Lawmakers Push FDA To Clarify Special Protocol Assessment Rescissions

June 19, 2014

by Erin Durkin

Senate and House appropriators are pushing FDA to explain the standards it uses for rescinding special protocol assessment (SPA) agreements. An industry expert said that FDA's lack of transparency when changing these agreements inspired the language appropriators tucked into report language accompanying their agricultural funding bills, and the congressional inquiry is backed by the Biotechnology Industry Organization.

James Healy, a non-executive director at Amarin, Hyperion, InterMune and other private biotech companies, a general partner at Sofinnova Ventures and a member of the board of directors of the National Venture Capital Association, said the language was included because FDA has started ignoring the scope of fully negotiated SPA agreements and recently rescinded a SPA after a successful clinical trial, without transparency and based on questionable basis weeks before an expected approval.tag

A SPA agreement is an agreement between a drug manufacturer and FDA on the design and size of studies and clinical trials that can be used for approval of a drug or biological product. The protocols that are eligible for SPA agreements are: animal carcinogenicity protocols, final product stability protocols and clinical protocols for phase three trials whose data will form the primary basis for an efficacy claim.

FDA's guidance on such agreements states that an agreement may not be changed by the manufacturer or the agency unless through a written agreement of the two entities or if FDA determines a substantial scientific issue essential to determining the safety or effectiveness of the drug.

"The Committee is concerned about questions that have arisen in connection with the rescission of a Special Protocol Assessment Agreement (SPA), including fundamental questions concerning FDA's adherence to the statutory and regulatory guidelines that apply to the SPA process as well as to questions concerning fairness to the sponsors," says the House bill report. House appropriators direct FDA to report to the appropriations committees of both the House and Senate the standards used by FDA to rescind a SPA.

Senate appropriators included similar language, and encouraged FDA to revise and re-issue after public comment its existing guidance regarding SPA agreements, including the statutory standards associated with the rescission of such agreements. House appropriators also directed this action.

The issue was also brought up at a House Energy and Commerce Committee hearing June 11, when Rep. Michael Burgess (R-TX) asked Mike Carusi, general partner of Advanced Technology Ventures who was a witness on behalf of National Venture Capital Association, about FDA potentially changing the rules of SPA agreements late in the game.

Carusi said that the intent of SPA agreements is terrific, but if a company is mostly through its clinical trials and FDA suddenly changes its standard for that drug to come to trial, the company would have to start the process all over. He said this could set a manufacturer three to four years back in clinical trials and potentially cost the company $50 to $100 million.

Healy said a recent example of FDA changing a SPA late in the agreement was Amarin's drug, Vascepa. The drug is approved to treat people with severe hypertriglyceridemia (>500 mg/dl), and Amarin was seeking to expand its indication to include people with high triglycerides (>200 mg/dl) on statin therapy. Healy said Amarin and FDA negotiated a SPA agreement in 2009 related to this expanded indication, but it wasn't until four years later in 2013 after the company had completed a successful phase three study and filed for an expanded approval to treat these additional patients that the agency informed the company that it would be rescinding the agreement, less than two months before the expected approval date.

Amarin revealed in its 8-K report from October 2013 that FDA cited results from other studies and trials which the agency said "fail to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dl). Thus, the FDA stated that it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dl."

FDA's actions "appeared to have ignored the SPA agreement, the deliberately high Congressional mandated rescission criteria and the agency's own guidance, including the requirement that the rescission basis rise to the level of a public health concern," said Healy. He said the FDA seems to have based its decision to rescind the SPA agreement on "underpowered, post-hoc, and exploratory analyses of data from different drug classes tested in different patient populations that was known to the FDA years before the SPA agreement was rescinded."

Healy said such actions by the agency will lower investor confidence in the drug development and approval process because they create uncertainty and risk, adding that investors have historically relied on the integrity and transparency of FDA's processes including SPA's.tag

BIO also expressed its concerns with FDA's protocol within these agreements. "The Special Protocol Assessment (SPA) process is intended to enhance predictability and consistency to drug development by ensuring that FDA and the Sponsors are in agreement on innovative clinical trials designs and study endpoints for the purpose of regulatory approval. However, it can often take several cycles of FDA review to achieve initial agreement on an SPA, which can lead to unnecessary delays in conducting trials," said Andrew Emmett, managing director for Science and Regulatory Affairs at BIO, in a statement to FDA Week. "Additionally, recent events have called into question FDA's procedures for adhering to its commitments under an SPA, especially in instances where there may be inconsistent interpretations of the underlying science supporting the SPA. BIO agrees with the report language on SPAs included in the House Agriculture Appropriations bill and we look forward to FDA's report to the committee regarding the standard by which FDA would rescind a SPA."