Cancer drug safety: time to re-focus on tackling adverse effects

Drug safety is once again under the spotlight. In a study presented at the European Society of Medical Oncology Congress (Oct 7–11, 2016; Copenhagen, Denmark), Paolo Bossi and colleagues showed that a substantial number of clinical trials testing targeted and immunotherapies have suboptimal reporting of adverse events, particularly with regards to recurrent or late toxicities. Additionally, the US Food and Drug Administration (FDA) announced on Oct 4, 2016, that 27 drugs and drug classes—several of which include cancer agents—have been put on their watch list because of worrying evidence of unacceptable adverse events. The regulator has also issued a boxed warning, their most prominent caution, for direct-acting antivirals for hepatitis C virus (HCV)—a common infection for patients with haematological malignancies and liver cancer. The FDA is concerned that there is a risk of hepatitis B reactivation when using HCV antiviral medication, which can cause severe complications in patients with cancer.

In this issue of The Lancet Oncology, we publish a Series of three Reviews focusing on the important issue of drug safety. At a time when the number of biological agents due to come off patent is increasing, and in the face of a market fuelled by escalating drug prices and pressure from pharmaceutical companies and patient groups alike for expedited drug approval, issues surrounding the safety and efficacy of agents such as biosimilars and generics are paramount. Substantial variation exists between high-income and low-to-middle-income countries with regards to manufacturing and supply chain regulation of generic drugs, despite countries such as India providing a large market share of generic drugs worldwide. Moreover, bioequivalence—a key consideration when comparing generic formulations with their trade-marked counterparts—can vary substantially, making appropriate regulation particularly important. Issues of safety and regulation are further compounded when approving biosimilars: despite nearly 10 years’ of experience in dealing with biosimilar agents, regulators still need to streamline and expedite approval processes, and improve ways of reducing cost. Thus, taken together, the importance of pharmacovigilance has never been greater. Given that multiple health-care systems encourage or enforce generic and biosimilar prescribing, sometimes without physician knowledge or consent, coupled with further potential complications created by generic or biosimilar switching during a course of treatment, pharmacovigilance needs to evolve beyond merely the uncovering, monitoring, and reporting of adverse events, to continual pre-marketing and post-marketing surveillance.

Although a focus on regulatory and policy issues is key to monitoring safety and efficacy, especially for newer agents, there are other ways in which drug safety can be improved. In a Personal View in this issue of The Lancet Oncology, Andrew Bottomley and colleagues set out their rationale for initiating the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Endpoints Data consortium. This initiative was developed on the grounds that heterogeneity in health-related quality of life data make it difficult to compare results across trials, and can hinder the application of research findings to inform product labelling, clinical guidelines, and health policy. This endeavour is laudable, especially since evidence has repeatedly shown that toxicity reporting by clinicians rather than by patients leads to under-reporting of adverse events, and that the use of non-standardised statistical approaches can result in different data interpretations. Initiatives such as these help to improve the quality of reporting within a clinical setting, while also relying more on patient-reported outcomes.

Although it is promising to see that the issue of drug safety, especially in oncology, is being given due attention, it is all too easy to forget that sometimes efforts do not match up to reality, as shown by recent FDA announcements. Therefore, it is vital to ensure that drug safety is monitored and developed at all levels of a product’s lifecycle—from research to manufacture, to distribution, regulation, and policy. Greater integration and harmonisation of these efforts will ensure that safety is maintained not only for existing drugs, but also for new agents that enter the market in years to come. Through continuous monitoring and surveillance by companies, regulators, physicians, and patients, we can work towards ensuring that medications act only towards curing the patient, rather than causing further harm.

http://thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30519-8/fulltext

https://www.thelancet.com/series/drug-safety