New FDA Guidance Addresses Common Issues in Orphan Drug Development

Regulatory NewsRegulatory News
| 17 August 2015 | By Michael Mezher 

The US Food and Drug Administration (FDA) has released a draft guidance intended to help drugmakers tackle common issues encountered in the development of drugs to treat rare diseases.


In the US, orphan drugs, or drugs used to treat rare diseases which affect fewer than 200,000 people, are given incentives, such as a longer period of marketing exclusivity, tax credits and user fee waivers.

These incentives were first instituted with the passage of the 1983 Orphan Drug Act, which sought to spur the development for rare conditions that often went overlooked by the pharmaceutical industry.

In recent years, orphan drugs have made up an increasing portion of FDA's approvals, and there has been progress toward treating many disease areas that were previously underserved.


FDA says its new guidance should help resolve some issues that are particularly challenging for orphan drug developers:

  • "Adequate description and understanding of the disease's natural history
  • Adequate understanding of the pathophysiology of the disease and the drug's proposed mechanism of action
  • Nonclinical pharmacotoxicology considerations to support the proposed clinical investigation or investigations
  • Reliable endpoints and outcome assessment
  • Standard of evidence to establish safety and effectiveness data
  • Drug manufacturing considerations during drug development"

While the issues addressed in the guidance also occur in other areas of drug development, the agency says these particular issues are "more acute with increasing rarity of the disorder" the drug aims to treat.

The guidance encourages companies to conduct research into disease pathophysiology, saying greater understanding of how diseases work can lead to the identification of meaningful biomarkers and distinct variations of individual diseases.

While companies should generally conduct nonclinical studies to determine toxicology information to show that a drug is "reasonably safe to conduct the proposed clinical mechanism of action," FDA says there are limited cases where companies may be authorized to conduct clinical studies before toxicology studies for certain "serious or life-threatening diseases where current treatments, if any, are inadequate."

The guidance also goes on to provide explanations of FDA's requirements and flexibilities for considering evidence of effectiveness and safety and includes a section covering chemistry, manufacturing and controls specifically geared toward issues encountered with drugs to treat rare diseases.

Natural History Studies

FDA is hoping to see more drugmakers conducting natural history studies to gain greater knowledge about the specific diseases.

A natural history study looks at the entire progression of a disease from just before its beginning, through each phase of the disease lifecycle, to its conclusion (patient is cured, symptoms managed or alleviated or patient dies). By conducting these studies, FDA says companies will be able to design more efficient drug development programs:

  • "Defining the disease population, including a description of the full range of disease manifestations and identification of important disease subtypes
  • Understanding and implementation of critical elements in clinical study design, such as study duration and choice of subpopulations
  • Developing and selecting outcome measures that are more specific or sensitive to changes in the manifestations of the disease or more quickly demonstrate safety or efficacy than existing measures
  • Developing new or optimized biomarkers that may provide proof-of-concept (POC) information, guide dose selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy. In some cases, biomarkers can be used for surrogate endpoints."
  • FDA also announced today that it will be funding the development of a natural history database for rare diseases in partnership with the National Organization for Rare Disorders (NORD).
Draft Guidance


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