for a U.S. discoverer to build a plant to make the drug, thus effectively preventing its marketing here, or restricting the marketing to only those drugs that have already been marketed abroad. We urge that restricted prescribing of drugs be rarely called for, and that invoking such a contingency should be limited to those extraordinary instances in which such limited approval is the only alternative to FDA rejection. The bill does not adequately recognize the fact that patients' responses to drugs differ enormously. One of the major things that we as physicians and clinical pharmacologists have to deal with when we administer drugs in medical practice is this tremendous interindividual variability. The "normal" dose of some drugs may vary as much as 4,000% depending on the drug, the patient's particular handling of the drug (e.g., due to genetic factors or age), and the disease situation. This makes it impossible to treat each patient according to rigidly defined rules and regulations concerning dose and route of administration. The distinguished cardiologist Paul Dudley White estimated from his extensive experience that at least half of his patients displayed some unusual, unanticipated response to drugs. This means that the drug labeling must never be seen as a recipe for treating patients in cookbook fashion, but should instead encourage the physician to use his judgment and experience in accordance with the established principles of clinical pharmacology and therapeutics. By freezing the drug's labeling and by using it to control medical practice, patients with rare characteristics and with severe disease will be denied optimal treatment. Elderly patients and the very young are other groups who would be particularly disadvantaged by such Iegislatively mandated cookbook medicine.
Recommendation for earlier access to advisory committees. Because of the reluctance in the past of some of FDA' s reviewing officers to make and keep to decisions, we recommend that a mechanism be made available to invoke the participation of the Scientific Advisory Committee at the outset of the Drug Development Investigation, permitting sponsors and
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monitors access as deemed necessary on controversial issues to help establish guidelines for the DDI studies, to help identify breakthrough drugs, and to make recommendations on licensure to the Commissioner. Effects on clinical research into new therapies in the U. S.
Effects on clinical investigators. The scientific community accepts the concept of stringent peer review. However, the information-disclosure requirements in the new bill open up clinical studies, and clinical investigators, to the legal adversary process in the scrutiny of clinical trials. Given the unsuitability of this process for arriving at scientific truth, and the ad hominem approach that tends to become part of such adversarial proceedings, clinical investigators will become wary of participating in drug studies. The bill provides investigator disqualification provisions that are needlessly arbitrary and insensitive. Scientific reputations deserve more protection and due process than this bill provides. Under its provisions, cl inic al investigators will become increasingly reluctant to undertake research in the United States, with resultant damage to the status of clinical pharmacology in this country. Compounding of the effects of existing regulations. The increase in regulations under the existing law is already having profound effects on the willingness of clinical investigators to perform studies in the United States. Early clinical research has been moving abroad rapidly since 1970. The new Bioresearch Monitoring Program, whatever its desirability, vastly increases the responsibilities and decreases the willingness of clinical investigators such as ourselves to participate in clinical investigations. Inevitably the result will be a further scarcity of clinical investigators in the U . S. and an acceleration of the move abroad of clinical studies. Moreover, FDA's requirements under the Bioresearch Monitoring Regulations will be difficult to meet abroad. They will have the effeet of thwarting other FDA regulations (promulgated in 1975) that recognized the need to assure the admissability of foreign data. The
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Bioresearch Monitoring Regulations will therefore worsen the delay in the availability of drugs in the U.S. and the need to repeat c1inical studies here on drugs whose efficacy and safety are already weIl established abroad. Thus, there are substantial legal and ethical objections to the effects that existing legislation will have, and related provisions in the new bill will compound the deleterious effects of these. We therefore recommend careful evaluation of the cost-effectiveness of existing and proposed regulations, considering in particular the existing Bioresearch Monitoring Regulations together with those parts of the new bill that bear on the same or related issues; the aim should be to sc rap those that serve little or no useful purpose despite great cost and diversion of resources.
Disclosure of information. Research data. There is to be an opening up of hitherto confidential data files at a very early stage and in a way that will deprive innovative firms of the financial benefits of research expenditures. There is little scientific knowledge about a new drug desired by the public or academic scientists that cannot be obtained from an adequate summary that is released at the time the application for marketing approval is being considered. Such a summary, and its adequacy, could best be prepared and judged by a nongovernmental advisory committee, whose existence could be mandated by law. To revise drastically the current system, substantially disregarding the incentives to private enterprise, will penalize the creative firms the most and will be detrimental to patients. Furthermore, the bill' s proposed timetable for the very early release of raw data, and the proposal for public hearings, introduces gratuitous opportunities for the capricious and malicious use-and misuse-of evidence about a drug under the spotlight of national media attention, thus prec1uding the balanced review that is possible under the present system. In this manner a useful drug could be condemned irrevocably by special interest groups, to the detriment of those patients who could otherwise benefit from it. The effect of all this will be to make the United States the last place in the world where a firm will choose to introduce-or
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even to undertake c1inical investigation of-a new product. As a result, there will be a further worsening of the drug lag, an acceleration of the current /light of American research investment, jobs and expertise abroad, and obvious adverse effects on the already unfavorable U.S. balance of trade. Wealthy Americans will continue to be able to go abroad for proved therapies that are delayed in reaching the U.S., while the poor will be even more adversely affected by any such measures that further delay the introduction of effective new treatments to the U.S. Patient package inserts. We agree with the concept of increasing information for patients, but would warn that the methodology for devising and using these in a way that will provide benefit, without harming a significant proportion of patients, has hardly begun to be devised. Recommendation: A patient package insert should be inc1uded only when the actual document has been thoroughly tested and, as a result of such tests, has been shown to have benefits that outweigh its hazards. FDA guidelinesfor clinical research. Clinical research guidelines are signposts that show how yesterday's drugs were developed. The effect of such guidelines will be to raise the standards of research at the lower end but to constrain innovation at its creative edge, where /lexibility is most needed. Moreover, we have serious concerns about the use of guidelines in view of the FDA policy that alternate designs "must be shown [to be] as appropriate as, or more appropriate than those in the guidelines." In summary, we predict that the bill' s new controls over c1inical investigation, taken cumulatively with the burgeoning regulations under the existing law, will seriously hamper c1inical investigation in the United States, to the patients' detriment. Other effects on drug innovation and on the drug regulatory process
Review points and time frames. The new proposal has even more points at which research is to be evaluated, and longer times for response, than at present. It is unrealistic to believe that these can be met, so the effect will
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inevitably be to slow the evaluation process. Postmarketing surveillance. While we support the concept of an improved postmarketing surveillance for both benefit and harm, the present proposals give the FDA too broad a mandate in requiring it and are being made before the outlines of feasible methodology are known. Since postmarketing surveillance is being increasingly used voluntarily by FDA and the industry, and since both the Joint Commission on Prescription Drug Use and the large FDA/ETIP methodology studies are already under way, we suggest waiting until the reports of the latter two groups are in before passing legislation on this issue-Iegislation that is otherwise bound to be scientifically outdated before it is passed. Consumer and expert representation on advisory committees. The bill proposes more consumer representation on FDA's advisory committees. We would fully support this if it meant genuine representation of the real consumers, i.e., those patients with a special interest in the disease category under consideration. We therefore strongly recommend that such consumer advocates be chosen from a list nominated by private disease-oriented foundations related to the specific drugs under consideration. Further with respect to advisory committees, the present conflict-of-interest interpretations actually have the effect of exciuding some who are the most skilIed experts on the subject in question. We would urge altering the current qualifications and disqualifications for membership on FDA advisory committees so as to ensure that such committees will be more optimally constituted of experts than they can be at present. Due process concerns
The bill seeks to put broad new powers into the hands of the Secretary of HEW, the FDA commissioner and his staff. Due process is a respected principle in American jurisprudence, but it is not served when officials are given powers that at times allow them to be detective, prosecuting attorney, judge, jury, and appeal court all rolled up into one. We feel there is cause for concern about due process in some of the bill' s provisions.
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Effects on the teaching of clinical pharmacology and therapeutics
Sound teaching in clinical pharmacology and therapeutics depends on a close relationship with research at the frontiers of both basic and ciinical pharmacology. The flight of ciinical pharmacological research from the D.S. will inevitably weaken the science of clinical pharmacology in this country, and thus lower the standard of teaching. Furthermore, the constraints on distribution and on prescribing for nonapproved uses, and the effect of these on the practice of medicine, will inevitably be reflected in the standards of teaching. This is not a beneficial effect of regulations. The questions of relative efficacy and safety
The bill provides for the Secretary to consider questions of relative efficacy and safety in determining whether a new drug should be admitted to the market. While relative efficacy and safety are key factors that are, and should be, routinely determined by physicians in the treatment of individual patients, we feel that access to the market is not the point at which this criterion can be effectively employed. There are several technical reasons for this. I. A drug's full effects are sei dom known at the time that it is submitted for admission to the market. Recognition of this fact is implicit in the bill' s desire to improve postmarketing surveillance (with which, as stated above, the Society agrees in principle but has reservations about the manner of implementation). Of particular importance is the fact that a drug's full utility may be discovered only years after marketing-sometimes in clinical areas where the drug was not initially even suspected of having efficacy. For example, the effects of ß-blockers in lowering blood pressure (they have become the most useful new anti hypertensive drug ciass discovered in the last decade) and in preventing secondary myocardial infarction mortality were not predictable at the time of marketing; discovery of these uses depended on the observations of astute ciinicians who already had the drug available for another use. Similarly, certain platelet-inhibiting drugsinitially introduced for unrelated conditions as
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widely divergent as pain and the treatment of gout-have recently been shown to have efficacy in the prevention of strokes and he art attacks. Such serendipitous clinical discovery of new uses for drugs is actually one of the major pathways of therapeutic progress and is increasing in importance. For this we need to have many drugs available with a wide range of molecular structures and mechanisms of action. By raising substantial hurdles at the premarketing stage, the comparative efficacy requirement would have an immediate dampening effect on the number of drugs available for serendipitous discoveries . 2. The second problem with imposing hurdIes of relative efficacy and safety on access to the market is that the scientific criteria-and even more so the regulatory criteria-are at present undefined. Often, patients can be found who respond to a new drug when they had not responded to an older one. How many such patients would have to be identified be fore the Secretary determined that this constituted superior efficacy: One patient? One thousand patients? One million patients? If the Secretary sets his cutoff (as he would have to) at some arbitrary level (e. g., 10% of the potential patient population), what happens to the therapeutic needs of those patients for whom the new drug is more effective but who constitute too small a minority to surmount the arbitrary regulatory threshold for conferring recognition of superior efficacy? Moreover, if the pattern of toxicity of the new drug is entirely different, on what grounds can the Secretary make the benefit-risk judgements the bill sets up? 3. The methodology for determining comparative safety and efficacy on a large scale is technically difficult. It requires complex experimental designs and analyses (which for some of these applications have not yet been developed) and large numbers of patients closely evaluated for subtle clinical effects. This means very costly clinical studies-even by comparison with today's large costs, which are for relatively unsophisticated designs. It is therefore highly likely that, if a relative efficacy requirement is imposed as a condition of marketing, drugs will drop by the wayside simply
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because the law's requirements go beyond our society's available technology and resources. By contrast, the relative clinical usefulness of such drugs for individual patients can be (and already is) deterrnined de facto in the course of ordinary clinical practice. If a range of more or less similar drugs exists for a given condition, it is simply routine practice for the patient, together with his physician, to find out which drug works best for hirn; for most drugs, this is the only appropriate point at which relative efficacy can be determined. The proposed national center for clinical pharmacology
We applaud the goals of increased support of general research and training in this field, but question the necessity for a new institution. (For example, most ofthe additional research needed to approve new drugs will not be feasible in a single center.) The NIH is already doing clinical pharmacology in many categorical disease areas, and the goals of this section could be achieved by increased funding through existing NIH institutes. If a clinical pharmacology institute is the only way to get adequate funding for academic and professional clinical pharmacology, we support it, and in that case we would strongly prefer to see it as an institute within NIH, not within FDA. The goal should be to assure continuing support for a discipline that will grow in importance in the years to come, not to create a politburo to oversee all drug research and usage. Evaluation of the effects of the Act
Section 202 embodies a most important and desirable aim, which we strongly endorse. However, 7 years after enactment is much too short a time to evaluate the effects of the Act, and a one-time evaluation is inadequate. For example, it took 8 years before the final regulations were published defining the "adequate and well-controlled clinical investigations" needed to implement the 1962 amendments' "substantial evidence" clause; and today, after an additional 8 years, the requirements for proof of efficacy are continuing to evolve and to rise
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stead ily as more regulations, guidelines, and administrative decisions are constantly being made. Given, in addition, the 6-year average time for investigation and approval of new drugs, the full effects of the changes that have already ftowed from the 1962 law cannot be measured until 1984- 22 years after those amendments were enacted. We recommend, therefore, that there should be: (J) A serious attempt to predict the bill' s impacts on all the factors mentioned before any bill is enacted (2) An ongoing attempt to measure any Act's impact after it is enacted, for as long as the Act remains in force (3) A positive statement requiring correction of those effects of the Act that are shown by the evaluation to have a deleterious impact on the health of patients (4) independence of the evaluative process from the Department of HEW. Conclusions
There are a number of other features in the bill that we support in addition to its opening
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statement of the need for therapeutic progress and its closing statement of the need to measure the law's effects. These include a less restrictive attitude than the present one toward exporting unapproved drugs, the elimination of personal gifts to physicians, steps to ensure the privacy of prescription data, and a more realistic definition of drug "safety." However, the present bill, although weil intentioned, is a ftawed document which we feel will not achieve significant amelioration of the serious deficiencies in drug development and regulation that were obviously in the minds of those who drafted the legislation. We make our recommendations with the primary thought of what this bill could do to the sick patient. We make them from our perspective of the present state of the art and the sciences of medicine, clinical pharmacology and therapeutics, bearing in mind the patient's dual needs: optimal treatment with existing therapies and-even more important-access to better therapies in the near future.
