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PREP science

The Institute’s review 'Clearing the Smoke: assessing the science base for tobacco harm reduction'  contained five main research conclusions and recommendations that are of direct relevance to PREPs:-

• Currently available data allow estimation, albeit imprecise, of a dose-response relationship between exposure to whole tobacco smoke and major diseases that can be monitored for evaluation of harm reduction potential.
• Although candidate disease-specific surrogate markers are currently available, further validation of these markers is needed.  In addition, other biomarkers that accurately reflect mechanisms of disease must be developed to serve as intermediate indicators of disease and disease risk.
• The evaluation of PREPs will be facilitated by the development of appropriate animal models and in vitro assays of the pathogenesis of tobacco-attributable diseases.
• Short-term clinical studies, and epidemiological studies in humans are required for comprehensive evaluations of PREPs.
• Long-term epidemiological studies of populations and/or pilot groups of users should monitor the incidence of disease or other adverse effects.

Regulation of PREPs is important and we note that the IOM recommended eleven regulatory principles including:

“Regulatory Principle 4:

Manufacturers should be permitted to market tobacco-related products with exposure-reduction or risk-reduction claims only after prior agency approval based on scientific evidence (a) that the product substantially reduces exposure to one or more tobacco toxicants and (b) if a risk reduction claim is made, that the product can reasonably be expected to reduce the risk of one or more specific diseases or other adverse health effects, as compared with whatever benchmark product the agency requires to be stated in the labeling.  The "substantial reduction" in exposure should be sufficiently large that measurable reduction in morbidity and/or mortality (in subsequent clinical or epidemiological studies) would be anticipated, as judged by independent scientific experts.”

Our approach to combustible PREP assessment

The IOM report gave encouragement to PREP development but did not detail which tests would need to be completed before a product could be characterised as a PREP. 

The report made it clear that more research was needed to develop and validate measures that would allow an assessment of whether a PREP was likely to result in some reduction in harm.

We have taken the IOM’s report as a starting point for research activities necessary to create a framework for the assessment of PREPs.

Our approach assumes that a considerable amount of data will need to be generated to give independent bodies a reasonable level of confidence in a PREP’s potential to reduce harm.  This data will include:

• smoke chemistry;
• smoking behaviour;
• in vitro assessment; and
• clinical research with biomarkers of exposure and potential harm.

Some methods are already established and available but in many areas the tests need to be developed and validated. 

We expect that the research programme to develop and validate biomarkers of potential harm will take many years and involve considerable consultation with other researchers.

Laboratory studies

One approach to making a candidate PREP is to take a technological development and incorporate it into a tobacco product.  Chemical laboratory tests then - under standardised conditions - assess the extent to which the levels of various smoke toxicants have been reduced, compared to a conventional cigarette. 

This is followed by biological tests - many still under development - using in vitro models to give an early indication of whether this might translate into a modified effect in smokers.  These stages establish that the candidate PREP may reduce exposure to smoke and have a potentially lower biological effect. 

Regulatory toxicological tests would also be undertaken - comparing the candidate PREP to conventional tobacco products - to provide some level of assurance that genotoxicity and cytotoxicity have not increased.

Clinical studies

The key characteristics of a PREP will depend on its performance in smokers and we will perform clinical studies as part of the PREP assessment framework. 

Clinical studies are complex and can evaluate numerous possible endpoints:

• smoker behaviour - the puffing and inhalation of the modified smoke;
• smoke constituent retention in the respiratory tract of users;
• physiological parameters; and
• biomarkers of exposure and potential harm - which may include molecular biological evaluations.

By performing such studies we are seeking to establish:

• whether the reduced toxicant exposure recorded in the laboratory from the candidate PREP is also seen in humans; and
• any potential benefit to candidate PREP users by recording whether the reduction in toxicant exposure leads to any biological changes that would be considered meaningful for health.

PREP technology development

We seek to apply the findings of our fundamental research to developing technologies which could be included in the development of products that could eventually be classified as PREPs.

Much of the detail of this work is commercially confidential, although on this website we describe the areas we are investigating.

Long-term assessment and evaluation

Long-term follow-up studies would ultimately be needed to determine whether PREP users experience lower levels of chronic disease than conventional cigarette smokers.  This may also include surveys of consumer behaviour trends as well as disease end-points.

Regulatory oversight of new or modified products aimed at reducing harm

Our position is that regulators should assess all new or modified products where the product aims to reduce harm and where the manufacturer wishes to make a claim that the product will reduce harm. 

In our view, regulators should consider both product performance and its potential to reduce harm, and wider social issues related to the potential effect on under-age use, on non-tobacco user adoption and rates of quitting. 

Manufacturers should provide regulators with data that demonstrates that the new or modified product reduces exposure to substances in tobacco or tobacco smoke thought to cause harm and has the potential to reduce risk and/or harm.

Regulators should encourage manufacturers and public health groups to work together on tests that could be used to assess new or modified tobacco products for their potential for reducing harm.

In assessing these new or modified products as having the potential for reducing harm, we believe that regulators should make comparisons with the most popular tobacco products in their country, taking into account the most likely consumer of the new or modified product. 

As part of this assessment, the net impact on public health of the introduction of such a new or modified product should be considered.

Regulators should apply a consistent approach to reduced harm claims across the marketplace.  All manufacturers should be required to apply for pre-marketing approval from their national regulators if they intend to make a public health claim about new or modified products which have the potential for reducing harm.