Regulatory response to contaminated valsartan
Menée au Danemark à partir de données portant sur 5 150 participants, cette étude de cohorte évalue l'association entre une exposition à de la N-nitrosodiméthylamine, liée à une utilisation de médicaments à base de valsartan contaminé, et le risque de cancer (durée médiane de suivi : 4,6 ans)
Regulators took rapid action, but exposed patients still require long term monitoring. Despite being limited by its short follow-up, the registry based cohort study by Pottegård and colleagues (doi:10.1136/bmj.k3851) provides reassuring interim evidence about the risk of cancer in patients treated with valsartan products contaminated with a probable human carcinogen (N-nitrosodimethylamine, NDMA).1 This study was planned, conducted, analysed, and published within three months from the notification of this quality issue to regulatory authorities.2 It would not have been possible without linking data from four Danish nationwide registries collecting information on prescriptions, cancer diagnoses, hospital admissions, mortality, and migration. The authors report no increase in overall cancer risk among users of potentially contaminated valsartan products followed up for a median of 4.6 years. This study alone cannot dispel doubts about the potential risk for patients in the longer term, but it helps inform decision making around this episode. It also illustrates the usefulness of national registries for examining the relations between risk factors and health problems and how research can give a prompt response whenever public health concerns emerge. How did regulatory agencies react to the safety concern affecting medicinal products containing valsartan? Europe, the United States, Canada, and Japan rapidly started their own investigations, with some international collaboration. Firstly, they mapped all the licensed medicines containing the active substance valsartan—an angiotensin II receptor blocker—supplied by the company that detected the impurity. They recalled the contaminated lots, amounting to more than 3000 products licensed at the national level or centrally by the European Medicines Agency.3 Branded medicinal products, not just generics, were affected. The Italian medicines agency, for instance, recalled more than 700 lots pertaining to about 100 medicinal products, licensed by 15 marketing authorisation holders.4 This affects a large number of patients, as valsartan alone or in combination with hydrochlorothiazide accounted for a total of 25.1 defined daily doses per 1000 inhabitants per day in Italy in 2017.5 Secondly, regulatory authorities are collecting information on the cause of this contamination; possibly related to a change in the manufacturing process in 2012. Although this needs confirmation, some will wonder whether the impurity could have been detected earlier. Possibly it could. Manufacturing processes must be checked and monitored for any known impurities that imply a risk—as with NDMA, which is a recognised probable human genotoxic compound. This task is the responsibility of the manufacturers themselves, but the marketing authorisation holders are responsible for the quality of the finished medicinal products they put on the market. Public authorities are called to authorise production sites and supervise the quality of pharmaceuticals with frequent, thorough inspections. (...)