Benefit-to-risk ratio

Epinephrine has a narrow benefit-to-risk ratio. Along with its therapeutic effects, when administered in recommended doses by any route, it potentially causes transient anxiety, fear, restlessness, palpitations, pallor, tremor, and headache. Although usually perceived as adverse effects, such symptoms indicate that a pharmacologically active dose of the medication has been absorbed. The desirable pharmacologic effects of epinephrine cannot be separated from the undesirable pharmacologic effects [10]. 

In anaphylaxis, epinephrine appears to have an optimal benefit-to-risk ratio when it is administered promptly by intramuscular injection [1-6]. 

The proposed review of PER in the United Kingdom, already considered necessary, was to correspond to the requirements under European Directives. These Directives required that throughout the Community proprietary medicinal products granted licences before 22 November 1976 should be reviewed by 20 May 1990. Indeed, the United Kingdom was among the first to complete this review on time. This review eliminated from the market all medicinal products that were released for clinical use previously without scrutiny and that were ineffective, imsafe or that had an unacceptable benefit to risk ratio. 

Unlike foods, including dietary supplements, the safety of a drug is based on a benefit to risk ratio. Benefit is an assessment of the drug s efficacy, balanced against any negatives with respect to a particular indication in a target population (24). Thus, a drug that is deemed safe to treat leukemia may not be safe to treat osteoarthritis. 

Consistent with these hypotheses is the finding that continuous infusion of the opioid into the epidural or intrathecal space provides optimal pain relief postoper-atively or in chronic, intractable pain.2 40 83 Continuous infusion is associated with certain side effects, especially nausea and constipation, as well as the potential for disruption of the drug delivery system.24 57 77 Problems with tolerance have also been reported during continuous administration,27 but it is somewhat controversial whether tolerance really develops when these drugs are used appropriately in the clinical management of pain (see section on Concepts of Addiction, Tolerance, and Physical Dependence ). Hence, the benefit-to-risk ratio for continuous epidural or intrathecal infusion is often acceptable in patients with severe pain. This method of opioid administration continues to gain acceptance.24 57... 

The barbiturates and meprobamate have been entirely superseded by the benzodiazepines and because of their low benefit-to-risk ratio (dependence producing, lethality in overdose, potent sedative effects) they should never be used as anxiolytics. Despite their popularity as short-term sedatives, antihistamines are ineffective anxiolytics, while the use of sedative antidepressants such as amitriptyline should be limited to the treatment of patients with symptoms of both anxiety and depression due to their limited efficacy and the poor patient compliance associated with their adverse effects. However, patients with panic disorder do appear to show a beneficial response to antidepressants (see Chapter 6). A similar argument... 

Ideally, the overall benefit to risk ratio would be carefully considered before making a go/no-go decision to prevent the premature termination of drugs which were potentially safer and perhaps more effective than the alternative. Sources of pharmacodynamic variability include genetics (e.g. of transporters or receptors) and demographics (e.g. developmental differences in the abundance of receptors or hormonal influence on the regulation of receptors). 

An example of improved efficacy of an enantiomerically pure version of a drug over the racemic version is provided by citalopram. The racemic version, known as Celexa, is marketed as an antidepressant. Studies on the resolved enantiomers have shown that the S-enantiomer is the active one and that it has a more rapid onset of action and a more favorable benefit-to-risk ratio than the racemate. As a result, (S)-citalo-pram (escitalopram or Lexapro) is now being marketed. Not only is this a better and safer drug, but the pharmaceutical company that developed citalopram was able to extend its markel exclusivity for an additional 3 years. 

In an effort to improve the benefit-to-risk ratio of PTH in the context of the uncertain relevance of the findings in rodents, it was strongly recommended that participation in clinical studies be limited to adults with severe osteoporosis who have completed bone maturation. It was further advised that any case of osteosarcoma (or other bone tumor) be immediately reported and long-term follow-up be conducted for patients treated with PTH. Importantly, subjects in clinical trials of PTH and PTH analogues should be informed about the occurrence of osteosarcomas in rodents. 

A challenging issue in nasal delivery is related to the safety aspects of excipients, especially absorption enhancers, in the formulation. For most kinds of enhancers, a direct relationship exists between absorptionenhancing ability and local toxic effect. However, the efficacy of some kinds of absorption enhancers may not be necessarily related to their damaging effects on the nasal epithelium. Thus the establishment of a benefit-to-risk ratio for nasal absorption enhancers is of major importance. 

In a meta-analysis of 10 studies of the use of amiodarone in patients with heart failure, the overall odds ratio for mortality with amiodarone compared with placebo was 0.79 (95 % Cl = 0.68, 0.92). The corresponding odds ratio for adverse effects was 2.29 (1.97,2.66) (36). The benefit to risk ratio of the use of amiodarone in these patients is not yet clear. The dosage of amiodarone in these studies varied from 50 to 400 mg/day, with an average of around 250 mg/day. 

The colloids, in particular albumin, are expensive solutions. Therefore, it is difficult to justify the additional cost of colloidal products unless the benefit-to-risk ratio is substantially greater than that associated with inexpensive crystalloid solutions. This does not appear to be the case based on randomized, controlled studies and meta-analyses comparing colloid and crystalloid solutions for acute circulatory insufficiency. Because other colloids, such as hetastarch, almost always have been compared with albumin and not with crystalloid solutions in published clinical studies (with no clinically important differences being found), there is no reason to suspect that these other colloids have any unique advantages as volume expanders. Adverse effects associated with colloids appear to be uncommon and generally are extensions of their pharmacologic activity (Table 24—4), but this is also true of crystalloids. The benefit-to-risk ratio appears to be similar for colloids and crystalloids thus, based on cost, crystalloids are preferred for initial treatment of circulatory insufficiency. 

This cruel experiment was unintentionally conducted in Peru in the 1980s. The result was a cholera epidemic affecting 300,000 people and causing 3,500 deaths. In the United States in 1994, problems in the water chlorination system of Milwaukee resulted in over a third of a million people being sickened by the protozoan, Cryptosporidium. Similarly, as discussed earlier in this book, the removal of DDT from Africa resulted in millions of deaths secondary to a resurgence of once-controlled malaria. The human trials have been done and, in retrospect, the benefit-to-risk ratio favors DDT and chlorine. Chlorine has not yet been banned. Why is there even any debate ... 

On this basis, a programme can be developed to accurately assess the potential toxicity of biotechnologically-derived pharmaceuticals and ultimately establish a benefit to risk ratio. Such a programme will provide the clinician with scientifically relevant data to support clinical trials of potentially greater complexity than those undertaken for conventional pharmaceuticals. At the same time, the data will be sufficient to allow regulators to approve applications for clinical trial programmes and marketing. 

Mass immunisation is an enormously effective public health measure and has saved more lives than any other medical intervention in the last century. A number of diseases have been completely eradicated and others rendered very uncommon as a result of mass immunisation programs. Immunisation rates are now reasonably high— 2010 figures reveal over 90% of Australian children were fully immunised against the key childhood diseases, somewhere between 85% and 97% in the UK, and more than 77% in the United States. A favourable benefit-to-risk ratio has been well documented, and the WHO recommends 95% vaccination coverage as a national target. ... 

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