Contaminated valsartan has so far not caused an increased incidence of cancer cases in Denmark

13 September 2018

A Danish registry study has examined if the cancer incidence rate is higher among people treated with the blood pressure lowering medicine Valsartan, which due to the risk of contamination was recalled from the market in July 2018. The study concludes that no increased cancer incidence can be seen at present.

On 4 July 2018, the Danish Medicines Agency stopped all sale of certain specific valsartan products from Danish pharmacies. The drug regulatory authorities in many other countries around the world did the same.

The recall was prompted by the discovery – firstly at a Chinese manufacturer of one of the active substances of specific valsartan products and later at an additional three manufacturers in China and India – of impurities (NDMA) that could potentially cause cancer. The preliminary assessment is that the impurities may have been present in the medicines in the past six years, and patients who have received treatment for a long time may have been exposed to these impurities for several years.

Together with researchers from the Department of Clinical Pharmacology and Pharmacy at the University of Southern Denmark, the Danish Medicines Agency has investigated if there are any signs at present of an increased incidence of cancer in the Danish patients who have been treated with valsartan products that may have been contaminated.

No over-representation of cancer cases at present

Pierre Quartarolo, co-author of the study and Director of the Danish Medicines Agency’s Pharmacovigilance and Medical Devices Division, says about the study:

"The study clearly shows that overall is there presently no over-representation of cancer cases among the persons who have received treatment with the recalled valsartan products. This is of course reassuring at the present time. However, it is important to keep in mind that cancer is a disease that develops slowly, and therefore the study does not remove concerns about consequences that could develop in the long term if certain valsartan products may have been contaminated with NDMA. It is therefore required that we conduct more studies, partly to monitor patients over several years, and partly to study more specifically the incidence of various cancer forms".

The study, which has just been published, is a so-called registry study conducted with data from the Danish health registries. The study covered a total of 5,150 patients aged 40 years and above who had no prior history of cancer and had used valsartan products in the period from 1 January 2012 to 30 June 2018. The study shows that within the relatively short observational period (median 4.6 years), no overall increased risk of developing cancer was detected among the group of patients that have been exposed to NDMA compared to patients in the group assumed not to have been exposed to NDMA.

The study Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: A Danish nationwide cohort study by Anton Pottegård, Pierre Quartarolo et al. has just been published in the peer-reviewed medical journal BMJ.

Read BMJ's editorial Regulatory response to contaminated valsartan here.

The study will be included in the overall review of the consequences of NDMA in valsartan, which is currently being conducted by the European Medicines Agency, EMA, according to a news update on the subject on the agency's web page.

Collaboration between regulatory authority and research institution

The study has been prepared in a collaboration between the Danish Medicines Agency and the University of Southern Denmark and is a good example of how valuable registry research is in a regulatory context, explains Pierre Quartarolo.

"Although the study only uses Danish data, the results are interesting for the entire world. It is quite unique that we in Denmark have so effective and comprehensive registries that we are able to correlate the relevant data so soon after the issue came to our knowledge.  It took only seven weeks from the discovery of the possible NDMA contamination of valsartan to the results were available in manuscript form – after that, a smooth and extraordinarily rapid process at BMJ made it possible to publish the results this quickly. The collaboration we have seen in this case between a regulatory authority and a research institution has proven extremely effective, and it is certainly a collaboration form we will pursue moving forward”, says Pierre Quartarolo, Director of Division at the Danish Medicines Agency.

Quotes from BMJ's editorial

"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)."

"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."

"Regulatory actions coupled with the generation of robust evidence are the keys to responding promptly to emerging public health concerns."

Read the full BMJ editorial here.