Challenges and opportunities when developing devices for rare disease populations

KEYWORDS:

• Adaptive Clinical Studies
• Early Feasibility Studies
• Expedited Access Pathway
• humanitarian use device (HUD)
• Orphan Product
• Orphan Product Grant Program
• Pediatric Device Consortium (PDC) Grant Program
• rare disease

The Orphan Drug Act Amendment of 1984 includes a definition of a rare disease as a disorder or condition that affects less than 200,000 persons in the United States.[1] Most rare diseases affect far fewer persons. While the population affected by each rare disease may be small, rare diseases affect approximately 30 million Americans.[2] Fostering innovation and device development for patients with rare diseases who may benefit from medical device therapy is of great importance to the United States Food and Drug Administration (FDA).

Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. The FDA requires the submission of data in a PMA to be sufficient to demonstrate a reasonable assurance of safety and effectiveness before devices are approved. In devices intended for rare diseases, the effectiveness criteria may be difficult to fulfill due to the small patient population and potential for variability. Stemming from the Safe Medical Devices Act (SMDA) of 1990, a device designated as a humanitarian use device (HUD) is eligible to enter the market via the Humanitarian Device Exemption (HDE) pathway rather than through submission of a PMA. HUDs are intended to treat or diagnose a rare disease or condition that affects or is manifested in fewer than 4000 new individuals in the United States per year. A HUD is eligible for approval via the HDE pathway as long as no other comparable device (other than another approved HUD or an investigational device) is available to diagnose or treat their disease or condition.[3] In contrast to a PMA, HDE applicants are by statute exempt from having to demonstrate a reasonable assurance of effectiveness; however, the safety standards for HDE and PMA applications are the same. Data to support HDE approval must demonstrate: (1) there is a probable benefit to health from the use of the device and (2) the probable benefit outweighs the risk of injury or illness from the use of the device, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Due to the smaller population size for HDEs, the amount of data submitted between an HDE and PMA may differ.[4] In addition, HDEs are not subject to the standard medical device user fees attached to regulatory review. As of 2015, 69 HDEs have been approved (for listing of approved HDEs: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/HDEApprovals/ucm161827.htm). Approved HDEs are subject to some restrictions such as the need for approval from relevant institutional review boards before use.[5]

Once on the market, HDEs must annually demonstrate continued compliance with the criteria for HUD designation after an HDE has been granted (21 CFR 814.126 (b)(1)(i)), including the criterion that the target population for use of the devices be 4000 or fewer individuals annually. These regulations authorize FDA to withdraw an HDE approval if a device no longer meets the eligibility requirements. This situation has been encountered in the past, for example, in the example of patent foramen ovale occluders.[6]

The FDA is committed to making US patients the first in the world to have access to high-quality, safe, and effective medical devices. Center for Devices and Radiological Health (CDRH) 2014–2015 Strategic Priorities [7] help device developers navigate the difficult and unique challenges of bringing to market new devices to treat rare diseases. CDRH is committed to improving US patient access to new devices by strengthening and streamlining the process of testing complex medical devices so that clinical trials are conducted in the United States in a safe, efficient, and cost-effective manner. To that end, CDRH established a new clinical trial program aimed at improved consistency in decision-making and enhanced interactions with industry.[7] Furthermore, FDA issued draft guidance documents on benefit–risk determinations for Investigational Device Exemptions [8] and on Adaptive Clinical Studies.[9]

Development of new products for treatment of rare diseases is especially challenging due to the small numbers of people affected, limited understanding of the natural history of the rare disease, and lack of well-defined study end points. These challenges translate to special considerations for clinical trials which are handled on a case by case basis. For example, a randomized trial may not always be feasible given the small number of potential subjects. Early Feasibility Studies (EFS) are small clinical studies designed to gain early insights into an innovative technology during the development process before starting a larger clinical trial. EFS often are a critical step in device innovation. A comprehensive educational module was developed by CDRH to help industry navigate the EFS process.[10]

Another development from FDA involved a final guidance document on a new, voluntary program known as the Expedited Access Pathway (EAP) for certain higher risk medical devices that demonstrate the potential to address unmet medical needs for life-threatening or irreversibly debilitating diseases or conditions and are subject to a PMA or are eligible for de novo requests.[11] The EAP program may be relevant to rare diseases which do not meet the population requirement for HUDs.

FDA is also working with industry, health-care professional organizations, and patient groups to help develop more effective, less costly, and less time-consuming ways to evaluate the safety and effectiveness of new devices.[12] One example of such a collaboration was the National Eye Institute (NEI)/FDA Endpoints Symposia,[13,14] sponsored by the Association for Research in Vision and Ophthalmology, aimed at exploring issues and challenges in ophthalmic clinical trial end points. In 2011, as part of the Endpoints Symposia, a symposium was held on functional vision outcomes and how they are used in retinal prosthesis clinical trials.[15] Discussions included techniques for measuring performance of real-world tasks, such as orientation, mobility, and activities of daily living, and the challenges of ensuring the reliability and validity of the measurements. A guidance document was subsequently published by FDA clarifying expectations from visual prosthesis clinical trials.[16] Establishing techniques for measuring performance of real-world tasks was instrumental for assessment of the Argus II Retinal Prosthesis System from Second Sight Medical Products, Inc – the first retinal prostheses to receive HDE approval.[17] This device is intended for patients aged 25 years and older with bare or no light perception vision caused by advanced retinitis pigmentosa, is designed to improve the visual function of patients, and may produce the sensation of light. Results of the clinical study showed that the system helped subjects: identify the location or movement of objects and people; recognize large letters, words, or sentences; and helped in other activities of daily life, such as detecting street curbs and walking on a sidewalk without stepping off.[17]

Many opportunities are available to support device innovation for rare diseases, sometimes with financial benefits. The FDA Office of Orphan Products Development (OOPD) administers two grant programs that allow for federal financial assistance: the Orphan Product Grants Program and the Pediatric Device Consortium Grants Program. The Orphan Products Grants Program supports the clinical development of products for use in rare diseases or conditions where no current therapy exists or where the proposed product will be superior to existing therapy. FDA provides grants for clinical studies on safety and/or effectiveness that will either result in or substantially contribute to market approval of these products. The products studied can be drugs, biologics, medical devices, or medical foods. Applicants for these grants must include documentation to support the estimated prevalence of the orphan disease or condition (or in the case of a vaccine or diagnostic, information to support the estimates of how many people will be administered the diagnostic or vaccine annually) and an explanation of how the proposed study will either help gain product approval or provide essential data needed for product development. Of note, the population limit for eligibility for the Orphan Products Grants Program is based on the Orphan Drug Act (i.e. ‘affects less than 200,000 persons in the United States’), as opposed to the limit stipulated in the SMDA of 1990 for HUDs (‘affects or is manifested in fewer than 4000 individuals in the United States’). Thus, Orphan Product Grants foster and encourage the development of new safe and effective medical products for rare diseases/conditions.

Since the inception of the program in 1983, OOPD has received over 2500 applications and has funded over 700 awards. The Orphan Grants Program has been used to bring more than 55 products to marketing approval. OOPD usually funds between 12 and 18 new grants per fiscal year.[18] Examples of devices that were funded and subsequently approved as HDEs include the Berlin Heart EXCOR pediatric ventricular assist device and Vertical Expandable Prosthetic Titanium Rib. The clinical trials for these devices are also exemplary of the creative approaches used to overcome the limitations in population size; for example, outcomes for the Berlin Heart EXCOR pediatric ventricular assist device were matched retrospectively with control patients from a registry of patients with mechanical circulatory support devices.[19]

The Pediatric Device Consortium (PDC) Grant Program is intended to encompass devices used in all pediatric diseases, not just rare diseases. The PDC Grant Program supports the development of nonprofit consortia designed to stimulate projects which will promote pediatric device development. The consortia will facilitate the development, production, and distribution of pediatric medical devices by: encouraging innovation and connecting qualified individuals with pediatric device ideas with potential manufacturers; mentoring and managing pediatric device projects through the development process, including product identification, prototype design, device development, and marketing; connecting innovators and physicians to existing Federal and non-Federal resources; assessing the scientific and medical merit of proposed pediatric device projects; and providing assistance and advice as needed on business development, personnel training, prototype development, and postmarketing needs.[20]

Conclusion

When it comes to finding ways to test new treatments for rare diseases, it is often impossible to rely on the same methods that are used for investigating treatments for more common, well-known diseases. Challenges in device innovation for rare diseases are real, yet there are many opportunities for success. Knowledge of common hurdles, past successes, grant programs, published guidance documents, and regulatory requirements offer tools and opportunities for pioneers in device development for rare diseases.

Expert opinion

Through a variety of strategies ranging from grant programs and HUD regulatory paths to innovative clinical trial designs and postmarket data collection, FDA is committed to helping patients suffering from rare diseases in the United States obtain access to high-quality, safe, and effective medical devices of public health importance first in the world. Early feasibility studies, adaptive clinical trials, and the expedited access pathway are only a few creative solutions that may provide assistance to developers of devices intended for rare diseases. Grant programs administered by OOPD offer an opportunity for financial benefits. Partnership between industry, health-care professional organizations, and patient groups is invaluable as it updates the agency on new technology, helps to clarify expectations to industry, and provides access to expertise necessary to evaluate clinical trial and product submissions for rare diseases. While the vast majority of rare diseases are still without FDA-approved treatments, the opportunities for device development are growing. FDA is committed to working with device developers to establish successful device development programs that include regulatory flexibility, creative approaches, and a scientifically sound basis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.