Name of document
Date released
Report: complex issues in developing drugs and biological products for rare diseases and accelerating the development of therapies for pediatric rare diseases including strategic plan: accelerating the development of therapies for pediatric rare diseases
July 2014
Guidance for Industry, Duchenne muscular dystrophy, developing drugs for the treatment over the spectrum of disease prepared and submitted by Parent Project Muscular Dystrophy (PPMD) to the FDA
June 25, 2014
There are a number of key hurdles common to the approval of all potential products to treat MD, either as a rare disease or as a form of MD, that can benefit from the advancement in DMD/BMD clinical drug development. To facilitate discussion of these hurdles, the first document, highlighting rare diseases, will be discussed, followed by a discussion of the Parent Project Muscular Dystrophy (PPMD) document, highlighting challenges that may have a wider applicability to non-DMD types of MD.
FDA’s report and strategic plan on the complex issues in developing drugs and biological products for rare diseases is a useful backdrop for insights into this complex problem. The report is the result of efforts that started in 2012 when the U.S. Congress passed the FDA Safety and Innovation Act, which mandated holding a public meeting to encourage and accelerate the development of new therapies for pediatric rare disease as well as issuing a report that includes a strategic plan to address such therapies. The FDA held that meeting on January 6–8, 2014, for the Agency to solicit input from various stakeholders. The important issues that were discussed at the meeting included:
The need for more comprehensive information about the natural history of most rare diseases.
The importance of public–private, public–public (interagency and intergovernmental), and international partnerships in providing resources and facilitating data collection.
Recommendations for greater involvement and a more active role for patients and caregivers in therapeutic product development.
The invaluable contribution of advocacy groups in the development process to educate and recruit patients, and to assist in endpoint selection.
The concept that patients’ and families’ willingness to accept risk for participation in clinical trials, and for adopting new therapies, may be greater for those affected by serious and life-threatening rare diseases.
Methods to overcome the challenges of trial design, such as flexible drug development programs, adaptive trial designs, enrichment strategies, and master protocols.
Endpoint development and acceptance for use in registration trials (e.g., patient reported outcomes and surrogates).
The ways in which benefit–risk assessments guide regulatory decision making.
Several important issues were raised that fell outside of the FDA’s jurisdiction, including issues dealing with reimbursement and the governance and management of patient registries. The reimbursement topic, while critically important to families with MD, is beyond the scope of this chapter. Patient registries are further discussed in Chapter 14.
Highlights of the FDA Report [1], as pertinent to MD, are provided below. Key hurdles and challenges are highlighted in italics.
Clinical Trial Design Issues
According to the report, and many researchers, to effectively study drugs that can be used to treat a disease, researchers must fully understand the disease’s natural history, the term used to describe how a disease would evolve if no treatment were given.
At present, the natural history of all nine types of MD is not fully known. Given the wide variation between the various types of MD, this issue is problematic.
The organization of natural history studies and disease registries is needed.
At present, these studies and registries are not standardized, transparent, nor compatible regarding data collection among multiple database holders.
There is no consensus on how to determine endpoints for clinical trials that are clinically meaningful to patients with rare diseases.
It was suggested at the FDA meeting that patient advocacy groups could be hubs for data collection and could help facilitate development of patient-reported outcomes for patients with specific diseases. Other sources could include published case studies, cross-sectional analyses, and prospective longitudinal natural history studies with information on phenotypic and genotypic characteristics of the disease, available biomarkers, and clinical manifestations.
According the FDA report, the greatest challenge in designing and interpreting clinical trials in rare diseases is the small numbers of patients available for clinical studies. Such small numbers of patients, if studied using conventional study design, are often unable to generate enough data to establish the efficacy and safety of the drug. Compounding this challenge is the fact that the few patients who are available for the study may exhibit varying signs of the disease or react to medications intended to treat their condition in different ways. New methods to address these challenges include various crossover designs, and use of historical control studies and enrichment strategies.
The Benefit–Risk Assessment
It was acknowledged that patients, physicians, and regulators are willing to accept greater risks when dealing with serious diseases, and that the FDA promotes transparency in informing patients through informed consent and appropriate product labeling once the product is approved.
Risk tolerance would be expected to change as more treatments became available for a particular condition.
Parents from both the panel and the audience agreed that delaying disease progression in order to give their child a more fulfilling childhood experience would be beneficial. The uncertainty of the level of risk of an experimental intervention in order to delay disease progression was contrasted with the certainty of progressive deterioration and death due to the disease in certain forms of MD.
An important decision that is made when developing products for the treatment of rare pediatric diseases is whether there are sufficient data to support giving an experimental product to a child. This decision becomes more critical in first-in-human testing of a product for rare and life-threatening diseases with no known treatments. The panelists focused on three concepts that help to inform this decision: (1) the desired clinical benefit; (2) the probability and nature of the harms (i.e., risks) that may be acceptable to attain those benefits; and (3) the amount of uncertainty about each that is tolerable.
The panelists agreed that when considering whether the risks of an experimental product are either “reasonable” or “justified,” both the type of harm that the product might cause, and likelihood that the harm may occur should be considered. There was consensus that patients’ and families’ attitudes about benefit–risk should be solicited as part of the process, but it was acknowledged that these attitudes may change over time, with disease progression. Patient advocates noted that stabilization may be seen as a reasonable benefit, as opposed to the ideal of a cure, and that even the risks for certain harms may be acceptable given the potential for slowed progression of the disease.
Long-Term Safety Concerns
Because clinical trials for rare disease therapies are often too small to definitively ascertain a drug’s complete safety profile, for example, failing to reveal uncommon adverse events (AEs), it is important to perform long-term safety assessments (e.g., pharmacovigilance).
Patient Registries
A patient registry is a list or database of patient information that scientists and researchers can use to keep track of patients who have participated in clinical trials, including all relevant study information, to monitor potential long-term health effects of a given therapy and shape future clinical trials.
The report discussed the value of patient registries in moving clinical research forward. Patient registries can: (1) improve patient recruitment; (2) identify possible patient cohorts for study; (3) serve as a lead-in to natural history studies; (4) integrate patient reported and clinical data from multiple sources into a single repository; (5) stimulate new research and lead to new scientific insights; and (6) enhance creative data mining within and across disorders. When developing a new registry, the following should be taken into consideration: (1) the purpose of the registry; (2) the process of data (identified and de-identified) collection, management, and analyses across multiple platforms; (3) the data curator’s role; (4) the type of informed consent needed (restricted or broad access); (5) Institutional Review Board and Federal Information Security Management Act requirements; (6) data sources (patient, family, care-giver, and healthcare provider); (7) uses of common and unique data elements; and (8) options for data updates. It is important to further develop partnerships and collaborations between stakeholders in the rare disease community, and to agree upon the use of common and unique data elements in order to contribute to the sharing of data.
In the context of addressing clinical trial hurdles, patient registries are another tool used to monitor outcomes in patients after the trial is complete. Patient registries allow for long-term follow-up of patients and can foster relationships among patients with rare diseases, their caregivers, healthcare providers, and drug developers. For additional information on patient registries, see Chapter 14.
Dose Selection
Other clinical trial challenges include determining the adequate drug exposure (what doses to study and what duration of exposure to assess) and the appropriate size for a safety database.
The report suggested, with regard to dose selection, that clinical trials should assess the safety of a range of doses, rather than focusing on a single dose. Suggestions, by panelists interviewed in the report, were made for ways to explore the safety of doses (e.g., adaptive dose finding, and use of biomarkers in dose finding and dose response).
Gene Therapy
The spectrum of diseases for which gene transfers or therapies (hereafter referred to as gene therapies) may be used is wide-ranging. Since children potentially have many years of life ahead of them, the issue of possible long-term permanent effects of gene therapy is critical. These issues include the need to address long-term safety risks for children and the requirement for long-term safety follow-up. This session focused on a discussion of the development of products with uncertainty regarding their long-term benefits and risks.
Gene therapy may provide the prospect of a cure or substantial amelioration of a condition after a single administration of the product. Patients may also incur gene-therapy-related harms, which may be prolonged or which may appear only after a long interval following treatment. For this reason, long-term follow–up is critical for gene therapy trials. The decision to participate in trials requiring long-term safety follow-up is based on the natural history of the disease, the stage of disease, and whether long-term follow-up is prohibitive. This decision is also dependent upon whether other treatment options exist.
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