In developing drugs to treat or prevent rare diseases, the overall challenge is designing and executing an efficient, effective development program while educating stakeholders, including FDA, about the disease or condition, the patient population, and appropriate endpoints to assess clinical benefit. The scientific and medical knowledge about a rare disease may be limited compared with more common diseases, with no clear development pathway and likely no clear clinical outcome measures and efficacy endpoints. Preliminary development may be hampered by a lack of appropriate animal models and the need to identify new biomarkers.  To conduct clinical studies, sponsors must understand how to identify patients, and often must expand clinical studies globally to recruit subjects in widely dispersed rare disease populations. Roughly half of orphan diseases occur in children, which means that companies must also address pediatric considerations.

These unique aspects of rare disease drug development programs carry through into unique challenges and considerations for the preparation and submission of the marketing application-a new drug application (NDA) or biologics license application (BLA)-to FDA for the treatment and proposed orphan indication. Inherently, based on more limited data, the marketing application for a drug to treat a rare disease must present a cogent and comprehensive rationale for seeking approval from FDA.

To support the benefit-risk profile of the drug, the marketing application must include full consideration of all relevant aspects of the disease and its natural history, appropriate definition of the patient population being treated, the strengths and limitations of the clinical outcome measures and efficacy endpoints, justification for the use of any biomarkers as surrogate endpoints, and sufficiently robust analyses of the limited available clinical data, relying in many cases on historical controls.

FDA regulatory landscape for rare diseases

There was a time when rare diseases were seldom considered for new therapies because of the risk that even an approved therapy wouldn’t be sufficiently profitable because of the limited market. To stimulate the development of drugs for small populations that desperately needed them, Congress and FDA took steps to stimulate development, beginning with the Orphan Drug Act of 1983, which created financial incentives to encourage companies to develop new drugs for rare diseases. The Federal Food, Drug, and Cosmetic Act defines a rare disease as a disease or condition that affects less than 200,000 persons in the U.S.

The overall success of the Orphan Drug Act is borne out by the fact that the number of orphan products in development has grown substantially in recent years. In 2018, the majority of novel drugs approved by FDA were for orphan indications (34 of 59). Over the past four years, FDA has granted well over 300 new orphan-drug designations each year, including 476 during 2017 and 337 during 2018, and this trend shows few signs of slowing.

To support sponsors in developing drugs to treat rare diseases, FDA issued two draft guidances focusing directly on aspects and issues that should be considered for rare disease drug development. In January 2019, FDA issued the updated draft guidance Rare Diseases: Common Issues in Drug Development, to assist sponsors in conducting more efficient and successful drug development programs for the treatment or prevention of rare diseases. In March, FDA also issued the new draft guidance Rare Diseases: Natural History Studies for Drug Development, to help inform the design and implementation of natural history studies that can be used to support the development of drugs to treat rare diseases.

One critical point that sponsors must keep in mind is that the Orphan Drug Act did not create a statutory standard for approval of orphan drugs that is different from the standard of approval of products for common conditions. FDA still needs substantial evidence of the drug’s effectiveness as well as sufficient safety information in order to assess the benefits and risks of the drug in treating the rare disease. As a reminder to industry, this point is stated explicitly up front in the FDA rare disease guidances. Sponsors must generate sufficient data to support approval of the treatment, including evidence of effectiveness and safety from appropriately designed, adequate, and well-controlled clinical studies.

However, as noted in the guidances, the regulations do allow FDA to exercise appropriate scientific judgment when determining the type and amount of data required for an individual drug development program. Historically, the agency has demonstrated considerable flexibility in working with sponsors in the development of rare disease product candidates.

In addition to the R&D incentives included with an orphan-drug designation (tax incentives, increased exclusivity, eligibility for grants, and exemption from paying prescription drug user fees), many serious or life-threatening rare diseases are also eligible for one or more of the expedited development and review programs offered by FDA. This option was described in the agency’s guidance Expedited Programs for Serious Conditions-Drugs and Biologics, issued in May 2014. For example, orphan products to treat serious or life-threatening diseases may qualify for FDA’s breakthrough therapy designation if there is sufficient preliminary evidence indicating that the product may demonstrate substantial improvement over existing therapies. Breakthrough therapy status provides increased support from FDA to attempt to accelerate the development timeline, including more intensive guidance along with organizational commitment from FDA to aid the sponsor during development, and opportunity for rolling submission and review of the marketing application. Drugs and biologics that are eligible for the accelerated approval program may be able to use a surrogate endpoint such as a biomarker that is considered likely to predict clinical benefit, rather than a clinical outcome, which can significantly reduce a product’s development timelines.

Orphan products may also qualify for priority review, for an indication where no adequate therapy exists or where the product provides a major advance in treatment. Note that compared to other mechanisms, seriousness of disease is not a factor. FDA has committed to review 90% of NDAs and BLAs with priority review status within eight months, compared to 12 months for a standard review.

The regenerative medicine advanced therapy (RMAT) designation is available to cell therapies, therapeutic tissue engineered products, human cell and tissue products, and gene therapies that are intended to treat a serious or life-threatening disease or condition and have preliminary clinical evidence that the product has the potential to address unmet medical needs. Many of these types of products target rare diseases. As described in FDA’s guidance Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, issued in February, the regenerative medicine advanced therapy designation provides many of the same benefits as breakthrough therapy in what may be a less burdensome pathway.

Since many rare diseases impact children, sponsors developing orphan products need to be very familiar with FDA pediatric regulations and guidance. Testing drugs in these populations have unique challenges, including ethical and safety considerations. To facilitate clinical development in pediatric rare diseases, FDA issued the guidance Pediatric Rare Diseases-A Collaborative Approach for Drug Development Using Gaucher Disease as a Model, which discusses possible approaches to enhance efficiency in these development programs.

Data needed to support marketing application

In the expedited programs guidance noted, FDA “acknowledges that certain aspects of drug development that are feasible for common diseases may not be feasible for rare diseases.” This reinforces the agency’s intent to exhibit an appropriate degree of flexibility in assessing what data are required to approve a new drug for a rare disease. However, the scope of data needed to gain approval of a new orphan treatment is still extensive, with some aspects unique to rare diseases, such as focusing on the condition’s natural history as a core part of the development program, and the need to explore clinical outcomes assessments to identify appropriate clinically meaningful endpoints for what is likely a novel indication.

An important tool to utilize early in development is the target product profile (TPP). Preparing a TPP as a roadmap through development will greatly assist in identifying what data and information need to be collected or generated throughout development to achieve the goal of product approval.

Understanding the natural history of the disease

Understanding and defining the disease state is critical in developing a therapy for a rare disease. As highlighted in FDA’s guidances, natural history studies are essential to inform every stage of development, from discovery to the design and conduct of adequate and well-controlled clinical studies to the marketing application. For many rare diseases, the actual mechanistic etiology of the condition is not understood. Natural history studies, which can be run concurrently with early preclinical development of a drug, will assist in defining the disease population, and data from these studies will aid the sponsor in selecting outcome measures and driving the design of clinical studies with the right clinical efficacy endpoints. It also provides greater understanding of what is needed for the duration of patient treatment and follow-up. Coupled with nonclinical studies, natural history studies can help identify biomarkers, which may later be needed as surrogate endpoints. Establishing a historical database from a well-designed prospective natural history study can advance the clinical development of the product by serving as historical controls in later development where placebo controlled studies may either not be possible or ethical.

FDA’s draft guidance states that a natural history study defines “the course a disease takes in the absence of intervention in individuals with the disease from the disease’s onset until either the disease’s resolution or the individual’s death.” In general, there are two types of natural history studies-prospective and retrospective. Retrospective studies rely on data from patient evaluations that have already occurred and can contain information from published studies, experience from disease experts, and data collected directly from patients. Prospective studies specify a data collection plan and then evaluate patients. Retrospective studies are often a good source of preliminary information, but may contain data issues that make them less useful than a prospective study. Additionally, the guidance outlines the potential utility of data and information from a natural history study to provide an untreated external control group for use as a comparator in a clinical study, with careful planning and assessment to address, for example, selection bias.

Nonclinical studies

In general, the requirements for a nonclinical development program for a drug to treat a rare disease are the same as the requirements for a nonclinical program targeting a common disease. The same regulations and ICH/FDA guidances and requirements apply, regardless of the size of the population, and there are no specific nonclinical guidance documents from FDA focused on rare diseases. Given the complexity of these conditions, there is potential for more complex preclinical development programs. Because rare diseases may not be as well understood, nonclinical studies may be used to better understand the mechanism of action and pharmacology of the drug in question. Gene therapies and cell therapies often require more complex nonclinical studies. Another challenge is that some rare diseases may not have existing animal models.

Clinical studies

As previously stated, despite the small patient populations for rare diseases, FDA still needs substantial evidence of efficacy from adequate and well-controlled clinical studies of the product and indication to meet the statutory standard for approval. Although FDA can exercise its scientific judgement and exhibit flexibility in the development of an orphan product, it falls on sponsors to engage the agency early and throughout the development program. This helps achieve alignment regarding study designs, endpoints, and the totality of efficacy and safety data required to support review of a marketing application. Some important clinical study considerations that are relatively unique to rare disease include:

• Making the most of a limited/rare patient population, which may mean expanding the geographic footprint of the studies in order to recruit subjects globally.

• Competing programs trying to utilize the same small population can lead to FDA recommendations based on what it thinks is best for the population, including steering toward drugs that have the best chance of success based on available data.

• Leveraging information from natural history studies to design the right studies with the most appropriate controls.

• Using patient reported outcomes (PROs) for both safety and efficacy can help identify endpoints that will be truly meaningful to the patient.

The right data analysis approach is critical as well. To that end, it’s important to engage with statistical experts who understand historical controls, appropriate techniques such as propensity score matching, data integration, and FDA expectations with regards to safety and efficacy analyses in limited populations.

The marketing application

The NDA/BLA is the culmination of the entire development program, incorporating all data and taking into consideration all guidance and feedback from FDA. A well-prepared marketing application tells the rare disease story and provides a clear and compelling explanation of the benefit-to-risk ratio of the drug and why it should be approved.

Given the relatively limited clinical data resulting from a rare disease development program compared to a more common disease, particular attention must be paid across the important components of the application. These include the integrated summary of safety (ISS), integrated summary of efficacy (ISE), clinical overview with the benefits and risks conclusions in Module 2.5, and proposed labeling. Use the ISS, ISE, and clinical overview to tie together the natural history of the disease, patient perspectives, clinical outcomes assessments and efficacy endpoints with support from nonclinical data regarding mechanism of action and pharmacology.

Use the TPP and a structured benefit-risk assessment approach to develop key messages from specific conclusions based on the evidence and uncertainties for the disease condition and the current treatment options, benefits and risks of the new drug, and risk management. No detail is too insignificant; for example, for small patient populations, a single serious adverse event could be a key safety signal that merits close attention in the application. If the TPP is being updated as a guide for collecting and analyzing data throughout development, the TPP along with conclusions from the benefit-risk assessment will provide the basis for the proposed product labeling.

Global clinical studies are common in rare disease drug development, and the acceptability of foreign clinical data should be addressed in these cases. Differences in intrinsic and extrinsic factors, including ethnic factors and standard of care, need to be assessed to justify extrapolation of foreign data to the U.S. patient population.

Document all critical agreements with FDA and explain how key agency concerns and considerations have been addressed. Provide all appropriate requests for waivers and deferrals for nonclinical and clinical studies, based on prior discussions with FDA, and include details of any preliminary agreements regarding potential postmarketing commitments. The agency has previously identified incomplete applications as a major problem area for orphan drug submissions, so prepare a detailed build list and a comprehensive refuse-to-file checklist to make sure nothing is missed.

Kevin Barber, PhD is VP, Regulatory Strategy and Submissions at Rho.