ALEXANDRIA, VIRGINIA—Since the 1983 passage of the Orphan Drug Act, the FDA has approved 162 orphan drugs and new chemical entities for noncancer rare diseases. The Orphan Drug Act grants the FDA flexibility in its review of these therapies, but has the FDA actually exercised flexibility in the approval process, and if it has, what is the nature and scope of that flexibility?

At the National Organization for Rare Disorders (NORD) Rare Diseases and Orphan Products Breakthrough Summit, Frank J. Sasinowski, MS, MPH, JD, reviewed the FDA’s track record with regard to the approval of novel orphan therapies. Mr. Sasinowski is a Director at Hyman, Phelps & McNamara, PC, a food and drug law firm specializing in the areas of new drug development, controlled substances, advertising, and health care law.

“Three years ago, at this very summit, I unveiled the analysis that had been done looking at how the FDA had approved the 135 orphan drugs and new chemical entities from the time the Orphan Drug Act was enacted through July 1, 2010,” Mr. Sasinowski said. “What I want to do today is present an update—what’s happened in the four years since 2010.”

A Bit of Background
In 1962, the food and drug laws were changed to require that the sponsor of a new drug show by substantial treatment effectiveness that a drug has a benefit. This was to be done through adequate, well-controlled studies, which was interpreted to mean two. But for rare disease therapies, that presented unique challenges. The Orphan Drug Act addressed some of these challenges but did not change the quantity of evidence that was necessary for approval.

In 1983, Mr. Sasinowski was working at the FDA. It was his original analysis of the Orphan Drug Act that led to the 1984 and 1985 amendments to the law that made it work. Of the 135 drug approvals reviewed for the original analysis, Mr. Sasinowski was personally involved in about 20%. Of the 27 approvals since the original analysis, Mr. Sasinowski was again involved in about 20%. “I know the law and I know how much evidence the FDA needs to make an approval,” Mr. Sasinowski said.

For his original analysis, Mr. Sasinowski gathered all the statistical and medical reviews of the 135 new chemical entities that were approved up to July 1, 2010. “It filled 27 boxes, and I personally read 27 boxes of medical and statistical information,” he said. He then classified each approval into one of three categories.

“The first thing I did was to see whether there were two adequate, well-controlled studies that met their primary end points by their prespecified primary analysis,” Mr. Sasinowski continued. “I classified those as ‘conventional.’ Those were not different from anything else—that is, they would have been approved if they were for hypertension. And that’s all I was going to do. I was just going to say conventional or not.” The ‘not’ category would mean regulatory flexibility.

But one senior FDA official, Dr. Robert Temple, suggested providing more detail. “So after I declared that an approval wasn’t conventional, I then determined whether it was based on administrative flexibility,” which was defined as one of those systems the FDA has in place (such as Subpart H, which is also called accelerated approval or fast track, or another formal regulatory system such as FDAMA 115), or if not approved under administrative flexibility, then the approval was classified as an example of case-by-case flexibility.

Ninety of 135 orphan drug approvals (67%) from 1983 to 2010 resulted from some exercise of FDA flexibility. “Two thirds of all the orphans that were approved were approved with some form of flexibility. This shows that the FDA was exercising reasonable, appropriate, science-based flexibility in its review and approval of these applications,” Mr. Sasinowski said. While the concept might not have been surprising, the numbers were. “It really startled people. This was a game changer.” People had a vague sense that the FDA was treating orphans different, “but until I did the analysis, no one knew what that really meant—no one at FDA, no one in industry, no one in academia or in the investment community,” Mr. Sasinowski said.

That Was Then, This Is Now
The original findings set the stage, but an update was needed. “We were looking to see whether that degree of lexibility that we saw in the first 27 years of the FDA’s implementation of the Orphan Drug Act was still occurring in the last four years,” Mr. Sasinowski said. He and his colleagues undertook an analysis of the 27 new orphan drugs approved in the past four years (again excluding cancer therapies), and the results were exactly the same as in the original analysis. About two-thirds of the approvals for rare disease therapies involved some form of flexibility. Specifically, 19 orphan products were approved through regulatory flexibility. Most of them (14) were approved with administrative flexibility. An additional five required case-by-case flexibility. The remaining eight products that were approved met conventional evidentiary requirements.

“The FDA is maintaining the same level of flexibility, which is commendable,” Mr. Sasinowski said. “The FDA continues to show the same degree of flexibility that it has since the beginning.”

—Glenn S. Williams

Exploring the FDA’s Flexibility With Novel Orphan Therapies