The impact of real world evidence on drug marketing approval and reimbursement

As opposed to Randomised Controlled Trials (RCTs) for controlled populations, the use of real world evidence is based on populations with considerable heterogeneity that can help in understanding the risks and benefits associated with medical products for a wide spectrum of illnesses and subjects with different degrees of healthcare access.

What is real world evidence/data?

Real world data (RWD) stands for any observational data generated from different healthcare provisions excluding experimentally generated data or trial data. The availability of real world data (RWD) has been steadily increasing worldwide. These data provide an alternative source of information that can be leveraged to produce evidence of drug safety, efficacy and effectiveness across the product life cycle.

Clinical trials have been and continue to be the primary tool for providing evidence of drug safety and efficacy for market authorisation decisions. While following specific patient populations in a highly specialised environment facilitate the collection of high-quality controlled data, it can limit the  in real world settings. Patients in RCTs are highly exclusive and may not reflect the target population who will be using the drug. Actual recipients in routine clinical practice present with various comorbidities, co-medications, genetic profiles and behaviours. Long-term effects of drugs are also difficult to assess in RCTs which are designed to show efficacy in a narrow time window.

Moreover, conducting clinical trials is not always feasible and thus may not always be deemed ethical for certain diseases/disorders (such as rare diseases) or patient populations, where excessive trial costs or small available patient populations may lead to constraints. Expanding data and evidence sources to include RWD/real world evidence (RWE) may address some of these concerns and offer new opportunities to gain insight into public health and advance health care, increasing both the extent and rate of drug access for patient populations. RWE may also provide supportive data that has greater external validity, as well as providing information on subpopulations (e.g. children, seniors and pregnant women), off-label use, misuse, adherence and to validate surrogate outcomes.

RWD is an umbrella term used to denote data on the effects of health interventions (e.g. safety, effectiveness, resource use etc.) that are not collected in the context of highly controlled RCTs. Instead, RWD can either be primary research data collected in a manner which reflects how interventions would be used in routine clinical practice or secondary research data derived from routinely collected data. Data collected include, but are not limited to, clinical and economic outcomes, patient-reported outcomes (PRO) and health-related quality of life (HRQoL) data. RWD can come from several sources, for example:

• Electronic health records (EHRs)
• Claims and billing activities
• Medical chart reviews
• Product and disease registries
• Patient-generated data including in home-use settings
• Data gathered from other sources that can inform about health status, such as home medical devices and wearable technologies
• Observational studies (e.g. cohort, case-control or case series)
• Pragmatic studies (also known as practical clinical trials), where patients may be randomised to treatments, but subsequent care and follow-up more closely resembles standard clinical practice than in a conventional RCT

Real world evidence is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD. RWE can be generated by different study designs or analyses, including but not limited to, randomised trials, including large simple trials, pragmatic trials and observational studies (prospective and/or retrospective).

Why is this happening now?

The use of computers, mobile devices, wearables and other biosensors to gather and store huge amounts of health-related data has been rapidly increasing. This data holds potential to allow us to better design and conduct clinical trials and studies in the healthcare setting to answer questions previously thought indeterminable. In addition, with the development of sophisticated, new analytical capabilities, we are better able to analyse these data and apply the results of our analyses to medical product development and approval processes.

All regulatory agencies accept RWD to supplement clinical trial data on the safety of pharmaceuticals (both pre- and post-approval). Real world studies may be conducted to meet post-authorisation data requirements requested by regulators. The FDA and the European Medicines Agency (EMA) have developed accelerated or conditional approval mechanisms, whereby drugs may be approved based on Phase 2 studies or surrogate outcomes, with subsequent evidence to be developed that confirms efficacy and safety.

Where does Health Canada stand in this process?

Health Canada already considers RWE during the pre- and post-market drug regulatory process to inform decision-making and their expertise in this area continues to evolve. They accept all relevant data in support of a drug’s efficacy and safety, including RWD, with no limits to study design or data source. There are several existing guidelines that can be used to characterise the quality of evidence in real world studies. To date, no specific guideline has been identified for implementation by Health Canada.

Health Canada and the Canadian Agency for Drugs and Technologies in Health (CADTH) recently announced their intent to co-develop an action plan to optimise the process for the systematic use and integration of RWE into both regulatory and reimbursement decision-making in Canada. When implemented, this will have a significant impact on how drugs are approved and paid for in Canada. The Health Canada project on ‘Strengthening the use of RWE for Drugs’ is an initiative under the Regulatory Review of Drugs and Devices, which aims to improve Canada’s ability to better leverage RWE throughout the drug development life cycle to optimise safety and efficacy, and overall, improve the accessibility, affordability and appropriate use of drugs.

Health Canada offers sponsors 15 key elements in the document, Elements of Real World Data/Evidence Quality throughout the Prescription Drug Product Life Cycle that should be considered for each research protocol, including data management and quality control and ethical and data protection issues. Health Canada also provides the requirements in the document, Optimizing the Use of Real World Evidence to Inform Regulatory Decision-Making for sponsors filing a drug submission with Health Canada containing RWE as pivotal evidence. 

Regulatory bodies are exploring ways in which RWE can play a larger role in initial market access decisions, extension of indications or in situations where there is considerable unmet need. There is also interest in how RWE can support or satisfy post-approval study requirements. As more information on the impact of RWE on drug marketing approval and reimbursement becomes available, the place of RWE in single-drug assessments will become clearer, which may be translated into the development of new processes and standards across the globe.

 

References:

1. Health Canada. Health Canada Guidance Document: Elements of Real-World Data/Evidence Quality throughout the Prescription Drug Product Life Cycle. Updated 05 March 2019. Accessed: 07 December 2022.
2. Canadian Agency for Drugs and Technologies in Health (CADTH). Use of Real-World Evidence in Single-Drug Assessments Environmental Scan. Published 26 May 2020. Accessed 07 December 2022.
3. United States Food and Drug Administration (FDA). Real-world data (RWD) and real-world evidence (RWE) are playing an increasing role in health care decisions. Updated 19 October 2022. Accessed 07 December 2022.
4. Tadrous M, Ahuja T, Ghosh B, Kropp R. Developing a Canadian real-world evidence action plan across the drug life cycle. Healthcare Policy. 2020 May;15(4):42.
5. Health Canada. Notice: Optimizing the Use of Real-World Evidence to Inform Regulatory Decision-Making. Published 16 April 2019. Accessed 07 December 2022.