On 9 February 2012, Dr. Robert Temple of the Center for Drug Evaluation and Research (CDER) gave a presentation1 to the National Pharmaceutical Council about the potential uses of Comparative Effectiveness Research (CER) results. Dr. Temple addressed the “asymmetry” between the standard for promotional drug claims – substantial evidence – and CER results, and outlined ways that pharmaceutical manufacturers could potentially disseminate information about CER.

Significantly, his presentation provided an interpretation of section 114 of the Food and Drug Administration Modernization Act of 1997 (21 USC 352(a)) (FDAMA 114), and to our knowledge, his presentation represents FDA’s first comprehensive interpretation of this provision in over a decade. For this reason, Dr. Temple’s statements reflect classic “podium policy” given that FDA has only articulated these informal principles in enforcement letters since FDAMA 114’s enactment in 1997.


In March 1995, FDA’s Division of Drug Marketing, Advertising and Promotion (DDMAC) issued a draft guidance titled, “Principles for the Review of Pharmacoeconomic Promotion.”2 It enumerated principles that the Agency would utilize when reviewing pharmacoeconomic3 (PE) claims in promotional materials, and those principles focused on the nature and degree of substantiation and the types of disclosure necessary to support the use of PE claims in pharmaceutical promotion. DDMAC stated that comparative PE claims, including cost-effectiveness and quality of life claims, must be substantiated by two adequate and well-controlled studies. 

Members of industry and health insurance plans widely objected to the 1995 draft guidance on the grounds that useful and relevant information about the costs and effects of treatments would never meet DDMAC’s standard. Based largely on these concerns, Congress amended section 502(a) of the FDAMA by adding Section 114 which:

  • Defines health care economic information (HCEI) as an analysis that identifies, measures, or compares the economic consequences of the use of the drug to the use of another drug, another healthcare intervention, or no intervention;
  • Restricts the audience of HCEI to formulary committees or similar entities;
  • States that HCEI will not be considered false or misleading if it is based on competent and reliable scientific evidence; and
  • States that HCEI will not be considered false or misleading if it directly relates to an approved indication.

Congress adopted the evidentiary standard used by the Federal Trade Commission (FTC), “competent and reliable scientific evidence” (rather than substantial evidence, which requires two adequate and well-controlled studies). The FTC standard is widely recognized as a flexible standard, but its practical meaning under FDAMA 114 in practice has been unclear. Until the recent Temple presentation, FDA has not issued any regulations or guidance articulating the scope or appropriate application of section 114, and has otherwise provided little insight on the subject.

Since 1997, DDMAC issued numerous objections to cost claims by manufacturers – and did so almost exclusively on the basis that the two therapies being compared were not comparable. DDMAC took the position that without substantial evidence that the therapies were comparable, there was no basis to compare costs. DDMAC has taken this position even where the active ingredients of the two therapies were the same. See Warning Letter to Cumberland Pharmaceuticals regarding Acetadote, August 2010. None of these letters cited FDAMA 114 or otherwise invoked the “competent and reliable” standard.

Dr. Temple’s 9 February 2012 presentation

According to Dr. Temple, FDAMA 114 does not allow clinical claims where “those claims do not satisfy FDA’s evidentiary standards…” for clinical claims. Slide 11, Temple Presentation (emphasis in original). Dr. Temple explained the difference between the evidentiary standard required when (1) the HCEI relates to the economic consequences directly related to the labeled effect of the drug, versus (2) when the claims are about economic consequences that follow from the labeled effectiveness of the product. In the first case, “any comparative claims must be supported by substantial evidence that directly compares the treatments in question (i.e. head-to-head clinical trials that provide a valid comparison of two drugs).” Slide 12 

In the second case, any comparative claims “can be supported by competent and reliable scientific evidence related to the consequences of an effect once the primary clinical outcomes have been established.” Slide 13 Thus, supporting evidence for HCEI depends on the component of the analysis involved:

  • Establishing the economic impact of a therapy would be based on economic analysis; and
  • Establishing the clinical outcome assumptions would be based on traditional means of establishing effectiveness. Slide 14

Dr. Temple seems to be saying that Section 114 allows sponsors of drugs approved based on head to head trials (e.g. non-inferiority designs) to make secondary cost comparisons that could support HCEI claims. This interpretation is consistent with FDA’s enforcement history, but again, it marks the first comprehensive interpretation of FDAMA 114 by FDA in over a decade. Moreover, his presentation takes a very conservative view of the statute. Arguably, if a company has head to head data regarding the clinical effectiveness of one drug to another, the usefulness of a secondary economic analysis is substantially less than it would be without such data. Moreover, as Dr. Temple acknowledges, this interpretation could require very large trials. 

Dr. Temple’s interpretation does not address comparisons across classes of drugs, instead focusing only on comparisons of one drug to another very similar drug. It is arguably inconsistent with congressional intent that HCEI analyses be more widely available for formulary members and insurers than prior to enactment (although Dr. Temple is careful to cite legislative history as support for his interpretation).

Interestingly, Dr. Temple also states that “there is no FDA view that drug companies are condemned to silence about their products outside of formal promotion or perhaps published articles,” and thus, companies can respond to negative CER assertions or data about their products made by payers, researchers, or governmental agencies, so long as the correction is not itself promotional. Slide 17


It may be the case that DDMAC’s enforcement letters over the past 15 years had already effectively written FDAMA 114 out of the statute – making its usefulness extremely low. Regardless, when read in their historical context, Dr. Temple’s statements appear quite bold. Although Congress presumably wanted to assure that pharmaceutical companies could make HCEI comparisons through a standard different from and presumably lower than the substantial evidence standard, FDA today believes that those claims can only be made after a head to head trial confirms the clinical benefit at issue. For those drugs that will reach the market based on head-to-head trials, this may not present a particularly large evidentiary hurdle. But, for all other drugs, it seems like 1995 all over again.