- Email: [email protected]
The FDA and The Lancet: an exchange
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
The FDA and The Lancet: an exchange Sir—Richard Horton’s May 19 commentary1 seriously misrepresents the regulatory review of alosetron tablets (Lotronex, GlaxoWellcome) by the US Food and Drug Administration (FDA) and its Center for Drug Evaluation and Research (CDER). Horton asserts that the approval and review process of Lotronex represent a “fatal erosion of integrity” within the FDA, that dissenting opinions on the drug have been suppressed, that scientists who raised issues about Lotronex “felt intimidated by senior colleagues and were excluded from further discussions” about the drug, and that some individuals within the FDA are engaged in so-called covert and private communications with GlaxoSmithKline. These misrepresentations and allegations are a disservice to the FDA, to The Lancet’s readers, and, most importantly, to patients with irritable bowel syndrome (IBS) and their health-care providers. The FDA is committed to making regulatory decisions that are scientifically based and that reflect the highest principles in public-health protection. The issues surrounding the review of Lotronex, especially the balance of benefit and risk, are among the most difficult and complex in today’s drugdevelopment environment. All drugs have risks; Lotronex carries risks such as ischaemic colitis and serious constipation. The record unequivocally shows that the FDA has identified, assessed, and publicised these risks, as well as seeking ways to monitor or manage them. For example, risks of Lotronex were publicly scrutinised at two meetings of FDA’s Gastrointestinal Drugs Advisory Committee—once on Nov 16, 1999, before Lotronex was approved, and once on June 27, 2000, after the drug had been marketed for several months when cases of ischaemic colitis and serious complications of constipation had emerged.2 Horton does not mention these meetings and takes no note of the FDA’s actions when these risks were identified (eg, warnings in
THE LANCET • Vol 358 • August 4, 2001
professional labelling; issue of guidelines for patients on risks; engagement of professional organisations and patients’ advocacy groups.) Horton fails entirely to grapple with the issue of the benefit of Lotronex and the need for effective therapies for patients with IBS. This drug is the first to provide symptomatic relief for patients with IBS, specifically in female patients with diarrhoea as the predominant bowel symptom. IBS can be debilitating at enormous physical, emotional, and social costs to patients. Horton virtually ignores the need for access to proven, effective medications for patients, and cites only from the petition submitted to FDA by the Public Citizen’s Health Research Group. The public record also contains a petition submitted by an IBS patients’ advocacy group, the Lotronex Action Group, earlier this year, which pleads that the FDA continue to make Lotronex available for patients. Such patients have been urgently appealing to FDA and GlaxoSmithKline for access to the medication, motivated the FDA believes, by sincere desperation for access to an effective treatment, not, as Horton suggests, because of an orchestrated campaign organised and financed by the firm. The assertion that the FDA’s review of Lotronex involves a covert or two-track process is completely unsupported by the facts. Review of Lotronex has involved several organisational elements within the agency and has incorporated the scientific assessments and recommendations of physicians, toxicologists, statisticians, and epidemiologists. Results of disciplinary-group meetings at all levels of management have been openly shared with the entire Lotronex review team, as have those of meetings or conversations with company officials and the FDA, irrespective of the level. Disagreements within the FDA in such drug-review processes are common, particularly on complex issues, and can involve individuals or groups at various levels. Yet, all individuals whom Horton described as
officials are scientists, who are consistently engaged in the review and decision-making that are critical to all drug regulatory activities. The FDA values such disagreements because they force reassessment of evidence and conclusions, as well as constructive dialogue. Despite disagreement, however, the FDA must make only one regulatory decision. Finally, Horton seems genuinely confused about the drug-withdrawal process in the USA. Voluntary withdrawal is most common for withdrawals related to toxic effects. The alternatives are time-consuming administrative hearings or imminenthazard procedures. To suggest voluntary withdrawal as an option for Lotronex was, therefore, not a concession by the FDA. The alternatives were untenable. It is hard to understand why a process that led to withdrawal is offered as an example of an internal struggle within the FDA or an undermining of reviewers’ views. Horton oversimplifies the FDA’s interactions with product sponsors and other stakeholders in drug development. To find out whether an appropriate balance on the benefits and risks of Lotronex can be achieved is complex and requires data, discussion, and an understanding of the diversity of perspectives within the Agency. He naïvely implies that listening to the concerns of stakeholders is synonymous with agreeing with stakeholders. In fact, responsible drug regulation requires understanding of diverse perspectives, whether the agency ultimately agrees or not. *Steven Galson, Sandra Kweder, Florence Houn, Victor Raczkowski, Peter K Honig Center for Drug Evaluation and Research, FDA, Rockville, MD, USA 1
2
Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet 2001; 357: 1544–45. Dockets management. www.fda.gov/ohrms/dockets (accessed July 12, 2001).
Sir—Richard Horton1 states that the integrity of reviewing registration applications at the FDA may be
415
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
compromised as a result of user fees from the pharmaceutical companies. We are reviewers at the Center for Drug Evaluation and Research and take issue with that assertion. The FDA has been assessing medical claims by use of the principles of evidence-based medicine for more than 60 years. Only about 10% of drugs in development reach the stage for filing a new drug application to register a marketing claim. Many potential applications are not filed because data are insufficient for registration and marketing approval, and would not pass FDA scrutiny. We are professionals who work on multidisciplinary teams comprised of chemists, clinical pharmacologists, microbiologists, physicians, statisticians, and toxicologists. Our review standards are based on accepted scientific principles and we believe our review process is thoughtful and thorough. It is open to scrutiny and input from advisory committees and consultants during the review process, and reviews are posted on the internet after approval. On average, 20% of new drug applications are not approved, and the proportion of non-approvals has been rising. Approval rate can, however, be a misleading statistic because of increasing consultation with the FDA by pharmaceutical companies before filing a new drug application and general improvements in the overall quality of clinical research, both of which could lead to higher approval rates. We are also aware that marketing approval of a product is an interim step in therapeutic development and we, as primary reviewers, continue to monitor products for safety after approval in addition to the formal FDA postmarketing approval surveillance and the spontaneous reporting of adverse events through the MedWatch system. Events that can lead to a label change or even withdrawal from the market might emerge only after marketing approval and subsequent increased use in different and larger populations than those studied for initial review. We have formal interactions with academic colleagues and institutions, patients’ advocacy organisations, professional societies, and consumer groups as well as the pharmaceutical industry, all of which expect impartiality and evidence-based determinations intended to protect US public health through the approval and monitoring of safe and effective drugs. We take pride and satisfaction in our work and publicly associate ourselves with the process of objective data evaluation and analysis. This letter was
416
not reviewed or authorised by the Center for Drug Evaluation and Research management. Richard C Adams, Javher Advani, Funmilayo Ajayi, Suliman Al-Fayoumi, Sayed Al-Habet, Eric Bastings, Kimberly Benson, Peter Bross, Margaret Brower, Yeh-Fong Chen, Judy Chiao, Gani Chico, Wen-Hwei Chou, Martin Cohen, Denise Cook, Patricia Cortazar, Ramzi Dagher, Daniel Davis, John Duan, Eric Duffy, Amy Ellis, Emmanuel Fadiran, John D Franolic, Valeria Freidlin, Gregory Frykman, Lesley Furlong, Steven Gitterman, Anwar Goheer, Mamata S Gokhale, Donna Griebel, Robert Harris, Hector Herrera, Xiao Hong, Ekopimo O Ibia, Amna Ibrahim, Sidney Jaffee, Rosemary Johann-Liang, Roswitha Kelly, Sharon Kelly, Hon-Sum Ko, Joyce Korvick, Doo Lee-Ham, Brad G Leissa, Linda Lewis, George Lunn, Patrick Marroum, Ram Mittal, Scott Monroe, Eileen E Navarro Almario, Nhi Nguyen, Parivash Nourjah, Armando Oliva, Thomas Papoian, Janice Pohlman, Joseph Porres, Hullahalli R Prasanna, Lilliam Rosario, Sandip Roy, Nashed Samaan, Haripada Sarker, Eugene L Schaefer, Nancy Scher, Bruce Schneider, Daniel Shames, Alla Shapiro, Arthur Shaw, Gerald Sokol, Janice M Soreth, Rajeshwari Sridhara, Khin Maung U, Kathleen Uhl, Lourdes Villalba, Robert M White, Grant Williams, Rebecca Wood, Teresa Wu, Peiling Yang.
*Steven Hirschfeld, Lydia Kieffer, W David McGuinn, Mark Rothmann, William C Timmer Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, 1451 Rockville Pike, HFD-I5O, Rockville, MD 20852, USA (e-mail: [email protected]) 1
Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet 2001; 357: 1544–45.
Sir—Richard Horton1 describes two important issues: the shortcomings in the FDA drug-reviewing process, and the responsibility of the editorial process. As FDA reviewers we have the freedom to discuss all issues we wish in our documents, and reviews are not edited by upper management. However, we are not always sufficiently able to dissuade upper management, and they may over-rule our recommendations. When they do so, they need to justify their positions in writing; thus, there should be documentation identifying the process, the discrepancies, and who is responsible for actions contrary to those posed by the primary reviewer. For approved products, this documentation can be accessed through the mechanism offered by the Freedom of Information Act. In my 10 years at the FDA, I have seen overrulings of primary reviewers without any ill consequences, and others that resulted in serious complications and in fatalities.
As per The Lancet’s role, it published the results of the original study and the reviewers did not judge that the drug was unsafe. Indeed, they agreed with the investigators. The FDA’s medical-officer review apparently raised some concerns about the potential of serious adverse events associated with this compound. This apparent discrepancy is not new. Conclusions and contents of scientific reports, in which pharmaceutical sponsors play an important part, differ, many times substantially, from the same material that is reviewed by the FDA. The FDA has access to all data, and may ask them for additional information and clarification on unresolved issues from the sponsors, and spends years following a product’s development. These are some of the benefits that most journals’ reviewers do not have. In addition, FDA reviewers have the ability to audit sites for the assessment of the veracity and integrity of the data. Papers submitted for publication generally add analyses that point to benefits in subgroups that the FDA deems improper if they were not prespecified in the original protocols. Researchers might decide to delete data that do not favour the drugs’ desired effects, or to provide information on data that do. I have seen papers published, with company support in leading journals, on data I reviewed and presented in public meetings discussing the FDA position, with conclusions different from those agreed with the company as reflected in these drugs’ labels. How do we explain these discrepancies? Declaration of conflict of interest is not enough most of the time. The leading researchers might be unaware that the statistical analyses are not proper, that they could exclude data that do not support the companies’ position, including inappropriate subgroup analyses, or the presentation of graphs or figures that could be construed as misleading. They might be excellent clinicians but they might not know how to properly address these issues and have to rely on the support of individuals whose motives differ from their own. Editors should not allow language that qualifies the nature of the adverse reactions or speculative language that obscures the findings. Researchers should list findings and state that a cause-and-effect relation was not ruled-out. Time will tell. Moreover, once we learn that adverse events indeed occur, we could link new reports to original reports to modify the initial claims.
THE LANCET • Vol 358 • August 4, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
The FDA and The Lancet: an exchange Sir—Richard Horton’s May 19 commentary1 seriously misrepresents the regulatory review of alosetron tablets (Lotronex, GlaxoWellcome) by the US Food and Drug Administration (FDA) and its Center for Drug Evaluation and Research (CDER). Horton asserts that the approval and review process of Lotronex represent a “fatal erosion of integrity” within the FDA, that dissenting opinions on the drug have been suppressed, that scientists who raised issues about Lotronex “felt intimidated by senior colleagues and were excluded from further discussions” about the drug, and that some individuals within the FDA are engaged in so-called covert and private communications with GlaxoSmithKline. These misrepresentations and allegations are a disservice to the FDA, to The Lancet’s readers, and, most importantly, to patients with irritable bowel syndrome (IBS) and their health-care providers. The FDA is committed to making regulatory decisions that are scientifically based and that reflect the highest principles in public-health protection. The issues surrounding the review of Lotronex, especially the balance of benefit and risk, are among the most difficult and complex in today’s drugdevelopment environment. All drugs have risks; Lotronex carries risks such as ischaemic colitis and serious constipation. The record unequivocally shows that the FDA has identified, assessed, and publicised these risks, as well as seeking ways to monitor or manage them. For example, risks of Lotronex were publicly scrutinised at two meetings of FDA’s Gastrointestinal Drugs Advisory Committee—once on Nov 16, 1999, before Lotronex was approved, and once on June 27, 2000, after the drug had been marketed for several months when cases of ischaemic colitis and serious complications of constipation had emerged.2 Horton does not mention these meetings and takes no note of the FDA’s actions when these risks were identified (eg, warnings in
THE LANCET • Vol 358 • August 4, 2001
professional labelling; issue of guidelines for patients on risks; engagement of professional organisations and patients’ advocacy groups.) Horton fails entirely to grapple with the issue of the benefit of Lotronex and the need for effective therapies for patients with IBS. This drug is the first to provide symptomatic relief for patients with IBS, specifically in female patients with diarrhoea as the predominant bowel symptom. IBS can be debilitating at enormous physical, emotional, and social costs to patients. Horton virtually ignores the need for access to proven, effective medications for patients, and cites only from the petition submitted to FDA by the Public Citizen’s Health Research Group. The public record also contains a petition submitted by an IBS patients’ advocacy group, the Lotronex Action Group, earlier this year, which pleads that the FDA continue to make Lotronex available for patients. Such patients have been urgently appealing to FDA and GlaxoSmithKline for access to the medication, motivated the FDA believes, by sincere desperation for access to an effective treatment, not, as Horton suggests, because of an orchestrated campaign organised and financed by the firm. The assertion that the FDA’s review of Lotronex involves a covert or two-track process is completely unsupported by the facts. Review of Lotronex has involved several organisational elements within the agency and has incorporated the scientific assessments and recommendations of physicians, toxicologists, statisticians, and epidemiologists. Results of disciplinary-group meetings at all levels of management have been openly shared with the entire Lotronex review team, as have those of meetings or conversations with company officials and the FDA, irrespective of the level. Disagreements within the FDA in such drug-review processes are common, particularly on complex issues, and can involve individuals or groups at various levels. Yet, all individuals whom Horton described as
officials are scientists, who are consistently engaged in the review and decision-making that are critical to all drug regulatory activities. The FDA values such disagreements because they force reassessment of evidence and conclusions, as well as constructive dialogue. Despite disagreement, however, the FDA must make only one regulatory decision. Finally, Horton seems genuinely confused about the drug-withdrawal process in the USA. Voluntary withdrawal is most common for withdrawals related to toxic effects. The alternatives are time-consuming administrative hearings or imminenthazard procedures. To suggest voluntary withdrawal as an option for Lotronex was, therefore, not a concession by the FDA. The alternatives were untenable. It is hard to understand why a process that led to withdrawal is offered as an example of an internal struggle within the FDA or an undermining of reviewers’ views. Horton oversimplifies the FDA’s interactions with product sponsors and other stakeholders in drug development. To find out whether an appropriate balance on the benefits and risks of Lotronex can be achieved is complex and requires data, discussion, and an understanding of the diversity of perspectives within the Agency. He naïvely implies that listening to the concerns of stakeholders is synonymous with agreeing with stakeholders. In fact, responsible drug regulation requires understanding of diverse perspectives, whether the agency ultimately agrees or not. *Steven Galson, Sandra Kweder, Florence Houn, Victor Raczkowski, Peter K Honig Center for Drug Evaluation and Research, FDA, Rockville, MD, USA 1
2
Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet 2001; 357: 1544–45. Dockets management. www.fda.gov/ohrms/dockets (accessed July 12, 2001).
Sir—Richard Horton1 states that the integrity of reviewing registration applications at the FDA may be
415
For personal use. Only reproduce with permission from The Lancet Publishing Group.
CORRESPONDENCE
compromised as a result of user fees from the pharmaceutical companies. We are reviewers at the Center for Drug Evaluation and Research and take issue with that assertion. The FDA has been assessing medical claims by use of the principles of evidence-based medicine for more than 60 years. Only about 10% of drugs in development reach the stage for filing a new drug application to register a marketing claim. Many potential applications are not filed because data are insufficient for registration and marketing approval, and would not pass FDA scrutiny. We are professionals who work on multidisciplinary teams comprised of chemists, clinical pharmacologists, microbiologists, physicians, statisticians, and toxicologists. Our review standards are based on accepted scientific principles and we believe our review process is thoughtful and thorough. It is open to scrutiny and input from advisory committees and consultants during the review process, and reviews are posted on the internet after approval. On average, 20% of new drug applications are not approved, and the proportion of non-approvals has been rising. Approval rate can, however, be a misleading statistic because of increasing consultation with the FDA by pharmaceutical companies before filing a new drug application and general improvements in the overall quality of clinical research, both of which could lead to higher approval rates. We are also aware that marketing approval of a product is an interim step in therapeutic development and we, as primary reviewers, continue to monitor products for safety after approval in addition to the formal FDA postmarketing approval surveillance and the spontaneous reporting of adverse events through the MedWatch system. Events that can lead to a label change or even withdrawal from the market might emerge only after marketing approval and subsequent increased use in different and larger populations than those studied for initial review. We have formal interactions with academic colleagues and institutions, patients’ advocacy organisations, professional societies, and consumer groups as well as the pharmaceutical industry, all of which expect impartiality and evidence-based determinations intended to protect US public health through the approval and monitoring of safe and effective drugs. We take pride and satisfaction in our work and publicly associate ourselves with the process of objective data evaluation and analysis. This letter was
416
not reviewed or authorised by the Center for Drug Evaluation and Research management. Richard C Adams, Javher Advani, Funmilayo Ajayi, Suliman Al-Fayoumi, Sayed Al-Habet, Eric Bastings, Kimberly Benson, Peter Bross, Margaret Brower, Yeh-Fong Chen, Judy Chiao, Gani Chico, Wen-Hwei Chou, Martin Cohen, Denise Cook, Patricia Cortazar, Ramzi Dagher, Daniel Davis, John Duan, Eric Duffy, Amy Ellis, Emmanuel Fadiran, John D Franolic, Valeria Freidlin, Gregory Frykman, Lesley Furlong, Steven Gitterman, Anwar Goheer, Mamata S Gokhale, Donna Griebel, Robert Harris, Hector Herrera, Xiao Hong, Ekopimo O Ibia, Amna Ibrahim, Sidney Jaffee, Rosemary Johann-Liang, Roswitha Kelly, Sharon Kelly, Hon-Sum Ko, Joyce Korvick, Doo Lee-Ham, Brad G Leissa, Linda Lewis, George Lunn, Patrick Marroum, Ram Mittal, Scott Monroe, Eileen E Navarro Almario, Nhi Nguyen, Parivash Nourjah, Armando Oliva, Thomas Papoian, Janice Pohlman, Joseph Porres, Hullahalli R Prasanna, Lilliam Rosario, Sandip Roy, Nashed Samaan, Haripada Sarker, Eugene L Schaefer, Nancy Scher, Bruce Schneider, Daniel Shames, Alla Shapiro, Arthur Shaw, Gerald Sokol, Janice M Soreth, Rajeshwari Sridhara, Khin Maung U, Kathleen Uhl, Lourdes Villalba, Robert M White, Grant Williams, Rebecca Wood, Teresa Wu, Peiling Yang.
*Steven Hirschfeld, Lydia Kieffer, W David McGuinn, Mark Rothmann, William C Timmer Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, 1451 Rockville Pike, HFD-I5O, Rockville, MD 20852, USA (e-mail: [email protected]) 1
Horton R. Lotronex and the FDA: a fatal erosion of integrity. Lancet 2001; 357: 1544–45.
Sir—Richard Horton1 describes two important issues: the shortcomings in the FDA drug-reviewing process, and the responsibility of the editorial process. As FDA reviewers we have the freedom to discuss all issues we wish in our documents, and reviews are not edited by upper management. However, we are not always sufficiently able to dissuade upper management, and they may over-rule our recommendations. When they do so, they need to justify their positions in writing; thus, there should be documentation identifying the process, the discrepancies, and who is responsible for actions contrary to those posed by the primary reviewer. For approved products, this documentation can be accessed through the mechanism offered by the Freedom of Information Act. In my 10 years at the FDA, I have seen overrulings of primary reviewers without any ill consequences, and others that resulted in serious complications and in fatalities.
As per The Lancet’s role, it published the results of the original study and the reviewers did not judge that the drug was unsafe. Indeed, they agreed with the investigators. The FDA’s medical-officer review apparently raised some concerns about the potential of serious adverse events associated with this compound. This apparent discrepancy is not new. Conclusions and contents of scientific reports, in which pharmaceutical sponsors play an important part, differ, many times substantially, from the same material that is reviewed by the FDA. The FDA has access to all data, and may ask them for additional information and clarification on unresolved issues from the sponsors, and spends years following a product’s development. These are some of the benefits that most journals’ reviewers do not have. In addition, FDA reviewers have the ability to audit sites for the assessment of the veracity and integrity of the data. Papers submitted for publication generally add analyses that point to benefits in subgroups that the FDA deems improper if they were not prespecified in the original protocols. Researchers might decide to delete data that do not favour the drugs’ desired effects, or to provide information on data that do. I have seen papers published, with company support in leading journals, on data I reviewed and presented in public meetings discussing the FDA position, with conclusions different from those agreed with the company as reflected in these drugs’ labels. How do we explain these discrepancies? Declaration of conflict of interest is not enough most of the time. The leading researchers might be unaware that the statistical analyses are not proper, that they could exclude data that do not support the companies’ position, including inappropriate subgroup analyses, or the presentation of graphs or figures that could be construed as misleading. They might be excellent clinicians but they might not know how to properly address these issues and have to rely on the support of individuals whose motives differ from their own. Editors should not allow language that qualifies the nature of the adverse reactions or speculative language that obscures the findings. Researchers should list findings and state that a cause-and-effect relation was not ruled-out. Time will tell. Moreover, once we learn that adverse events indeed occur, we could link new reports to original reports to modify the initial claims.
THE LANCET • Vol 358 • August 4, 2001
For personal use. Only reproduce with permission from The Lancet Publishing Group.