Working Procedures

B. SCIENTIFIC REVIEW AND EVALUATION

6. Evaluation and rationale

Evaluations of the strength of the evidence for cancer-preventive effects from studies in humans and experimental animals are made using standard terms. Similarly, an evaluation of the strength of the mechanistic evidence is given.

It is recognized that the criteria for these evaluation categories, described below, cannot encompass all factors that may be relevant to an evaluation of cancer-preventive effects. In considering all the relevant scientific data, the Working Group may assign the intervention to a higher or lower category than a strict interpretation of these criteria would indicate.

The evaluation categories refer only to the strength of the evidence that an intervention prevents cancer, and not to the extent of its cancer-preventive effects (potency). The evaluations may change as new information becomes available.

Evaluations are inevitably limited to the intervention as actually implemented and observed, for example to the cancer sites, conditions and duration of observation covered by the available studies.

(a) Cancer-preventive effects in humans

The evidence relevant to cancer prevention in humans is classified into one of the following categories:

Sufficient evidence of cancer-preventive effects: The Working Group considers that a preventive relationship has been established between the intervention and the risk of cancer in humans. That is, a preventive association has been observed in studies in which chance, bias, and confounding could be ruled out with confidence. A statement that there is sufficient evidence is followed by a sentence identifying the organ(s) or tissue(s) for which a preventive effect has been observed in humans. Identification of preventive effects in a specific organ or tissue does not preclude the possibility that the intervention may prevent cancer at other sites.

Limited evidence of cancer-preventive effects: A reduced risk of cancer is associated with the intervention for which a preventive effect is considered credible by the Working Group, but chance, bias, or confounding could not be ruled out with confidence.

Inadequate evidence of cancer­preventive effects: The available studies are not of sufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of a cancer-preventive effect of the intervention, or no data on the prevention of cancer by this intervention in humans are available.

Evidence suggesting lack of cancer-preventive effects: When several epidemiological studies show little or no indication of an association between an intervention and a reduced risk of cancer, a judgement may be made that the studies, taken together, show evidence of lack of a preventive effect. Such a judgement requires that the studies meet the standards of design and analysis described above. Specifically, the possibility that bias, confounding, or misclassification of the intervention or the outcome could explain the observed results should be considered and excluded with confidence.

(b) Cancer-preventive effects in experimental animals

Cancer-preventive effects in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis.

Evidence for cancer prevention in experimental animals is classified into one of the following categories:

Sufficient evidence of cancer-preventive effects: The Working Group considers that a causal relationship has been established between the intervention and a decreased incidence and/or multiplicity of spontaneous or chemically induced malignant neoplasms, or of an appropriate combination of benign and malignant neoplasms in an adequate number (four or more) of independent studies carried out at different times, or in different laboratories, or under different protocols.

Limited evidence of cancer-preventive effects: The data indicate a cancer-preventive effect, but are limited for making a definitive evaluation because, for example: (a) the evidence of a cancer-preventive effect is restricted to a small number (fewer than four) of experiments; or (b) the intervention decreases the incidence and/or multiplicity of benign neoplasms only.

Inadequate evidence of cancer-preventive effects: The studies cannot be interpreted as showing either the presence or absence of a preventive effect because of major methodological or quantitative limitations: unresolved questions regarding the adequacy of the design, conduct or interpretation of the study, or few or no data on cancer prevention in experimental animals are available.

Evidence suggesting lack of cancer-preventive activity: Adequate evidence from conclusive studies in several models shows that, within the limits of the tests used, the intervention has no cancer-preventive effects.

(c) Mechanistic data on cancer-preventive effects

Mechanistic and other evidence judged to be relevant to an evaluation of a cancer-preventive effect and of sufficient importance to affect the overall evaluation is brought forward to the evaluation.

The strength of mechanistic evidence supporting the cancer-preventive effect is evaluated, using terms such as ‘weak’, ‘moderate’, or ‘strong’. Indications that a particular mechanism operates in humans are strongest. The data may be considered to be especially relevant if they show in humans that the intervention in question has caused suppression of effects that are on the pathway to cancer. The mechanistic evidence can be strengthened by findings of consistent results in different experimental designs, by the demonstration of biological plausibility, and by coherence of the overall database.

The Working Group considers whether multiple mechanisms might contribute to cancer prevention, whether different mechanisms might operate in different dose ranges or at different sites, or whether separate mechanisms might operate in a susceptible group.

For complex interventions, such as food categories, the chemical composition and the potential contribution of different nutrients known to be present may be considered by the Working Group in its overall evaluation of cancer prevention.

(d) Overall evaluation

Finally, the body of evidence is considered as a whole, and summary statements are made that encompass the effects of the intervention with regard to cancer-preventive effects in humans. The overall evaluation is described according to the wording of one of the following standard categories. The categorization of an intervention is a matter of scientific judgement that reflects the strength of the evidence derived from studies in humans and in experimental animals, and from mechanistic and other relevant data.

  1. The intervention prevents cancer (Group A)

This category is used for interventions for which there is sufficient evidence of a cancer-preventive effect in humans.
The sites on which the evidence in humans is based are given.

  1. The intervention probably prevents cancer (Group B1)

This category is used for interventions for which there is limited evidence of a cancer-preventive effect in humans and sufficient evidence in animals. An intervention may also be classified in this category when there is limited evidence in humans, less than sufficient evidence in experimental animals, and strong supporting evidence from mechanistic and other relevant data that the mechanism(s) of prevention also operates in humans.

The sites on which the evidence in humans is based are given.

  1. The intervention possibly prevents cancer (Group B2)

This category is used for interventions for which there is inadequate evidence in humans, and sufficient evidence in experimental animals. An intervention may also be classified in this category when there is inadequate evidence in humans, limited evidence in experimental animals, and strong supporting evidence from mechanistic and other relevant data that the mechanism(s) of prevention also operates in humans.

  1. The intervention is unclassifiable as to its cancer-preventive effects (Group C)

This category is used for interventions for which the evidence is inadequate in humans and less than sufficient in experimental animals. Interventions that do not fall into any other group are also placed in this category.

  1. The intervention probably does not prevent cancer (Group D)

This category is used for interventions for which there is evidence suggesting lack of a cancer-preventive effect both in humans and in experimental animals.

(e) Rationale

The reasoning that the Working Group used to reach its evaluation is presented and discussed. This section integrates the major findings from studies in humans, studies in experimental animals, and mechanistic and other relevant data. It includes concise statements of the principal line(s) of argument that emerged, the conclusions of the Working Group on the strength of the evidence for each group of studies, and an explanation of the reasoning of the Working Group in weighing data and making evaluations. The human populations that were the subject of study should be identified. Additionally, important health concerns identified—such as adverse effects, including cancer-causing properties should be clearly addressed.

When there are significant differences in scientific interpretation among Working Group Members, a brief summary of the alternative interpretations is provided, together with their scientific rationale and an indication of the relative degree of support for each alternative.

Posted 5 July 2016