J ClinEpidemioi Vol.44,No. 8,pp.821-822, 1991
0895-4356/91 $3.00 + 0.00 Pergamon Press plc
Printed in Great Britain
Editorial PHARMACOEPIDEMIOLOGY
AND CLINICAL
RESEARCH*
GERALD A. FAICH PACT@ Inc., 150 Radnor-Chester
Road, Suite D200, St Davids, PA 19087, U.S.A.
(Received for publication 29 May 1991)
A new era of innovation and change in pharmaceutical development and clinical research is about to begin. Expanded application of pharmacoepidemiology will be central to this. Thus it is timely and fitting that this Journal provide a new forum for communication and education of pharmacoepidemiologic information. During my 8 year experience with epidemiology, postmarketing surveillance, and statistics at the Food and Drug Administration (FDA) and in a contract research setting. I have dealt with a broad array of pharmaceutical manufacturers and drug development issues. Based on this I have seen the emergence of several factors which inexorably must result in change from the status quo. I want to briefly review these and discuss their implications. There are at least five distinct factors stimulating change. The first factor is the continued shift in disease epidemiology and demography which will fuel a demand for new therapies. A large part of this shift is because populations of developed countries continue to age. This, combined with unanticipated major immigration from Latin American and Asia and an increase in urban poverty has contributed mightily to a shift in disease patterns. When disease patterns change a search for new therapies inevitably follows. The massive impact of the epidemics of Acquired Immune Deficiency Syndrome (AIDS) and age-related cancer, dementias and disabilities must drive opportunities and priori*Modified from a presentation made to the medical section of the Pharmaceutical Manufacturers Association, Naples, Florida, 15 April 1991. CE U/S-G
ties for pharmaceutical investment. Second, government involvement in clinical research will continue to grow. This involvement will likely include expanded research and funding by the National Institute of Health (NIH), increased outcomes research by the Agency for Health Care Policy and Research (AHCPR), changes in pharmaceutical funding by the Health Care Finance Administration (HCFA), and regulatory changes by FDA. A third change factor has been the very structure of the pharmaceutical industry itself. Mergers and consolidations have major budget and priority consequences that are bound to change the velocity of and mechanisms for conducting clinical research. Combined with globalization, these will have enormous impacts on the discovery, testing, regulation and marketing practices for pharmaceuticals. Lastly, information technology and changes in the way we are able to collect, process and manage data also have major implications for the manner in which we conduct clinical research. Of particular significance for pharmacoepidemiology will be several FDA policy decisions that are on the immediate horizon. The agency is grappling with decisions about the interpretation of what constitutes the “adequate and well controlled investigations” needed to substantiate safety and efficacy for drug approval [l]. Traditionally, the standard has been two randomized, well-controlled, clinical trials (RCTs). Now it seems that potentially more efficient, innovative and practical study designs may be allowed under certain circumstances. When the natural history of the underlying disease is 821
822
Editorial
relatively well defined, we may see some increased receptivity for non-experimental studies. The experience with AIDS drugs and recommendations of recent committees examining the approval of cancer drugs and FDA’s mission imply that the time for change may be upon us [2]. The role and acceptability of epidemiologically-grounded studies using cohort designs and descriptive technics is increasing. One example of this is the expanded availability approach to investigational drugs. This approach allows for the use of unapproved drugs outside of controlled trials and provides an opportunity and responsibility to use epidemiologic technics to gather useful safety information. Another important FDA initiative may be an increase in requests for the conduct of postapproval studies to enhance safety and efficacy data, This approval-with-conditions approach could speed approval, promote the use of pharmacoepidemiology, and greatly expand our knowledge base about pharmaceuticals. Indeed, the need to obtain further information about safety or effectiveness in actual practice demands the conduct of both descriptive and analytical postmarketing studies. A third current regulatory concern involves the need to control unsubstantiated advertising claims. With increased regulatory scrutiny of advertising may come the need to develop acceptability criteria for postapproval effectiveness and cost benefits studies. Hopefully, this need will not lead to requirements for the rigid documentation of epidemiologic studies similar to the ill-conceived Interagency Regulatory Liaison Group (IRLG) efforts of the early seventies [3]. Even worse, would be a retrogressive restriction of claims to those based only on information derived from acceptable randomized trials. Clinical trials cannot truly reflect the actual practice setting and we must pursue and use effectiveness and safety research outside trials. Obviously, the solution is to require that such studies be scientifically grounded and based on sound principles of pharmacoepidemiology. Instead of regulation, assessment of acceptability will require a study-by-study review by individuals who are expert in the area. In addition to the regulatory changes mentioned, perhaps the greatest impetus for an expanded role for pharmacoepidemiology will
derive directly from changes in study focus, technology and design. With improved detection of individual adverse reactions during clinical trials and after marketing has come a heightened awareness that such reactions must be quantitated if risk is to be assessed [4]. This provides considerable incentive to assemble relatively large cohorts of patients during the periapproval period just before (Phase IIIb) or after marketing Phase IV. In addition, prospeo tive and comparative postmarketing studies will be needed to assess cost effectiveness. These two applications of epidemiology combined with pressure for earlier access to promising drugs are likely to drive much research in the direction of epidemiologically based, simplified, clinical trials done at the end of the traditional clinical research period. Lastly, we will see an expansion of academic and free-standing contract research in the next few years. This is because the pharmaceutical industry has a need for scarce and specialized pharmacoepidemiologic skills and an imperative to better manage their internal human resources. This expansion will depend upon the provision of quality work, sound epidemiology and reliable performance by contractors. In the coming years we are destined to see a number of profound changes in clinical pharmaceutical research. These changes will be shaped by market, economic, and regulatory forces. It is likely there will be more emphasis on safety, cost effectiveness, postmarketing surveillance, approval with conditions, and the need for sound scientific bases for promotional claims. Cohort studies and other pharmacoepidemiologic approaches will become increasingly important. As a result of these changes we may see a speeding of drug approval and a increase in the appropriate use of pharmaceuticals based on an expansion in our knowledge about them. REFERENCES Temple RJ. Access, science and regulation. Drug Info J 1991; 25: I-11. Committee on the FDA. Final Report of tke Adhory dminbbadon. May CommltteeontkeFoodandDrugA 1991; U.S. Dept of Health and Human Services. Joint Committee on Governmental Affairs. Commentary: The Interagency Regulatory Liason Group Guidelines for Documentation of Epidemiologic Studies. Am J Epidemiol 1981; 114: 614-618. Faith GA. Postmarketing SurveiRance of Pmcriplion Druga New York: Clinical Medicine Research Institute; Oct. 1986.
0895-4356/91 $3.00 + 0.00 Pergamon Press plc
Printed in Great Britain
Editorial PHARMACOEPIDEMIOLOGY
AND CLINICAL
RESEARCH*
GERALD A. FAICH PACT@ Inc., 150 Radnor-Chester
Road, Suite D200, St Davids, PA 19087, U.S.A.
(Received for publication 29 May 1991)
A new era of innovation and change in pharmaceutical development and clinical research is about to begin. Expanded application of pharmacoepidemiology will be central to this. Thus it is timely and fitting that this Journal provide a new forum for communication and education of pharmacoepidemiologic information. During my 8 year experience with epidemiology, postmarketing surveillance, and statistics at the Food and Drug Administration (FDA) and in a contract research setting. I have dealt with a broad array of pharmaceutical manufacturers and drug development issues. Based on this I have seen the emergence of several factors which inexorably must result in change from the status quo. I want to briefly review these and discuss their implications. There are at least five distinct factors stimulating change. The first factor is the continued shift in disease epidemiology and demography which will fuel a demand for new therapies. A large part of this shift is because populations of developed countries continue to age. This, combined with unanticipated major immigration from Latin American and Asia and an increase in urban poverty has contributed mightily to a shift in disease patterns. When disease patterns change a search for new therapies inevitably follows. The massive impact of the epidemics of Acquired Immune Deficiency Syndrome (AIDS) and age-related cancer, dementias and disabilities must drive opportunities and priori*Modified from a presentation made to the medical section of the Pharmaceutical Manufacturers Association, Naples, Florida, 15 April 1991. CE U/S-G
ties for pharmaceutical investment. Second, government involvement in clinical research will continue to grow. This involvement will likely include expanded research and funding by the National Institute of Health (NIH), increased outcomes research by the Agency for Health Care Policy and Research (AHCPR), changes in pharmaceutical funding by the Health Care Finance Administration (HCFA), and regulatory changes by FDA. A third change factor has been the very structure of the pharmaceutical industry itself. Mergers and consolidations have major budget and priority consequences that are bound to change the velocity of and mechanisms for conducting clinical research. Combined with globalization, these will have enormous impacts on the discovery, testing, regulation and marketing practices for pharmaceuticals. Lastly, information technology and changes in the way we are able to collect, process and manage data also have major implications for the manner in which we conduct clinical research. Of particular significance for pharmacoepidemiology will be several FDA policy decisions that are on the immediate horizon. The agency is grappling with decisions about the interpretation of what constitutes the “adequate and well controlled investigations” needed to substantiate safety and efficacy for drug approval [l]. Traditionally, the standard has been two randomized, well-controlled, clinical trials (RCTs). Now it seems that potentially more efficient, innovative and practical study designs may be allowed under certain circumstances. When the natural history of the underlying disease is 821
822
Editorial
relatively well defined, we may see some increased receptivity for non-experimental studies. The experience with AIDS drugs and recommendations of recent committees examining the approval of cancer drugs and FDA’s mission imply that the time for change may be upon us [2]. The role and acceptability of epidemiologically-grounded studies using cohort designs and descriptive technics is increasing. One example of this is the expanded availability approach to investigational drugs. This approach allows for the use of unapproved drugs outside of controlled trials and provides an opportunity and responsibility to use epidemiologic technics to gather useful safety information. Another important FDA initiative may be an increase in requests for the conduct of postapproval studies to enhance safety and efficacy data, This approval-with-conditions approach could speed approval, promote the use of pharmacoepidemiology, and greatly expand our knowledge base about pharmaceuticals. Indeed, the need to obtain further information about safety or effectiveness in actual practice demands the conduct of both descriptive and analytical postmarketing studies. A third current regulatory concern involves the need to control unsubstantiated advertising claims. With increased regulatory scrutiny of advertising may come the need to develop acceptability criteria for postapproval effectiveness and cost benefits studies. Hopefully, this need will not lead to requirements for the rigid documentation of epidemiologic studies similar to the ill-conceived Interagency Regulatory Liaison Group (IRLG) efforts of the early seventies [3]. Even worse, would be a retrogressive restriction of claims to those based only on information derived from acceptable randomized trials. Clinical trials cannot truly reflect the actual practice setting and we must pursue and use effectiveness and safety research outside trials. Obviously, the solution is to require that such studies be scientifically grounded and based on sound principles of pharmacoepidemiology. Instead of regulation, assessment of acceptability will require a study-by-study review by individuals who are expert in the area. In addition to the regulatory changes mentioned, perhaps the greatest impetus for an expanded role for pharmacoepidemiology will
derive directly from changes in study focus, technology and design. With improved detection of individual adverse reactions during clinical trials and after marketing has come a heightened awareness that such reactions must be quantitated if risk is to be assessed [4]. This provides considerable incentive to assemble relatively large cohorts of patients during the periapproval period just before (Phase IIIb) or after marketing Phase IV. In addition, prospeo tive and comparative postmarketing studies will be needed to assess cost effectiveness. These two applications of epidemiology combined with pressure for earlier access to promising drugs are likely to drive much research in the direction of epidemiologically based, simplified, clinical trials done at the end of the traditional clinical research period. Lastly, we will see an expansion of academic and free-standing contract research in the next few years. This is because the pharmaceutical industry has a need for scarce and specialized pharmacoepidemiologic skills and an imperative to better manage their internal human resources. This expansion will depend upon the provision of quality work, sound epidemiology and reliable performance by contractors. In the coming years we are destined to see a number of profound changes in clinical pharmaceutical research. These changes will be shaped by market, economic, and regulatory forces. It is likely there will be more emphasis on safety, cost effectiveness, postmarketing surveillance, approval with conditions, and the need for sound scientific bases for promotional claims. Cohort studies and other pharmacoepidemiologic approaches will become increasingly important. As a result of these changes we may see a speeding of drug approval and a increase in the appropriate use of pharmaceuticals based on an expansion in our knowledge about them. REFERENCES Temple RJ. Access, science and regulation. Drug Info J 1991; 25: I-11. Committee on the FDA. Final Report of tke Adhory dminbbadon. May CommltteeontkeFoodandDrugA 1991; U.S. Dept of Health and Human Services. Joint Committee on Governmental Affairs. Commentary: The Interagency Regulatory Liason Group Guidelines for Documentation of Epidemiologic Studies. Am J Epidemiol 1981; 114: 614-618. Faith GA. Postmarketing SurveiRance of Pmcriplion Druga New York: Clinical Medicine Research Institute; Oct. 1986.
