Rare Diseases and Orphan Products Accelerating Research and Development (2010) / Chapter Skim
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Appendix B: Innovation and the Orphan Drug Act, 1983-2009: Regulatory and Clinical Characteristics of Approved Orphan Drugs
Appendix B: Innovation and the Orphan Drug Act, 1983-2009: Regulatory and Clinical Characteristics of Approved Orphan Drugs
Pages 291-308
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From page 291... ...
The author would like to acknowledge the helpful comments from Kui Xu and Anne Pariser at the FDA Office for Orphan Products Development and from members of the IOM committee. This work was also conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers)
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The market exclusivity incentive protects orphan drug manufacturers from competition for 7 years, which allows greater discretion in pricing.4 Additional benefits available to sponsors of orphan-designated products include close coordination with the Food and Drug Administration (FDA) throughout the drug's development, priority FDA review, and a waiver of drug application fees.
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. The FDA ranked 38 percent of these NMEs as "important" therapeutic gains and 48 percent as "moderate" therapeutic gains.10 Asbury reported that annual sales of 25 of 40 orphan drugs were less than $1 million, while annual sales of 3 were for greater than $100 million.
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Another review of orphan drugs conducted by Wellman-Labadie and Zhou included drugs approved from 1983 through May 2009.13 Charting the number of orphan approvals as a function of time, the authors found that an average of about eight orphan-designated drugs per year were approved, although the annual approval rates included a number of peaks (in the mid-1990s and mid-2000s) and valleys (early 1990s and early 2000s)
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, as well as a detailed analysis of smaller subsets of more recently approved orphan drugs. METHODS The primary source for this analysis was a public domain master list of orphan product designations and approvals published by the FDA OOPD.15 From this source, a list of all drugs with orphan product designations between January 1, 1983, and December 31, 2009, was extracted.
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For some approved drugs, individual product searches on the FDA website can also provide links to digital copies of the full FDA review packets. The review packets typically include the regulatory reviews by different FDA officers (medical, statistical, pharmacologic, etc.)
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FDA medical officers designate the particular trials used to support a drug's efficacy for a particular condition as either pivotal efficacy trials or supportive efficacy trials. Apart from efficacy trials, drugs may also undergo a number of other human trials that impact knowledge about the safety of the drug; such trials could include early-stage Phase I trials on healthy volunteers, as well as open-label continuations of efficacy trials for drugs intended to treat chronic diseases.
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; • the number of patients enrolled in efficacy trials; • the existence of a data safety monitoring board or independent review committee organized by the manufacturer to assist in evaluation of the efficacy trials; • the total number of human trials conducted by the manufacturer; • the total number of human subjects in whom the drug was tested; • whether the FDA identified methodological concerns about the clinical development trials; • whether published data were used to support the application; • whether the FDA convened an Advisory Committee to evaluate the drug prior to approval and, if so, whether the vote was unanimous; and • whether the FDA imposed postmarketing commitments on the manufacturer, and the nature of those requirements (i.e., additional trials, a patient registry, a Risk Evaluation and Mitigation Strategy [REMS]
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This process identified a subset of 279 separate orphan products among the original sample that were approved for 347 designations or indications. Within this subset, 233 products had a single approved orphan designation, 36 products had two designations, 5 products had three designations, 3 drugs had four designations, and 2 products had seven designations each TABLE B-1 Orphan Approvals for Somatropin Products (human growth hormone, hGH)
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classified as NMEs.18 Information about review status was assessed for drugs approved after 1992, when the priority review classification was created; among orphan products, 144 (70 percent) were listed as Priority drugs, whereas 61 (30 percent)
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Focusing on just those drugs approved before the year 2000 provides a fair assessment of the rate of generic competition, because the 7-year market exclusivity period is now over for that entire group. This analysis excluded • a number of orphan drugs because they were approved as biologic drugs under a BLA, for which no generic approval pathway existed;22 • some of the more complex hormones approved under NDAs (e.g., somatropin)
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For example, ambrisentan (Letairis) , approved in 2007 for pulmonary artery hypertension, is in the same drug class as the orphan drug bosentan (Tracleer)
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had also already been approved as orphan drugs for the condition.28 Similarly, five orphan products have been approved to treat pulmonary artery hypertension.29 This measure does not address whether different drugs were more or less effective for the particular condition, but in nearly all cases, head-to-head studies comparing two drugs approved for the same indication have not been conducted. Orphan Drug Clinical Trials Development Process The FDA lists 47 unique drugs approved for orphan designations between 2007 and 2009.30 In the final step of the analysis, the clinical trial development of these drugs was investigated in depth.
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The thin line represents the number of orphan drugs approved each year that were variations or members of the same class of previously approved drugs. Figure B-1 for which the details were not located included 9 clotting factors or immune globulins, 7 already-marketed drugs,31 and 1 other product.32 Of the 30 drugs for which the full medical officer reviews were analyzed, the NDA and IND dates were obtained for 17 of the products.
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In total, 13 orphan drugs in this sample were approved based on a single efficacy trial, including 8 based on a single Phase III trial, 4 based on a single Phase II trial, and 1 based on a single Phase I trial. The sample as a whole was approved on the basis of a median of two efficacy trials (IQR: 1-2)
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The sample was roughly evenly divided among "new" drugs, drugs already available in the United States or abroad, and variations of previous drugs, although the numbers of old drugs and drug variations approved as orphan drugs increased over the time period. The final subset consisted of the 30 products approved from 2007 to 2009 where full FDA medical officer reviews were available; in this sample, the clinical trial development process was analyzed.
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In addition, 14 medical officer reviews could not be obtained through the publicly accessible FDA website, a sample that included many replacement clotting factors and orphan drugs approved via a supplemental NDA pathway. Inclusion of these cases may have affected the proportions of efficacy and/or safety trials reported in this study.
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Monitoring the postapproval use of orphan drugs to evaluate potential safety concerns is important, especially for drugs approved despite serious methodological concerns expressed by FDA medical officer reviews. In the past, there have been cases where methodological concerns raised at the FDA level have not been translated adequately onto the label or in communications about an approved drug.40 38 Harris G
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