Multi-Company, Multi-Product Clinical Trials On The Cards For Rare Pediatric Diseases

Executive Summary

Industry is guardedly optimistic about a new joint proposal from US and EU regulators for companies to test their drugs for rare pediatric diseases together in single multi-product studies.


Developers of medicines for rare diseases in children should consider the possibility of testing their products in multi-company, multi-product studies, according to a joint proposal by regulators in the US and the EU. 

The proposal, published on July 3, seeks to facilitate the development of medicines for rare pediatric diseases, an area where there is typically only a small number of patients available to take part in trials.

Drug sponsors should also make better use of extrapolating available clinical data, the Food and Drug Administration and the European Medicines Agency say. They should extrapolate available data, including through appropriate modeling and simulation techniques, to predict how their product might work in children and adolescents based on studies conducted in adults or other pediatric populations.

The proposal, published as a “strategic collaborative approach” document, focuses on drug development for Gaucher disease, but its underlying principles can apply to other rare diseases in children, the agencies say. 

By testing the safety and efficacy of medicines developed by different companies in one single trial (so-called multi-arm, multi-company clinical trials), the same control arm would be used to compare more than one medicine under evaluation, the EMA explained. This would facilitate the clinical testing of drugs and reduce the total number of children included in trials.

Limitations Of Simultaneous Drug Development

The regulators recognize there are inherent limitations and challenges to conducting simultaneous drug development programs. Legal and regulatory issues concerning such things as governance and funding of a study (sponsorship), and eligibility for EU and US pediatric reward/incentives, would need to be dealt with on a case-by-case basis.

Developers who wish to use the new approach in their development plan are advised to seek scientific advice either from the EMA or the FDA separately, or request parallel scientific advice from the two regulatory authorities. The new document should not be interpreted as formal guidance, the agencies say.

“Specifics should be determined following discussions with the individual regulatory agencies if it is deemed appropriate and feasible by both the sponsors and the regulatory agency,” the regulators explain in a documentcomprising stakeholder comments on a draft version of the new approach.

“A multi-product, multi-company development programme raises certain regulatory/legal questions” – EFPIA

A range of other conditions would benefit from the new collaborative approach, according to one of the stakeholders’ comments. These include hepatitis C and Duchenne muscular dystrophy, the stakeholder said, adding that the approach “would be relevant for Fabry Disease and Pompe’s Disease where a number of new treatments are on the horizon.”

EFPIA Cautiously Optimistic

European pharmaceutical industry group EFPIA is cautiously optimistic about the new approach.

It told the Pink Sheet that while it welcomed the authorities' “openness to consider alternative clinical trial designs that address the specificities of small trial populations,” it had concerns. “A multi-product, multi-company development programme raises certain regulatory/legal questions,” it explained.

As well as the issue of governance and funding of a study, EFPIA said that questions are likely to include, but are not limited to, eligibility for and timing of pediatric reward/incentives, and the potential for a PIP (EU pediatric investigation plan) for a new product to be submitted during the course of such a program.

“Together with individual product characteristics (including route of administration), these must be taken into account in determining on a case-by-case basis whether a multi-arm, multi-company trial may be the optimal approach for a new compound,” it said.

Another important question EFPIA says needs to be considered is: when adopting a multi-product, multi-company study, would the PIP applicant be expected to develop additional clinical studies in pediatric patients depending on the specific medicinal product/mechanism of action, or would the EMA’s Paediatric Committee not require/waive additional studies?

“A multi-product, multi-company development programme may indeed take away some of the constraints around multiple studies competing for the same pool of eligible paediatric patients,” EFPIA commented. “Nevertheless, such a programme per se does not address most areas of unmet medical need.”

While questions remain, the trade group said it “welcomes the fact that platform, basket and other types of new, more collaborative trial types and designs continue to be investigated for all ranges of disease.” These will be considered in new, large-scale pilots within the framework of the EU’s public-private partnership, the Innovative Medicines Initiative, with the support of global heads of R&D, EFPIA said.

“This is also in line with the recently revised ICH [International Council for Harmonisation] E11 guideline which, in its addendum, promotes the use of innovative study design, which can be supported by regulators provided justified, appropriately conducted, and agreed beforehand with those regulators.”

Strategic Collaboration On Gaucher disease

As for the newly published strategic collaborative approach, the EMA and FDA discuss possible ways to enhance the efficiency of medicine development in Gaucher disease, a rare lysosomal storage disorder.

Gaucher disease is being used as a disease model, the document notes, clarifying that the principles in the document may be extended to other areas of drug development in rare diseases. In addition, different approaches may be proposed and the applicant should justify the specific choice of each new strategy, the document states.

“Due to differences in the regulatory requirements of both Europe and the United States, particularly regarding extrapolation of efficacy from adults to children, additional trials may be required to support an application for approval,” it adds.

The document deals with general considerations for study population, and practicalities in the design and execution of pediatric trials of drugs for Gaucher disease, and covers the use of extrapolation of efficacy data for the disease.

It also proposes a multi-arm, multi-company trial for non-neurological manifestations of Gaucher disease. This proposal covers issues such as study design features; study population and subset definition; number of study participants by pediatric subset (e.g., age, sex, severity or stage); main inclusion criteria; main exclusion criteria; study duration for participants; dosage, treatment regimen, and route of administration; controls; endpoints with times of assessment; statistical plan (SAP) including study conduct and analysis; measures to minimize pain and distress; and external independent data safety monitoring boards.