Drug Safety: Adverse Drug Reactions (ADR), Pharmacogenomics

Less than 5% of adverse drug reactions (ADRs) are reported to regulators, and equally alarming are estimates that more than 100,000 patients in the US alone die from ADRs each year. 

ADRs are responsible for at least 10% of all hospital admissions, yet 95% are never reported to regulators. This lack of information on ADRs and drug safety is particularly significant for children, as more than 75% of all marketed drugs have never been clinically tested in children. 

The POPi-led Canadian Pharmacogenomics Network for Drug Safety (CPNDS) represents a transdisciplinary consortium of experts from hospitals, universities, research institutes and Health Canada. The goal of CPNDS is to prevent ADRs in childhood by identifying predictive genomic markers for specific ADRs through active surveillance and pharmacogenomic research. CPNDS incorporates these markers into diagnostic tools that can be used to predict in whom serious ADRs are most likely before they occur. Alternative therapeutic recommendations can then be considered on the basis of a revised drug benefit/risk profile.

Current research:

Canadian Pharmacogenomic Network for Drug Safety (CPNDS)

Synopsis: The initial CPNDS surveillance site was established in September 2005, with 10 sites fully operational by 2008. 

As of June 2013, 6,200 ADR cases and 56,385 matched controls have been enrolled from across 13 pediatric academic health centres in Canada (BC Children's Hospital, Alberta Children's Hospital, Stollery Children's Hospital, Winnipeg Health Sciences Centre, London Health Sciences Centre, Hospital for Sick Children, Children's Hospital of Eastern Ontario, McMaster Children's Hospital, Kingston General Hospital, Hopital Sainte-Justine, McGill University Health Centre, Janeway Children's Health Centre, IWK Health Centre). 

Relevant biomarkers for four serious ADRs have been identified: anthracycline-induced cardiotoxicity, cisplatin-induced hearing loss, maternal codeine use and infant death, and carbamazepine-induced serious skin reactions due to prescription drugs in children. Ongoing studies include vincristine-induced peripheral neuropathy, the contribution of genetics to warfarin response and ADRs and several others. 

The CPNDS has also established 13 academic health centres (BC Cancer Agency Victoria, BC Cancer Agency Vancouver, University of British Columbia, Vancouver General Hospital, St. Paul's Hospital, BC Cancer Agency Kelowna, Winnipeg Health Sciences Centre, London Health Sciences Centre, Princess Margaret Hospital, Sunnybrook Health Sciences Centre, Kingston General Hospital, Centre Hospitalier de l'Université de Montréal (CHUM), Capital Health Halifax) for adult ADR studies to replicate the discoveries in children. Current adult pharmacogenomics studies include cisplatin ototoxicity in men with testicular cancer, anthracycline-induced cardiotoxicity, drug-induced liver injury in multiple sclerosis patients, drug-induced Stevens Johnson syndrome and bleomycin-induced pulmonary fibrosis.

CIHR Team Grant:  Drug Safety and Effectiveness Network (DSEN) Active Surveillance and Evaluation of Adverse Reactions in Canadian Healthcare (SEARCH)

Synopsis: The DSEN-SEARCH Team conducts active surveillance related to important drug safety questions raised by regulators and other decision makers in Canada through the Drug Safety and Effectiveness Network (DSEN). The first active surveillance project conducted by SEARCH is investigating the safety of inhaled corticosteroids in children and pregnant women.

CIHR Team Grant:  Drug Safety and Effectiveness Network (DSEN) Pharmacogenomics of Adverse Reaction EVents Nationwide Team (PREVENT)

Synopsis: The DSEN-PREVENT Team is identifying genetic variants associated with priority ADRs identified through DSEN. The first project is expanding and refining the genetic discoveries of anthracycline-induced cardiotoxicity in children.

Implementation of a Pharmacogenetic ADR Prevention Program in BC

Synopsis: This two-year project will develop an understanding of how best to use genetic markers to improve the safe use of drugs in patients.  

We are beginning our work with two pharmacogenetic tests designed to prevent cisplatin-induced hearing loss and anthracycline-induced cardiotoxicity. We are studying how the test results are utilized and understood by both clinicians and patients, before and after testing.  We are evaluating the economic burden of these ADRs and the cost-effectiveness of the pharmacogenetic tests.

Clinical Practice Guidelines for Pharmacogenetic Testing

Synopsis: Clinical practice guidelines for pharmacogenetic testing are urgently needed for clinical care. 

We have developed rigorous and practical guidelines to allow clinicians to make better-informed choices about the risk of specific genetically-mediated drug toxicities and the use of pharmacogenetic tests to help guide drug therapeutic decisions.. Clinical practice guidelines have been developed for cisplatin-induced hearing loss, anthracycline-induced cardiotoxicity, carbamazepine-induced serious skin reactions, warfarin dosing and ADRs, codeine-induced CNS depression and tamoxifen effectiveness.  

These guidelines have undergone significant internal review and are now being submitted to biomedical journals for publication.