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Blog: Successful Methods for Obtaining Orphan Drug Approval

Signed into law on January 4, 1983, the Orphan Drug Act (ODA) allows for granting special status to a drug or biological product (drug) to treat a rare disease or condition upon request of a sponsor. This status is referred to as orphan designation, or orphan status. For a drug to qualify for orphan designation, both the drug and the disease or condition must meet certain criteria specified in the ODA and US Food and Drug Administration’s (FDA) implementing regulations per 21 CFR Part 316. The FDA Office of Orphan Products Development (OOPD) evaluates the scientific and clinical data submission from sponsors to identify and designate products as promising for rare diseases or conditions.

Orphan status may be granted to drugs and biologics intended for the safe and effective treatment, diagnosis, or prevention of rare diseases/disorders that affect fewer than 200,000 people in the US, or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug. Designations are granted for a specific drug for use with a specific disease. The approval of orphan drugs, like all other drugs, is based upon evidence of the safety of the drug and efficacy for the treatment/prevention of disease.

When reviewing rare disease designations one must also consider FDA’s designation of breakthrough therapies: drugs intended to treat a serious condition when preliminary clinical data shows that the drug may demonstrate significant improvement over available treatments.

Sixty percent of the 87 breakthrough therapy drugs approved since 2013 are indicated for rare diseases. The FDA grants priority review to drugs that treat a serious condition.

The number of orphan drug approvals has increased in recent years as a result of novel agents and new indications. The majority of orphan drug products were initially approved to treat rare diseases and do not see growth in the non-rare sector. Approximately 12 percent of drug products were initially approved for a non-orphan designation and subsequently approved for orphan status. Since 1983, over 600 drugs and biologics have been developed and marketed for rare diseases. In contrast, since 1983 over 770 drugs and biologics have been developed and marketed for rare diseases, with more than 560 medicines in the current biologics pipeline. Cancer treatments and blood therapies have accounted for the highest number of drugs to receive orphan drug designations. In light of this seemingly successful uptick in approvals, only 5 percent of rare diseases currently have an approved method of treatment.

A sponsor seeking orphan designation for a drug must submit a request for designation to OOPD with the information required in 21 CFR 316.20 and 316.21. Each designation request must stand on its own merit. Sponsors requesting designation of the same drug for the same rare disease or condition as a previously designated product must submit their own data and information in support of their designation request. The granting of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. Safety and efficacy of a drug must be established through adequate and well-controlled studies.

The agency realizes that some aspects of the drug development process are not feasible for rare diseases. Therefore there is some flexibility in the application of regulations when discussing orphan drugs. However, there are several aspects of drug development that can impact the process potentially leading to more efficient development and more productive meetings with the FDA:

  • Adequate description and understanding of the disease’s natural history– a natural history study can provide information about the disease, guide the clinical studies, and aid the designing of an efficient drug development program.
  • Adequate understanding of the pathophysiology of the disease and the drug’s proposed mechanism of action is a valuable channel to assess drug development. Among other things this information can be used: to define study endpoints, determine when to treat patients as the disease progresses, and identify new biomarkers.
  • Nonclinical pharmacotoxicology considerations for the proposed clinical investigation or investigations— supporting the safety aspect of the drug and also providing additional information regarding the drug’s mechanisms of action. The data obtained will support early stage clinical study design including the following: selecting the dose level and regimen and route of administration. FDA acknowledges that for most rare diseases an animal disease model does not exist. FDA encourages early pre-IND meetings to discuss non-clinical development pathways.
  • Reliable endpoints and outcome assessment— for many rare diseases a well-characterized efficacy endpoint relevant to the disease is not available. Assessment tools should be developed or modified early in the process to allow adequate time to develop and evaluate the tools to be used in clinical studies.
  • Standards of evidence to establish safety and effectiveness. The requirement that a drug has substantial evidence to have its claimed effect is not waived for orphan drugs. Studies need to be able to “distinguish the effect of a drug from other influences, such as spontaneous changes in the course of a disease, placebo effect or biased observation.(FDA, 2018).”  Regulations govern the essential elements that determine if a study was adequate and well-controlled. The FDA encourages early and frequent communication throughout the development process to identify appropriate clinical trial designs for the patient population and the disease being studied.
  • Drug manufacturing considerations during drug development— Chemistry, Manufacturing, and Controls (CMC) development plans should be discussed openly, frequently, and begin early in the process to decrease developmental or approval delays related to manufacturing. Consideration should be given to changes in manufacturing and whether bridging studies might be required.

On June 29, 2017, the FDA unveiled a strategic plan, known as the Orphan Drug Modernization Plan, to completely eliminate the agency’s existing orphan designation backlog and ensure continued timely response to all new requests for designation with firm deadlines. Scott Gottlieb, M.D., former commissioner of the FDA, communicated on Sept 12, 2017 that review of all orphan drug designation requests older than 120 days was completed on August 28, 2017. He further stated that new policies are being implemented to ensure the 90 day review timelines are met to prevent backlogs. The article also cited several incentives that go along with the Orphan Designation:

  • Tax credits of 50 percent for expenses incurred during clinical research and testing
  • Prescription drug user fees are waived unless an indication for a non-rare disease or condition is designated
  • FDA grants seven years of marketing exclusivity upon approval

Gottlieb also noted that some sponsors are using orphan drug designations as a way to circumvent other public health goals established by Congress. The FDA will issue guidance documents and other policies to address these issues and to ensure sponsors are adhering to the appropriate regulations. The FDA will continue to issue guidance documents and other policies to address these issues and to ensure sponsors are adhering to the appropriate regulations. For instance, Rare Diseases: Common Issues in Drug Development Guidance for Industry was issued as a draft in January 2019 to replace the guidance issued in August 2015.  The incentives seem to be driving an increase in the number of investigative drugs targeting the treatment of rare diseases as approximately 300 of the 800 clinical trials involved treatment for rare diseases.

Alcami is an experienced partner for developing and manufacturing orphan indication drug products— supporting client projects in over 35 countries around the world. All of our facilities are in good standing with all regulatory authorities including DEA, EPA, OSHA with successful regulatory inspections from the FDA, TGA, PMDA, MHRA, Health Canada, MPA, IMB, and more. Our experts provide guidance on the latest industry guidelines and the best approach tailored to each client’s specific needs.

Editor’s Note: This post was originally posted in August 2018 and has been updated to reflect new information and statistics in regards to the topic from 2020.


FDA. (2018, July). CFR - Code of Federal Regulations Title 21. Retrieved from

About the Author
Andrea Young 
is the Supervisor of Regulatory Compliance at Alcami. She has over 18 years of experience in the pharmaceutical industry, and has spent nine years providing both internal and external support for regulatory related matters. She also has cons
iderable experience in Quality. Andrea has a Bachelor of Science degree in Biology from St. Bonaventure University, and an MBA from the University of North Carolina Wilmington.

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