At the close of my testimony before the subcommittee on July 25, I was requested by Mr. Kittrie (p.1040 of the stenographic report) to submit to you any additional thoughts I might have concerning the problem of compensation of those experts,- physicians or scientists, who engage in the testing of drugs for pharmaceutical companies and submit reports that are used by the FDA in considering New Drug Applications. On this matter I would say first of all that although payment for such services by drug companies is not desirable, the law should not prescribe how the evaluation by the manufacturer is made. It should, however, require disclosure by the manufacturer and the investigators of all the facts, including the qualifications of those who made the observations, their experience and facilities and the data upon which their evaluation was made. The FDA and its advisors would take all of these facts into consideration. I would recommend that the FDA, in addition, utilize panels of experts who are not specifically reimbursed or paid for this activity by the drug manufacturer in relation to the particular product being evaluated. Dr. Goodman proposed some mechanisms for doing this which essentially coincide with my own views except that he would exclude the Council on Drugs of the AMA under its current setup and I indicated that, with certain provisions and safeguards, that Council could be used for that purpose. In the recent past I have also felt that the Council would not be a suitable body to perform this function. I am enclosing a reprint of an address I gave before the Antibiotic Symposium in Washington in October 1959 which presents the background for my proposals and I have underscored my suggestions of the alternative methods of supporting the clinical investigators engaged in drug evaluatin You may, if you wish, include this reprint as part of the record since it embodies my reply to Mr. Kittrie's request. I was also requested by Dr. Blair to offer suggestions as to an alternative for the wording with respect to the patent provision, which would reconcile my concurrence with its laudable objective and also my desire to make it workable, more acceptable and yet protect the interests of those manufacturers who profess a genuine desire to introduce only better and more useful products. Of course I can make no claim to being a legal expert and hence am not sure that I am able to offer precise wording that would accomplish all of these purposes. I attempted in my prepared testimony to word the suggested change to cover the major objectives and meet the principle objections. The requirement for expert medical opinion through the FDA and its advisers to help the Commissioner of Patents would still be included. Only the provision that requires demonstration of significantly greater efficacy would be excluded as unworkable and not in the best public interest. Instead, I would suggest that the applicant for a patent be required to offer the Secretary of HEW, the FDA and their expert advisers, proof of all claims for the uniqueness, specifically useful properties and superiority over the drug before it was modified or combined. This is essentially as I had it in my prepared statement except that it requires proof of superiority if such is claimed by the patent applicant. I hope that these additional comments will be helpful to the Committee, but I would agree with Dr. Goodman that a better wording might be arrived at if a group of experts worked at it together. MF:X cc: Dr. John Blair Sincerely yours, Maxwell Finland, M. D. Associate Director Thorndike Memorial Laboratory The Challenge of New Drugs to the Clinical Investigator MAXWELL FINLAND Associate Professor of Medicine, Harvard Medical School; Associate Director. When I was first approached with the request to undertake the task now before me, my first reaction was clearly and, I thought, unalterably in the negative, as I was far from convinced that I was the person to do this, nor did I consider that this would be the proper time and place to air my views on this subject. Indeed, I suggested several outstanding persons who by both word and deed had already demonstrated their distinction in the field of clinical evaluation of drugs, who were much more suited to the task and could do it more effectively and authoritatively. However, the chairman of the program committee, not convinced by my reply, and in the manner nowadays customary among those in the unenviable position of having to get together some people to contribute within certain preconceived and prescribed areas that fit into their particular program for a meeting already scheduled.. called me long distance and reached me at a time when I was preoccupied with other matters. At the moment it seemed easier to say "yes" and get on with what I was doing than to spend the time arguing—so I accepted, which, of course, is what the program chairman always hopes will be the case. As the time of this meeting approached, it was difficult for me to formulate just what to say and how to say it. It seemed obviously appropriate to review the methods of setting up a therapeutic trial, how to choose the proper personnel, how to obtain, formulate, and evaluate the background data, pick the proper places and types of clinical material, how to record the observations, how to know when there are enough observations to provide a definite answer, and then how to analyze the observations so that they provide meaningful answers. However, this, as I have already intimated, has already been done by a number of well-qualified investigators both in this country and in Great Britain, and it would be presumptuous on my part to tackle this type of presentation. Moreover, I had to assume from the fact that the idea of asking some of those workers to accept this assignment was rejected that this was not what the program committee had in mind. Fortunately, I was assigned no special area that I was expected to cover other than the broad one of clinical investigation. My own experience in this field has extended over the past 30 years; it was concerned, at first, primarily with the specific therapy of pneumonia and then with the general area of therapy of acute infectious diseases. This has inevitably brought me face to face with the difficulties arising out of the availability of rapidly increasing numbers of new drugs, the products of the logarithmic growth phase of a highly prosperous industry that has succeeded in recruiting some of the country's best biological scientists and chemists who have devoted most of their efforts to this task. The availability of clinical facilities and of persons trained in the clinical evaluation of these new agents has lagged so far behind that it has been possible to subject only a very small proportion of the total new drug output to any but the most perfunctory type of clinica! trial. Moreover, the highly competitive nature of modern industry in this country-aided and abetted in no small measure by the fast-working and aggressive members of their sales forces, advertising industry, and the financial wizards behind them—has made it most difficult for the few clinical investigators who do expend their efforts in this field to be heard above the din and clatter that is so frequently raised even before they have an opportunity to get together the data on which to base an opinion and before they have adequate time to analyze, check, and evaluate these data and present them for critical appraisal among their peers through publication in reputable clinical and scientific journals. ROLE OF CLINICAL INVESTIGATOR It may be putting the cart before the horse to talk about the role of the clinical investigator in the discovery and development of new drugs without attempting to define what is meant by a clinical investigator. However, this, as we shall see, can best be done by defining his function. Perhaps the most important and the most intellectually satisfying function of the clinical investigator is to initiate ideas that lead to the possible discovery of new agents or to the application or adaptation of known or readily available agents to previously unsuspected uses. This can come only from careful clinical observations with meticulous attention to detail, and requires a keen and patient observer, or it may come from chance laboratory observations in the course of functional studies carried out during an evaluation of the diagnosis, functional status, or progress of the patient. An outstanding example is the development of modern treatment of pernicious anemia. This was based in the first instance on careful documentation of the dietary histories of patients and the recognition of the possible conditions in the patient under which remissions occurred and then putting them to the test by applying them to patients in relapse. Certain other important factors were necessary to bring out this discovery and to hasten its more definitive application. One was the recognition of the role of the reticulocyte as a measure of new red blood cell formation and maturation. Although it may have been possible to bring about improvement ir. patients without this test, the full development of the potentials of this form of treatment and its application and extension to other types of anemia were certainly hastened by the use of this simple laboratory test. A second role of the clinical investigator is to aid the laboratory scientists in initiating new agents in needed areas or in developing new drugs along lines of research that may already be developed but which the keen and knowledgeable clinical investigator recognizes as a possible answer to questions raised in the management of his patients. The development of the sulfonamide drugs, their application to the treatment of human infection, and indeed the whole course of modern chemotherapy is due in large measure to the thorough understanding of the nature and course of streptococcal infections and to the recognition of the significance of changes wrought in the first few patients with such infections to whom the first active members of this series were administered. The exploration of these drugs and the developments and improvements of this group of agents could not have been made and been advanced without careful clinical observations at each step, which sifted out the more active and less toxic agents. These advances, too, were accelerated by the development of simple methods of quantitating the drugs in body fluids and tissues. Although the chemists and pharmacologists working in the laboratories have made great progress toward the correlation of chemical structure and function, it still remains a fact that the major discoveries, at least in the field of infectious diseases, and particularly among the antibiotics, have been made empirically and without any reference to the chemical structure of the final product; this only followed, and sometimes much more slowly, after much more tedious efforts than were required to obtain the active product and determine its full value. Thus, millions of patients were cured and thousands of lives saved by the major antibiotics now available before their chemical nature was known, or even suspected, since many of them revealed new structures not previously known or recognized. Even in the development of sulfanilamide and its derivatives, it could hardly have been predicted that sulfanilamide was the active principal of Prontosil and that sulfanilamide would produce severe hemolytic anemia very frequently, but that the addition of certain moieties would result in reducing this toxic effect but bring out others, such as the severe nausea and vomiting from the pyridine derivative and the marked sensitizing effect of the thiazole derivative. None of these factors were predictable and they could be recognized and evaluated only by the clinician. A third and important function of the clinical investigator is to explore the possibilities of entirely new agents and principles developed by the laboratory scientist, for, no matter how profound and logical the thinking that goes into a new principle or a new product, or how brilliantly successful it may appear to be in the test tube or even in the mouse, the guinea pig, the rabbit, or even the dog. ultimately has to be administered to patients with illness, and it is on the effects on the patients and on their illness that the success or failure of a new drug depends. Moreover, there are diseases peculiar to man in which all of the aspects of activity can be tested only in the patients, since there are no counterparts or models in vitro or in animals. Here the investigator must have a deep appreciation of the background of the discovery, an understanding of what the scientist has done, what he must require the way of preliminary information obtainable in the laboratory that might be helpful in anticipating what may happen in the patient. This must be coupled with a thorough understanding of the disease and possible reactions of patients he is to choose as the proper subjects for the initial trial, the proper observations to make in the initial trials, and the proper preparations to make in the event of emergencies that might arise and that he must, if possible, anticipate. There is no place in such a scheme of things for the brash and the ruthless or for unbridled trial and error, for one must always think first and foremost of the paties: who is the subject of the clinical trial, to avoid, as far as possible, doing any harm This cannot always be done with certainty, so that it becomes necessary to weigh possible harm in the balance as against the possible good that may result to the subject and to others who may benefit from the new agent. This means that one takes risks only when they appear to be justified by the greater possibility of potential benefits. |