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.
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
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 product 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 populations may be particularly vulnerable.
Recognizing that regulations to protect the public’s health may also create 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 incentives 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 framework 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 below and presents summary data on orphan drug designations and approvals. 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 conducted 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 policies 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 combination products (e.g., those combining a drug and a device).
GENERAL FRAMEWORK FOR THE REGULATION OF DRUGS AND BIOLOGICS
This report generally uses the term drug to encompass both pharmaceuticals 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 action made the development of generic drugs much more attractive to industry. 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
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 Abbreviated 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 substantial 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 training 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 adequate 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;
employ suitable methods to assign study and control groups and otherwise to minimize bias;
use clear, reliable methods to define and assess responses of research participants; and
employ appropriate methods to analyze study results.
Generally, FDA has recognized the following types of controls in clinical trials: placebo concurrent control; dose-comparison concurrent control; 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.
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.
Regulation of Biologics
Biological products are made from living organisms and may be composed of cells or tissues or of sugars, proteins, or nucleic acids or complex combinations of these substances. Examples of such products include vaccines, 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 biologics 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 available 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, enzymes); 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. Because many patients with rare diseases have debilitating and life-threatening conditions for which no approved drugs are available and because the
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 investigational 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 advocacy 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 specific performance goals related to review times, sponsor requests for meetings, 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
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 expanded access program, FDA “must determine that:
Individual patient use, including in emergencies
FDA may permit an investigational drug to be used for the treatment of an individual 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.)
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
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, 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.
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 inhalation 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 postmarketing 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
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 corresponding 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 sponsor (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 explicitly 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 Pharmaceuticals 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
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,
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 designations 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 company 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.
FDA does not make public its negative decisions or the clinical assessments on which they are based, except when staff presentations to advisory committees detail negative assessments of the information presented by sponsors. Securities and Exchange Commission regulations for publicly traded companies may require that they publicly report failed trials and similar information that is relevant to investors or potential investors. These reports typically do not have the specificity found in an FDA review or a top-tier peer-reviewed medical journal (Fisher, 2002).
Some information about studies undertaken to support FDA approval may also be found elsewhere. In the 1997 FDA Modernization Act, Congress required sponsors of drugs intended for serious or life-threatening conditions to submit basic information about certain clinical trials to a publicly accessible database—what is now ClinicalTrials.gov (CDER-CBER, 2002a).5 The database became available online in 2000; as of April 2010, it included information on more than 89,000 trials (see http://clinicaltrials.gov/ct2/info/about). The Food and Drug Administration Amendments Act of 2007 required sponsors or principal investigators to submit to ClinicalTrials.gov “basic results” of certain studies performed in support of drugs and devices that FDA has approved (Section 801 of P.L. 110-85; see also Tse et al., 2009).
In 2010, as part of a “transparency” initiative at FDA, the agency published several draft proposals for comment (FDA, 2010b). Among the proposals are that the agency would disclose “when a drug or device is being studied and for what indication, when an application for a new drug or device has been submitted or withdrawn by the sponsor, whether there was a significant safety concern associated with the drug or device that caused the sponsor to withdraw an application, and why the agency did not approve an application” (Asamoah and Sharfstein, 2010, p. 3; see also Chapter 5). Another would allow the agency to explain that an orphan drug may represent an important therapeutic advance even if the application for the drug has been abandoned or withdrawn by the sponsor for business or other reasons. 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.
REGULATORY POLICY TO PROMOTE INNOVATION AND DEVELOPMENT OF ORPHAN DRUGS AND BIOLOGICS
SECTION 1. (a) This Act may be cited as the “Orphan Drug Act”. (b) The Congress finds that
there are many diseases and conditions, such as Huntington’s disease, myoclonus, ALS (Lou Gehrig’s disease), Tourette syndrome, and muscular dystrophy which affect such small numbers of individuals residing in the United States that the diseases and conditions are considered rare in the United States;
adequate drugs for many of such diseases and conditions have not been developed;
drugs for these diseases and conditions are commonly referred to as “orphan drugs”;
because so few individuals are affected by any one rare disease or condition, a pharmaceutical company which develops an orphan drug may reasonably expect the drug to generate relatively small sales in comparison to the cost of developing the drug and consequently to incur a financial loss;
there is reason to believe that some promising orphan drugs will not be developed unless changes are made in the applicable Federal laws to reduce the costs of developing such drugs and to provide financial incentives to develop such drugs; and
it is in the public interest to provide such changes and incentives for the development of orphan drugs.
Preamble to the Orphan Drug Act (P.L. 97-414)
As discussed in Chapter 1, enactment of the Orphan Drug Act in 1983 followed several years of effort by policy makers and advocates for people with rare diseases to understand and devise appropriate responses to industry reluctance to incur the costs of discovering and developing drugs for small or otherwise economically unattractive markets. 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). Except in its title, the 1983 law does not use the term orphan drug.
The initial statutory definition of rare disease or condition referred to “any disease or condition which occurs so infrequently in the United States that there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States of such drug” (see Sec. 526(a)(2) of the original act). After FDA and companies found it difficult to apply this definition, Congress in 1984 changed to the definition to specify that a rare disease or condition is one that affects “less than 200,000
persons” in the United States or affects “more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will be recovered from sales in the United States” (21 USC 360bb). A drug may also qualify for orphan status when it is intended for a subset of individuals with a particular disease or condition as long as the subset is medically plausible and affects fewer than 200,000 people in the United States. A number of orphan designations and approvals involve such subsets, for example, patients with a recurrent cancer or with a condition that is not responsive to standard treatments.6
Because rare is defined in terms of the U.S. population or market, the incentives of the Orphan Drug Act also apply to drugs for conditions that are uncommon in this country but may be very common worldwide. For example, in 2009, FDA approved artemether-lumefantrine (Coartem, NDA 22-268) as an orphan drug for treatment of acute, uncomplicated malaria, which is rare in the United States but not in many developing countries.7
Incentives for Orphan Drug Development
The Orphan Drug Act covers drugs and biologics. Except for the orphan products grants program, the incentives do not extend to medical devices (see Chapter 7). Box 3-2 summarizes the primary incentives for drug development provided by the Orphan Drug Act and other laws.
In economic terms, the Orphan Drug Act in combination with other FDA policies offers both “push” and “pull” incentives (see, e.g., Reich, 2000; Grabowski, 2005). Push incentives, which are intended to subsidize or lower research and other development-related costs, include research tax credits, orphan products grants, consultation with staff on acceptable research designs, and exemption from user fees. Pull incentives include the market exclusivity provision as well as the mechanisms to speed and facilitate review of drugs that were described earlier. The provision for
Primary Incentives Provided by the Orphan Drug Act
marketing exclusivity is generally regarded as the most significant incentive under the Orphan Drug Act.
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). To obtain a designation, sponsors are expected to describe the drug’s proposed use, provide evidence that the prevalence of the target condition or a medically plausible subset of a condition is below 200,000, and justify the drug’s promise for the proposed use. If sponsors are relying on the cost recovery rationale, they must submit supporting data related to the cost of their development activities (including the allocation of costs if the research involves more than one indication); costs for past and future production and marketing activities; projections of sales associated with the orphan indication; data on any overseas approvals and sales; and other information.
More than one sponsor can receive an orphan drug designation for the
same drug for the same indication. However, except under limited circumstances, only the sponsor that receives the first FDA approval can receive orphan drug marketing exclusivity. A manufacturer may obtain multiple orphan designations and approvals for different indications for the same product.
FDA can revoke an orphan designation if it finds significant inaccuracies or omissions in the data submitted in support of a designation (as authorized at 21 CFR 316.29). In 2007, FDA revoked the designation for a pancreatic enzyme product on the grounds that more accurate data indicated that the target population (people with exocrine pancreatic insufficiency) exceeded 200,000 at the time of designation (Wasserstein and Karst, 2007). (Designation is not affected if the target population grows to exceed 200,000 after designation but before approval.) In addition, if a sponsor fails to produce sufficient quantities of an approved orphan drug, the director of OOPD has authority—never invoked—to withdraw the product’s exclusive marketing rights (21 CFR 316.36).
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. Patent law provides an important means for innovators to protect their inventions or intellectual property from competitors. It gives patent holders the exclusive right to produce, use, or sell the patented invention for a specified period (35 USC 271(a)). Patents are issued by the U.S. Patent and Trademark Office and, under current law, extend for 20 years from the date of submission of the patent application.
By the early 1980s, the research and development process for new drugs combined with the time required for FDA review had reduced the effective patent life for the average new drug to well below the 17 years then available under patent law (Flannery and Hutt, 1985). In the Drug Price Competition and Patent Term Restoration Act of 1984 (P.L. 98-417, widely known as the Hatch-Waxman Act), Congress provided for the restoration of a portion of the patent term consumed by clinical studies and FDA review. In general, patent term restoration is limited to 5 years and an effective period of (postapproval) patent protection of 14 years.
The provisions on patent term restoration were part of a larger bill that established a pathway for FDA to approve generic versions of brand-name drugs. The goals were to make less expensive versions of brand-name drugs more widely available to consumers while still providing incentives for pharmaceutical companies to develop novel drugs (Mossinghoff, 1999;
Glover, 2007). To accomplish the latter objective, the legislation created two new “data exclusivity” rules.
The first exclusivity rule provides that truly innovative drugs—new chemical entities (also called new molecular entities)—receive a 5-year period of data exclusivity, during which the sponsor of a generic drug must submit a full New Drug Application that relies on its own preclinical and clinical data. At the end of 5 years (4, if the generic drug applicant chooses to challenge the innovator’s patents), the applicant can submit an ANDA that need only show that its product is the same as, and bioequivalent to, the innovator’s product.8
The second exclusivity rule provides that other applications for approval that are supported by clinical data (e.g., those involving new formulations of the drug) receive 3 years of exclusivity. Again, during the period of exclusivity, generic versions can be approved only if sponsors provide their own clinical data on safety and efficacy.9
In 1997, Congress enacted the Best Pharmaceuticals for Children Act (as part of the FDA Modernization Act) to encourage the testing of pharmaceuticals for children. If a company conducts pediatric studies in response to a written request from FDA and complies with various requirements relating to these studies, the law provides for an extension of 6 months to the exclusivity periods described above. 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. During the period of exclusivity, FDA cannot approve an application from a different manufacturer
for the same orphan drug and the same indication—even if that sponsor provides independent clinical data of safety and efficacy. An exception is available if the sponsor who has the orphan drug approval agrees to the additional approval or is found to be unable to supply sufficient quantities of the product.
Another exception is that under rather convoluted regulations, if a competitor demonstrates clinical superiority for its version of the same orphan drug for the same indication, then its version is not considered to be the “same drug.” Therefore, it may also be approved with orphan drug exclusivity.10 At least three products have been approved on the basis of this exception—oral fludarabine phosphate, octreotide acetate (Sandostatin LAR), and histrelin acetate (Supprelin LA) (Karst, 2009b) FDA’s regulations describing when one drug is the “same” as another for purposes of orphan drug exclusivity were drafted broadly to provide strong incentives for orphan drug development.
One analysis estimated that orphan drug exclusivity adds approximately 0.8 year of protection from competition beyond that typically provided by patents (Seoane-Vesquez et al., 2008). (The analysis was based on 99 relevant orphan new molecular entities [NMEs] out of a total of 115 compared to 421 relevant nonorphan NMEs out of a total of 520.) The authors of the analysis found that a relatively low percentage of orphan drugs classified as NMEs had a generic competitor enter the market immediately after the expiration of orphan exclusivity. They concluded that generic entry for many drugs was limited not only by orphan exclusivity but also by continuing patent protection as well as the small patient populations and low expected profits.
At FDA, the OOPD is generally responsible for promoting the development of products for rare diseases. Its specific tasks include designating orphan drugs (including reviewing claims about the prevalence of a rare
disease and the promise of a product), administering the orphan products grants program, and disseminating information to the public. Other responsibilities include reviewing and approving applications for the designation of a Humanitarian Use Device and administering the new grants program for pediatric medical device consortia (see Chapter 7). A 2001 study by the Office of the Inspector General of the Department of Health and Human Services concluded that the “Office of Orphan Products Development provides a valuable service to both companies and patients” (OIG, 2001b, p. 2).
As part of its information dissemination activities, the OOPD maintains a website with relevant information, including a database on designated and approved orphan drugs. Other initiatives include
offering workshops for companies, academics, and others on applying for orphan drug designation;
analyzing characteristics of orphan drugs, including the nature of rare conditions targeted and the reasons designated drugs do not progress to approval as a basis for identifying possible drugs worth further attention;
identifying promising candidates for orphan tropical diseases;
working with other governments, entities, or agencies to harmonize or coordinate policies and procedures internationally; and
cooperating with the National Institutes of Health to offer a course on the science of small clinical trials.
The OOPD recently posted a database of products that have received orphan status designation (which means that they have been found promising for treating a rare disease) and that also have already been approved by FDA for the treatment of some other disease (Goodman, 2010). These products have thus advanced a considerable way through the process of drug development and therefore may be less risky for companies than developing a new drug.
Roles of CDER in Orphan Drug Approval
As is the case for other drugs, CDER is responsible for reviewing and approving NDA applications for orphan drugs. In general, the review divisions of CDER are organized around therapeutic areas such as neurology and gastroenterology.
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
serving as the primary contact for the rare diseases community;
assisting developers of drug and biologic products in understanding and following relevant regulatory requirements;
coordinating the development of policies within CDER for the review an approval of drugs for rare conditions; and
encouraging collaboration among CDER scientists and clinicians.
The creation of this position is an important development. Realizing its promise will require adequate resources and staff support.
Overview of Orphan Drug Designations and Approvals
Since the beginning of the program, the OOPD has granted more than 2,100 orphan drug designations, and CDER has approved more than 350 for marketing. Only three drugs have been approved based on the cost recovery rationale (Timothy Coté, M.D., Director, Office of Orphan Products, May 2, 2010, personal communication; see also Karst, 2009b). Two of the three drugs were previously approved for use with common conditions.11
Appendix B presents summary data on approved orphan drugs. Highlights from this paper and other sources include the following:
The number of orphan drugs designated each year has grown substantially in recent years, increasing from 69 in 2000 to 165 in 2008 (Coté, 2010). The number of designated drugs gaining marketing approval in 2000 was 13 and in 2008, 15.
Of the orphan drugs approved from 1983 through 2007, 22 percent were biologics (Seoane-Vezquez et al., 2008).
Between 1983 and 2007, orphan-designated drugs had a shorter FDA review time on average (1.6 years) than nonorphans that were approved as new molecular entities (2.2 years) (Seoane-Vezquez et al., 2008).
Orphan drugs accounted for more than 30 percent of all drug approvals in 2008 (Coté, 2009).
From 2000 to 2008, orphan drugs accounted for 22 percent of the
innovative drugs (NMEs) approved by FDA and 31 percent of the innovative biologics (Tufts Center, 2010).
Oncology drugs dominate orphan drug approvals, accounting for 36 percent of approvals from 2000 to 2006 (Coté, 2010). The other categories accounting for more than 5 percent of approvals include drugs for metabolic disorders (11 percent), hematologic-immunologic disorders and neurologic disorders (7 percent each), infectious or parasitic disorders (6 percent), and cardiovascular conditions (5 percent).
Most drug approvals are for a single indication. A notable exception involves human growth hormone, versions of which account for 14 approvals involving 6 unique products (i.e., products that have the same manufacturer and the same ingredients). Among the 346 orphan drugs approved through 2009, there were 279 distinct products (Appendix B).
Among 108 qualifying orphan drugs that were approved under an NDA from 1984 to 1999 and were still available in 2010, 55 percent had generic equivalents on the market that were manufactured by a competing company (Appendix B).
As of early 2009, 33 previously approved orphan drugs were no longer on the market, of which 12 had no chemically identical approved alternative drugs (Wellman-Labadie and Zhou, 2009). In October 2009, a generic drug that was chemically identical to one of the 12 discontinued drugs (chenodeoxycholic acid [Chenix], approved in 1983) received a new orphan drug approval for the same indication (Chenodal, ANDA #091019).
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) nor at the lowest end of the range (diseases with affected individuals numbering in single or double digits). The median population prevalence for drugs with orphan designations is 39,000 (Coté, 2009). Of 326 products approved before 2009, 83 (25 percent) were for conditions with U.S. prevalence of less than 10,000 patients.12
As discussed in Chapter 1, very low prevalence rare diseases account for a substantial proportion of the conditions for which prevalence information was reported in the 2009 Orphanet prevalence report. Not surprisingly then, data reported by Heemstra et al. (2009) using an earlier Orphanet report (but excluding diseases with prevalence of less than 0.1/100,000) showed that the more common conditions (10/100,000 to 50/100,000) were more likely to have a U.S. or European orphan drug designation than the less common rare diseases.
Orphan Product Grants Program
Orphan product grants support the clinical development of products for use in rare diseases or conditions for which no current therapy exists or for which the proposed product will be superior to the existing therapy. The program extends beyond drugs and biologics to include medical devices and medical foods. Grant funding typically extends for up to 3 years for phase I trials and up to 4 years for phase II and III trials.13 In FY 2010, the amount available for orphan product grants (new and continuing projects) was approximately $15.2 million (Goodman, 2010).
As of May 2010, the online listing of grants showed that a total of 517 product research grants had been awarded over the life of the program; 70 grants were active at that time. Many of the grants involved early-stage clinical trials to develop initial information on safety and efficacy. Approximately a dozen grants were for studies of medical devices. The majority (approximately 90 percent) of the awards have gone to universities or other nonprofit organizations (Tufts Center, 2010).
By early 2010, FDA had approved or cleared for marketing 43 of the grant-supported products (Katherine Needleman, M.S., Director, Orphan Grants Program, FDA, March 10, 2010, personal communication). Of these approvals or clearances, 36 involved drugs (one of these was for a combination drug-device product) and 7 involved devices. According to a recent review, sponsors with orphan product grants reported that 22 percent of their clinical development programs led to approvals, whereas the approval success rate was 16 percent for major pharmaceutical or biotechnology companies (Tufts Center, 2010). Sometimes a grant will lead to useful knowledge about the use of a drug in the form of peer-reviewed publications (FDA, 2010c), 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. Such results may then attract industry funding to pursue further testing to support FDA approval. As discussed later in this chapter, funding for the program has lagged far behind in inflation and has thus limited the reach of this focused grant program.
Issues in the Orphan Drug Approval Process: Applying Standards and Identifying Problem Areas
Rare diseases present significant challenges to the system for approving drugs for entry to the market. The life-threatening and progressive nature of many rare diseases, combined with the small number of patients available to participate in clinical studies, often makes it impractical or impossible to conduct research using the same models used for more common conditions. A primary goal for FDA should be to facilitate development of therapeutics for rare disorders by promoting predictability, consistency, and reasoned flexibility in the regulatory process within and across its review units.
The committee was not able to find systematic information on the nature or consistency of FDA advice or judgments about adequate toxicology, carcinogenicity, or other preclinical studies for orphan drugs or about acceptable surrogate endpoints for studies involving such drugs. It is aware of concerns about the consistency of judgments across review divisions of CDER and the reasonable application of review criteria to studies of drugs to treat serious rare conditions that have no approved treatment. One of the recommendations at the end of this chapter calls a more detailed analysis of FDA approval (and disapproval) decisions than is possible with public data. Chapter 5 includes recommendations for NIH and the FDA Critical Path Initiative related to surrogate endpoints for rare diseases.
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 a variety of sources, it determined that the approvals of orphan drugs do not necessarily follow the pattern for approvals of drugs for common conditions, for which FDA often asks for evidence from two phase III trials. For example, Appendix B presents an analysis of medical officer reviews for drugs approved from 2007 to 2009. (Before 2007, these reviews were not consistently public.) For the 44 drugs approved during this period, the author located full medical officer reviews for 30. (The remaining 14 drugs included 9 clotting factors or immune globulins, 4 previously approved drugs, and 1 other product.) For the 30 drugs collectively, the medical reviews reported a total of 71 trials evaluating efficacy. The trials enrolled a median of 179 participants, and treatment lasted a median of 8.5 weeks. Of the 71 trials, 55 were considered pivotal trials that provided key
evidence of efficacy. They included 30 phase III studies, 17 phase II studies, 1 phase I study, and 4 phase IV studies (which were conducted following FDA approval of the drug for a different indication).
In this sample, 13 of the 30 orphan drugs 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. Among the 55 pivotal trials, 27 had a double-blind design, 5 were single-blind, and the remaining 23 did not have blinding. Twenty-six trials used placebo controls, and 11 used active comparators. Thirty-eight studies were randomized. Thirteen were single-arm studies.
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
Examples of Variations in Types of Efficacy Studies Accepted by FDA in Orphan Drug Approvals
In 2010, FDA approved carglumic acid (Carbaglu) for the treatment of acute hyperammonemia resulting from a deficiency of the enzyme N-acetylglutamate synthase (NAGS). NAGS deficiency is an extremely rare condition that can be fatal without treatment. The sponsor submitted data from a retrospective, unblinded, controlled case series for 23 patients who were treated for a median of 7.9 years (range 0.6 to 20.8 years). Complete data were available for 13 patients. The summary review stated that “although the retrospective case series data … are not derived from traditionally defined adequate and well controlled investigations, the plasma ammonia level data submitted for review do stand as evidence ‘on the basis of which it could fairly and responsibly be concluded by experts that the drug will have the effect it purports or is represented to have’” (Greibel, 2010, p. 1 quoting Section 505(d) of the Food, Drug, and Cosmetic Act). The approval letter from FDA specified a number of postmarket study requirements, including a registry to obtain long-term safety information over a 15-year period (Beitz, 2010).
Alglucosidase alfa (Myozyme) was approved in April 2006 as enzyme replacement therapy for Pompe disease, a rare autosomal recessive lysosomal storage disease. Without treatment, infants with the disease usually die by 18 months of age from respiratory and heart failure. Myozyme was approved based primarily on the results of a randomized, open-label, historically controlled study in 18 infantile-onset patients. The ventilator-free survival rate for the treated infants was 83 percent at 18 months of age compared to 2 percent survival in the age-matched historical comparison groups of 61 patients. Among other postmarket studies, the sponsor agreed to two long-term studies to collect additional clinical data, including growth and development information (Beitz, 2006).
Before colchicine (Colcrys) received orphan drug approval in 2009 for familial
considered sufficient to support approval. The first two examples, which have the least traditional evidence supporting approval, involve extremely rare conditions. The third example involves a drug that had never been approved by FDA but had a long history of use for gout (see note earlier in this chapter).
Some data point to differences in the evidence supporting approvals of orphan compared to nonorphan drugs. An analysis of accelerated approvals for NMEs in oncology found that 73 percent of those approved from 1995 through 2008 for nonorphan indications were supported by phase III studies compared to 45 percent of NMEs approved for orphan indications (Richey et al., 2009). The authors also found that the orphan NMEs were more likely than the regular NMEs to have difficulty completing the follow-up confirmatory studies. Another study by Mitsumoto and col-
Mediterranean fever (FMF), FDA had indicated to the sponsor that “in principle, the application for FMF could potentially rely solely on … published articles in the scientific and medical literature” since the drug had a long history of use (Roca, 2009, p. 10). (FDA required a dosing study to support approval of the drug for gout flares, an indication that is not rare.) In approving the application for FMF, FDA relied on three randomized, double-blind, placebo-controlled clinical trials (out of 74 studies cited by the sponsor) that involved a total of 48 participants. The sponsor incurred expenses for the literature review; the clinical trials had been funded by others. (See also discussion in Chapter 6.)
Sorafenib (Nexavar) has orphan drug approvals for treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. It was approved for the latter indication based on a randomized, double-blind, placebo-controlled, multicenter, international trial involving 299 study participants randomized to the investigational drug and 303 to a placebo. The primary endpoints were overall survival and time to progression. Overall survival for the test drug was 10.7 months versus 7.9 months for the placebo. The study was stopped early based on prespecified efficacy criteria (Llovet et al., 2008). The approval letter included reminders of postmarketing study commitments related to the earlier approval of the drug for renal carcinoma; it also specified additional postmarketing commitments (Justice, 2007).
Collagenase (Xiaflex) has orphan drug approval for treatment of Dupuytren contracture, a debilitating hand deformity. It was approved on the basis of results from two randomized, double-blind, placebo-controlled studies, one with 302 individuals with the condition, the other with 66 participants. The primary endpoint was proportion of patients who achieved a specified reduction in the contracture within 30 days after the final injection. For the larger study, 64 percent of the participants receiving the test drug achieved the specified response compared to 7 percent of those receiving the placebo. For the smaller study, the comparable figures were 44 percent and 5 percent (Rappaport, 2010).
leagues (2009) compared approvals for neurological drugs and found that of 20 recently approved nonorphan drugs, all had at least two randomized, placebo-controlled, double-blind clinical studies compared to 32 percent of the 19 approved orphan drugs. The mean number of trial participants in the former was 506 compared to 164 for the latter.
These analyses underscore the importance of sound alternative trial designs for use in studies involving small populations. They likewise support the importance of efforts undertaken by FDA and NIH to educate their personnel as well as investigators and sponsors about the most appropriate study designs.
Moreover, the analyses point to the need for more detailed examinations of CDER approvals, both to identify the extent and dimensions of variability in reviews and to assess the extent to which variability represents a reasoned approach to differences in the conditions and drugs being reviewed. These differences might relate to differences in the prevalence and nature of the disease, differences in mode of action of the drug, or other such factors. A recommendation at the end of this chapter calls for this kind of assessment as a basis for developing guidelines for CDER reviewers and providing guidance to sponsors.
Problems with Submitted Studies
FDA does not release medical reviews or other details when it rejects a sponsor’s application for approval of a drug. As a result, information about the problems with these applications—including problems with study designs as well as problems with the interpretation of study results—is often limited.
CDER staff have, however, identified a number of problem areas that may be encountered with sponsors of studies of drugs for common conditions but that may more often be encountered with sponsors of studies of orphan drugs, including academic investigators funded by NIH (Pariser, 2010). Box 3-4 summarizes some of the problems with applications and supporting studies. Certain of the cited problems involve primarily procedural or administrative issues (e.g., incomplete applications). Some of these problems may reflect sponsor inexperience with FDA policies and practices as well as situations in which guidance from FDA may not be sufficiently clear or specific, as discussed further below. 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.
Examples of Problem Areas for Sponsors Developing Evidence for Orphan Drug Approval
SOURCE: Pariser, 2010.
Concerns About FDA Reviews and Guidance
In addition to problems that FDA finds with submitted applications and research designs, some sponsors and investigators have raised questions about the quality and consistency of FDA reviews of orphan drugs, the appropriateness of its standards for approval, and the adequacy of current agency guidance (see, e.g., Radcliffe, 2009; Kakkis, 2010). Criticisms include
lack of adequate resources at CDER, including resources for advance meetings or other discussions with sponsors about trial design and outcomes measures and for development of written guidance;
inadequate reviewer understanding of the rare disease (including what constitutes an acceptable surrogate endpoint) 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
insufficient or delayed guidance for sponsors on various issues, including the use of “small n” study designs and methods and the specification of acceptable subsets of rare conditions to meet prevalence requirements 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 doing 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 implementation 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 methods 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 understanding and meeting regulatory requirements. The Associate Director will
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 development 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 reviews 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.
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 organizational 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, including 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
the new products and claims submitted to FDA for pre-market review and approval, the emergence of challenging safety problems, and the globalization 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 numbers 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 compared 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: “systems 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). Although 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 developments 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 Initiative, 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.
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, biologics, and devices).
Research Scope. Applications should fall within five broad categories:
This initiative will contribute to the overall goals of improving regulatory science 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 regulated some 5,000 domestic and foreign manufacturers of these pharmaceuticals. 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 funding 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.
The initiation of user fees allowed a considerable increase in staff conducting 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 dollars 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
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.
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 Development is viewed positively as a helpful resource and successful advocate, especially given its modest resources. The primary criticism is that its budget for orphan products grants is seriously inadequate. More generally, Congress 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 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) 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 collection of safety and efficacy data once an orphan drug is approved. Thus, the committee supports generally the recommendations of other IOM committees 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).
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 Leadership Council and the grants program described above. One area for further 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 contribute to variability and the development of criteria to guide reviews.
RECOMMENDATION 3-1: The Center for Drug Evaluation and Research (CDER) should undertake an assessment of staff reviews of applications for the approval of orphan drugs to identify problems and areas for further attention, including inconsistencies across CDER divisions 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, taking 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 example, 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 reviews. Depending on the results of its analysis of reviewer decisions and on consultations with experts in rare disorders and others, FDA could propose
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 developed to be consistent with statutory requirements and FDA’s broad responsibilities 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 appropriateness 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 specifically 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 Research 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 organizations 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.
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 specifically for NIH grant applicants. 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 development studies involving rare diseases are designed to fulfill requirements 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 assistance 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 diseases, 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 committee 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 development, 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 promising discoveries into approved products for people with rare diseases. It
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 advances 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 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.