The Institute of Medicine last week released its long-awaited report on the scientific evidence required to support designation of tobacco products as modified risk products under the Family Smoking Prevention and Tobacco Control Act [the Tobacco Act].
The report recommends that extensive scientific evidence, including findings from randomized controlled trials and longitudinal cohort studies, be required to show that potential reduced risk products will reduce individual health risks and improve the public's health on a population basis.
The report summarizes the rigorous nature of the scientific evidence required as follows: "The evaluation of the effect of MRTPs on public health will require a wide range of evidence and therefore will require many different types of study designs, including studies of the composition of MRTPs and studies of human exposure, human health effects, the likelihood of addiction and abuse, and the perception and understanding of the product by the public. Furthermore, the evidence must be able to reliably support predictions about the effect of marketing the product on public health, and therefore these studies must be properly designed and rigorously conducted. Study designs will need to include all relevant populations including populations at a high risk for tobacco use. Study designs must be able to not only support inferences about the mechanisms of the products effects, but they must also be able to support predictions about the products’ effects in the real world."
The report makes it clear that demonstration of reduced risk cannot be made based simply on laboratory or pre-clinical studies, but requires the conduct of clinical trials and long-term longitudinal cohort studies.
As the report states: "there is no proof that any individual constituent or group of constituents is responsible for a given disease. For a biomarker of exposure to be accepted as a biomarker of risk or a surrogate endpoint of disease, there should be a strong biological rational as well as compelling data from clinical and epidemiologic studies. Experimental designs, in particular randomized controlled trials (RCTs), provide data that can support the strong inferences about the effect of an MRTP on human health relative to conventional tobacco products. The use of appropriately designed clinical trials will be important to establish whether the use of the MRTP reduces exposure to toxicants or induces positive changes in surrogate markers as claimed by the manufacturer. An RCT is an effective means of examining acceptability and use of the MRTP, the ability of the MRTP to increase cessation in users of conventional tobacco products, and the likelihood that availability of the MRTP will lead to dual use. RCT methods can also produce evidence on whether and how much individuals use an MRTP after they have used it to help them quit conventional products, changes in perception of the MRTP with its continued use, and the MRTP’s ability to suppress tobacco withdrawal symptoms. It is important to recognize that no single RCT can address all of these areas, and each study should have a focused objective with a primary endpoint."
"Long, intensive, and robust observational studies of actual health outcomes may be required to fully evaluate the net effects of MRTPs relative to conventional tobacco products. Prospective cohort studies are obvious candidates for the evaluation of MRTPs, and will also be an essential tool to validating anticipated or claimed effects of marketed MRTPs on both individuals and on the public’s health."
"It is clear that no single class of evidence (e.g., preclinical, RCTs, consumer perception, epidemiologic) in itself will be sufficient to support an MRTP application."
Thus, not only must the applicant demonstrate an improvement in individual and population health through randomized controlled trials and long-term longitudinal studies, but multiple clinical trials are required.
Moreover, the report recommends that tobacco companies not be allowed to submit their own research findings: "the committee concluded that the tobacco industry currently lacks not only the trustworthiness, but also lacks the expertise, infrastructure, and other resources needed to independently produce the scientific evidence necessary to meet the public health standards set by the law."
Instead, the report insists that tobacco companies must contract with independent third parties to conduct the required research.
The Rest of the Story
The scientific requirements recommended by the IOM report are so rigorous that I believe the implementation of such standards would place an insurmountable, or virtually insurmountable, obstacle in the way of the development and marketing of truly reduced risk tobacco products. I believe that these standards would be a de facto death knell for the strategy of harm reduction as a tool for controlling tobacco-related disease in the United States.
The requirements for conducting long-term epidemiologic studies and randomized clinical trials to demonstrate reduced individual and population risk are so burdensome that they remove most of the incentive to develop such products, especially since there is no guarantee that long-term studies will support the approval of such products. In addition, the length of time required to conduct these studies is prohibitive in most cases.
Consider the need to demonstrate a reduction in cancer risk. Cancer takes many years to develop so one cannot simply conduct a two-year cohort study to determine whether a new type of cigarette will reduce cancer risk. It would take a minimum of perhaps ten years to know whether the product reduces cancer risk. Very few companies are going to want to expend the amount of money required to carry out such long-term studies, with no guarantee of success.
Moreover, the requirements for randomized clinical trials that include a control group of regular cigarette users cannot be followed while still conducting ethical research. You cannot ethically randomize human subjects to smoke regular cigarettes. I will write more about this in a separate post tomorrow.
The Two Pathways for Modified Risk Products
There are two possible pathways for modified risk tobacco products: the reduced risk pathway and the reduced exposure pathway. Reduced risk products are those for which the manufacturer wishes to claim that the product is safer than other products on the market. Reduced exposure products are those for which the manufacturer will not make any explicit health claim, but will merely inform consumers that it contains less of a certain constituent, or is free of a particular constituent.
For the reduced risk pathway, the IOM report makes it clear that the manufacturer must show that the product will reduce health risks to individual users and to the population as a whole. This is a very high scientific standard, one that can only be met through long-term epidemiologic studies with thousands of product users in order to establish the long-term relative risks of using these products.
However, this produces a catch-22 situation: A manufacturer cannot market a product until it demonstrates that it reduces individual risk. But a manufacturer cannot demonstrate that the product reduces individual risk unless it first markets the product. Receiving special FDA permission to test market the product in a small population will not allow the large sample size necessary to examine the effects of these products on cancer risk. Such studies require perhaps hundreds of thousands of users in order to have enough power to detect differences in cancer risk.
Thus, it is virtually, if not literally impossible for any reduced risk product ever to be approved by the FDA under these scientific standards.
For the reduced exposure pathway, the manufacturer need only show that the product does indeed decrease exposure to a particular constituent or constituents and that a corresponding reduction in health risk is "reasonably likely." This is possible to do with laboratory studies, so it is feasible to make the necessary demonstrations to the Agency.
However, there is a third requirement: the manufacturer must show that as it plans to package and market the product, consumers will not believe that the product reduces their risk. In other words, even though consumers know that the product reduces exposure, they must not believe that it reduces risk.
This, again, creates a nearly impossible task. If consumers are aware that a product reduces exposure to one or more harmful substances, they are naturally going to believe that it reduces their risk of disease. The only way to avoid this perception would be not to tell consumers that the product reduces exposure. But in that case, the new product is no longer a reduced exposure product and so it cannot be approved for marketing in the United States.
Thus, the FDA Tobacco Act creates another catch-22: A manufacturer cannot market a product as reduced exposure unless it can show that consumers will not perceive it to be less harmful. But consumers will only perceive that the product is not any less harmful if it is not marketed as reduced exposure.
This provision, in other words, makes it virtually, if not literally impossible to market a reduced exposure product. One would have to make very limited claims that do not result in consumers believing the product is any safer. But if consumers don't believe the product is any safer, then why would they want to switch to that product? It would not be cost-effective to market the product, because it surely would not compete with existing products on the market in the absence of any consumer belief that the new product is safer.
Consistency of the IOM Report Recommendations with the Tobacco Act
I need to make it clear that I am not criticizing the IOM report for an overly stringent interpretation of the Tobacco Act. It is my opinion, which I expressed before the Tobacco Act was even enacted, that the above implications of the modified risk tobacco product provisions of the Tobacco Act were exactly what Congress and the anti-smoking groups which supported the legislation desired.
So I believe that the IOM report is accurately outlining the rigorous scientific evidence that the statute requires. I believe that a major purpose of the FDA Tobacco Act was specifically to put a huge barrier in the way of modified risk products, which have long been despised by the anti-smoking groups (and usually with good reason). But the climate has changed (e.g., consider the development of electronic cigarettes, which contain no tobacco) and the law needs to change with the climate. Unfortunately, the Tobacco Act employs an old picture of the tobacco product space and inhibits a true harm reduction approach in favor of preventing deceptive marketing that characterized the previous century, when there was no federal regulation of tobacco products. The times have changed, but the Act's view of the times has not. As a result, the Act essentially nixes harm reduction as a viable tobacco control strategy in favor of protecting the existing high-risk cigarette market. Even the tobacco companies recognize that this is an antiquated view; they desire to bring reduced risk products into their portfolios.
The rest of the story, then, is that the Tobacco Act's modified risk provisions simply make no sense. It is essentially a hoax, designed to make it look like the policy makers and health groups are interested in protecting the health of smokers, but instead, if you actually read the fine print, you'll find that the law sacrifices the health of smokers by making it impossible for tobacco companies or public health groups to pursue a harm reduction strategy. The Act preserves the existing market of the highest risk tobacco products and stifles competition from alternative products that might truly reduce health risks. The IOM report's interpretation of the Act is perfectly consistent with the statute.
This is not science-based policy. It is protectionism. Protection of the status quo. Protection of the existing tobacco market. The anti-smoking groups are not interested in actually protecting the health of smokers by encouraging them to use potentially less harmful alternatives. Instead, they are protecting the highest risk products and making sure that smokers continue smoking these high-risk products and that they do not switch to products that could potentially save their lives, or at least greatly reduce their risk of disease.