Addressing the risks of medicines

Transcription

1 Addressing the risks of medicines A new governance strategy for pharmacovigilance 1 Mary Wiktorowicz, MSc. Ph.D. Chair and Associate Professor, School of Health Policy and Management

2 My presentation will address 3 key points: 1. Public confidence in Health Canada has eroded due to its lack of transparency and due process for public representation in the drug review process. 2. A new strategy for pharmacovigilance is needed. Insights from our research on international governance models will be offered to guide a more systematic approach. 3. Active surveillance should be arm s length from pharmaceutical companies, whose research results are frequently biased. 2

3 Adverse drug reactions (ADRs) one of the top 10 leading causes of death Patients are increasingly exposed to the harms of medicines. Markets for blockbuster drugs are so large that even risks that occur infrequently can lead to thousands of injuries, including the deaths and cardiac events associated with Vioxx (rofecoxib) and Bextra (valdecoxib). Avorn, J. (2005). Powerful medicines: the benefits, risks and costs of prescription drugs. New York: Random House. Moore, T., Cohen M., Furberg, C. (2007). Serious adverse drug events reported to the Food and Drug Administration, Archives of Internal Medicine 2007; Office of Inspector General. (2010). Adverse events in hospitals: national incidence among Medicare beneficiaries. Department of Health and Human Services. United States. Ross J., Madigan D., Hill K., Egilman D., Wang, Y., Krumholtz H Pooled Analysis of Rofecoxib Placebo- Controlled Clinical Trial Data, Lessons for Postmarket Pharmaceutical Safety Surveillance. Arch Intern Med 169 (21):

4 Pre-market drug review is recognized as incomplete 1. Brief randomized controlled trials (RCTs) do not detect the harms of long-term drug use (for chronic conditions). 2. There are too few subjects in clinical trials to identify rare sideeffects (that occur in less than 1 in 1500). 3. Due to off-label prescribing, the market for drugs can include patient groups who were never tested leaving these patients at particular risk (e.g. children, youth, seniors). 4. Demonstrating efficacy in an RCT sufficient for market approval short-term improvement in a surrogate marker compared to placebo often fails to answer doctors and patients more relevant questions i.e. long term effectiveness, mortality Ray, W, & Stein, C. (2006). Reform of drug regulation - beyond an independent drug-safety board. N Engl J Med 354, Stafford, R. (2008). Regulating off-label drug use - rethinking the role of the FDA. N Engl J Med, 358,

5 Spontaneous ADR reporting: Passive, slow, expensive & incomplete Example: FDA received approx. 82 ADR reports/year for digoxin (1990s) - did not seem to be a big problem. A systematic survey of US Medicare records over same time period revealed 202,211 hospitalizations for ADRs related to digoxin (Gotlieb 2005). Gottlieb, S. (2005). Opening Pandora s pillbox: using modern information tools to improve drug safety. Health Affairs, 24(4),

6 Health Canada s processes are not transparent The fundamental point of a regulatory agency is transparency to give the public - at whose behest the agency serves - confidence that it ensures due process in fulfilling its role. Regulatory agencies such as the CRTC ensure public representation within their mandate. Health Canada obscures its regulatory process from public purview and disallows a public perspective within its regulatory decisions. The Auditor General found Health Canada is not adequately fulfilling its responsibilities; the Toronto Star s reports attest it is losing public confidence. 6

7 Risk Management Plans - developed by manufacturers - are inadequate: Health Canada s Health Product Vigilance Framework (2012) notes that it will use Risk Management Plans as a vigilance strategy. Giezen and colleagues (2009) analysis of 18 RMPs in the European Union identified 169 safety concerns. Frau and colleagues (2010) found that RMPs were used to reassure the public as inadequately evaluated drugs entered the market. Frau, S., Pous, M, Luppino, M, Conforti, A. (2010). Risk management plans: are they a tool for improving drug safety? Eur J Clin Pharm, 66, Giezen, T., Mantel-Teeuwisse, A, Strauss, S/, Egberts, T., Blackburn, S., Persson, I., et al. (2009). Evaluation of post-authorization safety studies in the first cohort of EU risk management plans at time of regulatory approval. Drug Safety, 32,

8 Industry guided post-market studies are affected by conflict of interest Turner and colleagues (2008) re-analysed the data that pharmaceutical companies submitted to the FDA to support their new product applications. They found that pharmaceutical companies study results overstated the effectiveness and under-reported the harms associated with their products. As patient registries including those overseen by drug companies exclude a control group (that is not taking the drug), observational studies based on patient registries are not scientifically rigorous. Turner, E., Matthews, A, Linardatos, E., Tell, R.,Rosenthal, R. (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 358,

9 Increased funding for active surveillance of drugs by independent researchers is needed after they enter the market. Wiktorowicz, Mary, Lexchin, Joel, Moscou, Kathy Pharmacovigilance in Europe and North America: Divergent Approaches. Social Science and Medicine 75: Available online at: Wiktorowicz ME, Lexchin J, Moscou K, Silversides A, Eggertson L Keeping an eye on drugs...keeping patients safe. Active monitoring systems for drug safety and effectiveness in Canada and internationally. Commissioned by the Health Council of Canada. November 17, 2010 Wiktorowicz M, Lexchin J, Paterson M, Mintzes B, Light D, Morgan S, Holbrook A, Tamblyn R, Zaki E, Moscou K. Research networks involved in post-market pharmacosurveillance in the United States, United Kingdom, France, New Zealand, Australia, Norway and European Union: lessons for Canada. Canadian Patient Safety Institute,

10 FDA s Office of Surveillance and Epidemiology has received increased funding Real-world safety information is gathered from organizations such as the VA, research centres and health care insurers. It complements ADR reporting by strengthening signals generated through queries of large healthcare databases. the vision is that we ll be able to go in and in an intelligent systematic way query large health care databases to see if we can essentially answer this question in a different way...it s seen as a complement to spontaneous reporting to allow us to sort of further define things when we just have a small number of reports. US Key Informant 1 FDA, March 19,

11 US FDA s access to research networks The FDA and VA-MedSAFE Health Plan Dyadic Linkage Model: Memorandum of Understanding (MOU) VA Medical Center VA Medical Center VA Medical Center VA Medical Center Data Feedback VA-MedSAFE 2007 MOU FDA 1. Information sharing & robust inter-agency activities 2. Use tools & expertise to identify, validate & analyse risk 3. Build infrastructure to address the common need to evaluate the safety, effectiveness and use of drugs. 11

12 New Zealand Medsafe s access to research networks: New Zealand Pharmacovigilance Center at the Otago University Medical School Medical Center Medical Center Medical Center Medical Center ADRs reporting Feedback NZ Pharmacovigilance center Passive monitoring: Centre for Adverse Reactions Monitoring (CARM) Active monitoring: Intensive Medicines Monitoring Program (IMMP) Guidance Cooperative Agreement Studies & Reports Medicines Adverse Reactions Committee (MARC) Regulator (Medsafe) 12 Vaccine Monitoring Program Infrequent little grants Main funding Drug companies Inform about a study

13 FDA s Drug Safety Board The Drug Safety Board is essentially an advisory board to the Center [CDER] director it includes leaders in the Center for Drugs that are involved in the scientific review of regulated products. It does have members from outside the FDA but they re all government members [including] Veteran s Administration, Department of Defense, both of which have big healthcare systems the Agency for Healthcare Research and Quality, which is another federal agency, the National Institutes of Health and perhaps some others. The board meets basically on a monthly basis and it looks at the specific safety issues, it also reviews how CDER is communicating these messages as well - US Key Informant1-FDA, March 19,

14 A new strategy for the governance of pharmacovigilance is required in Canada Membership on a new pharmacovigilance committee should follow the FDA Drug Safety Board model, where in addition to Health Canada, would include representatives from DSEN, provincial government drug plans and experts with access to healthcare data bases that can support active surveillance. The Drug Safety and Effectiveness Network should be supported with increased funding to conduct independent studies. 14

15 Health Canada should obtain the authority to require post-market studies If Health Canada obtains authority to require post-market studies, it should not lower pre-market safety requirements, as its approach to progressive licensing suggests. Lowering premarket safety standards would diminish public confidence. Health Canada should require a black triangle on all new products in their first two years of marketing. In the UK, a black triangle appears on new drug products to support providers and patients vigilance in prescribing and taking new medicines. Given the safety concerns associated with new products - particularly fasttracked products that are more likely to be withdrawn due to safety concerns a black triangle is justified. Lexchin, Joel New Drugs and Safety: What Happened to New Active Substances Approved in Canada Between 1995 and 2010? Archives of Internal Medicine Published Online: October 8, doi: /archinternmed

16 Ensure Health Canada has the skills and resources to act on Adverse Drug Reaction Reports Health Canada captures less than ten percent of ADRs in its spontaneous adverse drug event reporting database. But it does not have the capacity to routinely analyze these ADR reports, or act on them to prevent further harms. Chris Turner, Health Canada response to questions at Post Market Drug Safety and Effectiveness Workshop May , University of Ottawa. 16

17 Joint initiatives should be developed between Health Canada and Provincial Ministries of Health As provincial health care plans have administrative data that tracks patients use of pharmaceuticals and can link it to health care use, joint initiatives should be developed to set priorities for monitoring the use of drugs in the real world drawing on these data bases. 17

18 Health Canada should require manufacturers to submit clinical trial data Example: The Adverse Drug Reaction of suicidal ideation in children and youth on SSRIs was found by the UK Expert Working Group on the Safety of Medicines; the FDA then re-analyzed pooled RCT data. Health Canada has the authority to require companies to submit clinical trial data, but generally only requests summary data for product reviews. Whittington,C., Kendall, T., Fonagy, P., Cottrell,D., Cotgrove, A., Boddington, E Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. The Lancet 363: Magnot Zito, J., Derivan, A., Greenhill, L.L Making Research Data Available: An Ethical Imperative Demonstrated by the SSRI Debacle. J. Am. Acad. Child Adolesc. Psychiatry, 43:5:

19 Conclusion A new strategy to address the harms of pharmaceutical drugs in Canada would: Develop a new pharmacovigilance governance process in which Health Canada collaborates with provincial counterparts and DSEN to access to data on the effects of medicines in the real world, and has authority to address issues with medicines. Increase funding for DSEN to commission independent studies to support Health Canada s regulatory decisions. Equip Health Canada with the authority and resources to fulfill its responsibilities; require transparency and inclusion of public representation. Prioritize the safety of Canadians higher than the proprietary interests of industry. 19