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New Drug: Caution Indicated: Comment on “New Drugs and Safety”

New Drug: Caution Indicated: Comment on “New Drugs and Safety” In assessing a new therapeutic drug, regulators at Health Canada and the US Food and Drug Administration (FDA) are entrusted with making critical and difficult scientific judgments that can affect the health of hundreds of thousands of patients in a matter of months after product launch. In drug evaluation, the cost of error may be high. Casualties in pharmaceutical disasters are measured in tens of thousands, and the population exposed to unsafe drugs often numbers in the millions.1 In a new research letter, Lexchin2 provides a valuable but basic report card for the drug approval decisions at Health Canada over a 16-year period. The first lesson from Lexchin's study is that serious safety issues were not detected or fully understood at approval for 1 out of 5 drugs, and 17 of the 434 drugs approved were later withdrawn for safety reasons. The results were worse for the subset of priority review drugs—those evaluated under deadline pressure because they were intended to treat a life-threatening disease or were thought to provide an important therapeutic advance. Of those drugs, 1 out of 3 was approved without a warning about a serious safety issue. A recent report from the Institute of Medicine for the United States suggests a future vision under which preapproval testing is only the first installment in a life cycle research program extending over many years.3 In a recent article in the Archives,4 my colleagues and I reported on a single year's major postmarket safety actions by the FDA and noted that 25 drugs received new boxed warnings and that the 181 safety actions that were approved in 2009 occurred a median of 11 years after initial approval. The scientific record required to support the approval of a new molecular entity, or in Canada a new active substance, typically amounts to hundreds of thousands of pages of densely written scientific reports. In vitro studies explore the mechanism of action. The chemical stability, human metabolization, and consistent manufacture of a new molecule require careful evaluation. Beneficial effects, high doses, and long-term exposure are examined in animal models that may or may not predict effects in humans. Hundreds to thousands of patients are exposed in preapproval clinical testing. Although many new drugs are intended for long-term use, the international standard requires that only a few hundred patients be exposed to these drugs for 12 months or more.5 Regulatory agency reviewers are faced with a formidable mass of scientific data that contain only modest amounts of information from direct patient testing. Therefore, important clinical questions may remain unanswered. There are increasing demands by legislatures, industry, medical professionals, and patients to make these difficult decisions even more quickly in both Canada and the United States. The current FDA “Expedited Drug Development Pathway” now includes provisions to reduce the number and size of clinical trials, to accept more limited evidence of efficacy, and to initiate drug review before the completion of testing. It also sets short review deadlines. In fiscal year 2011, a total of 16 of 35 new molecular entities (46%) received a priority review from the FDA, 13 (37%) received additional fast-track treatment, and 24 (69%) were approved in the United States earlier than in Europe or Canada.6 Getting faster access to newly developed, less thoroughly tested drugs is at best a mixed blessing. For the first 3 years after approval, new drugs should carry a special warning akin to the black triangle used in Britain. It should be prominent and mean to every physician, “New Drug: Caution Indicated.” Back to top Article Information Correspondence: Mr Moore, Institute for Safe Medication Practices, 101 N Columbus St, Ste 410, Alexandria, VA 22314 (tmoore@ismp.org). Published Online: October 8, 2012. doi:10.1001/2013.jamainternmed.610 Financial Disclosure: None reported. References 1. Wood AJ. The safety of new medicines: the importance of asking the right questions. JAMA. 1999;281(18):1753-175410328077PubMedGoogle ScholarCrossref 2. Lexchin J. New drugs and safety: what happened to new active substances approved in Canada between 1995 and 2010? [published online October 8, 2012]. Arch Intern Med. 2012;172(21):1680-1681Google ScholarCrossref 3. Psaty BM, Meslin EM, Breckenridge A. A lifecycle approach to the evaluation of FDA approval methods and regulatory actions: opportunities provided by a new IOM report. JAMA. 2012;307(23):2491-249222563032PubMedGoogle Scholar 4. Moore TJ, Singh S, Furberg CD. The FDA and new safety warnings. Arch Intern Med. 2012;172(1):78-8022232155PubMedGoogle ScholarCrossref 5. The extent of population exposure to assess clinical safety: for drugs intended for long-term treatment of non-life-threatening conditions, 1995. International Conference on Harmonisation website. http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/the-extent-of-population-exposure-to-assess-clinical-safety-for-drugs-intended-for-long-term-treatme.html. Accessed August 16, 2012 6. US Food and Drug Administration. FY2011 Innovative Drug Approvals. Silver Spring, MD: US Food and Drug Administration; November 2011 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

New Drug: Caution Indicated: Comment on “New Drugs and Safety”

Archives of Internal Medicine , Volume 172 (21) – Nov 26, 2012

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Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/2013.jamainternmed.610
Publisher site
See Article on Publisher Site

Abstract

In assessing a new therapeutic drug, regulators at Health Canada and the US Food and Drug Administration (FDA) are entrusted with making critical and difficult scientific judgments that can affect the health of hundreds of thousands of patients in a matter of months after product launch. In drug evaluation, the cost of error may be high. Casualties in pharmaceutical disasters are measured in tens of thousands, and the population exposed to unsafe drugs often numbers in the millions.1 In a new research letter, Lexchin2 provides a valuable but basic report card for the drug approval decisions at Health Canada over a 16-year period. The first lesson from Lexchin's study is that serious safety issues were not detected or fully understood at approval for 1 out of 5 drugs, and 17 of the 434 drugs approved were later withdrawn for safety reasons. The results were worse for the subset of priority review drugs—those evaluated under deadline pressure because they were intended to treat a life-threatening disease or were thought to provide an important therapeutic advance. Of those drugs, 1 out of 3 was approved without a warning about a serious safety issue. A recent report from the Institute of Medicine for the United States suggests a future vision under which preapproval testing is only the first installment in a life cycle research program extending over many years.3 In a recent article in the Archives,4 my colleagues and I reported on a single year's major postmarket safety actions by the FDA and noted that 25 drugs received new boxed warnings and that the 181 safety actions that were approved in 2009 occurred a median of 11 years after initial approval. The scientific record required to support the approval of a new molecular entity, or in Canada a new active substance, typically amounts to hundreds of thousands of pages of densely written scientific reports. In vitro studies explore the mechanism of action. The chemical stability, human metabolization, and consistent manufacture of a new molecule require careful evaluation. Beneficial effects, high doses, and long-term exposure are examined in animal models that may or may not predict effects in humans. Hundreds to thousands of patients are exposed in preapproval clinical testing. Although many new drugs are intended for long-term use, the international standard requires that only a few hundred patients be exposed to these drugs for 12 months or more.5 Regulatory agency reviewers are faced with a formidable mass of scientific data that contain only modest amounts of information from direct patient testing. Therefore, important clinical questions may remain unanswered. There are increasing demands by legislatures, industry, medical professionals, and patients to make these difficult decisions even more quickly in both Canada and the United States. The current FDA “Expedited Drug Development Pathway” now includes provisions to reduce the number and size of clinical trials, to accept more limited evidence of efficacy, and to initiate drug review before the completion of testing. It also sets short review deadlines. In fiscal year 2011, a total of 16 of 35 new molecular entities (46%) received a priority review from the FDA, 13 (37%) received additional fast-track treatment, and 24 (69%) were approved in the United States earlier than in Europe or Canada.6 Getting faster access to newly developed, less thoroughly tested drugs is at best a mixed blessing. For the first 3 years after approval, new drugs should carry a special warning akin to the black triangle used in Britain. It should be prominent and mean to every physician, “New Drug: Caution Indicated.” Back to top Article Information Correspondence: Mr Moore, Institute for Safe Medication Practices, 101 N Columbus St, Ste 410, Alexandria, VA 22314 (tmoore@ismp.org). Published Online: October 8, 2012. doi:10.1001/2013.jamainternmed.610 Financial Disclosure: None reported. References 1. Wood AJ. The safety of new medicines: the importance of asking the right questions. JAMA. 1999;281(18):1753-175410328077PubMedGoogle ScholarCrossref 2. Lexchin J. New drugs and safety: what happened to new active substances approved in Canada between 1995 and 2010? [published online October 8, 2012]. Arch Intern Med. 2012;172(21):1680-1681Google ScholarCrossref 3. Psaty BM, Meslin EM, Breckenridge A. A lifecycle approach to the evaluation of FDA approval methods and regulatory actions: opportunities provided by a new IOM report. JAMA. 2012;307(23):2491-249222563032PubMedGoogle Scholar 4. Moore TJ, Singh S, Furberg CD. The FDA and new safety warnings. Arch Intern Med. 2012;172(1):78-8022232155PubMedGoogle ScholarCrossref 5. The extent of population exposure to assess clinical safety: for drugs intended for long-term treatment of non-life-threatening conditions, 1995. International Conference on Harmonisation website. http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/the-extent-of-population-exposure-to-assess-clinical-safety-for-drugs-intended-for-long-term-treatme.html. Accessed August 16, 2012 6. US Food and Drug Administration. FY2011 Innovative Drug Approvals. Silver Spring, MD: US Food and Drug Administration; November 2011

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Nov 26, 2012

Keywords: drug evaluation,institute of medicine (u.s.),judgment,life cycle stages,animal model,vision,pharmacokinetics,pharmacy (field),drug development,disasters,drug approval

References