Wednesday, March 2, 2011

Unbalanced FDA Guidance on Substantial Equivalence

On January 5, the FDA issued “guidance” concerning an important provision of the Tobacco Act – the demonstration of substantial equivalence for tobacco products. This post will explain why the provision might result in a regulatory nightmare for tobacco harm reduction by threatening existing smokeless products and completely inhibiting new-product innovation. Intrepid readers might wish to read the entire 17-page document (here).

According to the Act, any tobacco product in the American market on February 15, 2007 – a seemingly arbitrary date – is not subject to FDA review. For any product that was changed or introduced between February 15, 2007, and March 22, 2011, manufacturers are required to submit a 905(j) report by March 22, assuring the FDA that the product is “substantially equivalent” to a predicate product that was on the market February 15, 2007.

What information does the FDA require in 905(j) reports? Under normal circumstances, a federal agency would interpret legislation by formulating proposed regulations, submitting them for public comment, and eventually publishing final regulations. However, because the FDA is under pressure to get this equivalence provision into place, the agency issued a guidance document which says, “In the future, FDA intends to initiate a rulemaking that would establish requirements and standards for substantial equivalence.” For now, the guidance only “provides recommendations on the form and content of section 905(j) reports.”

According to the FDA, “guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.” (emphasis in original)

The FDA “suggests” that manufacturers submit a vast amount of information in 905(j) reports, including side-by-side comparisons of each new product with its predicate with respect to:

1. Ingredients and their levels

2. Design features and other materials; description of the heating source and composition (these mostly apply to cigarettes)

3. Harmful and potentially harmful constituents. The Tobacco Products Scientific Advisory Committee has started to develop this list of over 100 agents (see this document).

In addition to these basic requirements, manufacturers may need to submit “additional data.” The FDA guidance elements for additional information relating to consumer perception, clinical, abuse liability and toxicology data are so sweeping that I include them verbatim:

4. “Consumer Perception Studies - data comparing consumer perceptions with respect to the new tobacco product and the predicate that could affect initiation, cessation, frequency of use, patterns of use, smoking behavior, and perceptions of harm or addictiveness.”

5. “Clinical data - data comparing the biomarkers of exposure and biomarkers of potential harm and human toxicity of the new tobacco product as compared to the predicate tobacco product …Your report should include a summary of all studies conducted. In addition, your pivotal studies should be submitted and include: final approved study protocols, statistical analysis plans, any modifications to the study(ies), raw data, analysis platforms, and full reports.”

6. “Abuse liability data - data comparing the abuse liability of the new tobacco product to the predicate tobacco product ... Abuse liability can be assessed by a battery of studies, such as animal models of conditioned place preference, drug discrimination and self-administration, and human behavioral pharmacology studies that assess self-administration and subjective effects of the new tobacco product.”

7. “Toxicology data - data comparing the toxicity of the new tobacco product to the predicate tobacco product ... Comparisons between the new tobacco product and the predicate tobacco product can be assessed by a battery of studies, including nonclinical studies such as in vitro and in vivo mutagenicity and clastogenicity studies, general toxicology studies that include hematological, clinical chemistry, and histopathological endpoints, toxicology studies designed to specifically address cardiac, respiratory, and reproductive/developmental toxicity and studies to assess the carcinogenic potential.”

If you have read this far, you may suspect that the agency is pursuing an anti-tobacco agenda. Even if the FDA’s “guidance” is not binding or “legally enforceable,” the agency’s “current thinking” on this issue is clear: Require tobacco manufacturers to spend millions of dollars to keep their existing tobacco products on the market, and prevent the introduction of new products. If the FDA upgrades its guidance to binding regulations, it could strangle the tobacco industry. It would not be surprising if most U.S. cigarette and smokeless products have been altered in some manner since February 15, 2007; any such changes would subject their manufacturers to the onerous new data-production regulations.

Will consumers be any safer for all the corporate and government expense? Will such sweeping regulations dissuade companies from attempting to introduce new and safer smokeless tobacco products?

Last week, R.J. Reynolds and Altria made separate announcements about test markets of dissolvable tobacco products (here). Reynolds announced it will resume test markets in Denver and Charlotte of Camel Orbs, Strips and Sticks, products that had been tested in Columbus, Indianapolis and Portland, Oregon, in 2009-2010. In March, Altria will introduce in Kansas Marlboro and Skoal Smokeless Tobacco Sticks, which are 2.5-inch-long wooden sticks coated with finely milled tobacco.

These are exciting developments, demonstrating that cigarette manufacturers are committed to offering smokers vastly safer smoke-free options. It would be a public health tragedy if the FDA used equivalence criteria to deny smokers these products, thus assuring the continued market dominance of deadly cigarettes.

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