3
Regulatory Framework for Drugs for Rare Diseases

Many people think of FDA as the judge—the agency that reviews the data and either gives a thumbs up or a thumbs down to each application. If it were only so easy. Before FDA can make any decision, we have to figure out what it means for a product to be safe and effective … we have to determine the right standards to apply.

Margaret Hamburg,

Commissioner of Food and Drugs, 2010


As highlighted by its commissioner, the work of the Food and Drug Administration (FDA) involves complex judgments about how the agency should fulfill its multiple, complex responsibilities. 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.

Certain regulatory requirements undoubtedly lead pharmaceutical companies to put aside some drug development efforts that they might otherwise initiate or continue. Generating the evidence to support approval of a drug is costly and time-consuming for companies, and the potential always exists that pivotal clinical studies will not support safety or efficacy. In addition, the way requirements are implemented may lead companies to put



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3 Regulatory Framework for Drugs for Rare Diseases Many people think of FDA as the judge—the agency that reviews the data and either gives a thumbs up or a thumbs down to each application. If it were only so easy. Before FDA can make any decision, we have to figure out what it means for a product to be safe and effective . . . we have to determine the right standards to apply. Margaret Hamburg, Commissioner of Food and Drugs, 2010 As highlighted by its commissioner, the work of the Food and Drug Administration (FDA) involves complex judgments about how the agency should fulfill its multiple, complex responsibilities. 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 short- age 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. Certain regulatory requirements undoubtedly lead pharmaceutical com- panies to put aside some drug development efforts that they might other- wise initiate or continue. Generating the evidence to support approval of a drug is costly and time-consuming for companies, and the potential always exists that pivotal clinical studies will not support safety or efficacy. In ad- dition, the way requirements are implemented may lead companies to put 

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 RARE DISEASES AND ORPHAN PRODUCTS aside some potentially beneficial, innovative products, for example, if they expect or encounter difficulties in obtaining answers to questions or advice on trial design or if the review of their applications for approval of a prod- uct is slow or inconsistent across FDA review divisions. When companies consider regulatory costs and uncertainties in addition to the expected size of the market, candidate drugs that could meet the needs of small popula- tions may be particularly vulnerable. Recognizing that regulations to protect the public’s health may also cre- ate barriers to market entry for new drugs and medical devices, Congress has created a variety of policies to encourage the development and speed the evaluation of innovative products to meet serious unmet health needs. A leading example is the Orphan Drug Act (P.L. 97-414), which provides protection from competition (i.e., exclusive marketing rights), tax credits for certain clinical development expenses, grant support, and other incen- tives for sponsors to develop drugs for people with rare diseases. Sponsors are usually for-profit pharmaceutical or biotechnology companies, but not- for-profit research organizations and even state agencies have occasionally sponsored applications for the designation and approval of an orphan drug. For example, the California Department of Health Services created the product, conducted the clinical trials, and received approval to market botulism immune globulin (BabyBIG) for treatment of infant botulism, a rare condition caused by Clostridium botulinum (Masiello and Epstein, 2003; Arnon, 2007). Development of the drug was supported by an FDA orphan products grant. Policies on orphan drug development operate within the broader frame- work of FDA regulations. This chapter, therefore, begins by reviewing the basics of drug and biological product regulation before discussing policies to encourage the development of drugs for small populations, specifically the Orphan Drug Act of 1983. The latter discussion also compares patent protections with protections provided by market exclusivity as defined be- low and presents summary data on orphan drug designations and approv- als. After a review of concerns about the adequacy of agency resources in relation to its responsibilities, the chapter concludes with recommendations that focus on the consistency and quality of FDA guidance and review of orphan drugs and the need to ensure that product development research funded by the National Institutes of Health (NIH) is designed and con- ducted to meet FDA requirements. Because the regulation of medical devices differs significantly from that for drugs, Chapter 7 examines the regulation of medical devices and poli- cies to encourage the development of devices for small populations. That discussion covers policies on diagnostic devices, including policies on the codevelopment of drugs and companion diagnostics and policies on com- bination products (e.g., those combining a drug and a device).

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 REGULATORY FRAMEWORK FOR DRUGS GENERAL FRAMEWORK FOR THE REGULATION OF DRUGS AND BIOLOGICS This report generally uses the term drug to encompass both pharma- ceuticals and therapeutic biological products. Many policies to promote the development of products for people with rare diseases apply to both types of products. This section discusses the basic regulation of drugs defined as chemical compounds, the regulation of biological products, and other general regulatory provisions (e.g., those intended to speed the approval of drugs for serious and life-threatening conditions) that may have particular relevance for orphan drugs. Basics of Drug Approval When Congress passed the Federal Food, Drug, and Cosmetic Act in 1938, it prohibited the misbranding of drugs (i.e., the making of false therapeutic claims) and required their labeling with directions for safe use (Swann, 2003). It also required sponsors of new drugs to notify FDA prior to their being placed on the market and to submit certain safety data to support their approval by the agency for marketing in interstate commerce. 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 ac- tion made the development of generic drugs much more attractive to indus- try. The Center for Drug Evaluation and Research (CDER) is responsible for administering these policies. For a sponsor that is ready to initiate clinical studies of a promising drug, whether for a common or a rare condition, the first formal step is to file an Investigational New Drug (IND) application. An IND application describes available information about the drug, for example, data from already conducted animal and other studies indicating that it is reasonable to initiate studies with human participants. The application also provides detailed information about the proposed initial clinical trial strategy. As described below, FDA has various mechanisms that allow consultation 1 This report defines efficacy as the achievement of desired results in controlled trials and effectiveness as the achievement of desired results in usual clinical settings. FDA statutes and regulations use the term effectiveness to describe positive results reported in clinical trials, although FDA review documents often employ the term efficacy rather than effectiveness to refer to clinical data used in approving a new drug.

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 RARE DISEASES AND ORPHAN PRODUCTS to assist sponsors in designing and conducting trials that will meet FDA standards. In many cases, a sponsor will seek assistance from FDA on the preparation of an IND application. 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), which FDA must review and approve before a drug can legally be marketed. For generic drugs, the requirement is for approval of an Ab- breviated New Drug Application (ANDA). Sponsors may file supplemental applications for approval of new indications for a drug, new formulations, and other purposes. To secure FDA approval to market a drug, sponsors must provide sub- stantial evidence of the drug’s safety and effectiveness for its intended use. As described in statute (21 USC 355(d)), substantial evidence means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific train- ing and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence. For many years, FDA interpreted the plural term “investigations” in the statute as requiring at least two phase III clinical studies to support new drug approval, with some rare case-by-case exceptions (e.g., drugs for a life- threatening or severely debilitating disease when one large, well-designed, multicenter study showed robust results) (53 Fed. Reg. 41516, 41521). In the FDA Modernization Act of 1997 (P.L. 105-115), Congress added a sentence clarifying that data from one adequate and well-controlled study, together with confirmatory evidence obtained before or after that study, can constitute “substantial evidence” of effectiveness for any new drug. FDA regulations specify further details about characteristics of ad- equate and well-controlled studies (21 CFR 314.126; see also CDER-CBER, 1998). Summarized, they state that studies and study reports should • provide a clear statement of purpose; • permit a valid comparison of the experimental group with a control group;

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 REGULATORY FRAMEWORK FOR DRUGS • employ suitable methods to assign study and control groups and otherwise to minimize bias; • use clear, reliable methods to define and assess responses of re- search participants; and • employ appropriate methods to analyze study results. Generally, FDA has recognized the following types of controls in clini- cal trials: placebo concurrent control; dose-comparison concurrent control; ose-comparison no-treatment concurrent control; active treatment concurrent control; and historical control. FDA may also accept results from uncontrolled trials as corroborating evidence. In principle, the agency may waive certain of the requirements. 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. For example, the agency recently issued one draft guidance document on the use of adaptive designs for clinical trials and another on noninferiority clinical trials.2 Some drugs currently on the market have never been approved by the FDA because they were on the market before enactment in 1938 of the Federal Food, Drug, and Cosmetic Act. In recent years, FDA has moved to require companies that sell such drugs to seek approval (Derbis et al., 2008). Colchicine (which is discussed in Box 3-3 and in Chapter 6) is an example of a previously unapproved drug that was approved for a common use and for an orphan indication in 2009. 2 The draft guidance defines an adaptive design clinical study “as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints” (CDER-CBER, 2010a, lines 66-69). The guidance notes that changes based on such analysis “may make the studies more efficient (e.g., shorter duration, fewer patients), more likely to demonstrate an effect of the drug if one exists, or more informative (e.g., by providing broader dose-response information)” (lines 38-40). A working group of the Pharmaceutical Research and Manufacturers of America has also developed materials on adaptive design, including training courses and white papers (see http://www.biopharmnet. com/doc/doc12004-01.html). The other CDER-CBER guidance document explains that noninferiority trials involve comparison of an investigational drug with an active treatment (an active control). They seek to demonstrate “that any difference between the two treatments is small enough to allow a conclusion that the new drug has at least some effect or, in many cases, an effect that is not too much smaller than the active control” (CDER-CBER, 2010b, p. 2). Such trials are more difficult to interpret because they depend on a result that is not directly measured (i.e., whether the active treatment had the effect expected). They may be used because investigators consider a placebo- or no-treatment controlled trial to be unethical or because they want to compare the efficacy of active treatments.

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 RARE DISEASES AND ORPHAN PRODUCTS Regulation of Biologics Biological products are made from living organisms and may be com- posed of cells or tissues or of sugars, proteins, or nucleic acids or complex combinations of these substances. Examples of such products include vac- cines, blood-based clotting factors, antitoxins, therapeutic proteins, and monoclonal antibodies. The regulatory status of this diverse set of products is not easily summarized, and the following discussion simplifies or ignores some details. For purposes of this report, the main points about the regulation of bio- logics are that most biologics are also drugs and as such are generally held to the same standards of safety and efficacy as apply to nonbiologic drugs. In addition, the incentives of the Orphan Drug Act (360bb(a)(1)) are avail- able to sponsors of biologics. Most biologics are approved on the basis of a Biologics License Application (BLA) as provided for in the Public Health Service (PHS) Act, although “by historical quirk” certain biologics have been approved as drugs under the Food, Drug, and Cosmetic Act (Schact and Thomas, 2009). (The location of regulatory authority in the PHS act reflects the early regulatory history of biologics, particularly that related to rules to ensure the safety of vaccines.) Title VII of the Patient Protection and Affordable Care Act of 2010 (P.L. 111-148) revised the definition of biological product under the PHS act to include all proteins (except for chemically synthesized polypeptides). As described later in this chapter, the law also created a pathway to FDA approval for “biosimilar” biologics that is analogous to that created for generic drugs. In 2003, FDA transferred responsibility for review and approval of most therapeutic biologics from the Center for Biologics Evaluation and Research (CBER) to CDER. The types of products transferred to CDER include most proteins intended for therapeutic use (e.g., interferons, en- zymes); agents that modify immune system response (other than vaccines and allergenic products); monoclonal antibodies; and certain other products intended to alter production of blood cells (FDA, 2009b). CBER continues to oversee vaccines, antitoxins, antivenins, venoms, allergenic products (e.g., allergy tests and shots), blood, and blood products. Thus, depending on the category, some orphan biologics are regulated by CDER and others by CBER. Treatment Use of Investigational and Certain Other Drugs Since the 1980s, Congress and FDA have created procedures to allow treatment use (i.e., other than research use) of investigational drugs. Be- cause many patients with rare diseases have debilitating and life-threatening conditions for which no approved drugs are available and because the

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 REGULATORY FRAMEWORK FOR DRUGS clinical trial process and drug approval process are lengthy, these patients and their families may be particularly anxious for access to a drug that has enough promise to be under investigation in a clinical trial. A major concern is that “treatment use” policies and their application should not jeopardize patient safety or impede the conduct of research to assess a drug’s safety and efficacy. In 2009, FDA issued revised regulations on treatment use of inves- tigational drugs. In general, the agency allows expanded access in three categories of patient populations: individual patients, intermediate-sized groups, and large groups.3 Box 3-1 summarizes the general determinations necessary to approve such use and also includes those that apply specifically to individual patient use. The conditions that must be satisfied in order to justify expanded use become more extensive as the size of the population to be treated increases. Although the rules provide that treatment use of an investigational drug should not compromise clinical study of the drug, this criterion may be hard to meet for a drug aimed at a very small population with few potential research participants. Speeding and Facilitating Review and Approval of New Drugs In the decades after Congress required FDA review of efficacy as well as safety and as the volume and complexity of applications for the approval of new drugs grew, pharmaceutical companies, patient and consumer ad- vocacy groups, and others complained that the length of time for reviews and decisions was excessive and costly. To provide additional resources for FDA and to speed reviews, the Prescription Drug User Fee Act of 1992 (P.L. 102-571) and subsequent renewals and revisions have authorized FDA to collect user fees from companies seeking approval of new drugs. FDA in consultation with industry, consumer groups, and others established spe- cific performance goals related to review times, sponsor requests for meet- ings, responses to sponsor appeals of decisions, and other processes. FDA strongly encourages sponsors of drugs for rare diseases to seek pre-IND meetings to discuss development strategy. 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) to a patient who is not otherwise eligible. The expanded access provision might be invoked, for example, when a REMS restricts an approved drug to patients who have certain lab test results and a particular patient does not meet that criterion. In commentary on the rules, FDA stated that it would monitor the impact of the rule on expanded access to drugs that are covered by a REMS.

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0 RARE DISEASES AND ORPHAN PRODUCTS BOX 3-1 Options for Patients to Obtain Access to Investigational Drugs When the Primary Purpose Is to Diagnose, Monitor, or Treat a Patient’s Disease or Condition To permit treatment of a patient with an investigational drug under an ex- panded access program, FDA “must determine that: (1) The patient or patients to be treated have a serious or immediately life- threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; (2) The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and (3) Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could sup- port marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.” Individual patient use, including in emergencies FDA may permit an investigational drug to be used for the treatment of an in- dividual patient by a licensed physician. . . . (1) The physician must determine that the probable risk to the person from the investigational drug is not greater than the probable risk from the disease or condition; and (2) FDA must determine that the patient cannot obtain the drug under another IND or protocol. . . . Safeguards (1) Treatment is generally limited to a single course of therapy for a specified duration unless FDA expressly authorizes multiple courses or chronic therapy. (2) At the conclusion of treatment, the licensed physician or sponsor must provide FDA with a written summary of the results of the expanded access use, including adverse effects. (3) FDA may require sponsors to monitor an individual patient expanded access use if the use is for an extended duration. (4) When a significant number of similar individual patient expanded access requests have been submitted, FDA may ask the sponsor to submit an IND or protocol. . . . SOURCE: 74 Fed. Reg. 40900. (Note: this excerpt excludes sections on options involving use by intermediate-sized and large groups.) intermediate-sized and large groups.) employees, but the adequacy of FDA resources to fulfill its responsibilities continues to be a major concern as discussed below (see, e.g., FDA Science Board, 2007; IOM, 2007; GAO, 2009a). 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

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 REGULATORY FRAMEWORK FOR DRUGS evidence that is needed to support approval (FDA, 2009a; Schact and Thomas, 2009). Sponsors of orphan drugs frequently qualify for these mechanisms, and one analysis indicated that applications for orphan drugs were more likely than other applications to have done so (Seoane-Vazquez et al., 2008). For applications that qualify for fast track status, companies submit modules of an NDA on an ongoing basis for a “rolling review” by FDA as the modules are submitted. This allows more frequent consultation with FDA on various issues related to the entire application for approval, includ- ing 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. In some cases, another option is accelerated approval, which allows the use of surrogate endpoints that are not considered well established but that are determined to be “reasonably likely to predict clinical benefit.” FDA rules define surrogate endpoint as “a laboratory or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and that is expected to predict the effect of the therapy” (57 Fed. Reg. 13234 at 13235; see also Fleming, 2005). FDA then requires postapproval studies to develop further evidence about benefits and risks based on clinical outcomes. According to a recent study by the Government Accountability Office (GAO), FDA used the accelerated approval process to approve 90 drugs based on surrogate endpoints between 1992 and November 20, 2008 (GAO, 2009a). Of these 90 drugs, 79 were for cancer, HIV/AIDS, or inha- lation anthrax. The successful and timely completion of the required postapproval studies has proved challenging. Products can remain on the market for an extended period without conclusive evidence of safety and clinical benefit (Fleming, 2005). The GAO report expressed concern that several required postmarket- ing studies remained open and that FDA did not have a satisfactory system for monitoring study progress. At the time of the GAO study, no drugs that had gone through accelerated approval had been withdrawn from the market based on the results of follow-up studies. Since then, one company has announced the withdrawal of such a drug (gemtuzumab ozogamicin for injection [Mylotarg]) after a postapproval study failed to demonstrate benefit (Pfizer, 2010). FDA announced that it would seek the withdrawal of one drug based on failure to complete required studies (Karst, 2010), and it could seek withdrawal for another drug after postmarket study findings did not confirm the preapproval studies (Stein, 2010). For priority reviews, FDA sets a goal of completing application reviews

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 RARE DISEASES AND ORPHAN PRODUCTS within 6 months compared to a standard review goal of 10 months. For orphan drug applications involving new molecular entities, a recent analysis reported that the proportion with priority review status increased from 35 percent for the period 2000 to 2002 to 50 percent in the period 2006-2008; for orphan products identified as “significant biologics,” the correspond- ing increase was from 17 to 67 percent (Tufts Center, 2010). In addition to granting priority review status directly, FDA may also award priority review vouchers when approving a drug for a neglected tropical disease; such vouchers can be used to obtain priority review for a subsequent drug application and can also be sold or otherwise transferred to another spon- sor (21 USC 360n). Another mechanism to facilitate review and, equally important, reduce regulatory uncertainty is the Special Protocol Assessment. It allows FDA to provide expedited assessment of the adequacy of certain clinical trial protocols and to reach agreements with sponsors on the design and size of trials to support efficacy claims in marketing applications (CDER-CBER, 2002b). Once an agreement is reached, it generally cannot be changed by FDA or the sponsor. 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). Requirements That May Apply After Marketing Approval When FDA grants approval to a sponsor to market a drug, it may specify certain postmarketing requirements. As noted above, postmarketing studies to develop additional evidence about benefits and risks are required for products approved under accelerated approval procedures. In addition, under the Pediatric Research Equity Act of 2003, FDA may require that companies conduct pediatric studies of drugs, but orphan drugs are ex- plicitly exempt from these requirements. As discussed later in this chapter, sponsors may also voluntarily commit to undertake specified postmarketing studies, including pediatric studies requested by FDA under the Best Phar- maceuticals for Children Act. As provided under the Food and Drug Administration Amendments Act of 2007, FDA may also require a postmarketing Risk Evaluation and Mitigation Strategy (REMS) if it determines that such a mechanism is necessary to ensure that the benefits of a drug outweigh its risks. A REMS might include (1) a medication guide to be distributed to patients with each prescription; (2) a communication plan for educating health care providers; or (3) one or more elements to ensure safe use (CDER-CBER, 2009). The latter might include special physician training or certification, certification

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 REGULATORY FRAMEWORK FOR DRUGS of dispensing pharmacies, provision of additional information for physi- cians, limitation of availability to patients in specified settings, patient monitoring and agreement to certain terms of use, and inclusion of patients in a registry. Such registries are not considered research, but postmarketing studies may be conducted using the information collected (e.g., clinical and laboratory data or outcomes data). The committee has no comprehensive information on the extent to which orphan drugs are approved with postmarketing study requirements or commitments or with REMS requirements. Later in this chapter, Box 3- 3 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. These descriptions include assessments by agency reviewers of the quality and results of the clinical trials submitted to support approval. Information from these reviews is presented in the next section of this chapter to illustrate the range of evidence that FDA may accept in particular cases. FDA now also makes available online the staff reviews and company presentations provided to its expert advisory committees when those groups have been asked for advice on a product application. Transcripts of the meetings may provide further information, for example, in responses to questions about the materials submitted. Staff analyses (and associated discussion) may also be available for drugs that are considered during an advisory committee meeting. Reviews for generic drugs are generally not publicly available.4 Notwithstanding FDA actions to provide more details about the basis for its approval of a new drug, many details about drug trials are treated as confidential and not made public by FDA. As discussed in Chapter 5, 4 For example, in 2009, FDA approved generic chenodeoxycholic acid as an orphan drug for the treatment of gallstones. The drug was approved for this indication in 1983 as one of the first orphan drugs but was subsequently withdrawn from the market. A summary of the 2009 FDA review, including any data on the safety and effectiveness generated since 1983, is not public, although it might be obtained eventually through an inquiry under the Freedom of Information Act. In 2004 and 2007, different companies received orphan drug designations for the drug’s use to treat cerebrotendinous xanthomatosis (CTX). (Orphan drugs designa- tions and approvals are found at http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index. cfm.) Advocates for patients with CTX noted the effort invested in obtaining the 2009 FDA approval (but did not note that the approval was for gallstones) and emphasized that the com- pany distributing the drug “has committed to ensuring that all CTX patients will have access” to the drug through a specialty pharmacy (CTXinfo.org, 2010). That company received a new orphan designation in 2010 for the CTX indication.

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00 RARE DISEASES AND ORPHAN PRODUCTS • insufficient or delayed guidance for sponsors on various issues, including the use of “small n” study designs and methods and the specifi- cation of acceptable subsets of rare conditions to meet prevalence require- ments for orphan drug designation (the second of which is an issue for the OOPD rather than CDER). More fundamental is the argument that different standards of evidence should be applied to approval for orphan drugs given the difficulties of do- ing conventional trials for many extremely rare conditions, including those conditions that progress over very long periods. The rationale is that even if a drug works, research may not be able to demonstrate safety and efficacy (especially if the effect is subtle) when only a few dozen patients are known to have the condition. As described above, FDA has, in fact, approved drugs for a number of extremely rare diseases on the basis of evidence that it judged met the standards for approval. Responses to Problems In response to some of the criticisms of the substance and the imple- mentation of the Orphan Drug Act, Congress in 2009 required FDA to appoint a review group to make recommendations about “appropriate preclinical, trial design, and regulatory paradigms and optimal solutions for the prevention, diagnosis, and treatment of rare diseases” (P.L. 111- 80). A second group is to focus on neglected diseases of the developing world. Within a year of establishing the review groups, FDA must report to Congress on its findings and recommendations, and approximately 6 months later it must issue guidance and internal review standards based on the recommendations. (These provisions have been informally termed the Brownback-Brown amendments to the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 [P.L. 111-80].) After considering the criticisms related to the adequacy of researcher and reviewer understanding of acceptable trial designs and analytic meth- ods for small populations, FDA and NIH collaborated on a multisession course on the science of small clinical trials. The course was first offered in 2009 to FDA and NIH staff and then revised and offered in 2010 to all interested parties. In 2010, registration closed after 1,300 participants enrolled. (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 under- standing and meeting regulatory requirements. The Associate Director will

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0 REGULATORY FRAMEWORK FOR DRUGS also coordinate work to develop CDER policies and procedures specific to the review and approval of orphan products and to promote training of CDER staff in relevant methodologies.14 FDA RESOURCES AND ORGANIZATION From a resource perspective, the strength of FDA support for the de- velopment of safe and effective products for people with rare diseases rests on at least two major elements. One involves resources for FDA generally but particularly the Center for Drug Evaluation and Research, which re- views most orphan drug applications. 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. A 2007 Institute of Medicine report on drug safety found that the FDA system was impaired by “serious resource constraints that weaken the quality and quantity of the science that is brought to bear on drug safety; an organiza- tional culture in CDER that is not optimally functional; and unclear and insufficient regulatory authorities particularly with respect to enforcement” (IOM, 2007, p. 4). The report noted the dependence of the agency on user fees and expressed concern that reporting requirements “associated with the user-fee program are excessively oriented toward supporting speed of approval and insufficiently attentive to safety” (p. 6). The report included many recommendations for strengthening the drug safety system, includ- ing the creation of a public-private partnership to “prioritize, plan, and organize funding for confirmatory drug safety and efficacy studies of public health importance” (p. 8) and increased funding to support drug safety and efficacy activities. Also in 2007, the FDA Science Board released a subcommittee report asserting that the “nation is at risk if FDA science is at risk” and that FDA science is indeed at risk (p. 2). The “demands on the FDA have soared due to the extraordinary advance of scientific discoveries, the complexity of 14 CDER has developed a number of policy and procedure manuals that are intended to promote consistency in staff advice and reviews on a range of topics, for example, statistical analysis and templates for reviews of NDAs. The Medical Policy Coordinating Committee “serves as a forum for CDER scientists and policy development staff to identify and discuss medical and medical-related regulatory issues that may call for the development and imple- mentation of medical and regulatory policies and guidances” (CDER, 2009).

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0 RARE DISEASES AND ORPHAN PRODUCTS the new products and claims submitted to FDA for pre-market review and approval, the emergence of challenging safety problems, and the globaliza- tion of the industries that FDA regulates,” whereas “resources have not increased in proportion to the demands . . . [so] that the scientific demands on the Agency far exceed its capacity to respond” (p. 3). In brief, the num- bers of personnel are insufficient, the agency is reactive rather than leading in the development of regulatory science, and its surveillance mission suffers from lack of staff and inadequate information technology. A group that lobbies for increased resources for FDA has compared FDA funding trends to those for the CDC and reported that the CDC and FDA had roughly equivalent funding in FY 1985 but that the budget for the former has grown at a compounded average rate of 11.4 percent compared to 7.1 percent for FDA. The CDC’s FY 2010 budget was $6.37 billion com- pared to $2.35 billion for FDA (Alliance for a Stronger FDA, 2009). The FDA Science Board report identified eight areas of scientific and technological advances that are particular challenging for the agency: “sys- tems biology (including genomics and other “omics”), wireless healthcare devices, nanotechnology, medical imaging, robotics, cell- and tissue-based products, regenerative medicine, and combination products” (p. 4). Al- though the report did not specify a particular level of increased funding, it suggested that another group’s recommended increase of 15 percent per year for 5 years “would still be insufficient . . . to initiate and support all the changes necessary” for the agency to fulfill its mission (p. 8). FDA has recognized the need to take advantage of scientific develop- ments to improve the way medical products are developed and evaluated. 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). In addition, the Advancing Regulatory Science Initiative is intended to strengthen the science base for product evaluation by providing better evaluation tools, standards, and pathways. It includes as one focus the setting of standards for products with people with unmet health needs (Hamburg, 2010b). Of note is that a research grants program to support the initiative is being funded primarily under the auspices of NIH with the NIH Common Fund providing $6 million and the FDA providing $750,000 for FY 2010 to FY 2012. Box 3-5 summarizes the research objectives. The announcement of the initiative included several examples of projects that might be funded and would reinforce elements of the Critical Path Initia- tive, for example, the development of new or improved biomarkers and the development of clinical trial strategies for more rapidly and efficiently evaluating the safety and efficacy of FDA-regulated products.

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0 REGULATORY FRAMEWORK FOR DRUGS BOX 3-5 NIH Request for Applications on Advancing Regulatory Science Through Novel Research and Science- Based Technologies (February 24, 2010) Purpose. This regulatory science initiative encourages grant applications that propose to study the applicability of novel technologies and approaches to the development and regulatory review of medical products (including drugs, biolog- ics, and devices). Research Scope. Applications should fall within five broad categories: (1) New tools and methodologies for assessing medical product safety and efficacy (including drugs, biologics, and devices and point of care diagnostics); (2) Novel information technologies and statistical models that can improve product evaluation and inform regulatory decisions; (3) Strategic design of research in “omics” and systems biology to better inform regulatory decision-making and support product development; (4) Research on rare diseases/small sample size populations; and (5) Novel approaches addressing optimal study designs for clinical trials. This initiative will contribute to the overall goals of improving regulatory sci- ence by supporting research in at least one area of medical product development ranging from in vitro and in vivo product characterization and evaluation through clinical studies and to a manufactured, approved product. SOURCE: NIH, 2010b. Center for Drug Evaluation and Research According to the 2007 Science Board report, in 2006 CDER regulated drugs accounting for $275 billion in pharmaceutical sales, and it also regu- lated some 5,000 domestic and foreign manufacturers of these pharmaceu- ticals. 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. For FY 2009, total fund- ing for the CDER was just over $656 million, of which about $300 million (45 percent) came from appropriations. In addition to resources, CDER and other FDA centers faced significant personnel challenges in recruitment, retention, performance, and professional development. The Science Board report noted the absence of good measures of performance in areas such as review of new product applications for safety and efficacy and the fact that neither CDER nor other parts of the agency could obtain all the expertise they needed without the involvement of external scientists.

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0 RARE DISEASES AND ORPHAN PRODUCTS The initiation of user fees allowed a considerable increase in staff con- ducting reviews of new drugs, from 600 in 1996 to 1,320 in 2004—a 125 percent increase that was associated with a substantial decrease in review times (IOM, 2007). FDA performance reports suggest that the agency has done better at meeting its goals for review times than its procedural goals such as timely response to requests for meetings. For example, the FY 2008 goal for scheduling what it terms type B meetings (which include pre-IND meetings, end of phase I meetings, end of phase II meetings, and pre-NDA- BLA meetings) was to have 90 percent scheduled within 60 days, but the actual performance was 58 percent as of September 2008 (FDA, undated). The goal for Special Protocol Assessments was to respond to a sponsor’s request for evaluation of a protocol design with 45 days; performance was near the goal at 86 percent. The importance of resources for meetings with sponsors is suggested by a 2006 consultant report that examined the review of NDAs. Sponsors that had met with agency staff were more likely to gain approval of their NDA at the first review than were sponsors that did not meet with FDA (Booz Allen Hamilton, 2008). A 2007 IOM report on drug safety argued that more staff resources were needed to take on a variety of tasks, many of them relevant to drugs for rare diseases. 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. The figure for the orphan products grants program includes an additional $1.2 million that was internally provided to the grants program in FY 2010 to support certain continuing and noncompeting awards (FDA, 2010c; Katherine Needleman, M.S., Director, Orphan Grants Program, FDA, September 3, 2010, personal communication). Although funding for the grants program rose in absolute and inflation- adjusted amounts for most of the program’s first dozen years, absolute funding has declined in some years since then. Funding in constant dol- lars has, in any case, been dropping since FY 1995. The Food and Drug Administration Amendments Act of 2007 increased the authorization for the grants program to $30 million through FY 2012, but appropriations remain at only about half that amount. Because funding has not kept pace

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0 REGULATORY FRAMEWORK FOR DRUGS with inflation, the grants program cannot operate at the same level as it did in the 1990s much less at an enhanced level to accelerate the orphan product development. RECOMMENDATIONS Most assessments credit the Orphan Drug Act with encouraging more investment by drug companies in the development of products for people with rare conditions. In general, the Office of Orphan Products Develop- ment is viewed positively as a helpful resource and successful advocate, es- pecially given its modest resources. The primary criticism is that its budget for orphan products grants is seriously inadequate. More generally, Con- gress is widely viewed as having provided inadequate resources for FDA to conduct or support a wide range of research and consultation to support its mission (see, e.g., FDA Science Board, 2007; IOM, 2007). This research includes, for example, work on biomarker identification and validation and research on the codevelopment of drugs and companion diagnostics that would benefit the development of products (including, in some cases, medical devices) 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 under- funded and understaffed agency provides an uncertain and in some respects weak and unstable environment for the maintenance of strong agency-wide efforts to (1) promote the development of orphan drugs; (2) offer high- quality, scientific and regulatory guidance to those engaged in orphan drug development; (3) provide sophisticated reviews of applications for drugs and biologics that appropriately apply statutory criteria to challenging data; and (4) establish and monitor reasonable requirements for continued col- lection of safety and efficacy data once an orphan drug is approved. Thus, the committee supports generally the recommendations of other IOM com- mittees and other groups for building a stronger FDA. With respect to orphan drug development specifically, the creation by FDA of the new position of Associate Director for Rare Diseases within CDER is a positive and important step. The Associate Director should be able to provide an important resource to CDER review staff. The creation of the position in itself should serve as a signal that the review of drugs and biologics intended for small populations needs special consideration and expertise related to appropriate research and analytic methods. Fulfilling the responsibilities assigned to the new position of Associate Director for Rare Diseases will take resources, including additional staff and support from senior FDA officials. As this report was being completed, legislation had been introduced to provide $1 million in funding that would support the hiring of staff (NORD, 2010).

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0 RARE DISEASES AND ORPHAN PRODUCTS In general, the new emphasis on rare diseases expertise in CDER should find further support in the agency’s increasing recognition of the need for advances in regulatory science, as shown by the new joint NIH-FDA Lead- ership Council and the grants program described above. One area for fur- ther attention is continued work on innovation in clinical trial and analytic strategies for small populations. A broad goal for the new rare disease initiative at CDER should be to promote reasonable consistency and at the same time reasoned flexibility in the review of similarly situated products (e.g., products for diseases with reasonably similar prevalence, targets, time frames of effect, and other characteristics). Evaluations of specific evidence, even when informed by solid understandings of trial design and clinical and scientific issues, may still have a subjective element; experts do disagree. The realm of subjectivity can, however, be constrained by an appreciation of the factors that contrib- ute to variability and the development of criteria to guide reviews. RECOMMENDATION 3-1: The Center for Drug Evaluation and Re- search (CDER) 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. CDER should make public the primary results of its assessment and consult with outside experts in developing the guidelines called for in this recommendation. The guidelines would be applied across CDER review divisions and would be adjusted to reflect advances in the biomedical and regulatory sciences. They might include supplemental materials, for ex- ample, a series of illustrations of successful applications, possibly involving templates for certain elements. The assessment might suggest the need for additional disorder-specific expertise to be recruited for sponsor consultations and some product re- views. Depending on the results of its analysis of reviewer decisions and on consultations with experts in rare disorders and others, FDA could propose

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0 REGULATORY FRAMEWORK FOR DRUGS to define one or more classes of rare conditions for which it would create tailored criteria for the approval of products and for the specification of requirements of longer-term assessments of safety and efficacy following approval. It could, for example, propose a special review class for rare disorders that are characterized by rapid progression and early death or severe and irrevocable loss of critical function. The criteria for this class would then cover major issues for trial design and application review (e.g., toxicology studies, carcinogenicity studies, surrogate endpoints, number and type of efficacy studies). The process for devising new guidelines and guidance would be de- veloped to be consistent with statutory requirements and FDA’s broad re- sponsibilities for protecting the public from unsafe and ineffective products. The recommendation above focuses on CDER because it is the locus of the majority of orphan drug reviews, but the agency should consider a similar analysis of CBER reviews and, in the meantime, apply the guidelines to CBER reviews when relevant. In conducting the analyses proposed above, FDA can be expected to develop a clearer understanding of the current adequacy of the evidence submitted with applications for orphan drug approvals, including the ap- propriateness of clinical trial designs. This understanding may, in turn, suggest how pre-IND and other meetings might help sponsors of drugs for rare diseases develop adequate preclinical and clinical evidence. It may also suggest the need for modifications in written guidance for sponsors. In addition to evaluating reviews of orphan drugs, CDER should spe- cifically examine the use of small clinical trials. This analysis should build on the educational work already undertaken by FDA and NIH. 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.

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0 RARE DISEASES AND ORPHAN PRODUCTS The identification of possible problem areas in clinical trial designs and drug approval reviews may also help guide efforts for CDER, the OOPD, and NIH to work collaboratively on mechanisms to ensure that NIH-funded product development studies are planned and conducted to be consistent with the requirements for FDA approval. These mechanisms would need to cover NIH grant reviews and other activities related not only to awards for phase III studies but also to awards for certain kinds of preclinical and early-phase clinical studies. One step could be for NIH to require investigators for preclinical studies of therapies for rare diseases to demonstrate their understanding of FDA procedures and requirements. In addition, NIH and FDA might also develop an education module specifi- cally for NIH grant applicants. More generally, timely meetings and other communications between FDA staff and sponsors should reduce the likeli- hood 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. NIH study section review of rare disease clinical trial applications should involve reviewers who are knowledgeable about clinical trials methods for small-populations. For all sponsors of drugs for rare dis- eases, CDER should have resources to support sufficient and adequate meetings and discussions with sponsors from the earliest stages of the development process. With respect to the Office of Orphan Products Development, the com- mittee was concerned about the low level of funding for the orphan grants program, which as described above, has for several years had a declining budget as calculated in constant dollars. Clearly, however, the funding history for the program does not reflect the scientific and technological advances described in Chapter 4. Notwithstanding increased interest by companies in orphan products and some initiatives by NIH that should assist orphan product devel- opment, the committee concluded that funding for the orphan products grants program is seriously inadequate and has undermined an important resource for nonprofit and commercial entities seeking to translate prom- ising discoveries into approved products for people with rare diseases. It

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0 REGULATORY FRAMEWORK FOR DRUGS would be reasonable to argue, at the minimum, for an increase to the $30 million authorized in the Food and Drug Administration Amendments Act of 2007. That would allow more qualified researchers to benefit from this focused product development program and take advantage of the expertise and experience of the Office of Orphan Products Development. In addition, the committee encourages FDA to work with NIH on a systematic process for referring to NIH worthy orphan product grant applications that FDA lacks funding to approve. FDA has, from time to time, done this, and the expectation of new resources at NIH as described in Chapter 5 provides a rationale for a more formal referral process. The next chapter reviews some of the scientific and technological ad- vances that are making it faster, easier, and less expensive to undertake basic discovery research to understand the biology of rare diseases and identify targets for therapeutic development. Chapter 5 examines the preclinical and clinical stages of drug development. 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 cri- teria 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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