n April 2019, Health Canada (HC) released its Quality of Evidence guidance intended to encourage pharmaceutical companies to bring forward drug submissions that incorporate evidence gathered from real life settings. This initiative is part of HC’s Regulatory Review of Drugs and Devices (R2D2) modernization process, which specifically flagged their intention to “make better use of real world evidence (RWE) to support regulatory decisions across a product’s lifecycle for both drugs and medical devices.”

This guidance is a concrete action by the federal regulator under its R2D2 process, as well as a commitment stemming from an October 2018 RWE workshop involving key partners (i.e., the Canadian Association for Population Therapeutics, the Institute for Health Economics, HC, and the Canadian Agency for Drugs and Technologies in Health). That workshop’s goal was to identify the value and application of RWE in supporting pharmaceutical regulatory and reimbursement decision-making, and the conditions upon which RWE will be considered of sufficient quality to inform decision-making.

The following provides an overview of the HC guidance, along with the FDA’s 2018 RWE standards and a case study showcasing the application of the FDA’s approach to Ibrance for advance breast cancer in men.

Health Canada

In April 2019, HC announced an initiative to encourage drug companies to bring forward drug submissions that include evidence gathered from real world experience, particularly as it relates to special patient populations. The overall goal is to help increase treatment options available to Canada’s most vulnerable populations, and to make Canada’s regulatory system more responsive to the needs of patients.

Health Canada’s Quality of Evidence Guide is intended to assist drug companies bringing forward products in cancer, pediatrics, rare diseases, and other special subpopulations. These tend to be situations where clinical trial data challenges may highlight the need for supplemental high-quality RWE that meets evidence requirements for approval.

The Guide provides overarching principles to guide the generation of RWE that are consistent with the regulatory standard of evidence established in Canada and internationally. It speaks to the elements that should be addressed in RWE study protocol development and discusses data quality concerns within submissions containing RWE. In addition, it encourages use of existing guidelines to ensure the quality of evidence in real world studies.

Health Canada remains committed to ensuring that regulatory decisions which incorporate RWE are based on high quality data collection methods as well as regulatory grade data sources and study designs. For instance, the Guide outlines elements of protocol and data development that reflect good research practices. In addition, HC intends to continue to develop principles to evaluate the quality of RWE across the drug product lifecycle to ensure access to safe and efficacious drugs.

While not as comprehensive as the FDA framework (see below), the development of this guidance helps Canada keep pace with regulators around the world who are taking concrete steps in their consideration of RWE to inform their decisions. The guidance will assist drug companies in collecting and submitting high-quality real world evidence that meets the evidence requirements for approval.

FDA RWE Framework Informs Canadian Dialogue

FDA has been examining the potential role of RWE for evaluating drug safety and effectiveness for several years. The 21^st Century Cures Act was enacted in 2016 with the intent of accelerating medical product development and allowing new innovations and advances to become available faster and more efficiently to patients who need them. The law had a particular focus on the use of real world data to support regulatory decision-making. CDER Director Janet Woodcock and colleagues published an overview of the program being developed, intended to evaluate the use of RWE to support approval of new indications for approved drugs or to satisfy post-approval study requirements, stemming from the Act.

In December 2018, FDA published a comprehensive framework to guide its overall RWE Program. In addition to setting out distinct definitions for real world data (RWD) and real world evidence, the framework provides clarity on the trial designs and studies that will be covered by the FDA’s RWE Program (e.g., pragmatic clinical trials, observational studies, etc.). It also goes into depth on how FDA has used RWD for evidence generation in the past, and its vision for generating evidence on safety and effectiveness moving forward. There is specific guidance for how the agency will evaluate RWD/RWE for use in regulatory decisions, as well as discussion of FDA’s commitment to stakeholder engagement as the RWE Program evolves.

Related to FDA’s work, the National Academies of Sciences recently published the outputs of a three-part workshop series which examined the potential role for and impact of RWE in medical product development.

With the sponsorship of FDA and the participation of a broad range of knowledge leaders from all aspects of the medical product development and adoption environment, workshop topics included:

• Aligning incentives and addressing barriers to support collection and use of high-quality evidence derived from real world data sources in health product review, payment, and delivery;
• Definitions surrounding the core components of RWE;
• Sources of data that are curated, standardized, and analyzed to derive RWE, such as safety surveillance, observational studies, registries, claims, or patient-centered outcomes research;
• Gaps in data collection activities, and priority areas and pilot opportunities that RWE incorporation could address;
• Standards and methodologies for collecting and analyzing RWE in support of new indications or post-approval studies, and the circumstances under which that evidence could be applied;
• Applications for using RWE to supplement traditional clinical trials, pragmatic/effectiveness trials, or routine clinical applications;
• Mechanisms for determining which discrete types of RWE could support regulatory decisions; and,
• Operational challenges and barriers for generating and incorporating RWE in the context of a learning health system and how clinicians can best be involved in the collection and utilization of RWE.

Ibrance: RWE Helps Expand US Indication

The company provided the results of an analysis of RWD from EHRs as additional supportive data to characterize the use of palbociclib in combination with endocrine therapy (aromatase inhibitor or fulvestrant) in male patients with breast cancer based on observed tumor responses in this rare subset of patients with breast cancer. Specifically, data for male patients were sourced from three databases: IQVIA Insurance database, Flatiron Health Breast Cancer database, and the Pfizer global safety database.

It appears that the rarity of this disease, coupled with its aggressiveness and current standards for treating male patients with breast cancer, had a role to play in this decision. Breast cancer is rare in males, with only 2,670 cases of male breast cancer estimated in the US in 2019—less than 1 percent of all cases of breast cancer. This means that fewer clinical trials including men are conducted, resulting in fewer approved treatment options for them.

In addition, men are more likely to be diagnosed at an older age, with a more advanced stage of disease. According to current clinical practice standards, male patients with breast cancer are treated similarly to women with breast cancer. While certain treatments are gender-neutral in their indication, others have only been studied in (and, therefore, approved for) women despite the fact that they are often prescribed for male patients.

In this case, FDA approval reflects a very broad approach to the assessment of this product, not only in terms of the RWD that were leveraged but also integrating the science underpinning the clinical approach to treatment for this patient group. It is a prime example of how RWE can play an important role in expanding the indicated uses of medicines that build upon approvals for other uses.

Health Canada has not yet approved Ibrance for this expanded indication. It will be important to pay close attention to how the Canadian regulator applies its new RWE guidance when and if the company seeks approval. The degree to which HC mirrors FDA’s broad approach will provide important insights into the utility of RWE for regulatory purposes in Canada.

Conclusions

Canada has a long history in developing infrastructure and research expertise to collect and assess administrative data and other real world insights. We’ve seen a significant evolution of technology, systems, tools, standards, and methodologies related to RWE generation over the past several years. With its recent announcement and guidance, Health Canada has taken an important step to align with other global regulators to enable the use of RWE in decision-making in support of timely patient access to important medications.

Implications

• The shift from “theory” to “reality” in applying RWE to regulatory decisions has progressed quickly in the US.
• The global RWE environment is moving forward quickly, demanding that the Canadian pharmaceutical policy environment keep pace to ensure clarity on the role that RWE will play in its pharmaceutical system.
• It is important for Canadian decision makers to align with international developments as they inform their own policy positions; we cannot afford an RWE approach that is significantly different from global practices.
• Canadian regulators and health technology assessment bodies must quickly adapt to these global and local changes to ensure that they create an environment for RWE that addresses the needs of Canadian patients, providers, and policy makers.

References available upon request.