The workshop was one of a series examining issues related to a proposal to establish a network of pharmaceutical research centres to conduct studies related to the "real world" use of prescription drugs by Canadians.

Focus: To consider how Health Canada (the regulator) and provincial and federal drug plans could make use of the real world safety and effectiveness data generated by such a network in order to strengthen decision making practices.

Context

Concerns about the safety and cost effectiveness of drugs have led to an international push to step up scrutiny of how prescription drugs are used after they are marketed (post-market surveillance). Some countries are ahead of Canada in setting up systems to collect such information, but it is still early days internationally, as everyone is "finding their way" and all face the challenge of putting "evidence through the policy process to the outcomes."

An abiding issue for all countries is that the information submitted by manufacturers to regulators to support market authorization decisions is not adequate/appropriate for the reimbursement decisions that drug plan managers must make. When a new drug is authorized to be sold, it has been tested on a limited number of individuals. There is typically little predictive knowledge for how it will behave in an individual patient or the broader "real world" patient population, and unanticipated and sometimes hard-to-recognize safety and effectiveness issues can arise.

International experience

Internationally, passive approaches to post-market surveillance include adverse drug reaction reporting (levels vary internationally) and monitoring, and requirements for drug companies to provide risk management plans as a condition of market authorization and conduct phase IV (post-market authorization) clinical trials. More active approaches to post-market surveillance that have been adopted in some countries include: tracking patients who are prescribed a targeted drug; setting up cohort studies for those using new drugs; regular surveys of prescribers and pharmacists; disease registries; database mining; electronic surveillance of emergency ward chart trials conducted by manufacturers; five year renewal for market authorization; and establishment of pharmacovigilance centres.

Regulatory agencies in France, New Zealand, the United Kingdom and the United States already have arrangements with one or more research networks, enabling them to commission research into drug safety and effectiveness. The European Medicines Evaluation Agency (EMEA) is working to establish a network.

Several countries have innovative systems for coordinating the research of regulators and drugs plans (for example, the U.S. Veterans Affairs and the U.K.'s GPRD (General Practice Research Database) program.

The situation in Canada

While some postmarket surveillance activities are being undertaken in Canada, at federal and provincial/territorial levels, there is limited coordinated information sharing between the federal regulator, and drug plan managers and drug researchers in individual provinces and territories, or among the latter. No one organization now has mandate and capacity to do post-market surveillance, however demand for this activity will increase with new federal progressive licensing legislation, which emphasizes a life-cycle approach to drug regulation.

Canada is, however, well positioned to establish the proposed national network given scientific expertise in the country, rich provincial data sources and the ability to link sources of related health care data. And in addition to producing evidence, the network would help to coordinate efforts and share information making better use of scarce resources and minimizing duplication.

Producing and using postmarket surveillance information

Health Canada now relies on a variety of sources for information related to post-market experience with prescription drugs. Sources include reports of adverse drug reactions (ADR) and signal assessment from Canada and other countries, risk communications from foreign jurisdictions, and scientific literature. Risks are assessed and prioritized. Risk management options include: requesting more safety information from market authorization holders (drug manufacturers); changing the pre-market assessment or requirements (e.g., requiring cautionary labelling); issuing risk communications; and, after certain conditions are met, withdrawing the product's license to market.

Some provincial initiatives provide examples of what the proposed network would do on an ongoing basis. Here are two examples of provincial postmarket surveillance initiatives. British Columbia is conducting a three-year trial to evaluate cholinesterase inhibitors (drugs for dementia). Five projects were initiated with the goal of providing sufficient information to Pharmacare to consider provincial eligibility for coverage. Ontario has established a drug innovation fund to pay for independent research on the impact and value of new and existing drugs across the health care system. Research would investigate assertions that drugs lead to downstream savings in the health care system, and the province hopes that funded projects will also support linkages between researchers, clinicians and drug policy decision makers.

Issues to be resolved

In Canada, different parties - including Health Canada, the provinces and territories, the Patented Medicines Price Review Board and the Common Drug Review - have varying information and timing needs. For Health Canada, a key challenge is integrating data on therapeutic effectiveness into the risk management decision-making process. More technical issues for regulators and drug plan managers alike include the need, given the wide range of types and sources of drug-related research, to establish hierarchies of evidence. A key issue is what action the regulator and drug plan managers can take if post-market surveillance uncovers significant problems, especially lack of efficacy or cost effectiveness issues, with already-marketed drugs. For example, it is very difficult for provinces to delist drugs unless there are significant safety concerns. In general, there is a lack of flexibility and agility in the system to respond to new information. For their part, drug plans have to develop expertise since they were not set up to easily deal with signals/safety issues after a drug is listed on the formulary. Nationwide, there is inconsistency in formulary policy and management and a challenge will be how to coordinate post-market surveillance resources among larger and smaller drug plans. Privacy and confidentiality rules can be an obstacle to transparency, and balancing overall societal interests with those of individuals, as well as managing expectations of different groups (for example, when patients and patient groups demand a drug even when biomedical evidence is lacking or negative), are ongoing challenges. Finally, there is often a lack of alignment between clinical practice guidelines and reimbursement guidelines.

Moving forward

Regulatory context: Workshop participants agreed about the need for: clarity of research methodologies; alignment to international standards; transparent evidence-based decisions about how the balance of risk to benefit was determined; and a standardized, consistent use of certain data sets to address certain types of questions that would address evidence gaps and feed back into integrated health decision making.

In Canada, answering questions around benefit risk issues for certain subpopulations (children, small population cancer, various metabolic diseases, personalized medicine issues, First Nations clients and others) is particularly difficult. Having a more clearly identified process and best practices, and "go- to" people around certain populations would be very beneficial. With small subgroups, it is often imperative to collect both national and international data to have a reasonable sample size, and a network would facilitate this.

Conversely, with off label use of drugs in subpopulations, it may be possible to answer questions in specially designed studies in one part of the country so that the results could be nationally applicable.

Public drug plan context: Workshop participants agreed on the need for transparency in decision-making practices and the need to educate the public, the media, patients, and politicians (patients often pressure politicians) about the issues. Education should facilitate the public's understanding of the decision-making process, and this would be helped by public involvement in drug plan decisions, as with the formation of Ontario's new Citizen's Council advisory body. Similarly, a speedy response to media reports would help promote the idea of post-market surveillance. In the United Kingdom, independent science media centres draw on experts who agree to respond within two hours to provide comments and context on news events and reports. Other initiatives that would aid a post-market surveillance project include: a process for bringing (drug impact) signals together for evaluation and application to the drug plan; independent guidance to doctors, pharmacists and the public about how a drug should be used when it is released; the use of the network to collectively discuss available evidence; and the creation of a network of drug plan managers (the information users) to facilitate use of evidence from the proposed drug effectiveness and safety network

In conclusion, both the regulatory and the drug plan participants at the workshop stressed the need to:

• include the requirement for pharmacovigilance data in provincial electronic health record initiatives and in Canada Health Infoway, in order to encourage "surveillance by design" and
• establish information sharing pathways between researchers and decision makers. A better communication network would facilitate method development, best practice sharing, leveraging policy decisions with respect to privacy legislation, database linkages, and gap awareness.

Finally, there may be greater willingness on the part of decision makers and the public to listen to the collective voice of an arm's length, independent drug effectiveness and safety network, as compared to the voice of individual stakeholders.