Opinion: As it turns 40, the Orphan Drug Act for rare diseases needs a refresh

This month marks the 40th anniversary of the Orphan Drug Act. Since it was signed into law in 1983, the FDA has approved more than 1,100 treatments for rare diseases. The act also created an industry that didn’t exist in the United States before its enactment, enabling the formation of companies to develop and commercialize therapies for rare diseases.

That said, a lot has changed in science and drug development since 1983. The human genome was sequenced in 2003. It is now possible to treat diseases with gene therapy, antisense oligonucleotides, messenger RNA (mRNA), noncoding RNA (known as small interfering RNA, or siRNA), and other gene-based modalities. New ways of conducting clinical trials have also emerged.

Given these scientific and technological advancements, it is time to reevaluate the 40-year-old Orphan Drug Act so it can usher in the next era of rare disease drug development.


Diseases with extremely small patient populations — ultrarare diseases — deserve to have the best science applied to their care and provide society the true benefits that ongoing research affords.

In 2022, many companies ceased development of their therapies for ultrarare diseases — especially gene therapies — due to the regulatory and commercial difficulties inherent in bringing them to market. Today, the promise of innovations in precision medicine remains out of reach for the rarest diseases, even though solutions may finally be on the horizon.


This is exactly the “orphan” situation that existed decades ago as companies abandoned products aimed at treating rare diseases which then, as now, are defined as those affecting fewer than 200,000 Americans. If legislators and the FDA don’t adapt the clinical and regulatory framework to keep pace with scientific advancements, innovation will continue to be stymied.

I believe that what’s needed to make drug development for ultrarare diseases more viable is the creation of a framework that is complementary to the incentive system the Orphan Drug Act created for rare diseases. This framework must include better access to the accelerated approval pathway using the best science to ascertain that drugs are treating the underlying cause of disease while shortening development time and reducing the extreme costs of ultrarare disease drug development.

In tandem with better treatments, better and faster diagnosis of these diseases is also needed. That requires widespread insurance coverage of genetic testing for individuals suspected of having a serious genetic disorder. Earlier diagnosis is essential for more effective treatment. Access to early and affordable diagnosis would also help solve two other big problems: it would support better care for underserved populations and it would provide a pool of patients to support clinical development of new therapies.

Just as Rep. Henry Waxman (D-Calif.) and Sen. Orrin Hatch (R-Utah) did with the Orphan Drug Act, a new set of leaders today must set the course for the next era of rare disease drug development to ensure continued innovation, cement America’s leadership in this space, and deliver much-needed treatments for people living with rare and ultrarare diseases.

It’s time for an Orphan Drug Act 2.0 that advances health equity

The challenges associated with conducting clinical trials for extremely small patient populations have been well-documented. As companies terminate programs due to barriers to developing therapies for ultrarare diseases, non-profit organizations, often founded by parents of children with rare diseases, have formed to develop treatments. Not all parents, however, can secure significant funding or quit their jobs to advance a treatment for their child’s disease, creating a problem in terms of health equity. In addition, the development of drugs by teams with more limited experience and without sufficient resources can be prone to failure or less effective development.

I believe that Congress should pass new legislation — I’ll call it the Orphan Drug Act 2.0 for now — that extends the current act, defines rare diseases affecting fewer than 2,000 people in the U.S. as ultrarare diseases, and creates a framework that encourages commercial development of therapies for such diseases.

Why 2,000? It serves as an appropriate threshold as it represents 1% of the number currently used to define rare diseases in the U.S. Rare diseases with larger populations, like hemophilia and sickle cell disease, have had more intrinsic interest in investment in developing treatments. Two thousand and fewer is also the size of populations in which the financial issues of drug development become a barrier. I see an ultrarare disease framework consisting of the following elements:

  • Qualifying biomarkers, particularly primary disease activity biomarkers, as primary endpoints in pivotal clinical trials for treatments targeting the underlying cause of disease
  • Accepting alternative designs and analyses for ultrarare diseases when traditional randomized studies are difficult to conduct
  • Offering a 50% tax credit to defray the cost of clinical trials, plus 10 years of marketing exclusivity, and waiver of application user fees

The ability to more easily qualify biomarkers is essential. When a company seeks to use a biomarker in lieu of a clinical endpoint, current regulatory practice is to make a case-by-case assessment, which is neither efficient nor effective. Given the standard position taken by regulatory authorities, companies rarely, if ever, get biomarkers accepted — even with good science supporting them. This cautionary approval practice has profoundly harmed the development of ultrarare disease therapies.

Needed here is a change in policy and specific guidance from the FDA with respect to how biomarkers can be qualified for use in clinical trials, especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical.

The capability to treat ultrarare diseases has vastly increased over the last 40 years. The scientific advancements that have made this possible have surpassed what the Orphan Drug Act was designed to achieve. What worked in 1983 isn’t working well in 2023. It’s time for a new framework and policies so people living with rare and ultrarare diseases and their families aren’t left behind.

Emil Kakkis, a medical geneticist, is the founder, president, and CEO of Ultragenyx Pharmaceutical, a company focused on developing treatments for rare and ultrarare diseases. He is also the founder of the EveryLife Foundation for Rare Diseases and currently serves on its board of directors.

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Source: STAT