Risk-benefit considerations

SHEEHAN D M (1998) Herbal medicines, phytoestrogens and toxicity risk benefit considerations. Proc Soc Exp Biol Med. 217 (3) 379-85. 

Regulatory authorities stipulate the need for ethical principles to be observed when conducting clinical trials. Clinical trials should never be conducted to gain knowledge per se. They should be based on risk-benefit considerations, informed consent, and respect for human individuals. Furthermore, subjects should be protected without being taken advantage of. 

It is important to include all age ranges that are of clinical importance. Development of an anti-asthma drug, for example, should include a programme of evaluation in children as well as adults because they will form a significant portion of the database and risk-benefit considerations will be different. Development of an anti-arthritis compound, on the other hand, will be undertaken predominantly in older patients and particularly detailed information on efficacy and safety in the elderly will be required. 

The nature of the drug and the intended patient population are important in determining whether an effect should be called adverse. For example, toxicity in a drug intended for patients with terminal illnesses or short life-expectancy might be viewed as acceptable in risk-benefit considerations, whereas the same effect in a drug intended for lifetime administration in a more benign condition could well be considered unacceptable. 

Once the animal studies are completed human studies can commence, moving through phase I (up to 50 naive patients to establish a sufficient immune response) phase (several hundred patients in several locations) to phase III in which expanded studies on as many as thousands of patients. The trials require to be randomized and closely controlled by being blinded to avoid bias in interpretation. The patients all have to provide informed consent and strict adherence to good clinical practices in accordance with ethical principles is required to ensure risk-benefit considerations justify the risks associated with all trials of this type. The safety of the patients is an overall requirement and trials must be supervised by the appropriate independent ethics committee or the local Institutional Review Board. 

This drug is a good illustration of the problems and difficulties of risk benefit considerations with drugs. It also illustrates how understanding the mechanisms underlying toxicity can help in this regard. 

In practice, the explorative profiling of enzyme induction is even less elaborate than performed for Drag XYZ because (i) it requires the use of enzyme substrates which are less amenable to inclusion in tolerability studies, and (ii) risk benefit considerations do not justify studies a with a range of dose levels. 

Guberman AH, Besag FM, Brodie MJ, Dooley JM, Duchowny MS, Pellock JM, Richens A, Stern RS, Trevathan E. Lamotrigine-associated rash risk/benefit considerations in adults and children. Epilepsia... 

Few biomarkers will become surrogate endpoints. However, characteristics supporting a biomarker maturing into a surrogate endpoint are (a) biologic plausibility, (b) successful application in prior clinical trials, and (c) presence of significant risk-benefit considerations. Table 17.1 presents a summary of these considerations... 

Although PUVA is apparently not responsible for any increased incidence of internal malignancy, risk benefit considerations with regard to melanoma and nonmelanoma skin cancers indicate an increased risk for melanoma, but no increase for nonmelanoma skin cancers, according to some authors, despite development of increased numbers of lentigines. Other investigators report an increased incidence of nonmelanoma skin cancers in association with PUVA. ... 

The microbial flora of the skin is part of any risk/benefit consideration for use of topical antimicrobials. Mainly, aerobic microorganisms are distributed over the surface of the body and are very numerous in particular areas, including the groin, axillae, and under fingernails and nail folds. The bacterial count on the skin seems to maintain an equilibrium between removal, death, and repopulation from the deep flora. Washing and scrubbing can delay the repopulation a few hours and removes large numbers of the skin bacteria, which are reestablished almost completely within 24 hours. 

Reasonable Risk— Exists when consumers (1) understand risk, (2) evaluate the level of risk, (3) know how to deal with the risk, and (4) accept the risk based on reasonable risk/benefit considerations. 

Walker, R. 1985. Sulphiting agents in foods Some risk/benefit considerations. Food Addit. Contam., Part A, 2 5-24. 

J. E. Brazy, V. Little, J. Grimm and M. Pupkin, Risk benefit considerations for the use of isoxsuprine in the treatment of premature labor, Obstet. Gynecol, 1981, 58, 297-303. 

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