Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years
Diverse Topics (Volume Eight): 1. Regulation, Ethics, Marketing and Education, Conflict of Interest
In each of the first seven volumes in this series interviewees reflect on their contributions to a particular area of research in neuropsychopharmacology.
Volume One: Starting Up (behavioral pharmacology); Volume Two: Neurophysiology (electrophysiology and brain imaging); Volume Three: Neuropharmacology; Volume Four: Psychopharmacology; Volume Five: Neuropsychopharmacology; Volume Six: Addiction; Volume Seven: Special Areas (child psychiatry, geriatric psychiatry, diagnosis and pharmacokinetics) (Ban 2011a; Salzman 2011).
Thus, in each volume the story of neuropsychopharmacology is told from a different perspective. In Volume Eight interviewees talk about their contributions on diverse topics. Presentation of these many stories does not focus on any particular area of research. Yet, the volume as a whole mirrors the changes which have taken place in the entire field during the past 50 years.
The Preface to Volume Eight also differs from the Preface to the other volumes. In all other volumes the first part of the Preface provides background information about interviewees’ research contributions, placing the contributions into a historical context (Ban 2011b). While the interviews in Volume Eight such background information may be found in prior volumes, in the first part of the Preface the larger framework of the development in neuropsychopharmacology that has been the subject of this series is discussed.
One of the essential prerequisites for neuropsychopharmacological research is the availability of psychotropic drugs with known therapeutic effects. During the 1950s several drugs were introduced by the pharmaceutical industry for the treatment of schizophrenia, depression, mania and anxiety disorders. Yet, it was not before the 1960s that approval of drugs for specific indications in clinical use, based on demonstrated efficacy, became a requirement in the United States for the distribution of a drug
The first Pure Food and Drug Act in the United States was introduced in 1906 (Barkan 1981), but until the early 1960s all regulations were related to safety requirements and to the separation of prescription drugs from over-the-counter medications. The scope of legislation was extended in 1962 with the enactment of the Kefauver-Harris Amendment (KHA) which stipulated: the effectiveness as well as the safety of a new drug has to be established before the drug is released for clinical use (Krantz 1966).
In addition to safety and efficacy, the KHA also stipulates: (1) drugs have to be produced in accordance with sound manufacturing practices; (2) the distribution and the use of investigational drugs have to be adequately controlled; (3) prescription drug labelling and advertising have to conform to governmental approval; and (4) provision has to be made by the manufacturer (distributor) for keeping records and reporting on the distribution and feedback of approved drugs, so that an ineffective or unsafe drug could be removed from the market, or its directions for use revised.
Extension of the legislation from proof of safety to efficacy has had a major impact on clinical research with psychotropic drugs. It has also led to the implementation of structured clinical drug development in three successive phases: Phase I, “human pharmacology,” starts when the new drug is first given to man, usually to normal subjects - its purpose is the determination of the drug’s preferred route of administration and safe dose range; Phase II, “clinical pharmacology,” includes the initial clinical trials for the treatment of a specific disease, or prophylactic purposes; and Phase III, “clinical investigation,” provides information on the efficacy, safety, optimum dose range and schedule of administration of the drug.
The single, most important influence on pharmacotherapy is the regulation that defines the requirements for approval of a new drug on prescription. To meet requirements of the US Food and Drug Administration (FDA), a drug must show a statistically significant difference (superiority) to placebo in two pivotal double-blind, randomized clinical trials which are of adequate sample size and statistical power. Furthermore, to meet the requirement that an ineffective or unsafe drug could be removed, the three-phase clinical development was supplemented with drug surveillance (Phase IV).
A resolution of the National Advisory Health Council in 1965 led to the establishment of Institutional Review Boards (IRBs). It also helped to build the clinical framework in which research with psychotropic drugs operates. The IRBs approve proposed research. Their primary objective is to ensure the safety of experimental subjects (ES) involved in the research. In 1966 the U.S. Surgeon General issued a policy statement in which various methods were listed to safeguard humans involved in National Institutes of Health (NIH) or, more generally, Public Health Service (PHS) supported research. Special policies were formulated for controlled experiments.
In 1966 the FDA amended its regulation with a policy statement formulated by Terry Goddard. The “Goddard Amendment” stipulated that whenever an investigational drug is used in human beings the investigators should obtain informed consent from the ES (Goddard 1966). At the time the amendment was introduced it served exclusively the protection of patients but by 1980s it became a protective shield (from litigation) for studying new drugs developed by drug companies. The amendment has had an impact on breaking the old paternalistic style of doctor–patient relationship. It also opened the path for “medical ethics” to play a steadily increasing role in medical universities.
Human experiments have been instrumental in the development of medical skills. Yet, until the mid-20th century human experiments were not controlled by legislation but by the informal code of approval of the scientific fraternity. In the middle of the19th century, Claude Bernard, in his Introduction to Experimental Medicine, asserted: “…it is the duty and the right of the physician to perform an experiment on man whenever it can save his life, cure him, or gain him some personal benefits.” But Bernard also insisted on “never performing on man an experiment which might be harmful to him to any extent, even though the result might be highly advantageous to science” (Bernard 1865). The first systematic presentation of the ethics on experimentation in humans was drawn up by the Nuremberg Military Tribunal after World War II and published in 1947 in a legal document titled “The Nuremberg Code.” The gist of the “laws” incorporated in this document are: (1) the ES must give voluntary (informed) consent prior to being included in an experiment; (2) the experiment should yield fruitful results for the good of society and its results should not be attainable by any other means; (3) the experiment must be based on prior animal studies and knowledge of the natural history of the disease; (4) the degree of risk involved in the experiment should not exceed the potential benefits of the research for society; and (5) the ES should be at liberty to bring the experiment to an end (Nuremberg Military Tribunals 1947).
The principles of the Nuremberg Code were revived in 1955 by the United Nations Third Committee on Social, Humanitarian and Cultural Questions and incorporated in 1964 in the “Helsinki Declaration” (HD), based on the “Declaration of Geneva” of the World Medical Association and the International Code of Ethics. The HD emphasizes that the “responsibility for clinical research always remains with the research worker” and “it never falls on the (experimental) subject” (Williams 2008). The Declaration has been endorsed by several nations and numerous medical associations; the Judicial Council of the American Medical Association recommended its adoption in 1966 at the annual convention of the Association.
During the second half of the 20th century clinical studies with psychotropic drugs became a large component of research in which human subjects are involved. To meet fully the obligations of ethical conduct, the “fruitful results for the good of society,” must be disseminated and integrated with the existing body of knowledge. Within our societal structure, it is the task of marketing to disseminate the findings in clinical research and it is the responsibility of education to integrate the new information with existing knowledge.
Marketing & Education
In the l950s the pharmaceutical industry was not ready for the dissemination of the rapidly growing body of information on psychotropic drugs. Means of communication were scarce. The first journal in neuropsychopharmacology, Psychopharmacologia, was launched in 1958 by Ernst Rothlin, the founding president of “Collegium Internationale Neuro-Psychopharmacologicum” (CINP), and Abraham Wikler; the second, International Journal of Neuropharmacology (now, Neuropharmacology), was founded in 1961 by Bernard Brodie, Erminio Costa, Silvio Garattini and Corneille Radouco-Thomas (one of the founders of CINP) with Costa and Radouco-Thomas as founding editors-in-chief (Costa 2003; Rothlin 1990). In 1966, to overcome the difficulties in the communication of information on psychotropic drugs, a World Health Organization Scientific Group on Research in Psychopharmacology recommended the development of an International Collaborative Reference Centers Network in Psychopharmacology (IRCNP). The IRCNP was launched in 1968 with regional and national reference centers around the world; its activities were coordinated by Alice Leeds from the Psychopharmacology Research Branch of the National Institute of Mental Health (NIMH) in Rockville, Maryland (Castellanos 2000; Vartanian 2000). Supported by NIMH, IRCNP published and distributed its journal, the Psychopharmacology Bulletin, with free copies to universities. It also compiled an International Directory of Investigatorsin Psychopharmacology, which included names, addresses, affiliations and field of research, and developed an index card system for the collection of data on the efficacy, safety and mechanism of action of psychotropic drugs (Ban 1978). In the same year the IRCNP was launched, the first data bank for clinical investigations was established in Washington DC, at George Washington University.
As time passed, industry developed the necessary marketing arms required to disseminate the information about their psychotropic drugs. By the 1980s the IRCNP withered away.
The objective of industrial marketing is to capture the largest possible market for a substance by persuading physicians to prescribe the drug. Industry is free to support research in order to generate findings that would attract attention to a substance or trigger speculations about possible advantages in prescribing it. The only limitation of marketing is that it has to adhere to the labelling and advertising approved by the FDA. Yet, by sponsoring studies using electrophysiological, biochemical, neuroimaging, molecular genetics and other advanced technologies in psychiatry, industrial marketing has had a major impact on the development of neuropsychopharmacology. It was also instrumental in transforming psychiatry, dominated by psychodynamics in the United States, into a medical discipline. Without this support, the replacement of the old cadre of psychoanalysts with neuropsychopharmacologists at the helm of psychiatric departments could not have taken place.
Parallel with the changes in psychiatry, the role of psychiatrists in the drug industry has changed from advisors on issues which required psychiatric knowledge in the 1960s and ‘70s to leaders of teams that generate the evidence in clinical investigations for regulatory approval of drugs in the 1980s. By the 1990s, psychiatrists working in the employment of industry were moving back and forth between industry and academia. They had become key players in the generation of information on which both, education in pharmacotherapy and marketing of psychotropic drugs, is based.
The signal difference between marketing and education is that marketing is focused on a drug with the objective of getting a particular product prescribed, whereas education is focused on the patient with the objective of selecting for each individual the optimal treatment by the discriminate use of available drugs. While sophisticated marketing tries to guide physicians to prescribe a particular product or give preference to a group of products in treatment, proper education equips physicians with the know-how to evaluate and integrate new information with the existing body of knowledge. At the core of education is the translation of information from preclinical research, which sets the stage for the clinical development of a psychotropic drug, and from clinical investigations upon which the prescribing of the drug in clinical practice is based. In the evaluation of pre-clinical information, the focus is on the separation of findings from interpretations. Findings are established relationships between research results in different areas of the field usually derived by hypotheses testing, whereas interpretations are assumed relationships prone to the fallacies of formal logic. In the evaluation of clinical information, the focus is on the recognition of the clinically relevant findings hidden behind statistically significant results. Without information on the “effect size,” “t” values, response rates, etc., the “p” valuesof statistical analyses indicate only the level of confidence, the probability that there is a treatment responsive group within the population studied (Ban 2011b; Belmaker, Bersudsky and Lichtenberg 2010).
A division of labour has evolved in clinical drug development during the past 50 years. It is based on a model in which it is the task of (governmental) regulatory bodies to ascertain that the drug released for clinical use is effective and safe relative to the risk of the disease itself; the task of industrial marketing is to disseminate information on the drug and to generate interest in prescribing it; and the task of (academic) education is to provide the necessary teaching so that the drug is prescribed in a discriminative manner. The confounding of roles and functions in this model has led to conflicts of interest and interfered with the optimal use of psychotropic drugs. It was also counterproductive for neuropsychopharmacological research.
Conflict of Interest
Prior to the 1980s little attention was paid to “conflict of interest” in science and medicine (Black 1974; Merriam-Webster 1985). At present, authors in most medical journals and speakers at most medical conferences are required to disclose their financial involvement with the pharmaceutical industry (Lemmens 2008). By focusing on financial motivation, current policies have distracted attention from the fact that in neuropsychopharmacology, a discipline in which pharmacological homogeneity of psychiatric populations is prerequisite for progress, the conflicting motivations (objectives) of marketing with education, instead of facilitating has interfered with the development of rational pharmacological treatment.
Introduction of psychotropic drugs during the 1950s focused attention on the pharmacological heterogeneity within psychiatric diagnoses (Ban 1987). There was a need to resolve this heterogeneity by developing a pharmacologically valid classification of mental illness (Freyhan 1959). To date, this has not happened (Klein 2008). Instead, to meet marketing needs, the randomized clinical trial was adopted for the demonstration of efficacy (compromising the term “effective” with the term “efficacy” adopted from statistics) in pharmacologically heterogeneous diagnostic populations (Ban 2006). The problem became compounded in the early 1990s with the replacement of single-center isolated clinical studies by multi-center centrally coordinated clinical studies designed by power statistics and to meet the necessary sample size requirement. Many of these studies were designed for the purpose of registration by regulatory authorities and for supporting possible advantages of new drugs. Moreover, the data collected in most of these studies are proprietary and communication, based on analyses of these data, is controlled by sponsoring drug companies. Since the findings of this research provide the evidence base for both marketing and education, by the end of the 20th century information related to the pharmacotherapy of mental illness has become controlled by industrial marketing.
Today, most “evidence-based” information is generated in multi-center studies and serves the purpose of guiding physicians to prescribe one or another psychotropic drug or group of drugs. Treatment guidelines, prepared by opinion leaders and endorsed by professional societies, are no exceptions (CINP Task Force 2007). By disqualifying papers from the first 30 years of pharmacotherapy on grounds of methodological shortcomings and summarizing findings in studies designed to create a market niche for each newly introduced drug, guidelines, task force reports, and experts’ reviews inadvertently justify the preferential prescription and inclusion in national drug formularies of the newest and most expensive drugs (Ban 2008).
The blurring of education and marketing in the communication of “evidence-based” information has encouraged educators in pharmacotherapy to pursue activities in conflict with their fiduciary interest, an ethical, legal issue. Addressing violations which are focused on this area exclusively, distracts attention from the heart of the problem. Until the pharmacological heterogeneity within the diagnostic groups is not resolved pharmacotherapy with psychotropic drugs will remain prone to one-sided marketing input and interests. Furthermore, with pharmacologically heterogeneous diagnoses the pharmacodynamic information generated by neuropharmacological research can be related only to the side effect profile of psychotropic drugs.
It is within this framework that the research and educational activities of interviewees took place in Volume Eight and in all other volumes of this series.
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April 18, 2019