	Background

FDA, an agency within the Department of Health and Human Services  (HHS), is responsible for overseeing the safety and effectiveness of drugs  marketed within the United States. The Use of Non-Inferiority Trials in Obtaining Evidence of a Drug’s Effectiveness

Once a drug sponsor identifies a promising chemical compound it believes  to be capable of curing or treating diseases, the sponsor may decide to  conduct clinical trials on humans to gather the evidence necessary to  demonstrate to FDA that the drug is safe and effective for its intended use. For example, in 1985 FDA substantially revised its  regulations including the provision addressing the characteristics of  adequate and well-controlled trials and the types of controlled trials that  can be used to gather evidence of a new drug’s effectiveness. 1.) This term is used to describe the concern  that successive generations of drugs approved based on non-inferiority  trials, with the active control changing in each new generation, could lead  to the adoption of decreasingly effective drugs and ultimately to the  approval of drugs that are no more effective than a placebo. One-Quarter of NDAs Included Evidence from Non-Inferiority Trials and FDA Approved a Majority of These Applications

One-quarter of NDAs submitted to FDA for review from fiscal years 2002  through 2009 included evidence from non-inferiority trials, and many of  these applications were for antimicrobial drugs. 2.) FDA approved the remaining 11 applications  based on other evidence, such as the superiority of the new drug  compared to a placebo or an active control. As of December 31, 2009, FDA  had decided not to approve 14 applications that included evidence from  dence from  non-inferiority trials. 3.) The number of pivotal non- inferiority trials used as primary evidence for these 18 NDAs ranged from  one to four, with an average of two pivotal non-inferiority trials supporting  the approval of each application. Half of the 18 NDAs FDA approved on the basis of non-inferiority trials  tested the effectiveness of the new drug against more than one active  control. These trials showed that the confidence interval for the  difference in the drugs’ effectiveness was within the non-inferiority  margin. FDA’s review therefore  minimized the potential for biocreep. Some Non-Inferiority Trials Were Poorly Designed and Did Not Provide Primary Evidence for Approval

While non-inferiority trials provided primary evidence of effectiveness to  support the approval of 18 NDAs, other non-inferiority trials were poorly  designed and did not provide such evidence. Of the other 25 NDAs that  included evidence from non-inferiority trials, FDA identified 9 applications  that included poorly designed non-inferiority trials. Some of the  concerns FDA identified with sponsors’ non-inferiority trials were  inappropriate use of non-inferiority trials for the indication being treated, inappropriate selection of an active control, including cases where the  drug was not FDA-approved or the sponsor did not provide an adequate  justification, and improper calculation or justification of the non-inferiority margin. FDA informed sponsors of its concerns with all of these applications’ non- inferiority trials prior to the sponsors’ submission of the NDAs. FDA Has Issued Detailed and Comprehensive Guidance on the Use of Non-Inferiority Trials to Establish the Effectiveness of New Drugs

In March 2010, FDA issued draft guidance on non-inferiority trials that  provides detailed recommendations on using these trials to provide  evidence of a new drug’s effectiveness. This March 2010 draft guidance  offers broader and more comprehensive information to supplement other  indication-specific guidance documents the agency previously issued. It explains the  key principles involved in using a non-inferiority trial to demonstrate the  effectiveness of a drug and provides detailed recommendations for such  trials, including how to select an active control and how to set the non- inferiority margin (that is, determining the maximum clinically acceptable  extent to which the new drug can be less effective than the active control),  among other things. FDA’s March 2010 guidance explains when non-inferiority trials may be  used to establish a drug’s effectiveness. However, some experts we  interviewed noted that such trials are difficult to design and interpret;  therefore, additional guidance on this topic may be helpful. Our review of FDA’s indication-specific guidance showed that the agency  has become more conservative in allowing evidence from non-inferiority  trials to demonstrate the effectiveness of new drugs. Second,  FDA has become more rigorous in its review of evidence from non- inferiority trials. Agency Comments

We provided a draft of this report to HHS for review. We received  technical comments from HHS, which we incorporated as appropriate. Appendix I: New Drug Applications Approved on the Basis of Evidence from Non-Inferiority Trials

The Food and Drug Administration (FDA) approved 18 new drug  applications (NDA) that were submitted from fiscal year 2002 through  fiscal year 2009 on the basis of evidence from non-inferiority trials. The  majority of these were antimicrobial drugs, such as those that treat  bacterial, viral, and fungal infections.
Why GAO Did This Study

Before approving a new drug, the Food and Drug Administration (FDA)--an agency of the Department of Health and Human Services (HHS)--assesses a drug's effectiveness. To do so, it examines information contained in a new drug application (NDA), including data from clinical trials in humans. Several types of trials may be used to gather this evidence. For example, superiority trials may show that a new drug is more effective than an active control--a drug known to be effective. Non-inferiority trials aim to demonstrate that the difference between the effectiveness of a new drug and an active control is small--small enough to show that the new drug is also effective. Drugs approved on this basis may provide important benefits, such as improved safety. Because non-inferiority trials are difficult to design and interpret, they have received attention within the research community and FDA. FDA has issued guidance on these trials. GAO was asked to examine FDA's use of non-inferiority trial evidence. This report (1) identifies NDAs for new molecular entities--potentially innovative new drugs not FDA-approved in any form--that included evidence from non-inferiority trials, (2) examines the characteristics of these trials, and (3) describes FDA's guidance on these trials. GAO reviewed NDAs submitted to FDA between fiscal year 2002 (the first full year that FDA documentation was available electronically) and fiscal year 2009 (the last full year of submissions), examined FDA's guidance, and interviewed agency officials.

What GAO Found

Evidence from non-inferiority trials was included in about one-quarter, or 43, of the 175 NDAs for new molecular entities that were submitted to FDA for review from fiscal years 2002 through 2009. Many of these applications were for antimicrobial drugs, such as those treating bacterial, viral, and fungal infections. As of December 31, 2009, FDA approved 18 of the 43 NDAs on the basis of evidence from non-inferiority trials. Of the remaining 25 NDAs, FDA approved 11 based on other evidence, such as proof that the new drug was more effective than a placebo (no treatment), and decided not to approve 14. The non-inferiority trials included in these NDAs varied with respect to their characteristics. FDA generally requires sponsors to provide evidence of a drug's effectiveness as shown in more than one trial. For the 18 NDAs that were approved based on evidence from non-inferiority trials, the number of non-inferiority trials used to provide primary support for approval ranged from one to four, with an average of 2 such trials per NDA. Half of these applications included non-inferiority trials that tested the effectiveness of the new drug against more than one active control. The non-inferiority margins--the maximum clinically acceptable extent to which the new drug can be less effective than the active control and still show evidence of an effect--ranged from 5 to 20 percent among trials that supported approval. Among the other 25, FDA identified nine NDAs that included poorly designed non-inferiority trials which did not provide primary evidence for approval. Some of these problems included an inappropriate selection of an active control and an improper calculation of a non-inferiority margin. FDA notified sponsors of its concerns with the poorly designed trials prior to the sponsors' submissions of all NDAs that included such trials. In March 2010 FDA issued draft guidance which focused solely on the use of non-inferiority trials. This guidance presents detailed and comprehensive recommendations on how non-inferiority trials may be used to provide evidence of a drug's effectiveness. For example, it provides advice on how to select an active control and how to set the non-inferiority margin, as well as how to interpret the trials. This guidance offers broad, generally applicable recommendations to supplement indication-specific guidance documents that FDA had previously issued. These indication-specific guidance documents include FDA's advice on many issues related to the development of drugs for particular indications, some of which are related to the use of non-inferiority trials. GAO's review of FDA's guidance showed that the agency has become more conservative in allowing evidence from non-inferiority trials to demonstrate a drug's effectiveness. First, FDA has limited the indications for which these trials may be used. Second, the agency has also become more rigorous in its review of evidence from non-inferiority trials. We sent a draft of this report to HHS for review. HHS provided us with technical comments, which we incorporated as appropriate.