GAO Issues Report on Surrogate Endpoint Accelerated Approvals; Calls for Enhanced Oversight

By Kurt R. Karst –      

A recent report from the Government Accountability Office (“GAO”), titled “FDA Needs to Enhance Its Oversight of Drugs Approved on the Basis of Surrogate Endpoints,” finds that weaknesses in FDA’s monitoring and enforcement process have hampered the Agency’s ability to effectively oversee postmarketing studies conducted under FDA’s accelerated approval regulations.  Senate Finance Committee Ranking Member Charles Grassley (R-IA) requested that the GAO examine FDA’s oversight of drugs approved under FDA’s accelerated approval regulations based on surrogate endpoints.  

In December 1992, FDA promulgated final 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 regulations, which are commonly referred to as “accelerated approval,” are located in Subpart H (21 C.F.R. § 314.500) of FDA’s drug regulations, and in Subpart E (21 C.F.R. § 601.40) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based: (1) on a demonstrated effect on a “surrogate endpoint” and a sponsor’s commitment to complete with “due diligence” the required postmarketing studies to demonstrate the product’s clinical benefits; or (2) on restrictions to assure safe use (that is, when FDA determines that a drug can be used safely only if distribution or use is modified or restricted).  (In clinical trials, a “surrogate endpoint” is an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms.)   Importantly, FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if a sponsor “fails to perform the required postmarketing study with due diligence,” or if “[a] postmarketing clinical study fails to verify clinical benefit.”  A list of accelerated and restricted approvals is available here. 

Interesting, the GAO report notes a shift in the types of products approved under the accelerated approval regulations:

Since FDA began using the accelerated process in 1992, there has been a general shift in approvals based on surrogate endpoints from applications for HIV/AIDS drugs to applications for cancer drugs.  In the first 9 years of the accelerated approval process, from 1992 through 2000, applications for drugs to treat HIV/AIDS made up 48 percent of the approvals, while applications for drugs to treat cancer made up 26 percent of these applications.  Conversely, from 2001 through 2008, applications for drugs to treat cancer made up over half—59 percent—of the applications approved, while drugs to treat HIV/AIDS accounted for only 18 percent of approved applications. [(See the figure below from the GAO Report)]

Percentage of Approved Applications Granted Accelerated Approval for Cancer and HIV/AIDS Drugs, June 19, 1992–November 20, 2008

According to the GAO report, from June 19, 1992, through November 20, 2008, FDA approved a total of 90 applications (for 64 different drugs) based on surrogate endpoints.  During that period, FDA required drug sponsors to conduct 144 postmarketing confirmatory studies associated with those surrogate endpoint accelerated approvals.  Of those 144 confirmatory studies, FDA classified 92 of them (64 percent) as “closed” (that is, the studies were completed or FDA released the sponsor from conducting the studies), and 52 of them (36 percent) as “open.”  Of the 92 closed studies, sponsors had fulfilled 73 of them (and FDA released sponsors from the remaining 19), according to the GAO report.  In general, “sponsors were able to fulfill about two-thirds of their study requirements in less than 5 years, with time frames ranging from 7 months to more than 12 years.  In contrast, nearly one-third, or 23, of these studies took over 5 years to fulfill,” with products to treat cancer comprising 61 percent of this group.

The GAO report is critical of FDA’s postmarketing study oversight and lack of enforcement of postmarket study requirements, stating that:

FDA has not been routinely monitoring the status of postmarketing studies, primarily because oversight of these studies is not considered a priority. Regarding its enforcement of postmarketing study requirements, we found FDA has not fully utilized its available enforcement tools, even when sponsors have failed to complete required studies.   

FDA reportedly has three initiatives in place to address oversignt weaknesses.  First, “to ensure FDA has current information on the status of open postmarketing studies and facilitate the timely review of [Annual Status Reports (‘ASRs’)], FDA retained [a]  contractor in 2008 to review ASRs for all postmarketing studies classified as open.”  Second “is the creation of a new tracking coordinator position within each medical review division with responsibility for a variety of tasks related to the tracking of postmarketing studies.”  And third is FDA's Web-based Document Archiving, Reporting and Regulatory Tracking System (“DARRTS”), which “should allow FDA staff greater access to information and provide enhancements over the current database, such as creating management reports on specific drugs and their respective studies.”

With respect to enforcing postmarket study requirements, the GAO report states:

FDA has not fully utilized its two enforcement tools – issuing administrative action letters and withdrawing a drug from the market in certain cases – to encourage and compel drug sponsors to complete required confirmatory postmarketing studies.  FDA has the discretion to issue administrative action letters to drug sponsors if 1) sponsors are late or fail to submit ASRs, or 2) FDA determines that sponsors are not sufficiently progressing in completing their studies.

Indeed, FDA has never withdrawn approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence or because a postmarketing study failed to verify clinical benefit (under either Subpart H or Subpart E).  (FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit.  Instead, FDA approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment.)   With respect to withdrawing approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence, the report states:

Our review of the 90 applications approved based on a surrogate endpoint under the accelerated approval process revealed several circumstances that appeared to meet the regulatory conditions for withdrawal, but FDA was hesitant to use its enforcement authority.  Specifically, we found that for 36 of the 90 applications, drug sponsors had not fulfilled their confirmatory study requirements by establishing the clinical effectiveness of those drugs.  This includes several applications for drugs that FDA had approved more than 10 years ago and for which sponsors had not yet completed all of their required studies, and others where the studies failed to confirm the drug’s clinical effectiveness. 

The example used in the GAO report of a sponsor not completing confirmatory studies is  Shire’s PROAMATINE (midodrine hydrochloride) Tablets, which FDA approved in September 1996 under the Agency’s Subpart H (surrogate endpoint) regulations for the treatment of symptomatic orthostatic hypotension.  (FDA  subsequently approved several generic versions of the drug.)  The labeling for PROAMATINE includes the following warning: 

The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

To verify the drug’s clinical benefit to conclude that the drug is safe and effective, FDA required the sponsor of PROAMATINE to conduct certain postmarketing studies.  According to FDA’s Postmarketing Study Commitments Database, the official status of the required postmarketing studies is “delayed.”  This makes PROAMATINE the accelerated approval with the longest outstanding commitment. 

We previously reported (here and here) on letters FDA has posted in a docket (Docket No. FDA-2007-N-0475) concerning the conduct and completion of confirmatory studies for PROAMATINE. 

An August 7, 2007 letter FDA sent to companies marketing approved versions of midodrine HCL raised the possibility that generic sponsors might conduct the required confirmatory studies, and also raised the possibility of withdrawing approval for all midodrine applications if those studies are not conducted.  FDA stated in an August 2008 letter that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved soon, we will issue a Notice of Opportunity for a Hearing on the Center’s proposal to withdraw the approval of the midodrine hydrochloride new drug application (NDA) (and all ANDAs referencing that NDA) pursuant to 21 CFR 314.530.” 

FDA took an even more forceful tone in an August 2009 letter stating again that “[i]f an application or supplement containing studies that verify clinical benefit for midodrine hydrochloride is not approved in a timely manner as described herein, we will issue a Notice of Opportunity for a Hearing on the Center's proposal to withdraw the approval of the midodrine hydrochloride NDA (and all abbreviated NDAs (ANDAs) referencing that NDA) pursuant to 21 CFR §§ 314.530; 314.150, and 314.151,” but adding that the required studies must have “50% enrollment by April 12, 2010,”  “100% enrollment by June 12, 2010,” and that full study reports of the requested trials must be submitted “on or before October 12, 2010.”  Whether FDA will take action to withdraw approval remains to be seen. 

The GAO report recommends that FDA clarify its enforcement authority under the accelerated approval process to identify – perhaps in a guidance document – the conditions under which the Agency would would utilize its expedited withdrawal authority if a sponsor either fails to complete required confirmatory studies with due diligence, or if completed studies fail to demonstrate the clinical effectiveness of the drugs.  FDA responded that in light of certain compexities and the need for a case-by-case assessment, the Agency “believes it would be difficult, if not impossible, to provide further clarification as to when it might utilize its authority to expedite withdrawal of drug approval on the basis of surrogate endpoints.”