New, Revised FDA Guidelines for Rare Diseases: Common Issues in Drug Development

An encouraging article recently published in Sickle Cell Anemia News announced that due to the urging of pharmaceutical companies and patient advocacy groups, the FDA has produced an updated draft “Guidance for Industry.” A large part of the update originates from feedback received after the prior draft was issued.

The FDA’s new guide discusses issues that arise involving rare diseases. It expands upon its 2015 version that covers the development of drugs used to treat rare diseases. One of its goals is to increase the efficacy of testing drugs in clinical trials.

Natural History (NH) and Biomarkers

The guide offers revisions on natural history studies and discusses ways in which they may be utilized as a measure of whether or not the treatment has promise.

The FDA draft suggests that there is a limited understanding of the natural history of rare diseases. It recommends that these studies be conducted as early as possible during a drug’s development.

Although natural history studies are generally not required for clinical trials, the FDA suggests reviewing existing studies to see if they may be applicable.

In this regard, the FDA has a long list of recommendations:

  • The NH studies  should be of reasonable length
  • Data is to be gathered from many different sources
  • Data should be based on features of the disease
  • Patients should be selected with varied stages of the disease
  • Select patients with varied  symptoms and traits
  • Standardize medical terminology and collection methods

The FDA asks that the data from the NH studies be made available to the public. Also see The NORD Natural History Study Database. 

Information on “efficacy endpoints” is also provided. Endpoints are defined as the ability of the new drug that is being tested to prove a substantial therapeutic benefit.

And in another section, the guide discusses how biomarkers could be identified. Biomarkers are used to analyze and predict the effect of treatment on a disease.

The Guide’s 24 pages include:

  • The evaluation of treatment substances in a non-clinical setting
  • A new entry about safety questions
  • More information concerning the process of manufacturing a compound
  • Quality issues concerning pharmaceuticals
  • Communicating with the FDA

CDER and CBER, two of the FDA’s Centers issued the draft.

The new Guide explains that increased knowledge of these rare diseases will enable the researchers to identify disease subtypes. It will also allow the researchers and sponsors to establish a more defined patient group and thus be able to match these patients to the goals of the trial.

The FDA and the patient advocacy groups are working together to design rare-disease clinical trials with improved endpoint goals rather than depend upon placebo groups.

The draft will be listed on the Federal Registry through NORD, at which time the agency will accept the posting of comments.


Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia (AML) six years ago. During this period of partial remission, Rose researched investigational drugs to be prepared in the event of a relapse. Her husband died February 12, 2021 with a rare and unexplained occurrence of liver cancer possibly unrelated to AML.

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