Rare Disease Products Mostly Approved With Regulatory Flexibility, NORD "Catalog" Finds

NORD makes the case that FDA should codify unconventional approaches by arguing that the agency already uses them for two-thirds of its orphan approvals.

The National Organization for Rare Disorders' campaign to get FDA to codify a flexible approach on approving orphan drugs is now bolstered by an analysis that concludes most of the agency's approval decisions for such products already use unconventional efficacy standards.

NORD's report, slated to be released by the association on Oct. 11, examines the 135 non-cancer orphan therapies approved as new molecular entities since the passage of the Orphan Drug Act in 1983 through June 2010.

The report classified approvals as one of three types: "conventional" (the classic standard of two adequate and well-controlled trials); "administrative flexibility" (formal, established mechanisms for scientific discretion, including accelerated approval and the May 1998 evidence guidance); or "case-by-case flexibility" (essentially a category by exclusion - approvals for which the efficacy evidence presented did not meet the criteria for either of the first two categories, but FDA still made a positive decision).

Conventional approvals accounted for 45 of the 135; those with administrative flexibility accounted for 32; and case-by-case flexibility accounted for the preponderance of approvals, with 58.

Those last two numbers are strong evidence that FDA routinely takes a flexible approach in orphan drug reviews, NORD argues, and the agency should formalize that methodology in such a way to create guide posts for sponsors and agency reviewers alike.

The catalog of FDA's past decisions can serve as an inspiration for reviewers to make similar decisions in the future, the association hopes.

The Latest Nudge

The report is NORD's latest attempt to nudge the agency towards more formal flexibility. Other efforts to get the agency to commit have included testimony at a public meeting last year, a citizen petition last month asking for specific guidance language, and, in the week before the report was released, letters to FDA asking for increased patient involvement in risk-based regulatory decisions.

NORD has so far stuck to the position that it does not want to reopen the Orphan Drug Act itself, for fear that a legislative effort to enshrine FDA flexibility could invite unwanted tinkering with other aspects of the program (Also see "NORD Says Orphan Drug Act Is Fine As Is, Wants To Work For Improvements Within System" - Pink Sheet, 29 Jun, 2011.).

But the group has employed congressional pressure in other ways; the public meeting where NORD testified in 2010 and the upcoming guidance it hopes to influence are the result of language included in Senate appropriations bills at its behest.

Replacing A "Half Truth" With A "Proud History"

NORD's report was written by Frank Sasinowski, chairman of the association's board and a director in the law firm Hyman, Phelps & McNamara.

In an interview, Sasinowski said that he hoped the report would "inform all the key stakeholders - not the least of which will be FDA's medical and statistical reviewers - who will then understand that FDA has a proud history of having exercised good scientific discretion" in orphan approvals.

"It's not that they've watered down the rules for orphans out of some sense of sympathy for people with rare diseases - not at all - it's good science. ... And what we have done for the first time is a systemic review so the whole world can see it," Sasinowski said.

Problems with the review of orphan drugs sometimes arise, Sasinowski said, when reviewers or advisory committee members more accustomed to the size and quantity of trials of products for prevalent conditions encounter the more limited datasets associated with orphan products.

"When advisory committees used to seeing massive trials with thousands of subjects for diabetes, hypertension, hyperlipidemia look at something [orphan] for consideration and it's got a single study in less than 30 people, they turn to the FDA and say, 'What are we to do with this?'"

"And too often what FDA would say is what I would characterize as a half truth. What FDA would say is, 'The 1983 Orphan Drug Act did not change the statutory standards for how much efficacy data need to be supplied in order to support a marketing application.' That is exactly correct," Sasinowski said.

"But to make the statement accurately reflect the FDA's history of actions on orphan drugs, the FDA should, in my opinion, also say - and sometimes has said, but should always say - 'And we, FDA, know how to apply scientific discretion and flexibly in interpreting and applying the statutory standards for efficacy'" of orphan drugs.

Surprisingly Strong Results

"There are some people inside FDA who fully embrace this, but there are other people inside FDA who might be unaware of it," Sasinowski said. But that shouldn't be seen as an FDA problem in particular, he said - because even he was surprised by the results of the study.

"I went into this whole process totally agnostic," Sasinowski said. "I probably have helped in a major way with about 30 of these 135 so it's not like I don't know this world. I know this world very well. And yet my guesstimate when I first laid out these categories was that maybe a third ... would manifest flexibility. It turns out two-thirds did."

"So even a person like me who spent 25 years working in this space, I didn't appreciate it. So how can you expect someone who is an FDA reviewer, who is primarily working on drugs for obesity and type 2 diabetes - prevalent diseases" - to take a different approach to datasets when reviewing a product for familial homozygous hypercholesterolemia?

Consistent Flexibility Over Time

Breaking the results down temporally shows FDA has exhibited flexibly consistently over the years. Of the orphan drugs approved in the 1980s, 14 (66.7%) showed some form of flexibility; in the 1990s, 38 approvals (64.4%) did, and in the 2000s, another 38 approvals (69.1%) showed flexibility.

And while six of the last 10 orphan products charted in the report were approved using conventional efficacy criteria, Sasinowski does not see this as a worrisome trend because of FDA's consistent track record of using scientific discretion when reviewing treatments for rare diseases.

What Flexibility Can Mean

As for what specifically FDA could do to show flexibility in its approval requirements for orphan drugs, NORD's report suggests, "for instance, where the potential number of subjects is limited, the degree to which FDA demands dose selection to be optimized in pre-approval studies may be reduced, as can FDA's requirements for validation of a patient-reported outcome instrument in a rare disorder population or proof of the sensitivity, specificity and clinical meaningfulness of a primary endpoint."

The report acknowledges that "given that each investigational therapy for a rare disorder will present unique features, NORD understands that the granularity of the requested statement of policy on rare disorder therapies may necessarily be limited."

Investors Are Also Audience

The report's impact should not be felt solely at FDA, NORD President and CEO Peter Saltonstall said in an interview.

"I thought it was really important to be able to demonstrate to potential investors and to patient organizations the fact that the FDA really has been flexible," Saltonstall said.

"They are willing to be flexible, willing to look at smaller populations, willing to think outside the box. And even though they always said that, no one has ever documented it."

"They are not perfect, but we wanted to demonstrate the fact that with orphan products they certainly have shown flexibility and for us that's a really important aspect of bringing companies and bringing investors into the space."

- M. Nielsen Hobbs ([email protected])