Emerging Topics in Real-World Evidence: Part 1

A Q&A with Dr. Peter Neumann, ScD

Dr. Peter Neumann is Director of the Center for the Evaluation of Value and Risk in Health at the Institute for Clinical Research and Health Policy Studies at Tufts Medical Center, and Professor of Medicine at Tufts University School of Medicine. His focus area is use of comparative effectiveness research and cost-effectiveness analysis in health care decision making.

In Part 1 of this two-part blog post series, Dr. Neumann discusses emerging topics in real-world evidence (RWE).

Q: Dr. Neumann, where do you see RWE having an increasing role?

A: We have been saying this for a long time. Real world evidence is playing an increasing role, but I think we’re just seeing it intensify in many, many ways including supporting regulatory decisions. We see the FDA using real world evidence to expand indications to support randomized trials and construct synthetic control arms with single arm trials. We’re seeing more examples of it all the time. Panalgo has a great two volume report on use cases of the FDA using real world evidence to support their regulatory decision making.

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Q: Do you have specific examples of drugs where the FDA used RWE to guide their approval?

A: One is Bavencio for metastatic Merkel cell carcinoma and Blincyto for B-cell precursor lymphoblastic leukemia. These are rare diseases with small single arm trials with all their limitations and uncertainty. The FDA decided to look at real world data to construct the counterfactuals, the control groups and do the best they can at controlling for confounders.

Another is the case of Ibrance for breast cancer in men. Ibrance proved with trials to be effective for women with breast cancer. But the question was, does it work with a small population of men with breast cancer? It’s challenging to do clinical trials with small populations, but real-world data and real-world evidence supported that Ibrance would work in men as well. The FDA approved the indication in men based on that real world evidence without forcing Pfizer to conduct a new trial.

The Zolgensma case is another example of how RWE is being used in the regulatory world. Zolgensma is the Novartis gene therapy drug for spinal muscular atrophy. Again, small populations in single arm trials submitted for approval but hard milestone endpoints so that they could review registries to see what was happening in the real world. The condition affects kids who in many cases wouldn’t be standing and sitting given their baseline conditions. But they’re in the trial, and even though it was not controlled, they were reaching these milestones in some cases. The real-world evidence was considered good enough for the FDA to support approval.

Q: In what other ways is RWE being used for making health care decisions?

A:  An overlooked area where RWE is being used is in the support of randomized trials and pragmatic trials and to help design clinical trials. There’s a longstanding use of real-world evidence in the safety field, of course, but also the data continues to improve the analytic techniques to support clinical guidelines and provide information on drug uses and potential benefits. There is also important analytic work going on comparing real world evidence to evidence from randomized trials. The FDA has its RCT Duplicate program that shows that in some cases, the real-world evidence can replicate the trial data. Not always, and its context dependent, and there are many issues to think through, but it’s important work and shows that that it can be done. Computers, mobile devices, wearables, biosensors, are all generating RWE that can be used as well, and we just didn’t have those sources 10 or 20 years ago.  It’s amazing the kind of information that we now have at our disposal that can be used in helping to inform health care decisions.

Q: How is RWE being used in your specific area of expertise?

A: My field is health technology assessment and health economics, both areas in which RWE is used a lot. Health technology assessment organizations are putting out guidance on real world evidence. ICER (the Institute for Clinical and Economic Review) in the U.S., NICE, the National Institute for Health and Care Excellence in the UK, as well authorities in France and Germany and elsewhere have all developed guidance on the use of real-world evidence.  Payers are using RWE to support coverage and reimbursement.

Q: How is the FDA evolving in its thinking about RWE?

A: Since the passage of the 21st Century Cures Act in 2016, the FDA has been releasing guidance after guidance on different aspects of real-world evidence, some on the medical device side, some on the drug side. Regulation of drugs and devices have some differences, but in both areas real world evidence can be used to help understand safety and efficacy post approval.

The FDA’s final guidance on electronic health records was released in 2018.In 2020, the FDA released its guidance on real-world data and real-world evidence for drugs and biologics where they discuss data quality. A year later came its guidance on complex trial designs for drugs and biologics, which includes some information on real-world evidence draft guidance on data standards. More guidance followed on electronic medical records and claims data and final guidance on registries. Throughout this process, the agency was hiring people with expertise in epidemiology and data science. So, the FDA is in a very different place than they were seven years ago. You can see as you read through these release documents, how the agency thinking about all of this, and trying to come up with best practices. As you read through these guidance releases and the statements one consistent message is that use of real-world evidence is almost always context dependent.

Q:  What will be the impact of the Inflation Reduction Act mandate that Medicare is required to negotiate drug prices?

A: The Inflation Reduction Act (IRA) is the first legislation on Medicare drug price negotiations. It reflects an important change from the 2003 Medicare Modernization Act that stated that Medicare could NOT negotiate prices centrally. The IRA put caps on out-of-pocket spending in Part D plans as well. There are also inflation rebates, so after drugs have launch prices, they’re going to be limited to how much they can increase the prices.

But price negotiations are understandably getting a lot of the attention. The IRA requires HHS to negotiate prices and it is no longer optional. Negotiations are going to start in 2026, but in September of 2023, a few months from now, CMS will release its first 10 drugs to be negotiated, and then over time it will increase the number of impacted drugs. Absent changes, as we go forward there are going to be tens and eventually hundreds of drugs subject to these negotiations. The key part that affects real world evidence is that negotiations don’t start until many years after a drug is launched. In contrast, most HTA elsewhere is done on launch prices. As the years go by there’s going to be much more discussion about how the drug has performed in the years since its approval. That’s the real-world evidence angle. But the idea is that companies are going to be making their arguments about why the drug price should be higher based on the value of the product. That proof is going to come largely from real world data and real-world evidence.

Q: Do you feel there are systems in place for transparency and documentation to accept the validity of RWE?

A: Certainly, there are best practice guidelines out there for collecting and using real world evidence. Those all emphasize transparency, pre specifying endpoints, posting protocols early and so forth. We are certainly making progress on these and other guidelines, but we need to have the right institutions and infrastructure to house protocols that are posted.  We could probably do much more in those areas.


Read part 2 now to hear Dr. Samy Suissa’s views on these topics.

Panalgo offers companies from across the healthcare ecosystem a powerful healthcare analytics platform, accelerating evidence generation and taking analytics capabilities to new heights. If you are interested in learning more about how Panalgo can support your organization – including preparation for the IRA – contact us today.