New drugs are generally approved on the basis of efficacy studies with adverse outcomes considered as a secondary issue. However, adverse effects/harms are just as important a consideration as efficacy. See Section 8An-1 in the annexe at the end of this chapter for a discussion of the use of the word harm in preference to risk.
It should be remembered that much of the data mentioned in Box 8.4 will not be publicly available when the drug is new. You should ask the pharmaceutical company to provide them.
Trials of efficacy usually involve hundreds of patients, and so a rare serious adverse effect, affecting say 1 in 500 patients taking a drug, is unlikely to show up in the initial trials. Ideally, information from as many of the sources listed in Box 8.4 as possible is needed to ascertain the full risk of harm from a drug. However, much important information will not be known when a drug is new, so it is reasonable to be cautious, and make an allowance for unknown harms.
Remember, the safety of a new drug cannot be known with certainty until it has been on the market for many years.15,16 For this reason new drugs need to be re-evaluated from time to time. As more information becomes available over time it becomes possible to use data from the various sources to ascertain the risk of harm. Watch out for any signals suggesting harm, by analysing as many data as possible, (even single case reports) from the sources listed in Box 8.4. To read more about assessing the risk of harm, including assessing causation and using animal data, and examples of the experience of the Japanese bulletins, The Informed Prescriber and Kusuri-no-Check [http://npojip.org], see the annexe at the end of this chapter.
Box 8.4: Data needed for full evaluation of risk of harm
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1) Preclinical data (see Section 8An-3)
• chemical characteristics, including similarities in structure to drugs that have caused serious harm (see Section 8An-3.2)
• pharmacological tests (general, efficacy, safety)
• toxicity tests (acute/single, subacute-chronic/repeat, carcinogenicity, genotoxicity, reproduction toxicity)
• pharmacokinetic data on absorption, distribution, metabolism and elimination (ADME), especially on area under the curve (AUC), Cmax, t½ of the active ingredients and metabolites. Is the drug eliminated via the liver or kidney or other routes?
2) Clinical data
• pharmacokinetic data on ADME, especially on AUC, Cmax, t½ of the active ingredients in humans and metabolites if necessary: Phase I studies
• dose-response data
• Phase II studies (small, preliminary efficacy and safety and dose finding or bridging trials)
• Phase III studies (larger, randomised controlled trials).
3) Post-marketing large-scale randomised controlled trials or comparative study for long-term efficacy and safety (Phase IV).
4) Post-marketing pharmacovigilance data (post-marketing surveillance).
5) Large scale long-term epidemiological observational mortality data.
6) Epidemiological studies (ecological, case-control, cohort studies), to provide a clear picture of safety profiles, including interactions and safety in at-risk groups (such as elderly people, children, pregnant women and patients with renal failure).
7) Systematic reviews or meta-analysis of those studies above.
8) Case report(s) including legal cases (law reports, evidence given in court) and reports sent to adverse drug reaction monitoring centres.
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