The US Food and Drug Administration (FDA) should formulate a Statement of Policy enshrining a more flexible approach to the approval and regulation of orphan drug products, argues the National Organization for Rare Disorders (NORD).

The organisation believes an explicit, formal policy statement will encourage more investment in, and research and development of, medicines for rare disorders – especially for the 20 million Americans with one of the 5,800 or so rare conditions for which there are still no FDA-approved therapies.

Feedback from stakeholders indicates that the US agency “delivers a consistent, repeated message that the statutory standards for safety and efficacy are the same for both rare disorders and prevalent diseases”, noted Frank Sasinowski, chairman of the NORD board of directors.

“What is not often heard is the companion portion that completes that statement,” he added – namely, “while the statutory standards are the same, the FDA interpretation and application of those same standards have historically been tailored by FDA to the unique facts of each particular medicine under FDA review”.

There are also FDA regulations and guidances expressing this flexibility, while the agency’s actions in response to marketing applications “eloquently embrace and express this concept”. Yet, Sasinowski warned, the message “apparently is not being heard by some of the key stakeholders in this system”.

Hence the need for a specific Statement of Policy including “an explanation and
affirmation of the FDA’s historic position that FDA flexibly applies the standards of safety and effectiveness with respect to therapies for those with rare disorders”.

Sasinowski was delivering the opening address at a two-day public hearing on Considerations Regarding FDA Review and Regulation of Articles for the Treatment of Rare Diseases, sponsored by the agency and held at its Office of Orphan Products Development in Silver Spring, Maryland.

As Tim Cote, director of the Office, pointed out in his opening remarks, an amendment to the FDA’s appropriations bill for 2010 required the agency to “convene a committee of expert FDA employees to consider the ways the Agency reviews articles [i.e., drugs, biologics and medical devices] to treat people with rare diseases, and consider policy improvements that might help people with rare diseases get better treatments faster”.

The opinions aired at the public hearing will help inform a report to Congress on orphan product development and regulation. This report, as well as a subsequent FDA guidance document, will be drafted by Dr Elizabeth McNeil, executive secretary of the so-called Section 740 Committee. Cote is chairman of the expert committee.

No policy at all

The existing FDA policy for the review of drugs and biologics for rare diseases “is no policy at all”, Cote acknowledged.

While “we’ve accumulated a large collection of new therapies for rare diseases, and the basis of their approvals has exemplified flexibility and reasonableness in FDA’s evidentiary demands, this has been done on a case-by-case basis”, he observed. “The process has been practical and very productive, but the policy remains no policy.”

The key question, Cote suggested, was how to find the right balance between speed and diligence in reviewing orphan products. “Today, FDA’s marketing approval means we know a drug really works, not that we think it might work, and that it’s reasonably safe. How do we defend that standard while reckoning with the great urgency of now experienced by the parent of a sick child?”

Since its enactment 27 years ago, the US Orphan Drug Act has proved “a resounding success”, with more than 350 new medicines for over 200 different rare disorders approved to date, Sasinowski told the hearing.

A recent review by the Tufts Center for Drug Development found that the number of orphan drug designations in the US had more than doubled over a decade, from 208 during 2000-02 to 425 in 2006-08.

However, many of the people affected by conditions for which no therapies are available “do not even see any research being conducted in their conditions”, Sasinowski added. “To NORD, this seems as though the proverbial low-hanging fruit have already been harvested in the first quarter of a century of the law’s existence, while the vast majority of therapies are currently out of reach of those in need of an FDA-approved medicine.”

As well as delivering a formal statement of policy, the organisation wants the FDA to reduce regulatory uncertainty around rare disease therapies. Given the knowledge gaps characteristic of the sector, it is “entirely understandable that FDA on occasion will find it difficult to concur in advance with a development programme, even the design of a registrational trial under a special protocol assessment”, Sasinowski commented.

“However, researchers, industry and FDA, as well as most importantly, persons with the condition, may find that sometimes a study needs to proceed because patients are suffering and cannot wait for the perfect trial design with the ideal primary endpoint to be eventually determined or developed and consensually accepted.”

BIO recommendations

Around one third of US orphan drug approvals over the last decade have gone to the biotechnology industry, which also wants to see better incentives for product development to fill the current gaps in provision.

“The challenges of developing orphan products are great and they require innovative policy and regulatory solutions,” said Sarah Radcliffe, executive vice president, health for the Biotechnology Industry Association (BIO), in written comments submitted to the FDA hearing.

“Further, many rare diseases affect far fewer patients than the 200,000 threshold in the Orphan Drug Act (ODA). For these diseases, the challenges are even more daunting.”

Among BIO’s policy recommendations are:

- Increased funding for the Orphan Drug Grant Program created by the ODA and administered by the FDA.

- A longer market exclusivity period for designated orphan product to match the 10 years available in Europe. At the moment, orphan products in the US get seven years of exclusivity.

- A more predictable approval pathway for orphan products, including publication of promised FDA guidance on clinical trial design and new methods of statistical analysis.
- A review of FDA standards used to determine the efficacy of rare disease products, taking into account the small patient populations involved.

- More guidance on the use of surrogate endpoints for orphan product approvals.
- Better communications processes at the FDA for rare disease stakeholders.