Beyond Fast Track for Drug Approvals
http://www.100md.com
《新英格兰医药杂志》
In the past decade, the primary strategy for discovering new drugs for the treatment of cancer has shifted from screening for cytotoxic compounds to seeking agents that block the key molecular pathways that lead to cancer. A flurry of recent approvals of so-called molecularly targeted agents suggests that this new approach is bearing fruit. However, when the Food and Drug Administration (FDA) approved gefitinib (Iressa) for the treatment of patients with advanced non–small-cell lung cancer in whom both platinum-based and docetaxel (Taxotere) chemotherapy regimens have failed, it was not without controversy. The statistical reviewer for the FDA concluded that the "data and results of the one, small, single-arm, phase II study do not support the sponsor's claim of efficacy," and Public Citizen, a nonprofit consumer-advocacy organization, admonished the FDA, in part, for approving a drug that produced objective responses in only 10 to 15 percent of the patients who took it.1,2,3 Observers in the medical community also criticized the study sponsor, AstraZeneca, for failing to define the subgroup of patients with lung cancer in whom the drug worked.4 Despite these concerns, the FDA used its accelerated approval mechanism to approve gefitinib as the first molecularly targeted treatment for lung cancer, an approval that was strongly supported by patient advocates,5 most oncologists, and the business community.6 In some patients, the drug does have a dramatic benefit, the advocates argued, and these patients have no other options.
The approval of gefitinib not only illustrates the scrutiny that a myriad of stakeholders place on contemporary FDA reviews; it also highlights substantive changes in FDA policy that warrant examination. Had AstraZeneca submitted the same data to the FDA for consideration 15 years ago, its application almost certainly would have been rejected. Even if the FDA had granted approval, it would have been delayed by several years pending the completion of additional clinical trials. What has changed? The FDA has introduced a series of programs, grouped under the fast-track rubric, that are designed to shorten review times and to allow for approvals at much earlier stages of clinical development, thereby addressing two major problems in the development of drugs. The effect of these programs, which have provided earlier access to new drugs, has been mostly salutary. The programs have also demonstrated the flexibility of the FDA in adapting and reacting to public health problems such as the AIDS epidemic. The fast-track programs, however, have not addressed an increasingly important aspect of drug development: promoting the use of targeted drugs in a more selective fashion. In this article, we discuss the fast-track programs and propose a new approval policy that would broaden their effect.
The Fast Track
The fast-track programs include a series of regulations designed to expedite the drug-development process and to enhance cooperation between the FDA and the pharmaceutical industry. Many of the programs came into existence in the early 1990s but were codified and formalized under the FDA Modernization Act in 1997.7 In a dramatic display of political mobilization, AIDS advocates who were lobbying for early access to antiretroviral agents in the 1980s provided the initial impetus for these programs; they were joined shortly thereafter by advocates from the cancer community, especially those concerned with breast cancer.8 The programs were not designed exclusively to benefit patients with AIDS or cancer, however, and pharmaceutical sponsors may apply for fast-track designation for their drugs in any therapeutic class as long as each drug is intended to treat a serious or life-threatening illness and as long as it addresses an unmet need for new therapy.
From an industry perspective, fast track has three major advantages. First, sponsors enjoy closer communication with the FDA throughout the planning of clinical trials and regulatory review. This communication has enhanced the predictability of FDA decision making, which is a major issue for drug sponsors in their attempts to manage risk. Second, drugs that have been given a fast-track designation are more likely to receive priority review once the application for a new drug has been submitted for approval. If priority review is granted, the target length of time for an FDA action is reduced from the 10-month standard to 6 months. Third, and most important, sponsors may, in certain instances, seek approval under the accelerated-approval mechanism. Using this mechanism, the FDA can grant a provisional approval on the basis of a surrogate measure of clinical benefit (e.g., tumor shrinkage) in a single, uncontrolled trial as long as the treatment addresses an unmet medical need for a serious or life-threatening illness and as long as the surrogate is reasonably likely to predict a clinical benefit. The FDA grants the approval conditionally, extracting the sponsor's agreement to complete confirmatory phase 4 trials in the post-approval period. If these trials do not confirm a clinical benefit, the drug can be withdrawn from the market. To date, however, the FDA has not pursued a single withdrawal, despite the fact that in the cases of only 6 of the 23 oncology-related approvals have the sponsors completed the phase 4 trials required for an upgrade to regular approval (Table 1).9 The regulatory standard for an accelerated approval is significantly less challenging than the standard for regular approval, since regular approval requires convincing evidence of a clinical benefit (e.g., prolonged survival or an improved quality of life), usually in controlled phase 3 trials.
Table 1. Accelerated Approval of Drugs for the Treatment of Cancer as of June 2004.
Patients have undoubtedly gained earlier access to new drugs through the accelerated-approval mechanism. Since 1992, when accelerated approval first became available, 16 of the 18 drugs approved to treat patients infected with the human immunodeficiency virus (HIV) initially gained marketing approval by this mechanism. The average review time for these agents was less than six months, which met the FDA's goal for priority review. In regard to cancer, the FDA granted its first accelerated approval in 1995; approximately one third of the 60 cancer drugs that have been approved since then have received accelerated approvals on the basis of surrogate measures of a clinical benefit. These approvals have provided access to new drugs for the treatment of HIV infection and cancer years earlier than would be possible under the regular-approval process. Though most accelerated approvals have been accorded to drugs in the areas of oncology or infectious diseases, the FDA is granting a growing number of such approvals outside of these two fields, as exemplified by the recent approval of treprostinil (Remodulin) for the treatment of pulmonary hypertension.
The Lag in Predictive Studies
It is certainly laudable for the FDA to grant early marketing approval for drugs used to treat life-threatening illnesses. It is also appropriate to expect that much of the drug development will occur after approval.10 However, up to this point the FDA has not compelled sponsors that benefit from accelerated approval to identify the specific subpopulations of patients who are likely to have a response to a given drug. We believe that the failure to identify such populations represents a missed opportunity. As compared with cytotoxic agents, targeted drugs hold the promise that we may be able to define precisely the groups of patients in whom they will be effective. This ability to define subpopulations of patients who are likely to have responses, which thereby avoids the medical and financial cost of ineffective therapies, is particularly critical in fields such as oncology. Wasting time with ineffective therapies may entail the loss of a window of opportunity for patients with cancer to receive an effective treatment. In some instances, such as when trastuzumab (Herceptin) is used to treat only those tumors that overexpress the human epidermal growth factor receptor 2 (HER2/neu), sponsors have been able to use molecular testing to identify the patients who are most likely to have a response. There is growing evidence that such selective approaches will be possible for other targeted agents. New studies of gefitinib, an epidermal growth factor–receptor inhibitor, indicate that certain mutations in the receptor are strongly associated with a clinical response.11,12 These mutations occur in only about 10 percent of patients with non–small-cell lung cancer, but they appear to make tumors exquisitely sensitive to inhibition of the receptor.
Despite the great promise of these approaches, the pharmaceutical industry has thus far invested only modestly in studies that predict responses to cancer drugs. Perhaps we should not expect it to do so. Market theory suggests that sponsors will invest in the research necessary to identify subgroups of patients who are likely to have responses only if this process helps them to achieve approval for marketing, gives them a competitive advantage over another product, or increases their market share. For any given indication in oncology, for example, none of these incentives to define the subgroup of patients who are likely to have responses may apply. First, single-agent response rates as low as 10 to 15 percent have been adequate to win FDA approval for indications in oncology for which no other treatments are available (Table 1). Defining subgroups of patients who are likely to have responses, which could boost response rates in a selected group, may therefore not be necessary for initial approval. Second, there are only a small number of approved therapies for many indications in oncology; as a result, many newly approved drugs for specific indications will have essentially no competition. Patients with cancer and their oncologists will use these new agents despite low rates of response and despite enormous costs, which for some cancer agents can exceed $15,000 per treatment. Finally, selecting a subgroup of patients who are likely to have responses could, in the short term, limit the size of the market for an approved drug for use against tumors that express the relevant molecular profile. Thus, pharmaceutical sponsors may not have a financial incentive to define subgroups of patients who are likely to have responses as they seek the broadest marketing indications possible.13
There are additional reasons why pharmaceutical sponsors have failed to define subgroups of patients who are likely to have responses in the trials of their drugs. First, with few exceptions, the scientific determinants of responses to cancer drugs are neither obvious nor readily accessible to study in humans, and enhancing our understanding of them will require substantial investments of time and capital. Second, the process of developing new drugs is intrinsically complex, expensive, and fraught with risk.14 On average, sponsors must subject more than 10 drugs to clinical testing before 1 gains approval. The high failure rate, in turn, drives the average cost of developing those drugs that do gain approval to more than $800 million, by some estimates.15 Although the pharmaceutical industry has historically enjoyed healthy profit margins, "blockbuster" drugs earn most of the revenues. It is unlikely, for example, that in the short term a cancer drug targeted to a tumor with a narrowly defined molecular profile could achieve revenues on the level of those for a cholesterol-lowering drug. Third, much of the innovation in the development of drugs occurs in small biotechnology companies, the vast majority of which are not profitable. Many of these companies were formed in the boom period of the 1990s, when investment in biotechnology exceeded $200 billion. The lack of breakthrough success for many high-profile drugs has dampened the enthusiasm of investors, and companies are finding it increasingly difficult to raise capital. Continuous undercapitalization pressures sponsors to subject their candidate drugs to clinical testing at the earliest possible point and to obtain approval as soon as possible, with the simplest possible strategy.
A Proposal for Selective Approval
Can the situation be remedied? We believe it can. The fast-track programs, which have already facilitated earlier approvals of drugs, could be expanded to encourage the use of targeted drugs in a more selective manner. To promote these efforts, we propose a new FDA approval mechanism for targeted drugs, which we call "selective approval." Although the mechanism could be used for other classes of therapeutic drugs, we recommend that it be piloted for cancer drugs. Under this mechanism, a targeted cancer drug that demonstrates consistent antitumor responses in early efficacy trials could be submitted for selective approval, but only if the sponsor has initiated studies to identify subgroups of patients who are likely to have responses. These studies ideally would have begun in the earliest phases of development of a given drug, with the use of such tools as gene-expression profiling, gene sequencing, proteomics, and molecular imaging. These studies would not need to be completed by the time of selective approval. At the time of the review, the FDA would negotiate the specific details of the sponsor's commitment to conduct phase 4 studies after obtaining selective approval. Progress would be reviewed annually, and approval could be withdrawn if the sponsor had not met post-approval conditions. Because the identification of subgroups of patients who are likely to have responses is in the public interest, the sponsor could form a partnership with the National Institutes of Health (NIH) to fulfill these obligations or could use the expertise of academic centers, but the sponsor would assume the ultimate responsibility for initiating and completing the studies.
The proposed selective-approval mechanism is intended to complement the fast-track programs. Sponsors could still obtain accelerated approval, but only for those drugs that lacked a clearly defined molecular target or that, for other reasons, might prove difficult to study as single agents. Sponsors would continue to be able to seek regular approval without the formal requirement for post-approval studies of selectivity if their drugs had clear clinical benefits in controlled trials. The evidence required for selective approval would be identical to that already established for accelerated approval, and the conversion of selective approval to regular approval would require either a major improvement in the selection of patients or the completion of randomized trials. Unlike accelerated approval, the selective-approval mechanism would be available for all new targeted cancer drugs and would create a financial commitment on the part of the sponsor. Specifically, we propose that the FDA require that a minimal percentage of drug sales (e.g., 5 percent) be allocated either to studies focused on identifying subgroups of patients who are likely to have responses or to the NIH for its sponsorship of related research. This financial commitment would continue until the drug qualified for regular approval, until the sponsor had successfully identified subgroups of patients who are likely to have responses, or until the drug had been withdrawn from the market.
The effect of this new mechanism, if successful, would be profound and would extend beyond the field of cancer. The inability to predict responses in patients has compromised drug development in many classes of therapeutic agents, but it presents a particular problem for cancer drugs. The characterization of subgroups of patients who are likely to have responses would reduce the needless cost of ineffective therapy and the size of clinical trials, and it might even broaden the range of indications to include diseases with common molecular features but with dissimilar pathologic manifestations. Many specialties in medicine have become too accustomed to low response rates and have emphasized the search for new drugs without making a sufficient effort to define the markers of response. The pharmaceutical industry, the NIH, and the FDA must cooperate in setting goals beyond that of early approval. Molecular techniques have been developed to identify populations of patients who are likely to have responses to targeted drugs, and this is the next important step in the rationalization of therapy.
Supported in part by a grant from the National Cancer Institute (R25T CA 92203) and by an unrestricted Health Outcomes Research Grant from the PhRMA Foundation (both to Dr. Roberts).
Dr. Roberts reports having received speaking fees from Roche Laboratories and AstraZeneca. Dr. Chabner reports having served as a consultant for, and owning equity in, PharmaMar, Cell Genesys, Gloucester Pharmaceuticals, Cephalon, Oncotech, and Kosan Biosciences and is a board member of Kosan Biosciences.
We are indebted to Dr. Steven Hirschfeld of the FDA for his helpful comments on a previous version of this article.
Source Information
From the Division of Hematology–Oncology, Massachusetts General Hospital and Harvard Medical School, Boston (T.G.R., B.A.C.); the Program on the Pharmaceutical Industry, Massachusetts Institute of Technology, Cambridge, Mass. (T.G.R.); and the Institute for Technology Assessment, Massachusetts General Hospital, Boston (T.G.R.).
Address reprint requests to Dr. Roberts at Massachusetts General Hospital, Cox 640, 100 Blossom St., Boston, MA 02114, or at troberts@partners.org.
References
Food and Drug Administration. Statistical review of Iressa. (Accessed July 9, 2004, at http://www.fda.gov/cder/foi/nda/2003/21-399_IRESSA_Statr.pdf.)
Letter to the FDA expressing concerns about the pending approval of the cancer drug gefitinib (IRESSA) (HRG publication #1665). Washington, D.C.: Public Citizen, May 2003. (Accessed July 9, 2004, at http://www.citizen.org/publications/release.cfm?ID=7242.)
Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149-2158.
Castro M. The simpleton's error in drug development. J Clin Oncol 2002;20:4606-4607.
Food and Drug Administration. Oncologic Drugs Advisory Committee 72nd Meeting, Silver Spring, Md., September 24, 2002. (Accessed July 9, 2004, at http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3894T1.htm.)
FDA to cancer patients: drop dead. Wall Street Journal. September 24, 2002:A18.
Food and Drug Administration. Guidance for industry: fast track drug development programs — designation, development, and application review. September 1998. (Accessed July 9, 2004, at http://www.fda.gov/cber/gdlns/fsttrk.pdf.)
Anderson LF. Cancer and AIDS groups push for changes in drug approval process. J Natl Cancer Inst 1989;81:829-831.
Mitka M. Accelerated approval scrutinized: confirmatory phase 4 studies on new drugs languish. JAMA 2003;289:3227-3229.
Gelijns AC, Rosenberg N, Moskowitz AJ. Capturing the unexpected benefits of medical research. N Engl J Med 1998;339:693-698.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
Danzon P, Towse A. The genomic revolution: is the real risk under-investment rather than bankrupt health care systems? J Health Serv Res Policy 2000;5:253-255.
Roberts TG Jr, Lynch TJ Jr, Chabner BA. The phase III trial in the era of targeted therapy: unraveling the "go or no go" decision. J Clin Oncol 2003;21:3683-3695.
DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003;22:151-185.(Thomas G. Roberts, Jr., M)
The approval of gefitinib not only illustrates the scrutiny that a myriad of stakeholders place on contemporary FDA reviews; it also highlights substantive changes in FDA policy that warrant examination. Had AstraZeneca submitted the same data to the FDA for consideration 15 years ago, its application almost certainly would have been rejected. Even if the FDA had granted approval, it would have been delayed by several years pending the completion of additional clinical trials. What has changed? The FDA has introduced a series of programs, grouped under the fast-track rubric, that are designed to shorten review times and to allow for approvals at much earlier stages of clinical development, thereby addressing two major problems in the development of drugs. The effect of these programs, which have provided earlier access to new drugs, has been mostly salutary. The programs have also demonstrated the flexibility of the FDA in adapting and reacting to public health problems such as the AIDS epidemic. The fast-track programs, however, have not addressed an increasingly important aspect of drug development: promoting the use of targeted drugs in a more selective fashion. In this article, we discuss the fast-track programs and propose a new approval policy that would broaden their effect.
The Fast Track
The fast-track programs include a series of regulations designed to expedite the drug-development process and to enhance cooperation between the FDA and the pharmaceutical industry. Many of the programs came into existence in the early 1990s but were codified and formalized under the FDA Modernization Act in 1997.7 In a dramatic display of political mobilization, AIDS advocates who were lobbying for early access to antiretroviral agents in the 1980s provided the initial impetus for these programs; they were joined shortly thereafter by advocates from the cancer community, especially those concerned with breast cancer.8 The programs were not designed exclusively to benefit patients with AIDS or cancer, however, and pharmaceutical sponsors may apply for fast-track designation for their drugs in any therapeutic class as long as each drug is intended to treat a serious or life-threatening illness and as long as it addresses an unmet need for new therapy.
From an industry perspective, fast track has three major advantages. First, sponsors enjoy closer communication with the FDA throughout the planning of clinical trials and regulatory review. This communication has enhanced the predictability of FDA decision making, which is a major issue for drug sponsors in their attempts to manage risk. Second, drugs that have been given a fast-track designation are more likely to receive priority review once the application for a new drug has been submitted for approval. If priority review is granted, the target length of time for an FDA action is reduced from the 10-month standard to 6 months. Third, and most important, sponsors may, in certain instances, seek approval under the accelerated-approval mechanism. Using this mechanism, the FDA can grant a provisional approval on the basis of a surrogate measure of clinical benefit (e.g., tumor shrinkage) in a single, uncontrolled trial as long as the treatment addresses an unmet medical need for a serious or life-threatening illness and as long as the surrogate is reasonably likely to predict a clinical benefit. The FDA grants the approval conditionally, extracting the sponsor's agreement to complete confirmatory phase 4 trials in the post-approval period. If these trials do not confirm a clinical benefit, the drug can be withdrawn from the market. To date, however, the FDA has not pursued a single withdrawal, despite the fact that in the cases of only 6 of the 23 oncology-related approvals have the sponsors completed the phase 4 trials required for an upgrade to regular approval (Table 1).9 The regulatory standard for an accelerated approval is significantly less challenging than the standard for regular approval, since regular approval requires convincing evidence of a clinical benefit (e.g., prolonged survival or an improved quality of life), usually in controlled phase 3 trials.
Table 1. Accelerated Approval of Drugs for the Treatment of Cancer as of June 2004.
Patients have undoubtedly gained earlier access to new drugs through the accelerated-approval mechanism. Since 1992, when accelerated approval first became available, 16 of the 18 drugs approved to treat patients infected with the human immunodeficiency virus (HIV) initially gained marketing approval by this mechanism. The average review time for these agents was less than six months, which met the FDA's goal for priority review. In regard to cancer, the FDA granted its first accelerated approval in 1995; approximately one third of the 60 cancer drugs that have been approved since then have received accelerated approvals on the basis of surrogate measures of a clinical benefit. These approvals have provided access to new drugs for the treatment of HIV infection and cancer years earlier than would be possible under the regular-approval process. Though most accelerated approvals have been accorded to drugs in the areas of oncology or infectious diseases, the FDA is granting a growing number of such approvals outside of these two fields, as exemplified by the recent approval of treprostinil (Remodulin) for the treatment of pulmonary hypertension.
The Lag in Predictive Studies
It is certainly laudable for the FDA to grant early marketing approval for drugs used to treat life-threatening illnesses. It is also appropriate to expect that much of the drug development will occur after approval.10 However, up to this point the FDA has not compelled sponsors that benefit from accelerated approval to identify the specific subpopulations of patients who are likely to have a response to a given drug. We believe that the failure to identify such populations represents a missed opportunity. As compared with cytotoxic agents, targeted drugs hold the promise that we may be able to define precisely the groups of patients in whom they will be effective. This ability to define subpopulations of patients who are likely to have responses, which thereby avoids the medical and financial cost of ineffective therapies, is particularly critical in fields such as oncology. Wasting time with ineffective therapies may entail the loss of a window of opportunity for patients with cancer to receive an effective treatment. In some instances, such as when trastuzumab (Herceptin) is used to treat only those tumors that overexpress the human epidermal growth factor receptor 2 (HER2/neu), sponsors have been able to use molecular testing to identify the patients who are most likely to have a response. There is growing evidence that such selective approaches will be possible for other targeted agents. New studies of gefitinib, an epidermal growth factor–receptor inhibitor, indicate that certain mutations in the receptor are strongly associated with a clinical response.11,12 These mutations occur in only about 10 percent of patients with non–small-cell lung cancer, but they appear to make tumors exquisitely sensitive to inhibition of the receptor.
Despite the great promise of these approaches, the pharmaceutical industry has thus far invested only modestly in studies that predict responses to cancer drugs. Perhaps we should not expect it to do so. Market theory suggests that sponsors will invest in the research necessary to identify subgroups of patients who are likely to have responses only if this process helps them to achieve approval for marketing, gives them a competitive advantage over another product, or increases their market share. For any given indication in oncology, for example, none of these incentives to define the subgroup of patients who are likely to have responses may apply. First, single-agent response rates as low as 10 to 15 percent have been adequate to win FDA approval for indications in oncology for which no other treatments are available (Table 1). Defining subgroups of patients who are likely to have responses, which could boost response rates in a selected group, may therefore not be necessary for initial approval. Second, there are only a small number of approved therapies for many indications in oncology; as a result, many newly approved drugs for specific indications will have essentially no competition. Patients with cancer and their oncologists will use these new agents despite low rates of response and despite enormous costs, which for some cancer agents can exceed $15,000 per treatment. Finally, selecting a subgroup of patients who are likely to have responses could, in the short term, limit the size of the market for an approved drug for use against tumors that express the relevant molecular profile. Thus, pharmaceutical sponsors may not have a financial incentive to define subgroups of patients who are likely to have responses as they seek the broadest marketing indications possible.13
There are additional reasons why pharmaceutical sponsors have failed to define subgroups of patients who are likely to have responses in the trials of their drugs. First, with few exceptions, the scientific determinants of responses to cancer drugs are neither obvious nor readily accessible to study in humans, and enhancing our understanding of them will require substantial investments of time and capital. Second, the process of developing new drugs is intrinsically complex, expensive, and fraught with risk.14 On average, sponsors must subject more than 10 drugs to clinical testing before 1 gains approval. The high failure rate, in turn, drives the average cost of developing those drugs that do gain approval to more than $800 million, by some estimates.15 Although the pharmaceutical industry has historically enjoyed healthy profit margins, "blockbuster" drugs earn most of the revenues. It is unlikely, for example, that in the short term a cancer drug targeted to a tumor with a narrowly defined molecular profile could achieve revenues on the level of those for a cholesterol-lowering drug. Third, much of the innovation in the development of drugs occurs in small biotechnology companies, the vast majority of which are not profitable. Many of these companies were formed in the boom period of the 1990s, when investment in biotechnology exceeded $200 billion. The lack of breakthrough success for many high-profile drugs has dampened the enthusiasm of investors, and companies are finding it increasingly difficult to raise capital. Continuous undercapitalization pressures sponsors to subject their candidate drugs to clinical testing at the earliest possible point and to obtain approval as soon as possible, with the simplest possible strategy.
A Proposal for Selective Approval
Can the situation be remedied? We believe it can. The fast-track programs, which have already facilitated earlier approvals of drugs, could be expanded to encourage the use of targeted drugs in a more selective manner. To promote these efforts, we propose a new FDA approval mechanism for targeted drugs, which we call "selective approval." Although the mechanism could be used for other classes of therapeutic drugs, we recommend that it be piloted for cancer drugs. Under this mechanism, a targeted cancer drug that demonstrates consistent antitumor responses in early efficacy trials could be submitted for selective approval, but only if the sponsor has initiated studies to identify subgroups of patients who are likely to have responses. These studies ideally would have begun in the earliest phases of development of a given drug, with the use of such tools as gene-expression profiling, gene sequencing, proteomics, and molecular imaging. These studies would not need to be completed by the time of selective approval. At the time of the review, the FDA would negotiate the specific details of the sponsor's commitment to conduct phase 4 studies after obtaining selective approval. Progress would be reviewed annually, and approval could be withdrawn if the sponsor had not met post-approval conditions. Because the identification of subgroups of patients who are likely to have responses is in the public interest, the sponsor could form a partnership with the National Institutes of Health (NIH) to fulfill these obligations or could use the expertise of academic centers, but the sponsor would assume the ultimate responsibility for initiating and completing the studies.
The proposed selective-approval mechanism is intended to complement the fast-track programs. Sponsors could still obtain accelerated approval, but only for those drugs that lacked a clearly defined molecular target or that, for other reasons, might prove difficult to study as single agents. Sponsors would continue to be able to seek regular approval without the formal requirement for post-approval studies of selectivity if their drugs had clear clinical benefits in controlled trials. The evidence required for selective approval would be identical to that already established for accelerated approval, and the conversion of selective approval to regular approval would require either a major improvement in the selection of patients or the completion of randomized trials. Unlike accelerated approval, the selective-approval mechanism would be available for all new targeted cancer drugs and would create a financial commitment on the part of the sponsor. Specifically, we propose that the FDA require that a minimal percentage of drug sales (e.g., 5 percent) be allocated either to studies focused on identifying subgroups of patients who are likely to have responses or to the NIH for its sponsorship of related research. This financial commitment would continue until the drug qualified for regular approval, until the sponsor had successfully identified subgroups of patients who are likely to have responses, or until the drug had been withdrawn from the market.
The effect of this new mechanism, if successful, would be profound and would extend beyond the field of cancer. The inability to predict responses in patients has compromised drug development in many classes of therapeutic agents, but it presents a particular problem for cancer drugs. The characterization of subgroups of patients who are likely to have responses would reduce the needless cost of ineffective therapy and the size of clinical trials, and it might even broaden the range of indications to include diseases with common molecular features but with dissimilar pathologic manifestations. Many specialties in medicine have become too accustomed to low response rates and have emphasized the search for new drugs without making a sufficient effort to define the markers of response. The pharmaceutical industry, the NIH, and the FDA must cooperate in setting goals beyond that of early approval. Molecular techniques have been developed to identify populations of patients who are likely to have responses to targeted drugs, and this is the next important step in the rationalization of therapy.
Supported in part by a grant from the National Cancer Institute (R25T CA 92203) and by an unrestricted Health Outcomes Research Grant from the PhRMA Foundation (both to Dr. Roberts).
Dr. Roberts reports having received speaking fees from Roche Laboratories and AstraZeneca. Dr. Chabner reports having served as a consultant for, and owning equity in, PharmaMar, Cell Genesys, Gloucester Pharmaceuticals, Cephalon, Oncotech, and Kosan Biosciences and is a board member of Kosan Biosciences.
We are indebted to Dr. Steven Hirschfeld of the FDA for his helpful comments on a previous version of this article.
Source Information
From the Division of Hematology–Oncology, Massachusetts General Hospital and Harvard Medical School, Boston (T.G.R., B.A.C.); the Program on the Pharmaceutical Industry, Massachusetts Institute of Technology, Cambridge, Mass. (T.G.R.); and the Institute for Technology Assessment, Massachusetts General Hospital, Boston (T.G.R.).
Address reprint requests to Dr. Roberts at Massachusetts General Hospital, Cox 640, 100 Blossom St., Boston, MA 02114, or at troberts@partners.org.
References
Food and Drug Administration. Statistical review of Iressa. (Accessed July 9, 2004, at http://www.fda.gov/cder/foi/nda/2003/21-399_IRESSA_Statr.pdf.)
Letter to the FDA expressing concerns about the pending approval of the cancer drug gefitinib (IRESSA) (HRG publication #1665). Washington, D.C.: Public Citizen, May 2003. (Accessed July 9, 2004, at http://www.citizen.org/publications/release.cfm?ID=7242.)
Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003;290:2149-2158.
Castro M. The simpleton's error in drug development. J Clin Oncol 2002;20:4606-4607.
Food and Drug Administration. Oncologic Drugs Advisory Committee 72nd Meeting, Silver Spring, Md., September 24, 2002. (Accessed July 9, 2004, at http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3894T1.htm.)
FDA to cancer patients: drop dead. Wall Street Journal. September 24, 2002:A18.
Food and Drug Administration. Guidance for industry: fast track drug development programs — designation, development, and application review. September 1998. (Accessed July 9, 2004, at http://www.fda.gov/cber/gdlns/fsttrk.pdf.)
Anderson LF. Cancer and AIDS groups push for changes in drug approval process. J Natl Cancer Inst 1989;81:829-831.
Mitka M. Accelerated approval scrutinized: confirmatory phase 4 studies on new drugs languish. JAMA 2003;289:3227-3229.
Gelijns AC, Rosenberg N, Moskowitz AJ. Capturing the unexpected benefits of medical research. N Engl J Med 1998;339:693-698.
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-2139.
Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500.
Danzon P, Towse A. The genomic revolution: is the real risk under-investment rather than bankrupt health care systems? J Health Serv Res Policy 2000;5:253-255.
Roberts TG Jr, Lynch TJ Jr, Chabner BA. The phase III trial in the era of targeted therapy: unraveling the "go or no go" decision. J Clin Oncol 2003;21:3683-3695.
DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003;22:151-185.(Thomas G. Roberts, Jr., M)