Abstract
The special issues of the Journal of International Medical Research provide readers with an opportunity to learn more about various important issues in health care, research, or policy from several perspectives. This special issue present articles on the theme of risk–benefit analysis of medicines. Medicines provide therapeutic benefits (the successful treatment of the condition for which the drug is indicated) and other types of benefits such as improved quality of life. Unfortunately, medicines also carry risks of adverse drug reactions, which can vary from minor symptoms (such as nausea, vomiting, or headache) to rare, severe reactions (such as anaphylactic reaction, liver failure, or cancer).
A new chemical entity, upon emerging from the drug discovery process, is tested extensively in animals (preclinical research) and humans (clinical trials) to establish its risk–benefit profile. In preclinical research, the efficacy data for a new chemical entity are obtained from specific animal models of the target disease among various species and strain of animals, whereas safety data are obtained from various toxicological studies. The sponsor submits all information from preclinical studies to regulatory authorities in the form of an investigational new drug application. The risk–benefit ratio from preclinical studies determines whether a candidate drug is suitable for first-in-human testing. If found suitable, the drug undergoes testing in various phases of clinical trials for risk–benefit analysis, a continuous process. After successful completion of all phases of clinical trials, regulators assess the information available at that specific moment, in the form of a new drug application, with regard to the risks and benefits, and authorized the product if the benefits outweigh the risks. This balance is valid at a given point of time, but may change later once the drug is on the market as a result of exposure in a large number of patients, concomitant medications and diseases, long-term exposure, confounding factors, and uncontrolled conditions. For example, benefit might be 90% and risk 15% when the first periodic safety update report (PSUR) is submitted. These percentages might have changed when the fourth PSUR is submitted (benefit 80% and risk 50%). Thus, multiple drugs that were initially found to be very successful in a number of patients were unfortunately later found to cause serious side effects, resulting in their withdrawal from the market. So, to enhance patient safety and protect public health, periodic re-examination of the risk–benefit balance is needed to ensure that the balance remains favourable. This periodic re-examination is reported as a PSUR, a document that provides an assessment of the risk–benefit balance of a medicinal product to the regulatory bodies on a defined timeline during the post-authorization phase. However, at all phases (preclinical, clinical, and post-marketing), risk–benefit analysis remains an important and complex undertaking.
The risk–benefit profile of medicines has dual aspects. In some cases, new findings indicate a better safety profile or increased therapeutic benefit of a drug, but can sometimes uncover side effects that render the safety profile of the drug less favourable. Drugs (even those with “blockbuster” status) that have been on the market for years can be withdrawn following a revised risk–benefit analysis. For example, thalidomide was marketed in 1957 as a sedative-hypnotic drug, and later used to alleviate morning sickness in pregnant women. Unfortunately, this drug led to various birth defects and was withdrawn from the market because of its unfavourable risk–benefit profile.
The risk–benefit analysis of drugs can be justified by the introduction of risk management measures such as restricted use in special populations (such as children, pregnant women, or older patients). For example, to avoid birth defects, no female patient starts isotretinoin therapy if pregnant, and female patients on isotretinoin therapy avoid becoming pregnant. However, there are some exceptional cases where a drug with an unfavourable risk–benefit profile is later shown to have a positive outcome. A well-known example is the relaunch of thalidomide to treat multiple myeloma, using a risk management plan to avoid tragic consequences to the foetus if exposure occurs during pregnancy. This example highlights the need for risk–benefit assessment of medicinal products. A drug with a questionable safety profile may be acceptable in oncology but not for the treatment of less severe disorders.
The risk–benefit assessment of drugs is independent of the existence of alternative therapeutics, but it is clear that when such alternatives are available for a particular indication, regulatory authorities will favour drugs with more favourable risk–benefit profiles. Looking to the future, the results of risk–benefit assessments of medicines will continue to be of enormous interest and may provide additional motivation for investigating the use of medicines in the treatment of various pathological conditions.