The passage of the 21st Century Cures Act at the tail end of 2016 gave precision medicine proponents and diagnostics developers reason for optimism, though detractors fear the bill gives industry players too much leeway in the name of innovation and at a cost to public health protections.

Following the presidential elections and amid the transition to a new administration in Washington DC, policy experts believed that the still nascent precision medicine field may not secure a place amid shifting priorities. Particularly uncertain was the fate of multi-agency government-funded projects, such as the Precision Medicine Initiative and Cancer Moonshot.

Around this time, the US Food and Drug Administration also announced it would hold off on regulating all laboratory-developed tests. For the lab industry this was welcome news. For others who felt that the public’s health would be better protected if the FDA stepped in and oversaw such tests, this was a sign that the agency was buckling to political pressure under an administration that was generally anti-regulation.

The year-end bipartisan push to clear the Cures Act through the Senate with a 94 to 5 vote eased some of these concerns. The bill authorized $4.8 billion over the next decade for the National Institutes of Health — of which $1.4 billion will go to the President’s Precision Medicine Initiative (PMI), $1.8 billion to the Cancer Moonshot, and $1.6 billion to the BRAIN initiative. The FDA will get $500 million — not nearly enough, say critics of the bill, for all the work the bill tasks the agency with. Supporters of the bill, meanwhile, believe that these funds, if used the right way, could advance precision medicine and medical innovation.

“Today, with the 21st Century Cures Act … we are bringing to reality the possibility of new breakthroughs to some of the greatest health challenges of our time,” President Barack Obama said at the bill signing ceremony earlier this month. Then, referencing the goal of enrolling 1 million participants into the PMI, he added that “this spring, with the help of this legislation, the NIH plans to launch a groundbreaking research cohort, inviting Americans across the country to participate to support the scientific breakthroughs of tomorrow.”

Supporting precision medicine

The nearly 1,000-page legislation includes a laundry list of provisions that policy experts have flagged as being friendly to precision medicine efforts.

For example, the Personalized Medicine Coalition highlighted that the law instructs FDA to publish guidelines on collection of patient experience data and its use in drug development. Moreover, the FDA must publish periodic reports on how it uses such information in regulatory decisions and publicly share patient experience data for approved products. At a time when the field is focused on biotechnology and genetics in drug development, this feature of the law ensures that patients’ voices are also incorporated, President Obama said at the bill signing ceremony.

“Although we spend a lot of time talking about the molecular implications for treatments, the whole idea of personalized medicine is to find what is the right treatment for a particular patient,” Daryl Pritchard, PMC’s VP of science policy, said. “To do that you need to gather not just that molecular information, which helps target treatments, but also the information from the patient, the practical and value-based information, that will also ensure that their treatments are safe and effective.”

At a time when the field is focused on biotechnology and genetics in drug development, this feature of the law ensures that patients’ voices are also incorporated.

The FDA is already doing this. For example, earlier this year the agency invited patients and providers to weigh in on the types of information they want to receive from genetic tests. This was part of a series of public workshops the agency hosted to explore regulations for tests based on next-generation sequencing — a technology many believe will be the workhorses of a more predictive and preventive healthcare system.

The Cures Act also requires FDA to establish a process for the review and approval of tools used in drug development, such as a new biomarker, which is an essential part of advancing drugs targeted for a molecularly defined patient population. Once a tool is approved by the FDA in a setting, the law says it can be used in any drug development program as long as it is applied specifically in the setting where it has approval.

Another piece of the law instructs the HHS Secretary to advance standards that would allow a pharmaceutical company to use data generated by another company when developing drugs targeting the same genetic or protein marker that show up in rarely in patients. Because it’s so difficult for one entity to collect data on rare biomarkers and perform studies with the necessary statistical significance, this provision, as well as aspects of the PMI and Cancer Moonshot, are aimed at encouraging data sharing around rare variants.

Precision drugs directed at rare patient subpopulations are difficult to study in traditional randomized-controlled trials, and, as a result, pharmaceutical companies are increasingly embracing new clinical trial designs, such as basket trials. These studies enable the simultaneous investigation of different drug-biomarker hypotheses across many arms. Recognizing this trend, another provision in the Cures Act requires the FDA to hold public meetings and advance guidelines on how data from adaptive or other novel clinical trial designs can be used in drug development.

The law also tells FDA to create intercenter institutes in specific disease areas, which attests to the reality that personalized medicine often involve not just a drug, but also diagnostics that identify patients at risk for a condition, when their disease is progressing, and whether they’ll benefit from a treatment. These intercenter institutes will streamline product reviews, keep up the expertise in a particular disease setting, and maintain close ties with patients and the research community.

Improving cross-center coordination within the FDA has been a top priority for Friends of Cancer Research, an oncology-focused policy organization. The Cures Act adopted the group’s proposal to create interdisciplinary institutes with the FDA, and earlier this year Vice President Joe Biden announced the launch of an Oncology Center of Excellence at the FDA during a Cancer Moonshot summit.

It’s fitting that Richard Pazdur, current head of FDA’s Office of Oncology and Hematology Products, will serve as acting director of this center of excellence. Pazdur lost his wife to ovarian cancer last year, and has openly discussed how the experience energized his efforts to streamline the review process, get treatments to market faster, and gather input from patients.

This is the right thing to do, but it’s going to encourage more individuals to get involved in research.

Win for device and Dx companies

On the diagnostics front, the FDA has for the time being backed off its plans to regulate LDTs, which the agency had maintained was necessary for the safe and effective use of diagnostics during a time of rapid industry growth. Throughout the year, given intense pushback from lab and pathologist groups against FDA’s draft guidance on the topic, some policy experts left open the possibility that an industry-backed, legislative solution may find its way into the Cures Act.

That didn’t happen, but the law does address the agency’s role in spurring innovation and regulating tests more broadly. For example, the law amends the criteria for humanitarian device exemptions — a designation that brings incentives for developing devices for rare conditions. Now, devices for a disease that impacts 8,000 people can qualify for the exemption, whereas previously, tests for conditions impacting fewer than 4,000 people could qualify.

“This difference is night and day for diagnostic innovators,” said Khatereh Calleja, senior VP of technology and regulatory affairs at AdvaMed, a medical device trade association. The expansion of the exemption criteria will allow manufacturers more flexibility, she said, and incentivize the development of tests for more molecularly defined patient subsets, rare infectious diseases, and pediatric indications.

Other wins for diagnostic and device manufacturers in the law include provisions for improving the CLIA waiver process; enhancing reporting on anti-microbial resistance and use of antimicrobial drugs; and creating an “efficient and flexible” review pathway for devices that are “breakthrough technologies.”

The law defines breakthrough technologies as those used in the context of a life-threatening illness, when the technology is a significant advance over other approved devices, and when it addresses an unmet need. “You can contemplate products such as companion diagnostics, among others, that would potentially benefit under such a pathway,” Calleja said.

Enhanced privacy protections

While the legislation seems crafted with an eye toward a future where molecularly informed treatments will be more commonplace, the Cures Act also includes provisions that strengthen privacy protections for people participating in research where they’ll share identifiable, sensitive information, such as their genetic risks for diseases and the maladies that run in their families.

Currently, researchers can request certificates of confidentiality, which allow them to deny requests from third parties who ask for data that can be used to identify study subjects. However, researchers aren’t required to obtain such certificates. Under the new law, the HHS secretary will automatically issue these certificates for research where identifiable data are collected.

“This reduces the burden for the researcher and requires [the certificates] to be used,” when law enforcement or other non-research entities ask for this data, said Derek Scholes, American Society of Human Genetics’ director of science policy. “This is the right thing to do, but it’s going to encourage more individuals to get involved in research.”

This provision is timely since millions of consumers have gotten tested through firms such as Ancestry.com and 23andMe, and next year, the NIH is hoping to begin enrolling a million research participants into the PMI. Consumers may not fully appreciate that genetic data, once shared, can be used to identify them, though the risks can vary depending on the type of information shared. When they understand this, some may not want to participate in research, and their fears aren’t abated when they hear how at least one consumer genomics company revealed to law enforcement investigating a murder case the identity of a donor in its database.

There have also been concerns, Scholes said, that the public could use the Freedom of Information Act to request personally identifiable information stored in federal genetic databases such as dbGaP. The privacy provisions in the Cures Act — originally introduced in separate legislation by Senators Elizabeth Warren (D-MA) and Mike Enzi (R-WY) — now makes explicit that this data are off limits to FOIA requests.

[T]he FDA they don’t seem to be worried [the legislation] will weaken their regulatory oversight. They see opportunity, really.

Balancing innovation and public health

Although the Cures Act received broad bipartisan support in Congress, Warren and Bernie Sanders (I-VT) were among the five Senators who voted against the bill, arguing that it gave too much away to the drug industry. The bill, which the pharmaceutical industry lobbied hard for, allows FDA to approve new drugs based on “data summaries” instead of more detailed clinical trial information and clears pharma companies to promote off-label uses of treatments to insurers.

Warren criticized that these provisions deteriorate FDA’s oversight powers. She further pointed out that even the funding provided to research entities, such as the NIH, isn’t assured since it still needs to be appropriated yearly.

There were others who shared Warren’s concerns, and pushed back against intense industry lobbying. For example, the consumer rights advocacy group Public Citizen called out a part of the bill that would allow FDA to use peer-reviewed, published data for approval of high-risk devices. The organization said this was a “risky shortcut” that would jeopardize the public health.

Ultimately, the supporters won out, without any public objections from the FDA or other agencies impacted by the bill. “In my conversations with the FDA they don’t seem to be worried [the legislation] will weaken their regulatory oversight,” PMC’s Pritchard said. “They see opportunity, really.”

FDA has a dual role to advance innovation and protect the public health, and it’s unclear where things will end up following the Cures Act. At the least, the law does allow for a reconsideration of how things are done right now, according to Pritchard.

On the agency’s blog, FDA Commissioner Robert Califf wrote that the Cures Act will improve the agency’s ability to hire and retain experts, support ongoing efforts to modernize clinical trial designs, and enhance the agency’s efforts to expedite drugs and tests to market. Importantly, the law rightly recognizes that patient voices must be included in the development of medical products, Califf wrote.

“We really view this as a win-win” for patients and for companies trying to bring new products to market quickly and at lower cost, AdvaMed’s Calleja agreed. “This is a really important legislation and a nice way to end the year.”

At the bill signing ceremony, Biden, who presided over the Senate for the last time in passing the bill, reflected that the Cures Act shows that politicians can still come together to do consequential things that matter to the American people.
 

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