- Email: [email protected]
Industry sponsored clinical trials in rheumatology: past, present and future
Indian Journal of Rheumatology 2006 September Volume 1, Number 2; pp. 78–81
Perspective
Industry sponsored clinical trials in rheumatology: past, present and future A Aggarwal
INTRODUCTION We have come a long way since the first double-blind, randomized, controlled clinical trial (RCT) was conducted by the Medical Research Council of UK in the year 1948. Currently about 55 new RCTs are being reported every day. The field of clinical trials has seen several other changes over this period. There has been a shift from public-funded drug trials to industry-sponsored ones, and most trials now are done in multiple centres in different countries. In addition, the trials are increasingly being conducted by contract research organizations rather than by academic medical centres, and recruit a larger proportion of patients from private clinics than from university-based hospitals. Have these paradigm shifts in the field of clinical trials compromised the quality and ethics of scientific research?
INDUSTRY-SPONSORED CLINICAL TRIALS Drug industry is associated with clinical trials in two ways: (a) industry-sponsored studies, and (b) investigatorinitiated, industry-funded studies. The former are initiated by the industry, usually to determine the safety and efficacy of a new drug for a primary indication or of a previously known drug for a new indication. These are done to obtain data that are necessary to get approval for marketing the drug, and usually involve comparison of the new agent with a placebo or against an active comparator. In this, the drug company is associated with all aspects of trial. In contrast, in the investigator-initiated, industry-funded clinical trials the industry’s role is limited, and may be confined to merely providing drugs or funds.
ARE INDUSTRY-SPONSORED CLINICAL TRIALS NECESSARY? Drug development is a time-consuming and an expensive process. It has been estimated that nearly one billion US dollars are spent in research and development, and in preclinical trials for each drug that goes into human trials.1 This is followed by several phases of clinical studies in humans. The initial phase I human trials are meant to assess the safety, pharmacokinetics and pharmacodynamics of the drug in a few, usually 20–25, healthy persons. Studies in the phase II provide further data on the drug’s safety and preliminary data on its efficacy in a particular condition; these studies typically include 50–100 persons with the disease of interest. Phase III studies assess the efficacy and safety of the drug in a large patient population, usually numbering from a few hundred to a few thousand; the results from these studies are necessary for the regulatory authorities to give approval for marketing the drug. Their large size often mandates that these trials be multi-institutional, and even multi-national, so that the required number of subjects can be enrolled over a reasonable time period and the results are available soon. Well planned drug trials need a lot of money and most governmental agencies are not keen to fund drug trials; thus, the onus for these falls on the pharmaceutical industry. Phase III studies are the ones that physicians are more likely to be associated with. Participation in industrysponsored clinical trial is useful to clinicians. Such participation not only provides them an opportunity to offer cutting-edge treatment options to their patients, but also serves to promote scientific temper and may have an educational value. Further, such participation provides these clinicians opportunities to attend international meetings and workshops, and may provide them some financial gain.
Department of Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. Correspondence: Dr. Amita Aggarwal, email: [email protected]
Industry sponsored clinical trials in rheumatology
Indeed some clinicians may participate in the trials for financial gains and not for their scientific curiosity.
THE PAST (BEFORE 1995) In the past, most clinical trials were funded by government or public-funded organizations. During that period, even industry-funded trials were usually done in academic department setting in large institutions. Most of these trials were initiated by investigators and the pharmaceutical industry merely provided the drugs with little control over protocol development, data analysis and publication. However, importantly for rheumatologists, few drugs, except NSAIDs,2 were developed specifically for use in rheumatic diseases during this period.
THE PRESENT (1995–NOW) The advent of biologicals has changed the scenario of clinical trials drastically, particularly so in rheumatology. The first RCT for a biological compound (anti-TNF antibody; cA2, Infliximab) was done in the year 1994.3 Since then, several new biologicals, including tumour necrosis factor antagonists (Infliximab, Etanercept, Adalimumab), interleukin (IL)-1 receptor antagonists, IL-6 receptor antibody (MRA), anti-CR20 (Rituximab), and inhibitors of adhesion molecules and co-stimulatory molecules have been developed for the treatment of rheumatic diseases. This has had a cascading effect on the number of the industry-sponsored clinical trials in rheumatology. These industry-sponsored trials are in general well planned and executed, and are usually sufficiently powered to assess efficacy and common side effects.4 These studies have added significantly to our understanding of disease biology and therapeutic options. However, the recent controversy over clinical trials on Rofecoxib (Vioxx®; Merck) has thrown up a major debate on industry-sponsored trials both in general and in the field of rheumatology.5 It has now become clear that the VIGOR trial,6 which compared the efficacy and safety of Vioxx in rheumatoid arthritis to that of naproxen, underreported the cardiac events that occurred during the study period in patients receiving this drug, leading to an under-estimation of adverse events. Further, the authors of this report attributed the differences in the adverse events between the Vioxx-treated and control group (receiving naproxen) to the cardio-protective effect of naproxen, than to an increased risk with Vioxx. This trend of increased cardiovascular risk
Perspective
79
with Vioxx was observed in subsequent studies published in 2001 too. However, despite these warning signs, it took 4 years for the drug to be withdrawn from the market,5 indicating the failure of post-marketing surveillance. Later, another coxib drug, namely valdecoxib (Bextra®) was also withdrawn for the same reason. These events raise the question—does pharmaceutical industry sponsorship influence research results? The answer to this appears to be in the affirmative. In a recent analysis of 324 consecutive clinical trial reports, the experimental drug was recommended as the treatment of choice in 49% of trials (104) funded by non-profit organizations, 56.5% of trials (92) funded by both non-profit and for-profit organizations, and 67.2% of trials (137) funded by for-profit organizations,7 suggesting the existence of a bias. The trials funded by for-profit organizations were five times more likely to recommend the experimental drug as treatment of choice in comparison to trials funded by non-profits organization.8 In another study that analyzed papers presented at the annual meeting of the American College of Rheumatology in the year 2001, all the 45 industry-sponsored RCTs favoured the sponsor’s drug, thus violating the principle of equipoise.9 These findings may have two explanations, namely (a) design bias, and (b) publication bias. Design bias arises from frequent use of placebos rather than currently available drugs as comparators in industry-sponsored trials.4 This makes it easier to show the study drug as beneficial. However, the industry argues that design bias increases scientific efficiency, decreases drug development costs, and limits the number of subjects required for a trial, thereby reducing the aggregate risks to trial participants.9 The second type of bias, i.e. ‘publication bias’ refers to differences in the publication record of trials with unfavourable findings, i.e. those which show the experimental drug in poor light (low efficacy or high toxicity) in comparison to placebo or active control. It has been shown that time duration from completion of the trial to its publication is almost twice as long for negative drug trials than that for positive trials.10 In some cases, drug manufacturers have even resorted to legal action to block the publication of unfavourable trial results. What has been even more disconcerting is the reports of some questionable practices the conduct of industrysponsored clinical trials. One of these is the practice of ‘incentive enrollment’ or ‘limited-period enrollment’; this entails competition among participating physicians to enroll patients in the study, with the level of funding for each investigator depending on the number of patients enrolled. The industry argues that this method ensures rapid recruitment of study subjects and hence early completion of the study. However, this strategy may pressurize the investigators,
80
Indian Journal of Rheumatology 2006 September; Vol. 1, No. 2
sometime inducing them to resort to non-ethical means to enroll a larger number of patients.11 In addition, the companies sponsoring drug trials may provide undue inducement to patients using glitzy advertisement in the lay media and financial incentives, often couched in the form of reimbursement for travel and lost wages lost. Thus, the patients may elect to enroll in a study for financial gains without fully understanding the risks involved. A recent trial of TGN1412 in the United Kingdom, in which some healthy volunteers participated primarily for money, is a case in point.12 Thus, it is clear that ‘all is not well’ with the industrysponsored drug trials and something needs to be done.
THE FUTURE We have to accept that industry sponsored trials are here to stay. It is unlikely that public funding will ever be adequate for development of new drugs, at least in the foreseeable future. Remedial steps to rectify the problems with the existing system of funding and conducting drug trials would ensure that all patients are protected without adversely affecting the drug discovery process. Various suggestions have been made in this regard. 1. An independent authority to conduct trials: An international independent agency, for instance under the aegis of the World Health Organization, can be setup for planning and conducting drug trials, including identifying investigators, randomization, data analysis and publication. This should help reduce bias. 2. Academician-led studies: Another suggestion is to make the companies ‘let go’ of clinical trials and allow only academics to lead drug trials. This may help plan studies that are more relevant to day to day clinical practice. Further, such a step may increase transparency in drug trials.13 3. Independent review boards or data management centres: Independent boards comprising of representatives from medicine, pharmaceutical industry, legal profession and the lay public could undertake continuous analysis of accrued data. This would permit early termination of a trial if an unforeseen adverse event or a high rate of toxicity occurs. These boards could also undertake ongoing interim review of the progress of a trial including recruitment, adherence to treatment, participant safety, intervention benefit and overall trial quality. This requires that investigators report all serious or unexpected adverse events to the competent authorities and to the Ethics Committee as soon as possible; the
Aggarwal
current European guidelines mandate that this should be done no later than 15 days of the first knowledge of such an event by the sponsor.14 4. Registration of all trials: Registration of all clinical trials should be made mandatory and the data from these trials should be accessible all over the world.15 Some countries have already taken steps in this direction. Indeed in May 2006 WHO has made a 20-point list of details to be disclosed for registration of drug trials. 5. Mandatory phase IV studies: Post-marketing surveillance and reporting should be made mandatory for a fixed time period after the introduction of a new drug. The time period could vary depending on the type of the drug. A limited license may be issued pending the results of phase IV data. In UK, drug safety data are rereviewed after 5 years of approval. 6. Comparison with active drug: It is easier to show a drug to be beneficial using placebo-controlled studies. However, in real life, the choice is between the new drug and the existing treatment. Thus, it should be mandatory to show that a new drug has efficacy at least equivalent to the currently accepted drug before permission to market it is granted. This will prevent development of new drugs by the pharmaceutical industry merely to ensure the continued use of ‘on-patent’ drugs, and to render the drugs that have become ‘off-patent’ obsolete. Further, head-to-head trials of drugs made by different pharmaceutical companies should be encouraged. It may also be possible to pitch pharmaceutical companies against each other in these trials. This approach will increase the independence of clinical investigators and provide answers to questions relevant for patient care, viz. which of several anti-TNF agents is the best for patients with rheumatoid arthritis.16 Finally, a word of caution to the Indian medical profession. India is fast becoming a hub for industry-sponsored drug trials because of easy availability of a large number of patients as well as physicians.17 This transition needs a close monitoring and regulation. Mandatory registration of all drug trials with bodies like, the Drug Controller General of India or the Indian Council of Medical Research, and easy availability of their results, preferably through an electronic database over the Internet, to all scientists and medical researchers is immediately needed. Further, clinical trial units should be set up in large academic hospitals; these units should have state-of-the-art facilities, ethical and regulatory framework for the conduct of drug trials. Further, the Indian Council of Medical Research or another equivalent body should be charged to act as a watchdog for protecting the interests of the trial participants. These steps will go a long way in infusing confidence in patients on the
Industry sponsored clinical trials in rheumatology
need to conduct drug trials and will help India play a major role in development of new drugs.
Perspective
7.
8.
REFERENCES 1.
2.
3.
4.
5.
6.
DiMasi JA, Hansen RW, Garbowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22: 151–85. Rochon PA, Gurwitz JH, Simms RW, et al. A study of manufacturer supported trials of non-steroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994; 154: 157–63. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 44: 1105–10. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. Br Med J 2003; 326: 1167–70. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364: 2021–9. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8.
9.
10.
11.
12. 13. 14. 15. 16. 17.
81
Ridker PM, Torres J. Reported outcome in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations. JAMA 2000–2005; 295: 2270–4. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 2003; 290: 921–8. Fries JF, Krishnan E. Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development. Arthritis Res Ther 2004; 6: R250–5. Ioannidis JP. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. JAMA 1998; 279: 281–6. Brown JB. Recruiting human subjects: pressures in industry sponsored clinical research. Department of health and human service USA, 2000. http://news.bbc.co.uk/2/hi/uk_news/england/london/ 4809322.stm accessed on May 23, 2006. Greener M. Drug safety on trial. EMBO Reports 2005; 6: 202–4. Gennary B. Academic clinical research in the new regulatory environment. Clin Med 2005; 5: 39–41. Dickersin K, Rennie D, Registering clinical trials. JAMA 2003; 290: 516–22. Silman AJ. Clinical trials in rheumatology: an uncertain future? Nature Clin Pract 2006; 2: 171. Joshi VR. Feasibility of clinical trials in India. Indian J Rheumatol 2006; 14: 30–2.
Industry–doctor relationship Interesting information on the relationship between doctors and industry sponsors of clinical trials is provided by the following two case studies: 1. Ethics case study: When are industry-sponsored trials a good match for community doctors? Published in the March 2001 issue of ACP-ASIM Observer. Full text of this article is available at http:// www.acponline.org/journals/news/mar01/ethics.htm This article discusses how practising doctors are
approached by a pharmaceutical company for collaboraton in a clinical trial and the ethical issues involved. 2. Miller FG, Shorr AF. Ethical assessment of industrysponsored clinical trials. A case analysis. Chest 2002; 121: 1337–42. Available at http://www.chestjournal.org/ cgi/reprint/121/4/1337 The case analysis deals with methodological and recruitment issues pertaining to an industry-sponsored randomized controlled trial
Perspective
Industry sponsored clinical trials in rheumatology: past, present and future A Aggarwal
INTRODUCTION We have come a long way since the first double-blind, randomized, controlled clinical trial (RCT) was conducted by the Medical Research Council of UK in the year 1948. Currently about 55 new RCTs are being reported every day. The field of clinical trials has seen several other changes over this period. There has been a shift from public-funded drug trials to industry-sponsored ones, and most trials now are done in multiple centres in different countries. In addition, the trials are increasingly being conducted by contract research organizations rather than by academic medical centres, and recruit a larger proportion of patients from private clinics than from university-based hospitals. Have these paradigm shifts in the field of clinical trials compromised the quality and ethics of scientific research?
INDUSTRY-SPONSORED CLINICAL TRIALS Drug industry is associated with clinical trials in two ways: (a) industry-sponsored studies, and (b) investigatorinitiated, industry-funded studies. The former are initiated by the industry, usually to determine the safety and efficacy of a new drug for a primary indication or of a previously known drug for a new indication. These are done to obtain data that are necessary to get approval for marketing the drug, and usually involve comparison of the new agent with a placebo or against an active comparator. In this, the drug company is associated with all aspects of trial. In contrast, in the investigator-initiated, industry-funded clinical trials the industry’s role is limited, and may be confined to merely providing drugs or funds.
ARE INDUSTRY-SPONSORED CLINICAL TRIALS NECESSARY? Drug development is a time-consuming and an expensive process. It has been estimated that nearly one billion US dollars are spent in research and development, and in preclinical trials for each drug that goes into human trials.1 This is followed by several phases of clinical studies in humans. The initial phase I human trials are meant to assess the safety, pharmacokinetics and pharmacodynamics of the drug in a few, usually 20–25, healthy persons. Studies in the phase II provide further data on the drug’s safety and preliminary data on its efficacy in a particular condition; these studies typically include 50–100 persons with the disease of interest. Phase III studies assess the efficacy and safety of the drug in a large patient population, usually numbering from a few hundred to a few thousand; the results from these studies are necessary for the regulatory authorities to give approval for marketing the drug. Their large size often mandates that these trials be multi-institutional, and even multi-national, so that the required number of subjects can be enrolled over a reasonable time period and the results are available soon. Well planned drug trials need a lot of money and most governmental agencies are not keen to fund drug trials; thus, the onus for these falls on the pharmaceutical industry. Phase III studies are the ones that physicians are more likely to be associated with. Participation in industrysponsored clinical trial is useful to clinicians. Such participation not only provides them an opportunity to offer cutting-edge treatment options to their patients, but also serves to promote scientific temper and may have an educational value. Further, such participation provides these clinicians opportunities to attend international meetings and workshops, and may provide them some financial gain.
Department of Immunology Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. Correspondence: Dr. Amita Aggarwal, email: [email protected]
Industry sponsored clinical trials in rheumatology
Indeed some clinicians may participate in the trials for financial gains and not for their scientific curiosity.
THE PAST (BEFORE 1995) In the past, most clinical trials were funded by government or public-funded organizations. During that period, even industry-funded trials were usually done in academic department setting in large institutions. Most of these trials were initiated by investigators and the pharmaceutical industry merely provided the drugs with little control over protocol development, data analysis and publication. However, importantly for rheumatologists, few drugs, except NSAIDs,2 were developed specifically for use in rheumatic diseases during this period.
THE PRESENT (1995–NOW) The advent of biologicals has changed the scenario of clinical trials drastically, particularly so in rheumatology. The first RCT for a biological compound (anti-TNF antibody; cA2, Infliximab) was done in the year 1994.3 Since then, several new biologicals, including tumour necrosis factor antagonists (Infliximab, Etanercept, Adalimumab), interleukin (IL)-1 receptor antagonists, IL-6 receptor antibody (MRA), anti-CR20 (Rituximab), and inhibitors of adhesion molecules and co-stimulatory molecules have been developed for the treatment of rheumatic diseases. This has had a cascading effect on the number of the industry-sponsored clinical trials in rheumatology. These industry-sponsored trials are in general well planned and executed, and are usually sufficiently powered to assess efficacy and common side effects.4 These studies have added significantly to our understanding of disease biology and therapeutic options. However, the recent controversy over clinical trials on Rofecoxib (Vioxx®; Merck) has thrown up a major debate on industry-sponsored trials both in general and in the field of rheumatology.5 It has now become clear that the VIGOR trial,6 which compared the efficacy and safety of Vioxx in rheumatoid arthritis to that of naproxen, underreported the cardiac events that occurred during the study period in patients receiving this drug, leading to an under-estimation of adverse events. Further, the authors of this report attributed the differences in the adverse events between the Vioxx-treated and control group (receiving naproxen) to the cardio-protective effect of naproxen, than to an increased risk with Vioxx. This trend of increased cardiovascular risk
Perspective
79
with Vioxx was observed in subsequent studies published in 2001 too. However, despite these warning signs, it took 4 years for the drug to be withdrawn from the market,5 indicating the failure of post-marketing surveillance. Later, another coxib drug, namely valdecoxib (Bextra®) was also withdrawn for the same reason. These events raise the question—does pharmaceutical industry sponsorship influence research results? The answer to this appears to be in the affirmative. In a recent analysis of 324 consecutive clinical trial reports, the experimental drug was recommended as the treatment of choice in 49% of trials (104) funded by non-profit organizations, 56.5% of trials (92) funded by both non-profit and for-profit organizations, and 67.2% of trials (137) funded by for-profit organizations,7 suggesting the existence of a bias. The trials funded by for-profit organizations were five times more likely to recommend the experimental drug as treatment of choice in comparison to trials funded by non-profits organization.8 In another study that analyzed papers presented at the annual meeting of the American College of Rheumatology in the year 2001, all the 45 industry-sponsored RCTs favoured the sponsor’s drug, thus violating the principle of equipoise.9 These findings may have two explanations, namely (a) design bias, and (b) publication bias. Design bias arises from frequent use of placebos rather than currently available drugs as comparators in industry-sponsored trials.4 This makes it easier to show the study drug as beneficial. However, the industry argues that design bias increases scientific efficiency, decreases drug development costs, and limits the number of subjects required for a trial, thereby reducing the aggregate risks to trial participants.9 The second type of bias, i.e. ‘publication bias’ refers to differences in the publication record of trials with unfavourable findings, i.e. those which show the experimental drug in poor light (low efficacy or high toxicity) in comparison to placebo or active control. It has been shown that time duration from completion of the trial to its publication is almost twice as long for negative drug trials than that for positive trials.10 In some cases, drug manufacturers have even resorted to legal action to block the publication of unfavourable trial results. What has been even more disconcerting is the reports of some questionable practices the conduct of industrysponsored clinical trials. One of these is the practice of ‘incentive enrollment’ or ‘limited-period enrollment’; this entails competition among participating physicians to enroll patients in the study, with the level of funding for each investigator depending on the number of patients enrolled. The industry argues that this method ensures rapid recruitment of study subjects and hence early completion of the study. However, this strategy may pressurize the investigators,
80
Indian Journal of Rheumatology 2006 September; Vol. 1, No. 2
sometime inducing them to resort to non-ethical means to enroll a larger number of patients.11 In addition, the companies sponsoring drug trials may provide undue inducement to patients using glitzy advertisement in the lay media and financial incentives, often couched in the form of reimbursement for travel and lost wages lost. Thus, the patients may elect to enroll in a study for financial gains without fully understanding the risks involved. A recent trial of TGN1412 in the United Kingdom, in which some healthy volunteers participated primarily for money, is a case in point.12 Thus, it is clear that ‘all is not well’ with the industrysponsored drug trials and something needs to be done.
THE FUTURE We have to accept that industry sponsored trials are here to stay. It is unlikely that public funding will ever be adequate for development of new drugs, at least in the foreseeable future. Remedial steps to rectify the problems with the existing system of funding and conducting drug trials would ensure that all patients are protected without adversely affecting the drug discovery process. Various suggestions have been made in this regard. 1. An independent authority to conduct trials: An international independent agency, for instance under the aegis of the World Health Organization, can be setup for planning and conducting drug trials, including identifying investigators, randomization, data analysis and publication. This should help reduce bias. 2. Academician-led studies: Another suggestion is to make the companies ‘let go’ of clinical trials and allow only academics to lead drug trials. This may help plan studies that are more relevant to day to day clinical practice. Further, such a step may increase transparency in drug trials.13 3. Independent review boards or data management centres: Independent boards comprising of representatives from medicine, pharmaceutical industry, legal profession and the lay public could undertake continuous analysis of accrued data. This would permit early termination of a trial if an unforeseen adverse event or a high rate of toxicity occurs. These boards could also undertake ongoing interim review of the progress of a trial including recruitment, adherence to treatment, participant safety, intervention benefit and overall trial quality. This requires that investigators report all serious or unexpected adverse events to the competent authorities and to the Ethics Committee as soon as possible; the
Aggarwal
current European guidelines mandate that this should be done no later than 15 days of the first knowledge of such an event by the sponsor.14 4. Registration of all trials: Registration of all clinical trials should be made mandatory and the data from these trials should be accessible all over the world.15 Some countries have already taken steps in this direction. Indeed in May 2006 WHO has made a 20-point list of details to be disclosed for registration of drug trials. 5. Mandatory phase IV studies: Post-marketing surveillance and reporting should be made mandatory for a fixed time period after the introduction of a new drug. The time period could vary depending on the type of the drug. A limited license may be issued pending the results of phase IV data. In UK, drug safety data are rereviewed after 5 years of approval. 6. Comparison with active drug: It is easier to show a drug to be beneficial using placebo-controlled studies. However, in real life, the choice is between the new drug and the existing treatment. Thus, it should be mandatory to show that a new drug has efficacy at least equivalent to the currently accepted drug before permission to market it is granted. This will prevent development of new drugs by the pharmaceutical industry merely to ensure the continued use of ‘on-patent’ drugs, and to render the drugs that have become ‘off-patent’ obsolete. Further, head-to-head trials of drugs made by different pharmaceutical companies should be encouraged. It may also be possible to pitch pharmaceutical companies against each other in these trials. This approach will increase the independence of clinical investigators and provide answers to questions relevant for patient care, viz. which of several anti-TNF agents is the best for patients with rheumatoid arthritis.16 Finally, a word of caution to the Indian medical profession. India is fast becoming a hub for industry-sponsored drug trials because of easy availability of a large number of patients as well as physicians.17 This transition needs a close monitoring and regulation. Mandatory registration of all drug trials with bodies like, the Drug Controller General of India or the Indian Council of Medical Research, and easy availability of their results, preferably through an electronic database over the Internet, to all scientists and medical researchers is immediately needed. Further, clinical trial units should be set up in large academic hospitals; these units should have state-of-the-art facilities, ethical and regulatory framework for the conduct of drug trials. Further, the Indian Council of Medical Research or another equivalent body should be charged to act as a watchdog for protecting the interests of the trial participants. These steps will go a long way in infusing confidence in patients on the
Industry sponsored clinical trials in rheumatology
need to conduct drug trials and will help India play a major role in development of new drugs.
Perspective
7.
8.
REFERENCES 1.
2.
3.
4.
5.
6.
DiMasi JA, Hansen RW, Garbowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003; 22: 151–85. Rochon PA, Gurwitz JH, Simms RW, et al. A study of manufacturer supported trials of non-steroidal anti-inflammatory drugs in the treatment of arthritis. Arch Intern Med 1994; 154: 157–63. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 44: 1105–10. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. Br Med J 2003; 326: 1167–70. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364: 2021–9. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343: 1520–8.
9.
10.
11.
12. 13. 14. 15. 16. 17.
81
Ridker PM, Torres J. Reported outcome in major cardiovascular clinical trials funded by for-profit and not-for-profit organizations. JAMA 2000–2005; 295: 2270–4. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA 2003; 290: 921–8. Fries JF, Krishnan E. Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development. Arthritis Res Ther 2004; 6: R250–5. Ioannidis JP. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. JAMA 1998; 279: 281–6. Brown JB. Recruiting human subjects: pressures in industry sponsored clinical research. Department of health and human service USA, 2000. http://news.bbc.co.uk/2/hi/uk_news/england/london/ 4809322.stm accessed on May 23, 2006. Greener M. Drug safety on trial. EMBO Reports 2005; 6: 202–4. Gennary B. Academic clinical research in the new regulatory environment. Clin Med 2005; 5: 39–41. Dickersin K, Rennie D, Registering clinical trials. JAMA 2003; 290: 516–22. Silman AJ. Clinical trials in rheumatology: an uncertain future? Nature Clin Pract 2006; 2: 171. Joshi VR. Feasibility of clinical trials in India. Indian J Rheumatol 2006; 14: 30–2.
Industry–doctor relationship Interesting information on the relationship between doctors and industry sponsors of clinical trials is provided by the following two case studies: 1. Ethics case study: When are industry-sponsored trials a good match for community doctors? Published in the March 2001 issue of ACP-ASIM Observer. Full text of this article is available at http:// www.acponline.org/journals/news/mar01/ethics.htm This article discusses how practising doctors are
approached by a pharmaceutical company for collaboraton in a clinical trial and the ethical issues involved. 2. Miller FG, Shorr AF. Ethical assessment of industrysponsored clinical trials. A case analysis. Chest 2002; 121: 1337–42. Available at http://www.chestjournal.org/ cgi/reprint/121/4/1337 The case analysis deals with methodological and recruitment issues pertaining to an industry-sponsored randomized controlled trial