Maintaining Integrity and Credibility in Industry-Sponsored Clinical Research Richard P. Schwarz, Jr, PhD Sterling Research Group, Malvern, Pennsylvania 19355
ABSTRACT: There have been recent, heightened concerns about the integrity and credibility of industry-sponsored clinical research. While attributable to a variety of factors, the potential consequences are a decrease in the ability of the biomedical research enterprise to produce innovative methods for the diagnosis and treatment of disease, with possible adverse implications for the health and well-being of the public. A specific example of a recent industry-sponsored clinical trial is presented as an approach to attempt to avoid any suggestion of fraud, error, or biased interpretation, in a way in which the integrity of the process will not be called into question and the credibility of the results will be maximized. Fraud and falsehood only dread examination; truth invites it.
Thomas Cooper (1878)
INTRODUCTION Recently, there have b e e n h e i g h t e n e d concerns over the integrity and credibility of results emerging from clinical research studies in general and from i n d u s t r y - s p o n s o r e d clinical research in particular. There is w h a t I w o u l d call, for w a n t of a better description, the "integrity/credibility shortfall." A few examples bear this out. In February 1989, a clinical investigator in N e w Jersey was s e n t e n c e d to 4 years in jail and $2 million in fines to be paid in restitution to nine pharmaceutical c o m p a n i e s [1]. H e was convicted of criminal fraud involving falsification a n d fabrication of data in 18 i n d u s t r y - s p o n s o r e d clinical trials on nine different drugs over 9-1/2 years. In the fall of 1988, both the general press a n d the pharmaceutical i n d u s t r y press r e p o r t e d the possibility of bias in patient selection and data interpretation from a clinical trial of the biotechnology p r o d u c t Imreg-1 for the treatm e n t of AIDS a n d AIDS-related complex [2]. W h e t h e r these concerns were justified or not, the credibility of the emerging results from these trials was d a m a g e d b y just the fact that these issues w e r e discussed. During the past few years, several academic clinical investigators, working o n b o t h National Institutes of Health (NIH)-sponsored a n d industry-spon-
Address reprint requests to: Richard P. Schwarz, Jr, PhD, Director, Clinical Development, Greenwich Pharmaceuticals, 423 Sargon Way, Unit A, Horsham, PA 19044. Received June 14, 1990, revised April 15, 1991. Adapted from a speechgiven at the Annual Meeting of the Societyfor Clinical Trials, May 18, 1989, Minneapolis, MN.
ControlledClinicalTrials12:753-'760(1991) © ElsevierSciencePublishingCo., Inc, 1991 655 Avenueof the Americas,New York,New York10010
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R.P. Schwarz sored clinical trials, have come under suspicion because they held significant financial positions in securities of the firms sponsoring the trials [3,4]. As always, this conflict of interest, whether real or apparent, can be very damaging to the integrity and credibility of the investigator, the sponsor, and the research process in general. In February 1989, a Food and Drug Administration (FDA) staff member went on record criticizing some academic experts w h o "lend their names to a drug that patently lacks substantial evidence of effectiveness" and is "eloquent evidence that money talks" [5]. These statements, if substantive, are serious; however, even if not, the reputations of the participants and the credibility of the results from the trials are seriously jeopardized. A series of events particularly damaging to public confidence in industrysponsored clinical research has been the disclosures of mid- to late-1989 involving falsification of results from bioavailability studies of generic versions of innovator drug products [6]. This has led to criminal indictment, conviction, and sentencing of several key officials in the FDA and generic pharmaceutical firms [7], and is cited as the principal reason for the resignation of the FDA commissioner [8]. Of a more general nature, but equally important are the concerns being raised due to emerging closer relationships between government agencies w h o sponsor biomedical research, such as the NIH, and industrial support of research being conducted through these government agencies [9]. While it should be emphasized that this does not automatically mean that such arrangements are wrong and that they could not benefit all parties concerned in a fair manner, legitimate concerns are raised over potential conflicts of the proper use of public funds versus pursuit of private interests [10]. Finally, in such an atmosphere of concerns regarding integrity and credibility of clinical research, two congressional committees are investigating all the aspects and situations described above [11,12]. It therefore becomes increasingly likely that Congress, in carrying out its responsibility of protecting the public interest, may introduce controls that could have a restraining effect on the clinical research process in general.
INTEGRITY AND CREDIBILITY Since scientists hold the strong belief that the research process possesses--indeed, must possess---the qualities of integrity and credibility, the words are so frequently used that they can lose their meaning. By integrity, it is meant that in all phases of the conduct of research and all aspects and interactions with others w h o are a part of that process, there is a firm, unyielding adherence to a code of moral and ethical values. In short, the research process must be relentlessly honest and open. The attribute of credibility means that the participants involved and the research results generated must possess the characteristics of believability and trustability. This is a feature that, while related to integrity, is distinct from it. The participants and the results obtained from a research effort can possess integrity; however, if their actions and the process in general take place in an environment of real or apparent conflict of interest or without full disclosure, their credibility can come into question. In discussing the issue of integrity and credibility in industry-sponsored clinical research, a basic assumption must be made: to be in the position of
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defending one's integrity and credibility is untenable. The issue simply can't come up without major damage being done to both the research program under consideration and the reputations of those impugned. In short, if the integrity of the data or concern over biased interpretation are even called into question, irreparable damage to the credibility of an industry-sponsored trial or program can occur. The remainder of this discussion will focus on three issues: 1. What is the source or cause of the problem that has led to increasing concerns over the integrity and credibility of industry-sponsored clinical research? 2. What are its consequences? 3. What solutions and safeguards should be applied? SOURCE OF THE PROBLEM
Although somewhat arbitrary, four underlying reasons for w h y there are concerns over the integrity and credibility of industry-sponsored clinical research can be identified. The first reason is that the magnitude of industry-sponsored research is considerable. In recent years, the amount of funding and the presence of industry in clinical research have dramatically increased. The data in Figure 1 compare the research and development expenditures of the NIH with the research and development expenditures of the approximately 100 U.S. research-intensive pharmaceutical firms, as represented by the Pharmaceutical Manufacturers Association (PMA). In 1977, the NIH spent about twice as much on biomedical research as PMA companies. In the last 10 years, however, PMA companies have caught up and n o w meet or, in the most recent year, actually exceed the NIH in terms of total R&D spending [13].
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1979
1981
1983
1985
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Figure 1 R&D expenditures by NIH and PMA firms.
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R.P. Schwarz To put this in a more focused perspective in terms of clinical research, Table 1 shows the expenditures for clinical research in the United States by the PMA member firms. In the last 10 years, the total amount has increased over fourfold, from $237 million in 1977 to over $1 billion in 1986 [14]. The increases are accelerating in a dramatic manner. There is no question that industry-sponsored clinical research has become a significant presence in the U.S. biomedical enterprise. Second, it is an understatement to say that pharmaceutical firms must succeed in producing new drugs with significant medical uses that can be marketed profitably. This is a fundamental fact of life, with increasing economic pressure for success being brought to bear. Third, academic investigators feel both self-imposed and externally imposed pressure to succeed in clinical investigations related to drug development. It is hard to conceive of a physician-investigator who would not want a new therapeutic entity or procedure to be successful, since the result would be an improvement in the diagnosis and treatment of disease. It is also a generally accepted fact of life that participation in an effort that generates a successful therapeutic approach increases opportunities for additional research related to the general topic at hand. This is true whether one is talking about research funded in the public interest or that in the private interest. Fourth, in the past few years, there has arisen increasing concern about the conduct of research in general, both in the public and in the private sectors. This is an inevitable consequence of some of the more highly visible scandals involving fraud in research, with which both the scientific community and the general public are familiar, and which have had most unfortunate consequences for both these parties.
CONSEQUENCES If, for reasons that are either justified or unjustified, society in general and the research community in particular become suspicious of the results of industry-sponsored clinical research, the costs to society are clearly high, even if diffuse and difficult to estimate. Although one must argue for integrity and credibility in any h u m a n undertaking, it is vitally important in something as crucial as clinical research. This is because this process is the pivotal step in producing and introducing new therapeutic medicines, devices, and procedures for use by practicing clinicians. If the integrity and credibility of the process is called into question, our ability to produce new methods for the diagnosis and treatment of disease will be compromised. The ultimate penalty will be paid in decreased benefits to the public health. It's that simple, as well as that serious.
Table 1
U.S. Clinical R&D Expenditures by PMA Member Firms Clinical R&D Year Expenditures ($ millions) 1977 236.9 1981 425.4 1986 1021.9
Source: PMA Annual Survey.
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SOLUTIONS A N D SAFEGUARDS Two general classes of solutions and safeguards that should be applied to industry-sponsored clinical research can be identified. When these are invoked, the general reaction is that they are "motherhood statements," which are self-obvious and indisputable. However, it is generally found that whenever one examines retrospectively whether the intent and spirit of these principles are fully applied to a clinical research effort, the objective answer is that the process fell short on some of the principles and could have done better in general. First, one must create a positive and open environment in which concerns over integrity and credibility are highly unlikely. This could be seen as a "preventive medicine" approach. The second principle is that one should introduce checks-and-balances to detect fraud, error, or biased interpretation.
Creating a Positive and Open Environment There are various ways in which one can create a positive and open environment in industry-sponsored clinical research, but three are particularly important. First, when an industrial sponsor is in the concept development phase of either an overall clinical program or an individual clinical protocol, it is productive to incorporate and encourage independent, objective advice and critique into this process. Consultants should be asked to be objective, hardnosed, and critical. Since drug development is often a process of increasing disillusionment and disappointment, objective consultants can be helpful by pointing out direct, unbiased approaches that will answer the question in an open and impartial manner. Second, it is advisable to incorporate the same critical point of view into the medical and statistical analysis and interpretation phase w h e n the trial or trials are completed. Occasionally, when an industrial sponsor has completed a protocol or program, it is reluctant to expose the findings to what might be considered to be a contrarian or opposing point of view. This is almost certain to happen eventually; thus, there is no point in avoiding it, and quite often the most productive critique and consultation comes from those w h o begin with an opposing point of view, as compared to those w h o are favorably disposed to a more positive view of the trial's findings. Third, the sponsor should commit to full disclosure and publication of all the trial's findings. It is possible to do this without compromising the proprietary needs that firms in competition with each other always have. As soon as possible after the proprietary needs for confidentiality have been fulfilled, the results should be fully disclosed to the academic and practicing medical communities.
Introduce Checks-and-Balances The second class of solutions and safeguards, i.e., incorporating checksand-balances into the process, is equally important. First, although it is believed to be standard practice, the sponsor must commit to a thorough program of trial monitoring. All too often in the phar-
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R.P. Schwarz maceutical industry, inadequate trial monitoring is done. Medical directors and clinical research associates and other sponsor staff must relentlessly supervise and survey all aspects of trial implementation, conduct, data retrieval, and other scientific, medical, and administrative aspects consistent with FDA and other health agency regulations for the conduct of clinical research. Although to investigators and the sponsor it often seems like a nuisance, the more thorough and extensive monitoring is done, the better are all concerned. Second, a vigorous role by the corporate quality assurance group goes a long way toward ensuring the integrity of the conduct of a trial and the quality of the database produced. This group, which usually reports to the senior corporate officer for research and development, is charged with the responsibility of assuring the corporation that all aspects of clinical trial implementation, conduct, and analysis were carried out in accordance with regulatory agency regulations and in an environment free from potential error or fraud [151. Third, it is critical that one involve objective, external consultants, w h o are blinded to the study treatment code, in any part of the clinical research process that involves assessment of potentially subjective end points and the results and recommendations derived from such. The Anturane Reinfarction Trial [16] has served as an example of h o w an otherwise well-conducted clinical trial can lose credibility when this is not done [17,18]. Fourth, avoid conflict of interest (real or apparent) on the part of all participants in the trial. In planning a clinical program or trial, it's important to include not only those investigators w h o are scientifically and emotionally partial to a point of view favorable to the drug, but also potential detractors and those with a neutral point of view. In addition, it is imperative that financial conflict of interest be scrupulously avoided [19]. Reasonable reimbursement and honoraria can always be provided, without leading the research community that receives the results to believe that the judgment of the investigators was compromised by excessive reimbursement or provision of other financial interests [20,21].
A REAL-LIFE EXAMPLE
N o w that these motherhood statements have been made, it may be helpful to consider an example of an approach from one organization (the Sterling Research Group) that fulfills a good number of the principles previously identified. It cannot be claimed that the approach is universally applicable or even always desirable, or that it solves all the problems or that it couldn't be done better. It's simply one group's attempt to prevent any question whatsoever of fraud, error, or biased interpretation in a very important clinical trial, in a way in which integrity will not be called into question and the credibility of the results will be maximized. The Sterling Research Group has been conducting the PROMISE (prospective, randomized, oral milrinone survival evaluation) trial of the phosphodiesterase inhibitor milrinone in congestive heart failure. This trial contains many features that are pertinent to the solutions and safeguards previously identified. Five of them are particularly noteworthy. First, the protocol for this 90-center trial with over 800 patients was developed by an independent steering committee of clinical investigators. The
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company had input and advice into this process and held final veto power over any protocol which would be totally unacceptable in terms of achieving the scientific and medical objectives of the company. However, we allowed the investigators considerable freedom to develop what they felt was the most objective, scientifically valid protocol to answer the question of the effect of oral milrinone on long-term survival in congestive heart failure. Second, the trial monitoring (for administrative purposes and database assimilation) is done by the sponsor's staff at the Sterling Research Group in Malvern, Pennsylvania. All of the trial monitoring staff are masked to the treatment identity, from the inception of the trial through the final locking of the database and medical/statistical analysis. Third, a Data Analysis Center at the University of Wisconsin, Madison has been commissioned. They receive the database, as assimilated by the Sterling Research Group, and have independent authority in all aspects of trial analysis and database audit functions. In addition, the participating clinical centers submit to the Data Analysis Center (independently of the sponsor) notification forms for randomization and outcome events. This allows for an independent check of the key information in the trial by the Data Analysis Center, in addition to the more routine database audit functions. Sterling Research Group statistical and medical staff consult with this group and provide input and feedback; however, the final authority for trial analysis rests with this center. Doing it in this manner ensures an independent and objective approach to data analysis. Fourth, an independent data monitoring committee, or policy board, has been commissioned that is composed of physicians, scientists, and biostatisticians who are not affiliated with the Sterling Research Group and who are not investigators conducting the trial. The director of the Data Analysis Center, the principal investigator of the study, and Sterling Research Group staff serve in an ex-officio role on this committee, but have no official voice in the deliberations, and no vote in the decisions and recommendations emerging from this committee. Finally, despite the four features mentioned above, it is important to consider what should be done if an aberrant or suspicious trend were detected in the accumulating data by either the sponsor or the Data Analysis Center. If this occurs, one party should notify the other and undertake an immediate, thorough examination of the problem. If this reveals anything other than a completely obvious error that is fully explainable and correctable, and not at all suggestive of fraud, the matter should be referred to the data monitoring committee for further independent investigation on their part. CLOSING THOUGHTS All scientists must be deeply committed to maintaining integrity and credibility in everything involved in research. Because of this, physicians and scientists fred the discussion of fraud, error, or biased interpretation unsettling and distasteful, and have a right to react with visceral repugnance at the very mention of these words in the same sentence as scientific research, since such an environment can paralyze scientific advancement. As distasteful as the issue may be, however, it cannot be avoided. Scientists involved in biomedical research must also be cognizant of their role as citizens of a self-governing society. It is not enough to ask society for
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R.P. Schwarz u n q u e s t i o n i n g trust, nor can it be a s s u m e d that scientists are different from other h u m a n beings and totally incapable of error, deceit, misrepresentation, or bias. The scientific c o m m u n i t y m u s t be vigilant for this, since n o t h i n g less than the viability of the biomedical science enterprise is at stake. This is a vitally i m p o r t a n t responsibility--one that m u s t n e v e r be taken lightly.
Eternal vigilance is the price of liberty. Wendell Phillips (1875)
REFERENCES 1. Dickinson J: Stiffest penalty for clinical fraud: nine companies. Dickinson's FDA, February 15, 1989, p. 7 2. F-D-C Reports: Imreg's Imreg-1 Treatment IND has December 4 Deadline. F-D-C Reports, November 14, 1988, p. 7 3. Booth W: Conflict of Interest Eyed at Harvard. Science 242:1497-1499, 1988 4. Chase M: Bad chemistry: Mixing science, stocks raises questions of bias in the testing of drugs. Wall Street Journal, January 26, 1989, p. 1 5. Agency, firm tangle over expert witness testimony. Washington Drug Letter, February 6, 1989, p. 2 6. F-D-C Reports: FDA is reviewing authority to revoke NDAs obtained through corrupt practices. F-D-C Reports, July 17, 1989, p. 9-11 7. Dickinson J: Chronology of major events involving generic drugs. Dickinson's FDA, October 15, 1989, p. 4--6 8. Ingersoll B: Chief of FDA to step aside after five years. Wall Street Journal, November 14, 1989, p. 3 9. NIH/ADAMHA Patent Policy Board. Policy statement of cooperative research and development agreements and intellectual property licensing. Office of Invention, National Institutes of Health, Bethesda, MD, March 27, 1989 10. Booth W: NIH scientists agonize over technology transfer. Science 243:20-21, 1989 11. F-D-C Reports: Representative Dingell's scientific misconduct proposal. F-D-C Reports, April 17, 1989, p. 8 12. F-D-C Reports: Scientific conflict of interest hearings before Representative Weiss (D-NY). F-D-C Reports, May 8, 1989, p. 11-12 13. Pharmaceutical Manufacturer's Association: 1988 Annual Report. PMA, Washington, DC, p. 4-5 14. Harbeck FA: Pharmaceutical Manufacturer's Association, Annual Survey, Washington, DC, 1988 15. Donahue JJ: Research quality assurance. In The Clinical Research Process in the Pharmaceutical Industry, Marcel Dekker, New York, 1986 16. The Anturane Reinfarction Trial Research Group: Sulfinpyrazone in the prevention of sudden death after myocardial infarction. N Engl J Med 302:250-256, 1980 17. Temple R, Pledger GW: The FDA's critique of the anturane reinfarction trial. N Engl J Med 303:1488-1492, 1980 18. Anturane Reinfarction Trial Policy Committee: The anturane reinfarction trial: reevaluation of outcome. N Engl J Med 306:1005-1008, 1982 19. Relman AS: Economic incentives in clinical investigation. N Engl J Med 320:933934, 1989 20. Healy B, Campeau L, Gray R et al.: Conflict of interest guidelines for a multicenter clinical trial of treatment after coronary-artery bypass-graft surgery. N Engl J Med 320:949-951, 1989 21. F-D-C Reports. Merck research conflict of interest policy prohibits investment in stock after enrollment in clinical trial. F-D-C Reports, July 10, 1989, p. 4-5
ABSTRACT: There have been recent, heightened concerns about the integrity and credibility of industry-sponsored clinical research. While attributable to a variety of factors, the potential consequences are a decrease in the ability of the biomedical research enterprise to produce innovative methods for the diagnosis and treatment of disease, with possible adverse implications for the health and well-being of the public. A specific example of a recent industry-sponsored clinical trial is presented as an approach to attempt to avoid any suggestion of fraud, error, or biased interpretation, in a way in which the integrity of the process will not be called into question and the credibility of the results will be maximized. Fraud and falsehood only dread examination; truth invites it.
Thomas Cooper (1878)
INTRODUCTION Recently, there have b e e n h e i g h t e n e d concerns over the integrity and credibility of results emerging from clinical research studies in general and from i n d u s t r y - s p o n s o r e d clinical research in particular. There is w h a t I w o u l d call, for w a n t of a better description, the "integrity/credibility shortfall." A few examples bear this out. In February 1989, a clinical investigator in N e w Jersey was s e n t e n c e d to 4 years in jail and $2 million in fines to be paid in restitution to nine pharmaceutical c o m p a n i e s [1]. H e was convicted of criminal fraud involving falsification a n d fabrication of data in 18 i n d u s t r y - s p o n s o r e d clinical trials on nine different drugs over 9-1/2 years. In the fall of 1988, both the general press a n d the pharmaceutical i n d u s t r y press r e p o r t e d the possibility of bias in patient selection and data interpretation from a clinical trial of the biotechnology p r o d u c t Imreg-1 for the treatm e n t of AIDS a n d AIDS-related complex [2]. W h e t h e r these concerns were justified or not, the credibility of the emerging results from these trials was d a m a g e d b y just the fact that these issues w e r e discussed. During the past few years, several academic clinical investigators, working o n b o t h National Institutes of Health (NIH)-sponsored a n d industry-spon-
Address reprint requests to: Richard P. Schwarz, Jr, PhD, Director, Clinical Development, Greenwich Pharmaceuticals, 423 Sargon Way, Unit A, Horsham, PA 19044. Received June 14, 1990, revised April 15, 1991. Adapted from a speechgiven at the Annual Meeting of the Societyfor Clinical Trials, May 18, 1989, Minneapolis, MN.
ControlledClinicalTrials12:753-'760(1991) © ElsevierSciencePublishingCo., Inc, 1991 655 Avenueof the Americas,New York,New York10010
753 0197-2456/91/$3.50
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R.P. Schwarz sored clinical trials, have come under suspicion because they held significant financial positions in securities of the firms sponsoring the trials [3,4]. As always, this conflict of interest, whether real or apparent, can be very damaging to the integrity and credibility of the investigator, the sponsor, and the research process in general. In February 1989, a Food and Drug Administration (FDA) staff member went on record criticizing some academic experts w h o "lend their names to a drug that patently lacks substantial evidence of effectiveness" and is "eloquent evidence that money talks" [5]. These statements, if substantive, are serious; however, even if not, the reputations of the participants and the credibility of the results from the trials are seriously jeopardized. A series of events particularly damaging to public confidence in industrysponsored clinical research has been the disclosures of mid- to late-1989 involving falsification of results from bioavailability studies of generic versions of innovator drug products [6]. This has led to criminal indictment, conviction, and sentencing of several key officials in the FDA and generic pharmaceutical firms [7], and is cited as the principal reason for the resignation of the FDA commissioner [8]. Of a more general nature, but equally important are the concerns being raised due to emerging closer relationships between government agencies w h o sponsor biomedical research, such as the NIH, and industrial support of research being conducted through these government agencies [9]. While it should be emphasized that this does not automatically mean that such arrangements are wrong and that they could not benefit all parties concerned in a fair manner, legitimate concerns are raised over potential conflicts of the proper use of public funds versus pursuit of private interests [10]. Finally, in such an atmosphere of concerns regarding integrity and credibility of clinical research, two congressional committees are investigating all the aspects and situations described above [11,12]. It therefore becomes increasingly likely that Congress, in carrying out its responsibility of protecting the public interest, may introduce controls that could have a restraining effect on the clinical research process in general.
INTEGRITY AND CREDIBILITY Since scientists hold the strong belief that the research process possesses--indeed, must possess---the qualities of integrity and credibility, the words are so frequently used that they can lose their meaning. By integrity, it is meant that in all phases of the conduct of research and all aspects and interactions with others w h o are a part of that process, there is a firm, unyielding adherence to a code of moral and ethical values. In short, the research process must be relentlessly honest and open. The attribute of credibility means that the participants involved and the research results generated must possess the characteristics of believability and trustability. This is a feature that, while related to integrity, is distinct from it. The participants and the results obtained from a research effort can possess integrity; however, if their actions and the process in general take place in an environment of real or apparent conflict of interest or without full disclosure, their credibility can come into question. In discussing the issue of integrity and credibility in industry-sponsored clinical research, a basic assumption must be made: to be in the position of
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defending one's integrity and credibility is untenable. The issue simply can't come up without major damage being done to both the research program under consideration and the reputations of those impugned. In short, if the integrity of the data or concern over biased interpretation are even called into question, irreparable damage to the credibility of an industry-sponsored trial or program can occur. The remainder of this discussion will focus on three issues: 1. What is the source or cause of the problem that has led to increasing concerns over the integrity and credibility of industry-sponsored clinical research? 2. What are its consequences? 3. What solutions and safeguards should be applied? SOURCE OF THE PROBLEM
Although somewhat arbitrary, four underlying reasons for w h y there are concerns over the integrity and credibility of industry-sponsored clinical research can be identified. The first reason is that the magnitude of industry-sponsored research is considerable. In recent years, the amount of funding and the presence of industry in clinical research have dramatically increased. The data in Figure 1 compare the research and development expenditures of the NIH with the research and development expenditures of the approximately 100 U.S. research-intensive pharmaceutical firms, as represented by the Pharmaceutical Manufacturers Association (PMA). In 1977, the NIH spent about twice as much on biomedical research as PMA companies. In the last 10 years, however, PMA companies have caught up and n o w meet or, in the most recent year, actually exceed the NIH in terms of total R&D spending [13].
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Figure 1 R&D expenditures by NIH and PMA firms.
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R.P. Schwarz To put this in a more focused perspective in terms of clinical research, Table 1 shows the expenditures for clinical research in the United States by the PMA member firms. In the last 10 years, the total amount has increased over fourfold, from $237 million in 1977 to over $1 billion in 1986 [14]. The increases are accelerating in a dramatic manner. There is no question that industry-sponsored clinical research has become a significant presence in the U.S. biomedical enterprise. Second, it is an understatement to say that pharmaceutical firms must succeed in producing new drugs with significant medical uses that can be marketed profitably. This is a fundamental fact of life, with increasing economic pressure for success being brought to bear. Third, academic investigators feel both self-imposed and externally imposed pressure to succeed in clinical investigations related to drug development. It is hard to conceive of a physician-investigator who would not want a new therapeutic entity or procedure to be successful, since the result would be an improvement in the diagnosis and treatment of disease. It is also a generally accepted fact of life that participation in an effort that generates a successful therapeutic approach increases opportunities for additional research related to the general topic at hand. This is true whether one is talking about research funded in the public interest or that in the private interest. Fourth, in the past few years, there has arisen increasing concern about the conduct of research in general, both in the public and in the private sectors. This is an inevitable consequence of some of the more highly visible scandals involving fraud in research, with which both the scientific community and the general public are familiar, and which have had most unfortunate consequences for both these parties.
CONSEQUENCES If, for reasons that are either justified or unjustified, society in general and the research community in particular become suspicious of the results of industry-sponsored clinical research, the costs to society are clearly high, even if diffuse and difficult to estimate. Although one must argue for integrity and credibility in any h u m a n undertaking, it is vitally important in something as crucial as clinical research. This is because this process is the pivotal step in producing and introducing new therapeutic medicines, devices, and procedures for use by practicing clinicians. If the integrity and credibility of the process is called into question, our ability to produce new methods for the diagnosis and treatment of disease will be compromised. The ultimate penalty will be paid in decreased benefits to the public health. It's that simple, as well as that serious.
Table 1
U.S. Clinical R&D Expenditures by PMA Member Firms Clinical R&D Year Expenditures ($ millions) 1977 236.9 1981 425.4 1986 1021.9
Source: PMA Annual Survey.
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SOLUTIONS A N D SAFEGUARDS Two general classes of solutions and safeguards that should be applied to industry-sponsored clinical research can be identified. When these are invoked, the general reaction is that they are "motherhood statements," which are self-obvious and indisputable. However, it is generally found that whenever one examines retrospectively whether the intent and spirit of these principles are fully applied to a clinical research effort, the objective answer is that the process fell short on some of the principles and could have done better in general. First, one must create a positive and open environment in which concerns over integrity and credibility are highly unlikely. This could be seen as a "preventive medicine" approach. The second principle is that one should introduce checks-and-balances to detect fraud, error, or biased interpretation.
Creating a Positive and Open Environment There are various ways in which one can create a positive and open environment in industry-sponsored clinical research, but three are particularly important. First, when an industrial sponsor is in the concept development phase of either an overall clinical program or an individual clinical protocol, it is productive to incorporate and encourage independent, objective advice and critique into this process. Consultants should be asked to be objective, hardnosed, and critical. Since drug development is often a process of increasing disillusionment and disappointment, objective consultants can be helpful by pointing out direct, unbiased approaches that will answer the question in an open and impartial manner. Second, it is advisable to incorporate the same critical point of view into the medical and statistical analysis and interpretation phase w h e n the trial or trials are completed. Occasionally, when an industrial sponsor has completed a protocol or program, it is reluctant to expose the findings to what might be considered to be a contrarian or opposing point of view. This is almost certain to happen eventually; thus, there is no point in avoiding it, and quite often the most productive critique and consultation comes from those w h o begin with an opposing point of view, as compared to those w h o are favorably disposed to a more positive view of the trial's findings. Third, the sponsor should commit to full disclosure and publication of all the trial's findings. It is possible to do this without compromising the proprietary needs that firms in competition with each other always have. As soon as possible after the proprietary needs for confidentiality have been fulfilled, the results should be fully disclosed to the academic and practicing medical communities.
Introduce Checks-and-Balances The second class of solutions and safeguards, i.e., incorporating checksand-balances into the process, is equally important. First, although it is believed to be standard practice, the sponsor must commit to a thorough program of trial monitoring. All too often in the phar-
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R.P. Schwarz maceutical industry, inadequate trial monitoring is done. Medical directors and clinical research associates and other sponsor staff must relentlessly supervise and survey all aspects of trial implementation, conduct, data retrieval, and other scientific, medical, and administrative aspects consistent with FDA and other health agency regulations for the conduct of clinical research. Although to investigators and the sponsor it often seems like a nuisance, the more thorough and extensive monitoring is done, the better are all concerned. Second, a vigorous role by the corporate quality assurance group goes a long way toward ensuring the integrity of the conduct of a trial and the quality of the database produced. This group, which usually reports to the senior corporate officer for research and development, is charged with the responsibility of assuring the corporation that all aspects of clinical trial implementation, conduct, and analysis were carried out in accordance with regulatory agency regulations and in an environment free from potential error or fraud [151. Third, it is critical that one involve objective, external consultants, w h o are blinded to the study treatment code, in any part of the clinical research process that involves assessment of potentially subjective end points and the results and recommendations derived from such. The Anturane Reinfarction Trial [16] has served as an example of h o w an otherwise well-conducted clinical trial can lose credibility when this is not done [17,18]. Fourth, avoid conflict of interest (real or apparent) on the part of all participants in the trial. In planning a clinical program or trial, it's important to include not only those investigators w h o are scientifically and emotionally partial to a point of view favorable to the drug, but also potential detractors and those with a neutral point of view. In addition, it is imperative that financial conflict of interest be scrupulously avoided [19]. Reasonable reimbursement and honoraria can always be provided, without leading the research community that receives the results to believe that the judgment of the investigators was compromised by excessive reimbursement or provision of other financial interests [20,21].
A REAL-LIFE EXAMPLE
N o w that these motherhood statements have been made, it may be helpful to consider an example of an approach from one organization (the Sterling Research Group) that fulfills a good number of the principles previously identified. It cannot be claimed that the approach is universally applicable or even always desirable, or that it solves all the problems or that it couldn't be done better. It's simply one group's attempt to prevent any question whatsoever of fraud, error, or biased interpretation in a very important clinical trial, in a way in which integrity will not be called into question and the credibility of the results will be maximized. The Sterling Research Group has been conducting the PROMISE (prospective, randomized, oral milrinone survival evaluation) trial of the phosphodiesterase inhibitor milrinone in congestive heart failure. This trial contains many features that are pertinent to the solutions and safeguards previously identified. Five of them are particularly noteworthy. First, the protocol for this 90-center trial with over 800 patients was developed by an independent steering committee of clinical investigators. The
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company had input and advice into this process and held final veto power over any protocol which would be totally unacceptable in terms of achieving the scientific and medical objectives of the company. However, we allowed the investigators considerable freedom to develop what they felt was the most objective, scientifically valid protocol to answer the question of the effect of oral milrinone on long-term survival in congestive heart failure. Second, the trial monitoring (for administrative purposes and database assimilation) is done by the sponsor's staff at the Sterling Research Group in Malvern, Pennsylvania. All of the trial monitoring staff are masked to the treatment identity, from the inception of the trial through the final locking of the database and medical/statistical analysis. Third, a Data Analysis Center at the University of Wisconsin, Madison has been commissioned. They receive the database, as assimilated by the Sterling Research Group, and have independent authority in all aspects of trial analysis and database audit functions. In addition, the participating clinical centers submit to the Data Analysis Center (independently of the sponsor) notification forms for randomization and outcome events. This allows for an independent check of the key information in the trial by the Data Analysis Center, in addition to the more routine database audit functions. Sterling Research Group statistical and medical staff consult with this group and provide input and feedback; however, the final authority for trial analysis rests with this center. Doing it in this manner ensures an independent and objective approach to data analysis. Fourth, an independent data monitoring committee, or policy board, has been commissioned that is composed of physicians, scientists, and biostatisticians who are not affiliated with the Sterling Research Group and who are not investigators conducting the trial. The director of the Data Analysis Center, the principal investigator of the study, and Sterling Research Group staff serve in an ex-officio role on this committee, but have no official voice in the deliberations, and no vote in the decisions and recommendations emerging from this committee. Finally, despite the four features mentioned above, it is important to consider what should be done if an aberrant or suspicious trend were detected in the accumulating data by either the sponsor or the Data Analysis Center. If this occurs, one party should notify the other and undertake an immediate, thorough examination of the problem. If this reveals anything other than a completely obvious error that is fully explainable and correctable, and not at all suggestive of fraud, the matter should be referred to the data monitoring committee for further independent investigation on their part. CLOSING THOUGHTS All scientists must be deeply committed to maintaining integrity and credibility in everything involved in research. Because of this, physicians and scientists fred the discussion of fraud, error, or biased interpretation unsettling and distasteful, and have a right to react with visceral repugnance at the very mention of these words in the same sentence as scientific research, since such an environment can paralyze scientific advancement. As distasteful as the issue may be, however, it cannot be avoided. Scientists involved in biomedical research must also be cognizant of their role as citizens of a self-governing society. It is not enough to ask society for
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R.P. Schwarz u n q u e s t i o n i n g trust, nor can it be a s s u m e d that scientists are different from other h u m a n beings and totally incapable of error, deceit, misrepresentation, or bias. The scientific c o m m u n i t y m u s t be vigilant for this, since n o t h i n g less than the viability of the biomedical science enterprise is at stake. This is a vitally i m p o r t a n t responsibility--one that m u s t n e v e r be taken lightly.
Eternal vigilance is the price of liberty. Wendell Phillips (1875)
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