Tuesday, December 20, 2011

IOM Recommendations Place Insurmountable Obstacle in the Way of New Reduced Risk Products By Requiring Research that Cannot Ethically Be Conducted

Yesterday, I provided my evaluation of the IOM report on modified risk tobacco products, opining that the rigorous scientific standards recommended by the report to support a modified risk product application place a nearly insurmountable obstacle in the way of the development of truly reduced risk products, and therefore serve as a death knell for harm reduction as a viable strategy to reduce the disease and death caused by cigarettes in the United States. I noted that the report is consistent with the clear intentions of the politicians and anti-smoking groups which supported the Tobacco Act, which I believe was intended to protect the existing high-risk cigarette market.

Today, I reveal an additional reason why the IOM report recommendations place an insurmountable obstacle on the development and approval of new reduced risk tobacco products. This one is not a logistic or economic obstacle, but an ethical one.

The Rest of the Story

The IOM report recommends that a new tobacco product that wishes to be marketed as a reduced risk product must be tested in a clinical trial in comparison to a regular (existing) product. Specifically: "Any clinical trial should include at least two control conditions—usual brand use and cessation—to allow examination of the relative effects of the MRTP on biomarkers of exposure or risk."

Suppose that a company wishes to demonstrate that a new cigarette - Brand X - reduces individual risk. The IOM recommendations require it to conduct a clinical trial comparing Brand X to an existing cigarette brand. Thus, one group of subjects would be randomized to switch to brand X, and another group of subjects would be randomized to continue to smoke their usual brand.

In my view, this is an unethical research protocol, and I would hope that no IRB in the country would approve such a protocol. Because of the known severe risks of cigarette smoking, it is not ethical to randomize subjects to a condition characterized by smoking cigarettes as usual. No IRB would or should approve such a protocol.

In fact, the only condition in which a randomized clinical trial involving cigarettes is ethically appropriate is when the study is designed to assess smoking cessation (or at least reduction in smoking). For example, one could test a new product designed to help smokers quit by randomizing smokers to receive either the new product or usual cessation care (i.e., nicotine replacement therapy). But you can't include a control group which is instructed to continue to smoke their regular cigarettes.

You can easily see how the IOM report's basic strategy of requiring clinical trials to demonstrate reduced risk of tobacco products is fundamentally flawed. In order to compare a new product with an existing product in a randomized clinical trial, you need to randomize subjects to either smoke the new cigarette or their usual cigarette. But it is unethical to instruct subjects to continue to smoke regular cigarettes.

If the subjects don't continue to smoke their regular cigarettes, then the clinical trial falls apart because you need a large sample of subjects who continue to smoke their usual brand in order to maintain an adequately sized control group. That smokers quitting would harm the scientific value of the study is a serious ethical breach that cannot be tolerated.

Imagine a randomized clinical trial of electronic cigarettes compared to regular cigarettes. Such a study, according to the standards recommended by the IOM report, would be required. No IRB in its right mind would approve a trial in which subjects were randomized to either use electronic cigarettes or to smoke Marlboros. Clearly, such a study cannot be done. The IOM recommendations amount to a catch-22 by which companies can never produce the scientific evidence that is required to achieve reduced risk product status.

The rest of the story, then, is that the IOM report is recommending that in order to obtain approval of a tobacco product as a modified risk product, a company must conduct randomized clinical trials that are unethical. Elsewhere, of course, the report emphasizes that all scientific studies must meet basic ethical standards. Thus, the result is a recommendation which places an insurmountable obstacle before companies wishing to develop reduced risk products.

The IOM report proposes a system of scientific study of reduced risk cigarettes by which these products would be studied using the typical pharmaceutical drug model. Companies would have to apply for an IND (Investigational New Drug) application and after preclinical studies, conduct phase II and phase III clinical trials, which - as I noted above - would be unethical. Not only is this a catch-22, but this regulatory model makes a travesty of the FDA's regulation of pharmaceuticals by placing cigarettes in the same category as drugs.

The IOM report states: "In the case of a truly new product (where nothing similar is sold elsewhere) an Investigational New Drug application model could be the most appropriate approach. In such cases, then, the FDA could require that preclinical laboratory testing be completed before moving to animal or human studies (e.g., phase I), which would have to be justified by significant findings in the laboratory work. If preclinical findings pointed to potential reduced exposure, then the FDA could authorize phase II or III trials to explore the experience of reduced exposure in larger human populations under controlled conditions (e.g., RCTs)."

This proposal, in my view, would undermine the entire FDA system of drug regulation. Tobacco products are not drugs and they should not be treated as such, even if they are potentially lower risk compared to traditional cigarettes. The IND/randomized clinical trial approach is appropriate for pharmaceutical products that are going to be regulated under the federal Food, Drug, and Cosmetic Act (FDCA). But it is not appropriate for tobacco products, which are recreational products not intended to prevent or treat any disease. Putting them into that category does not make any sense.

It should seem pretty clear at this point that what the IOM report is doing is trying to fit a square peg into a round hole. The regulatory scheme created by the FDA Act for tobacco products simply doesn't fit these products. The scheme would be appropriate for pharmaceutical drugs, but it just doesn't fit for recreational (and inherently hazardous) tobacco products.

Now, I am convinced more than ever that the Tobacco Act must be amended by Congress if there is to be any meaningful and effective national harm reduction strategy to reduce the disease and death caused by cigarettes and other tobacco products.

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