How To Conduct A Multi-Company Trial For Rare Pediatric Diseases

US FDA draft guidance suggests efficacy endpoints for testing multiple drug products in the same clinical trials; advances an FDA-EMA joint proposal promoting innovative approaches for development of Gaucher disease medicines.

The US FDA is casting a spotlight on a new approach to the development of drugs for rare pediatric diseases in which companies would test multiple product candidates in the same clinical trial.

FDA and the European Medicines Agency suggested this course of action in a joint proposal to promote the use of innovative approaches in the development of medicines for Gaucher disease, which was published in July. FDA is advancing the idea with a draft guidance describing how this strategy could be implemented.

The draft guidance, "Pediatric Rare Diseases – A Collaborative Approach for Drug Development Using Gaucher Disease as a Model," discusses the key features of a multi-arm, multi-company trial to demonstrate safety and efficacy in treatment-naïve pediatric patients with Gaucher disease Type I, including the main inclusion criteria, relevant age groups, suggested efficacy endpoints and study duration.

The agency said the general principles presented in the guidance may be extended to other areas of drug development in rare diseases.

"People should really look at this draft guidance. very smart approach for rare diseases," former FDA Commissioner Robert Califf tweeted.

FDA announced the draft guidance in a Federal Register notice slated for publication Dec. 7. It notes that the guidance was originally a document developed as part of a strategic collaboration between FDA and EMA to enhance drug development for Gaucher disease. The joint plan was released for public comment in 2014.

FDA said its draft guidance is an updated version of the document with no fundamental changes to the original content. Comments on the guidance are due 60 days from publication.

The proposal is getting much more attention with the release of the draft guidance, which FDA highlighted in a news announcement on its website.

"Working with our European regulatory colleagues at the EMA, the FDA has drafted an approach to pediatric rare disease drug development that could eliminate the need for certain clinical studies and, when pediatric clinical studies are needed, could reduce the total number of patients who would receive a placebo instead of a potentially helpful drug," Janet Woodcock, director of the Center for Drug Evaluation and Research, stated.

Former FDA Commissioner Robert Califf praised the guidance in a Twitter post. "People should really look at this draft guidance. very smart approach for rare diseases. With ubiquitous EHR's we should have: 1) great system for finding rare dz patients so they can participate in trials & be helped by tx; 2) a tremendous post-market system," he wrote.

Will Additional Clinical Trials Be Necessary?

When the EMA and FDA joint plan was released, the European Federation of Pharmaceutical Industries and Associations welcomed its consideration of alternative clinical trial designs for small trial populations. However, it said the approach raises regulatory and legal questions, such as the eligibility for pediatric rewards and incentives, and whether an applicant would be expected to develop additional clinical studies in pediatric patients depending on the specific product and mechanism of action. (Also see "Multi-Company, Multi-Product Clinical Trials On The Cards For Rare Pediatric Diseases" - Pink Sheet, 4 Jul, 2017.)

In comments on the draft joint proposal, the Biotechnology Industry Organization (now the Biotechnology Innovation Organization) encouraged FDA to publish the collaboration approach in the Federal Register for public comment so it could be formally considered as agency guidance.

BIO asked the agencies to clarify aspects of the proposed multi-product, multi-company study, including the requirements governing "sponsorship" and the eligibility of individual products for specific designations, such as orphan designation. It also urged the agencies to discuss with industry ways to establish and leverage the utility of registration studies.

Extrapolation of Efficacy Data

Gaucher disease is a lysosomal storage disorder, an inherited disease that causes the build-up of fatty substances in the body due to the lack of enzymes to break them down. It is estimated to affect 6,000 individuals in the US. The guidance notes that the current standard of care in the pediatric Gaucher population in the US is enzyme replacement therapy (ERT).

The draft guidance says that previous approval of ERT for Gaucher disease in adult patients has been based upon demonstrated clinical improvements in hepatosplenomegaly and improvements in biochemical endpoints (hemoglobin and platelet levels).

"For drug development in pediatric rare diseases, it may be necessary to develop, validate and employ age-specific endpoints," the guidance states.

FDA notes that extended follow-up in a prospective study is necessary to evaluate the long-term safety and efficacy of treatment on disease manifestations in pediatric populations. The agency says patient registries are an adjunctive tool for monitoring safety and efficacy, and it recommends across-registry agreements on a uniform set of core data elements to be collected by all existing or future Gaucher disease registries.

The guidance says extrapolation of efficacy can be considered when the course of the disease and the expected response to a drug product would be sufficiently similar in the pediatric and reference population, i.e., adult or other pediatric age population.

Whenever new studies in children are deemed necessary, modeling and simulation should be used to optimize pediatric studies (e.g., design, sample size, starting doses, timing of sampling, and number of samples) and particularly to inform the dosing rationale, the guidance states.

Multi-Arm, Multi-Company Trial

The guidance includes a two-and-a-half-page table detailing the strategy for designing a multi-arm, multi-company drug development program. It applies only to systemic (non-neurological) manifestations of Gaucher disease in treatment-naïve patients with Type I and Type III phenotypes across all pediatric ages. It is not intended for neurological manifestations of the disease, for which there are currently no approved drug products.

"Although such a program can be very challenging, the aim of the strategic plan is not only to facilitate agreement on individual applications, but also to address the feasibility of developing multiple drug products for a rare disease in a time-efficient manner," the guidance states.

The proposed study design is a double-blind, controlled, randomized, multi-center, multi-arm, multi-company noninferiority or superiority trial to evaluate the efficacy and safety of "product A," "product B," product C," etc., compared to a single ERT drug product in pediatric patients with Gaucher disease Type I and Type III.

The main objective would be to evaluate noninferiority or superiority of the new drug product(s) to an approved ERT treatment. The study population would include male and female pediatric patients, from birth to younger than 18 years. And the treatment period would be two years with long-term monitoring of primary and secondary endpoints and safety conducted in an extension study.

The guidance says relevant endpoints should be chosen based on the mechanisms of action of the selected drug products and should consider the heterogeneity of the pediatric population.

Promoting Novel Trial Designs

The draft guidance reflects FDA's interest in novel clinical trial designs. It is in line with draft guidance the agency issued in November on regenerative medicine therapies for serious conditions. In that document, FDA said it might be useful for sponsors to compare several different investigational agents to each other and to a common control in studies of therapies to treat rare diseases. (Also see "Regenerative Medicine Clinical Trials: US FDA Supports Studies Comparing Multiple Agents" - Pink Sheet, 16 Nov, 2017.)

This kind of approach has been used in the oncology arena. For example, in the I-Spy 2 Phase II platform trial, 12 therapies from nine sponsors were evaluated in eight genetically defined subgroups.

FDA's Woodcock and Office of Biostatistics Director Lisa LaVange touted the use of master protocols to study multiple therapies and/or multiple diseases in a New England Journal of Medicine article published in July. (Also see "Master Protocols Are Both Welcome And Inevitable – US FDA's Woodcock" - Pink Sheet, 6 Jul, 2017.)