Clinical trials are essential to the development of safe and effective medical products, yet their controlled structures do not reflect real-world clinical and home settings, and therefore do not yield generalizable results. Physicians, patients and payers all have a vested interest in gaining a more complete benefit-risk profile of a drug in order to get the right drug to the right person at the right time. Because of this, regulatory authorities are paying increased attention to randomized pragmatic trials and non-interventional real-world studies of effectiveness and safety. 

Real-world evidence and emerging frameworks

Frameworks for assessing and using real-world data in premarket regulatory activities are still being developed. This uncertainty has left biopharma, and emerging biopharma, unsure of when and how to consider the use of real-world evidence in their development and life-cycle management programs. However, changes are beginning to be made.

Recognizing the potential importance of real-world evidence to make drug development faster and more efficient, the 21st Century Cures Act directs the FDA to establish frameworks for the use of real-world evidence for indication expansions, post approval safety studies and historical comparator studies. The development of these frameworks requires defining evidentiary standards for data collection, data validation, and research methodologies. Due to the high degree of variation among different conditions in routine clinical care of commonly observable outcomes and of treatment effect sizes, it is possible that guidance will be therapeutic area-specific. 

Real-world evidence is already used by regulators for approvals and label expansion, while guidance is being developed, when traditional clinical trial approaches are either unethical or not feasible, such as in oncology and rare diseases in the pre-market space.    

We are also starting to see increased efforts to use real-world evidence in premarket activities for common conditions when studies include well-controlled data collection and commonly observable outcome measures, and when results can be validated. For example, in limited cases, regulators have accepted protocols with synthetic cohorts used as real-world comparators for label expansion. 

The benefits of real-world evidence

The costs of drug development are challenging for all companies, but particularly for developing biopharma companies. Because real-world evidence can cut the timeline and reduce the overall cost of clinical trials, through more efficient generation and use of data, it has the potential to play an important role for small and medium enterprises, or for companies launching into niche indications. 

A model comparing a randomized clinical trial and a randomized pragmatic trial found that the real-world approach cost almost a third of the cost of the controlled trial. The table below shows how the costs are reduced in these real-world-studies.

See Dreyer NA.  Advancing a framework for regulatory use of real-world evidence: When real is reliable. Therapeutic Interventions and Regulatory Affairs 2018; 52(3) 362-368. http://journals.sagepub.com/doi/full/10.1177/2168479018763591

Real-world evidence in wider use

Before use of real-world evidence in regulatory decision-making becomes routine, more use cases need to be defined, evaluated, and then applied to different situations.  We may expect that evidentiary criteria will vary depending on the study circumstances since real-world evidence established as relevant and reliable in one context of use, such as post-market drug safety, will not necessarily be useful in another, such as indication expansion. Requirements for each clinical question will include:

• reliable study designs, data, and data collection techniques
• confirmation that data sources are relevant and relatively reliable 
• approaches to address variability of treatments effect sizes and disease progression timelines 

Building frameworks for use of new data sources is a dynamic process; based around multi-stakeholder meetings, conferences, and workshops between stakeholders in the pre-competitive space. These activities result in outlines of issues to work through, criteria to define, use cases and pilot projects to begin to test initial ideas and assumptions. These processes are transparent by design, and should be inclusive of all stakeholders, including small and large pharma, biotech, and medical devices companies. 

Emerging biopharma can play an essential role in helping to define the framework for, and confidence in the application of the routine use of real-world evidence. The panel discussion I participated in at this year’s BIO International conference acknowledged a key challenge. The FDA Center for Drug Evaluation and Research (CDER) needs more use cases to inform its guidance development, yet the industry is reluctant to develop and submit protocols using real-world evidence without greater confidence that the data will be accepted by the FDA.

In response, the FDA is encouraging companies to communicate with the Agency early when a real-world evidence approach is being considered. This will allow the agency to become aware of developing activities, and provide meaningful feedback before time and resources have been spent on developing the idea. The panel generally agreed that this should be the next step in the roadmap toward greater use of real-world evidence. 

By working together, and with the FDA and other regulatory authorities to develop the right evidence and analysis, biopharma can start to leverage real-world evidence to accelerate their drug development.

At IQVIA, we have participated in various workshops and industry discussions to share our experiences and develop use cases to serve as models for regulators to develop guidance documents. To learn more about this, visit our Real World Values and Outcomes Regulatory Use page. 

About the Author

Marni Hall is Vice President of Clinical Evidence in the Center of Advanced Evidence Generation at IQVIA, where she reports to the Chief Scientific Officer in our Real-World and Analytics Solution Division. In this role Hall is leveraging her expertise in regulatory science, drug safety, and patient-centricity, providing scientific oversight and strategic direction on the expanded use of real world evidence for regulatory and other uses. 

A research scientist by training, Dr. Hall spent nearly two decades at the intersection of science and policy. She started her career studying biochemistry, toxicology and molecular epidemiology at Columbia University. After serving as program director in the Public Health Group of External Medical Affairs at Pfizer, Hall joined the FDA’s Office of Planning and Informatics in 2008 as a Principal Analyst. In this role, she initiated and led the development of the data standards plan for the Center for Drug Evaluation and Research (CDER). In 2011, she was appointed Director of Regulatory Science within the Office of Surveillance and Epidemiology (OSE) for CDER. Hall became and expert at sourcing and analyzing big data sets, including adverse event reports, claims, and other data useful to risk assessment and risk management activities. Then at PatientsLikeMe, Dr. Hall served as the Senior Vice President of Research and Development, Informatics, and Policy, where she oversaw delivery of commercial research programs and execution of an agenda for use of patient-generated health data in clinical and regulatory decision making. 

Hall holds bachelor of science degrees in chemistry and in society, technology, and policy from Worcester Polytechnic Institute. She also holds a master’s degree in the public health from Columbia University’s Mailman School of Public Health as well as a master of science degree in biochemistry and a PhD in toxicology from Columbia University’s Graduate School of Arts and Science.