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3 Regulatory Framework for Drugs for Rare Diseases
Pages 73-110

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From page 73...
... One area of complexity involves judgments about what evidence is sufficient to support the agency's approval of medicines intended for people with rare diseases. More broadly, both FDA and Congress face complicated assessments and, often, a shortage of definitive information when they weigh the potential for a policy to promote the public health by encouraging innovation and access to new therapies against the potential for that policy to expose the public to unsafe or ineffective products.
From page 74...
... , tax credits for certain clinical development expenses, grant support, and other incentives for sponsors to develop drugs for people with rare diseases. Sponsors are usually for-profit pharmaceutical or biotechnology companies, but notfor-profit research organizations and even state agencies have occasionally sponsored applications for the designation and approval of an orphan drug.
From page 75...
... In 1962, Congress added a requirement that FDA assess the effectiveness of new drugs before approving them, gave FDA increased authority over clinical studies used to support applications for approval, and established policies to promote good manufacturing practices.1 In 1984, Congress defined a route for the approval of generic copies of previously approved brand-name drugs by eliminating the requirement that sponsors of generic drugs conduct their own clinical trials of safety and effectiveness. This action made the development of generic drugs much more attractive to industry.
From page 76...
... Sponsors are required to keep the FDA informed of changes in trial strategy. If the sponsor concludes that the results of its clinical trials will support FDA approval of a drug, then the sponsor files a New Drug Application (NDA)
From page 77...
... As discussed below, it has sometimes done so in approving orphan drugs. In addition to regulations, FDA has developed a number of documents that provide additional guidance to industry on the design and conduct of trials to support approval.
From page 78...
... Because many patients with rare diseases have debilitating and life-threatening conditions for which no approved drugs are available and because the
From page 79...
... Sponsors of orphan drugs are exempt from user fees, but they benefit generally from the additional resources the fees provide to FDA. The fees collected by the agency have allowed it to hire hundreds of additional 3 In addition, the regulations provide for the use of the expanded access mechanism to allow a physician to provide an approved drug that is subject to a Risk Evaluation and Mitigation Strategy (REMS)
From page 80...
... . For drugs that are intended for use with serious or life-threatening conditions for which unmet needs for treatment exist, FDA has instituted additional options -- fast track status, accelerated approval, and priority review -- to speed reviews and provide more extensive and timely guidance to sponsors about the nature of the
From page 81...
... This allows more frequent consultation with FDA on various issues related to the entire application for approval, including sections on preclinical studies; early phase I and phase II clinical trial results; and phase III studies. Most important, as the final clinical trials are completed and the results are reviewed, all of the other modules of the NDA are essentially completed.
From page 82...
... Normally, Special Protocol Assessments are available only after the end of phase II trials. However, for sponsors of drugs for rare conditions, they can be arranged after the end of phase I trials (Anne Pariser, Associate Director for Rare Diseases, FDA, May 14, 2010, personal communication)
From page 83...
... Later in this chapter, Box 33 includes examples of orphan drugs approved with postmarketing study provisions. Access to Information on Clinical Data to Support FDA Approvals In response to 1996 and subsequent legislation, CDER has begun to post information on the basis for its judgments about new drugs, including those approved as orphan drugs.
From page 84...
... In general, the provision of more information about the reasons that drugs that are not approved or are withdrawn before approval would be particularly valuable to guide possible further investigation of drugs proposed for the treatment of rare diseases. 5 The act required the Secretary of Health and Human Services (through the Director of the National Institutes of Health)
From page 85...
... Early analyses of the problem tended to refer to drugs of limited commercial value with later descriptions referring to orphan drugs for rare diseases (see, e.g., Interagency Task Force, 1979)
From page 86...
... Except for the orphan products grants program, the incentives do not extend to medical devices (see Chapter 7)
From page 87...
... Before sponsors can apply to have a drug approved under the Orphan Drug Act and before sponsors are eligible for incentives such as orphan products grants, they must apply for and receive an orphan designation for the drug from the FDA's Office of Orphan Products Development (OOPD)
From page 88...
... . Exclusivity and Patents The incentives provided by market exclusivity for orphan drugs need to be understood in the context of both patent law and other policies granting exclusivity for drug sponsors.
From page 89...
... Thus, for example, the 5-year prohibition on the submission of an abbreviated application becomes 5 years and 6 months. The market exclusivity incentive for orphan drugs is broader than the various types of exclusivity discussed above.
From page 90...
... Its specific tasks include designating orphan drugs (including reviewing claims about the prevalence of a rare 10 The regulatory language, which was added in the early 1990s, reads as follows: "Same drug means: (i) If it is a drug composed of small molecules, a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds)
From page 91...
... Recently, FDA announced the creation of a new position within CDER, the Associate Director for Rare Diseases, who will serve as the center's lead person on issues involving orphan drugs and rare diseases. Responsibilities will include
From page 92...
... . • Orphan drugs accounted for more than 30 percent of all drug approvals in 2008 (Coté, 2009)
From page 93...
... . Although the committee heard criticisms that the incentives and processes for promoting orphan drug development have been more effective in stimulating drug development for the more common rare conditions than for very rare conditions, data on orphan designations suggest that approvals are concentrated neither in the higher reaches of the rare diseases prevalence range (100,000 to <200,000)
From page 94...
... , but the sponsor may not pursue the additional work needed for approval of a product. An orphan products grant may offer the only funding available to academic researchers to develop proof-of-concept results indicating that their product works on a targeted disease.
From page 95...
... Evidence of Efficacy Accepted by FDA Following the standards described earlier, FDA approves orphan drugs on the basis of clinical studies that are considered adequately controlled and sufficient to establish efficacy when the nature of the population and condition for which the drug is intended are taken into account. The committee found no comprehensive information on the characteristics of studies used to support orphan drug approvals.
From page 96...
... Box 3-3 presents examples of the different kinds of efficacy studies that FDA has accepted in approving orphan drugs. The examples suggest considerable variability and flexibility in the evidence that FDA has BOX 3-3 Examples of Variations in Types of Efficacy Studies Accepted by FDA in Orphan Drug Approvals In 2010, FDA approved carglumic acid (Carbaglu)
From page 97...
... . Some data point to differences in the evidence supporting approvals of orphan compared to nonorphan drugs.
From page 98...
... Other problems, in particular, the lack of natural history studies, reflect the challenges and expense of rare diseases research and orphan product development as mentioned in Chapter 2.
From page 99...
... that is the subject of a particular approval application; • variability in reviewer understanding of trial designs and analytic methods that have been designed for studies involving small numbers of participants; • inconsistency in the application of review standards across the review divisions of CDER; and
From page 100...
... (This information was provided at the registration site for the program, http://small-trials.keenminds.org/.) In addition, as discussed above, FDA recently created the position of Associate Director for Rare Diseases to provide a central resource within CDER and to assist developers of orphan drugs and biologics in understanding and meeting regulatory requirements.
From page 101...
... The second involves resources for the Office of Orphan Products Development, which is the focal point for efforts to promote orphan product development and directly funds grants for that purpose. Agency-wide Concerns Although concerns about the adequacy of FDA funding and capacities are hardly new, they have been particularly intense in recent years.
From page 102...
... For example, the Critical Path Initiative, which was created in 2004 and emphasizes public-private collaborations, has focused on certain areas of particular relevance to products for rare diseases, including improving the development of biomarkers and modernizing the science of clinical trials (FDA, 2009d)
From page 103...
... For FY 2006, the report showed total funding of just under $508 million of which about $298 million (58 percent) came from congressional appropriations with the rest provided by user fees.
From page 104...
... These tasks include the development of more consistent approaches to risk-benefit assessment, the release of more information on safety and effectiveness, and the creation of a public-private partnership for planning confirmatory drug safety and efficacy studies. Office of Orphan Products Development Within FDA, the FY 2010 budget for the Office of Orphan Products Development is $22.1 million, including $15.2 million for the orphan products grants, $3 million for the pediatric device consortia grants, and $3.8 million for program administration including salaries and program operations.
From page 105...
... for rare conditions. Although the committee focused on FDA activities related to products for rare diseases rather than the agency overall, it concluded that an underfunded and understaffed agency provides an uncertain and in some respects weak and unstable environment for the maintenance of strong agency-wide efforts to (1)
From page 106...
... should undertake an assessment of staff reviews of ap plications for the approval of orphan drugs to identify problems and areas for further attention, including inconsistencies across CDER divi sions in the evaluations of applications that appear to present similar issues for review. Based on this assessment, CDER should • develop guidelines for CDER reviewers to promote appropriate consistency and reasoned flexibility in the review of orphan drugs, tak ing into account such considerations as the prevalence of the disease, its course and severity, and the characteristics of the drug; and • use the analysis and the review guidelines to inform the advice and formal guidance provided to sponsors on the evidence needed to support orphan drug approvals.
From page 107...
... RECOMMENDATION 3-2: The Center for Drug Evaluation and Re search should evaluate the extent to which studies submitted in support of orphan drugs are consistent with advances in the science of small clinical trials and associated analytic methods. Based on its findings, CDER should work with others at FDA, NIH, and outside organiza tions and experts, as appropriate, to • adjust and expand existing educational programs on the design and conduct of small clinical trials; • specify which CDER and NIH personnel should complete these educational programs; • revise guidance for sponsors on trial design and analysis and on safety and efficacy reviews of products for rare diseases; and • support further work to develop and test clinical research and data analysis strategies for small populations.
From page 108...
... More generally, timely meetings and other communications between FDA staff and sponsors should reduce the likelihood that the investment of sponsors and research participants with rare diseases will be used unproductively or even wasted. RECOMMENDATION 3-3: To ensure that NIH-funded product de velopment studies involving rare diseases are designed to fulfill require ments for FDA approval, NIH and FDA should develop a procedure for NIH grantees undertaking such studies to receive assistance from appropriate CDER drug review divisions that is similar to the assis tance provided to investigators who receive orphan products grants.
From page 109...
... Although the recommendations in the next two chapters focus on NIH and private-sector activities, Chapter 5 includes a recommendation for FDA's Critical Path Initiative to define criteria for the evaluation of surrogate endpoints for use in trials of products for rare conditions. Overall, the recommendations in the next two chapters should not only help accelerate rare diseases research and orphan product development but also increase the likelihood that marketing applications based on NIH-funded research meet the standards for FDA approval.


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