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Orphanet J Rare Dis. 2015 Feb 10;10:16. doi: 10.1186/s13023-014-0195-4.

Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

Author information

  • 1EveryLife Foundation for Rare Diseases, Novato, CA, USA.
  • 2BioMarin Pharmaceutical Inc., Novato, CA, USA.
  • 3Genzyme Corporation, Cambridge, MA, USA.
  • 4Synageva BioPharma Corp., Lexington, MA, USA.
  • 5Vertex Pharmaceuticals, Cambridge, MA, USA.
  • 6Genzyme Corporation, Cambridge, MA, USA.
  • 7Parent Project Muscular Dystrophy, Middletown, OH, USA.
  • 8Shire, Lexington, MA, USA.
  • 9Shire, Lexington, MA, USA.
  • 10Pfizer Inc., Cambridge, MA, USA.
  • 11Sarcoma Foundation of America, Damascus, MD, USA.


For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into FDA approvals for rare disease therapies. The focus of this paper is on the situation in the Unites States, but the recommendations are reasonably applicable to any jurisdiction.

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