Industry awaits FDA on rules for real-world evidence
FDA Commissioner Scott Gottlieb has shifted the agency's focus toward improving efficiency and speeding drugs to market, with a near-record number of approvals during his first year.
A big part of that ambition is expected to be the use of real-world evidence (RWE) — or data collected outside of randomized clinical trials.
"People recognize that there is data out there that isn't being used to support safety and efficacy," noted Sonali Gunawardhana, a former FDA attorney and current counsel at Wiley Rein LLP, in an interview.
The rise of technologies like electronic medical records, insurance claims databases, fitness wearables and even social media has allowed biopharma companies to gather data about use of drugs outside the clinical trial setting. But having that data and doing something with it are very different things. And how the FDA treats that data is still in flux.
"We needed to generate better evidence, grounded in representative populations and practice, at a lower cost," former FDA Commissioner Robert Califf told BioPharma Dive.
"The majority of important questions are not being answered by the current system, leaving consumers, patients and clinicians with tremendous uncertainty and guess work in practice," he continued. "Embedding studies and trials in the 'real world' is the way to generate much more evidence in more representative situations at a much lower cost."
As payers increasingly aim to pay for value over volume, life science companies are boosting their investing in RWE studies. More than half of those surveyed in a recent Deloitte analysis said they are "significantly increasing their capacity in the space."
Getting definitions right
Use of RWE, as it's typically known, did not start with Gottlieb. In fact, it's something the FDA has been trying to bring into focus for the last several years.
Going back to December 2015, Califf, then FDA's Deputy Commissioner for Medical Products and Tobacco, wrote a blog post for FDAVoice discussing the need to define what real-world evidence really is.
"Data are best understood as raw measurements of some thing or process. By themselves they are meaningless; only when we add critical context about what is being measured and how do they become information. That information can then be analyzed and combined to yield evidence, which in turn, can be used to guide decision-making," wrote Califf in 2015.
Despite the clear interest from Califf and now Gottlieb, FDA has given little guidance on the use of RWE.
The agency got a push on that front from the bipartisan 21st Century Cures Act, enacted in December 2016. Meant to accelerate the discovery, development and delivery of cures — in addition to providing about $4.8 billion in funding to the NIH — the act set guidelines for how and by when the FDA must establish a framework for using RWE.
That framework must be established in collaboration with industry stakeholders and be implemented within two years of the act's enactment. The FDA is also required to issue a draft guidance within a five-year timeframe that lays out the circumstances appropriate to use such evidence, as well as standards and methodologies for collecting and analyzing that information.
But Califf has spoken out publicly about the misconceptions of the Cures Act, noting the wording of the original bill made it seem that the data wasn't meant to be collected in a randomized fashion. The FDA clarified this in later legislation.
"The initial bill erroneously had language that would have excluded randomized trials from RWE. This would have been a huge mistake. The FDA did a great job and got it fixed when the User Fees were passed," said Califf in an email to BioPharma Dive. "'Traditional RCTs' are not RWE, but randomization within practice, cluster randomization of sites and trials done at home are examples of randomization that is RWE. 'Real world' refers to the source of data, not to the research design," he added.
Getting the definitions and intentions of the FDA straight will be one of the priorities for the agency, Gottlieb noted during an address to the National Academy of Sciences in September.
"The fact is there's often no single truth standard when it comes to the evidence used to support medical decisions. Clinical choices are made all the time, based on a mosaic of information of various precision and certainty. That continuum includes real world evidence, as well as the facts gleaned from rigorous and carefully fashioned trials ... and a lot of evidence constructs in between," he said.
He added that randomized, placebo-controlled clinical trials are still the gold standard for data collection to the FDA.
Collection of data is one of the biggest challenges facing the adoption of RWE into the regulatory framework. More often than not, for example, the codes and diagnoses physicians use in electronic medical records don't reflect the true problem with the patient. Instead, they may be aimed to get maximum reimbursement from payers and the more accurate information may be kept in other notes or records.
"Ideally, we'd like to have a system where providers have the right incentives to enter clinically relevant information into EMRs at the point of care," added Gottlieb.
But don't expect RWE to become the norm. Gottlieb and the FDA are moving toward a model where data collected in the real-world setting would enhance, but not replace, randomized clinical trials.
Moving quicker on medical devices
While the agency might be a little behind on implementing these policies for drugs, it has been moving more quickly for medical devices. The FDA committed to adding 15 full-time employees during the Medical Device User Fee negotiations in 2016 to be dedicated to developing and implementing a RWE framework in the medical device realm and in July 2016 released draft guidance for the medical device manufacturers.
"The Centers tend to operate pretty independently, but if one adopts something and it works, usually the others will look at that too," said Gunawardhana of the various branches of the FDA.
Eight medical devices and six technologies have won new indications based on RWE since the guidance was put in place, Gottlieb noted in that September speech.
"In these cases, we're using robust evidence that was generated in less time and at a lower cost than in the past, in some cases saving one to two years of development time. Increasingly, medical device makers are also meeting their post-market study requirements by leveraging real world data sources," the Commissioner said.
Yet, the agency has made clear that the guidance for medical devices is not directly translatable to drugs and biologics. That's largely because medical devices are usually evolutionary products that tend to be based on earlier versions of the same product, whereas drugs can have completely new mechanisms.
Expect the industry to follow the FDA's moves on this closely.
A chronic problem for the industry has been the need for two sets of data — the data the agency uses to approve a drug, and the data needed by payers to provide reimbursement for a product. Having a regulator that is more open to all types of patient data could help speed drugs through the regulatory system, reduce development costs and better align the FDA with payers.
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