ULTRA Bill Introduced in the House; Legislation Seeks to Permit Broader Use of Scientific Data to Support Surrogate Endpoints for “Ultra Orphan” Drug Approvals

January 2, 2012

By Kurt R. Karst –      

Representatives Cliff Stearns (R-FL) and Ed Towns (D-NY) recently introduced H.R. 3737, the Unlocking Lifesaving Treatments for Rare-Diseases Act (“ULTRA”).  The bill would amend the FDC Act to “improve access to the existing accelerated approval pathway for patients with life threatening ultra-rare genetic diseases with the added attribute of promoting private investment in new biotechnology companies and job growth in the United States,” according to a statement issued by Rep. Stearns.  More specifically, the bill would amend FDC Act § 506 (titled “Fast Track Products”), added to the statute by the 1997 FDA Modernization Act, to permit FDA to approve an application for a drug designated both as an orphan drug and as a fast track product using a “surrogate endpoint” as defined in proposed FDC Act § 506(e)(2).  In addition, the orphan disease or condition must affect a “small number of patients in the United States,” which is short-hand for an ultra-rare or ultra-orphan disease – a disease or condition with a U.S. prevalence that some have pegged at 6,000 or fewer people (see here).

FDC Act § 506 is generally considered to have codified FDA’s December 1992 accelerated approval regulations, under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments.  These accelerated approval regulations are located in Subpart H (21 C.F.R. Part 314) of FDA’s drug regulations, and in Subpart E (21 C.F.R. Part 601) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit and a sponsor’s commitment to complete with due diligence the required postmarketing studies to confirm the product’s clinical benefits.  A surrogate endpoint is an alternative measurement of the symptoms of a disease or condition that is substituted for measurements of observable clinical symptoms.  Surrogate endpoints are expected to predict clinical benefit (or harm, or lack of benefit or harm).

Specifically, under FDA’s accelerated approval regulations at 21 C.F.R. § 314.510, “FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity” (emphasis added).  Similarly, under FDC Act § 506(b), FDA “may approve an application for approval of a fast track product under [FDC Act § 505(c)] or [PHS Act § 351] upon a determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit” (emphasis added). 

For more prevalent diseases, there may be independent clinical data that make a surrogate endpoint reasonably likely to predict clinical benefit; however, “[m]ost ultra-rare diseases do not have the same pre-existing body of clinical management or historical study data currently required to utilize the [accelerated approval] pathway,” according to a recent article co-authored by Dr. Emil D. Kakkis of the Kakkis EveryLife Foundation For Rare Diseases on the potential effects on investment in the development of treatments for low prevalence rare diseases with  improved access to accelerated approval.  Thus, according to the article, “[w]ith this essential requirement for independent clinical data, the [accelerated approval] pathway is virtually unavailable for novel drugs developed for untreated ultra-rare diseases.”  The Kakkis EveryLife Foundation was a major driving force behind H.R. 3737 – see here and here – and worked with Rep. Stearns to build support for the legislation. 

To address the issue raised by Dr. Kakkis, ULTRA would amend the law to provide that for a product for an ultra-rare disease or condition designated both as an orphan drug and as a fast track product, FDA “may use a surrogate endpoint for the approval of the drug as a fast track product based on the existence of reasonable scientific data that support and qualify the relevance of the surrogate endpoint to the disease state and treatment.”  In addition, the legislation says that FDA “shall not require clinical treatment data or other historical clinical data on the surrogate endpoint as a prerequisite to assessment of the surrogate endpoint under this subsection if such data are not available;” however, FDA “may take into consideration any reliable clinical data that are readily available and published.”  The bill would also require FDA to issue guidance “providing details and options for qualifying surrogate endpoints without clinical data” within one year of the date of enactment of ULTRA.