Well, it’s done.
Today, the Senate passed the 21st Century Cures Act, a bill designed to weaken the FDA and empower pharmaceutical companies, sending it to President Obama’s desk. There’s no way Obama won’t sign it, as it contains provisions funding his Precision Medicine Initiative, and he supported it all along. For all its flaws, I knew the bill’s passage was inevitable since after the election, when Senate Majority Leader Mitch McConnell stated that the bill was a priority. I knew it even more when the Senate linked the bill to the “Cancer Moonshot” initiative spearheaded by Vice President Joe Biden in the wake of his son Beau’s death from brain cancer. After all, 21st Century Cures Act funds the “Cancer Moonshot” initiative.
The first time I wrote about the 21st Century Cures Act, I thought there were some good provisions in it, such as increasing funding for the NIH, but that it had a fatal flaw—several, actually. However, those fatal flaws derived from the idea that, if we only relax the “stifling” regulations of the FDA that, if you believe proponents of the bill that’s soon to become law, the magic of the free market would unleash the creativity of private industry and academia to open the spigot and let the cures to all sorts of diseases flow. The bill didn’t go very far in 2015, but by summer 2016 it was still around, still containing the same flaws, still being pushed by the same characters. I discussed both times how the central premise of the bill, that the FDA is too strict, that its “out of control” regulations are hampering medical innovation and slowing drug approval unduly while (of course) people are dying in droves waiting for the cures that government is keeping from the people, is simply not true.
Let’s recap before moving on, remembering that the bill that passed is actually in some ways than it was when I last wrote about it. The central premise of the bill is ideological nonsense. It turns out that radical reform involving weakening the FDA is not needed. The FDA already has the tools to do what the 21st Century Cures Act demands without weakening patient protections or scientific rigor. In fact, the FDA, despite being underfunded, is actually remarkably efficient at new drug approvals, evaluating nearly all new drug applications within 6 to 10 months, an impressive turnaround for such complex assessments. It’s been pointed out that the FDA actually acts more rapidly than most European regulatory agencies. Basically, there is no evidence that the FDA hampers overall medical innovation, nor is there evidence that the FDA’s current requirements lead to higher drug prices or cost lives. None of that stopped passage of the bill. Unfortunately, the argument fooled a lot of people, including, to its utter shame, the American Society of Clinical Oncology (ASCO), which urged passage.
The full bill is a massive 824 pages long; so reading the whole thing in a short period of time is not feasible. As I mentioned before, not all of it is bad. There are actually some provisions I can totally get behind, such as increasing the NIH budget, and, even though I’m more skeptical than most about the hype surrounding “precision medicine,” I can support funding President Obama’s Precision Medicine Initiative. I’m also less impressed with the promise of “high risk, high reward” research because much of the rhetoric touting examples of such research relies a lot on the 20/20 nature of hindsight. I like to refer to the example of Herceptin, a drug whose inventor, Dennis Slamon, often portrays as having been a hard sell to fund and whose development was a triumph of such “high risk” research. The truth is less dramatic, and in fact much of the research was federally funded. The problem, of course, is that there are really no hard data and science to support the belief that funding more risky projects will result in more dramatic advances or payoffs than a more conservative approach. Advocates of such an approach always have anecdotes of scientists whose ideas were later found to be validated and potentially game-changing who couldn’t get NIH funding, but how often does this really happen? No one knows, and often such anecdotes, when examined critically, are found to be—shall we say?—a bit embellished. Of course, the vast majority of “wild” ideas are considered “wild” precisely because they are new and there is no good evidence to support them. Once evidence accumulates for them, they are no longer considered quite so “wild.” More importantly, most advocates of funding much more risky projects are looking through what we doctors like to call the “retrospectoscope,” which, as we say, always provides 20-20 vision. We know today that the scientists whose anecdotes of woe describing the depradations of the NIH were indeed onto something. How many more proposed ideas that seemed innovative at the time but ultimately went nowhere?
That’s not to say it’s not worth funding some riskier projects, but it’s not necessarily productive earmark a lot of money for such projects, most of which will end up being wasted on projects that go nowhere because they are risky and a large proportion of them would be expected to fail. A far better approach would be to increase NIH funding in general. When funding is tight, the NIH becomes a lot more conservative in choosing which grant applications to fund. When funding is looser, study sections evaluating grants become more willing to take risks on good ideas that are more “out there.” This leads to a mix of “safer” projects expected to produce incremental advances along with some riskier projects. On the other hand, there isn’t anything wrong with one provision of the bill, which instructs the director to set up “Eureka Awards” to identify and fund areas of biomedical research that “could realize significant advancements through a prize competition.” Such a competition is probably not much more than a gimmick, unfortunately, but it probably won’t hurt anything either.
So what aspects of this bill won ASCO’s backing? I will admit that these do include some good:
- Increasing interoperability of Electronic Health Records and preventing the practice of intentional information blocking.
- Providing much needed supplemental funding for the National Institutes of Health and the Food and Drug Administration.
- Requiring transparency for expanded access programs.
- Requiring use of centralized Institutional Review Boards when appropriate.
- Encouraging data standardization, such as requirements for ClinicalTrials.gov.
- Refining Sunshine Act provisions to ensure necessary access by physicians to Continuing Medical Education and peer-reviewed literature.
- Allowing for patient-focused drug development.
- Clarifying the definition of a “clinician-led clinical data registry.”
- Providing funding to address the nation’s opioid crisis.
All of this sounds fairly innocuous. For instance, if there’s one thing I learned in writing about “right-to-try” laws is that transparency regarding companies’ requirements for expanded access programs is often lacking. Providing more transparency to this process was about the only aspect of the federal right-to-try law that I didn’t find objectionable. Also, who could object to increased funding to address the nation’s opioid addiction crisis? There’s a problem, though. There’s no guarantee that that increased funding will continue. The increased funding is not mandatory and would be subject to whatever Congress’ whims happen to be during appropriation battles every year.
As for some of the rest, it’s not exactly clear what “patient-focused” drug development tools will entail. All it states is that “Secretary 3 shall make public a brief statement regarding the pa4 tient experience data and related information, if any, submitted and reviewed as part of such application,” including “patient experience data” and “information on patient-focused drug development tools.”
Particularly disgusting to me is ASCO’s support for “refining Sunshine Act provisions,” which actually meant exempting companies from reporting payments made to doctors for receiving continuing medical education sessions, medical journals, or textbooks and thereby roll back requirements for reporting such payments to a federal database (OpenPayments) that tracks financial relationships between companies and physicians. Thankfully, that provision of the bill was so controversial that it was removed from the bill after Senator Chuck Grassley (R-Iowa) threatened to put a hold on the entire bill unless the language was removed.
Unfortunately, the now removed language exempting reporting payments to physicians for continuing medical education was just one example of how, to get the good stuff in this bill, one has to accept a whole lot of bad stuff. The very worst provisions of the bill are provisions that would significantly weaken the FDA in several ways. Yes, some of the worst parts of the bill have been expunged, but a lot of bad remains. For instance, in an earlier draft of the bill, there was a provision that would have farmed out the certification of safety of medical devices after modification by their manufacturers to third parties, circumventing the FDA altogether. That provision is gone. Another troubling provision would have allowed shorter or smaller clinical trials to get medical devices approved, also gone.
Other questionable provisions have simply mutated:
One of the most troubling provisions in the previous draft of the bill would’ve created a program for the use of “clinical experience” evidence in drug approvals. Rather than relying on the gold standard of randomized clinical trials, this provision “would[‘ve] require the Secretary to establish a draft framework for implementing” such evidence. The new draft keeps this provision but changes the term “clinical experience” to “real world evidence” (section 3022). To be sure, this provision gives enormous discretion to the Secretary to limit (and maybe even reject) the use of such evidence. But in light of recent high-profile clinical trial failures, most notably just two days ago, we ought to be concerned about claims that the FDA is too slow and imposes too stringent requirements on drug approvals.
I looked at exactly what the bill says about “real world evidence.” It’s not encouraging:
(1) IN GENERAL.—Not later than 2 years after the date of enactment of the 21st Century Cures Act, the Secretary shall establish a draft framework for implementation of the program under this section.
(2) CONTENTS OF FRAMEWORK.—The frame work shall include information describing—
(A) the sources of real world evidence, including ongoing safety surveillance, observational studies, registries, claims, and patient-centered outcomes research activities;
(B) the gaps in data collection activities;
(C) the standards and methodologies for 2 collection and analysis of real world evidence; and
(D) the priority areas, remaining chal5 lenges, and potential pilot opportunities that the program established under this section will address.
All of these are well and good. I’ve actually co-directed an effort to use observational studies and an outcomes database to improve patient safety and the quality of care. Such tools, however, are poor at demonstrating efficacy of a drug, although they can demonstrate safety.
Worse, the bill undermines informed consent, as I discussed before. The provision is still there that would add another category of research for which it is acceptable to forego informed consent. Normally, it is only acceptable to skip informed consent when it is not feasible or it is contrary to the best interests of the subject. Add to that now that it would be acceptable to forego informed consent when “the proposed clinical testing poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of the human subject.” As Merrill Goozner put it and I agreed, even if the risk is minimal, why would the authors of this legislation waive a central tenet of international agreements designed to protect the rights of human subjects in clinical trials? I didn’t understand either (and still don’t), particularly since the act doesn’t define “minimal risk” or specify who determines whether a study is minimal risk. Presumably it would be the Institutional Review Board, and I know that there are standards for what constitutes “minimal risk research” in the code governing human subjects protection (for instance, blood draws are generally considered “minimal risk” as is the use of archived clinical specimens, such as tissue), but the wording of this provision is a bit vague. Moreover, the number of studies that would be facilitated by such a change in the requirement for informed consent must be vanishingly small.
SEC. 3033. Accelerated Approval for Regenerative Advanced Therapies (page 179 et seq): Creates an expedited review pathway for “regenerative medicine” products that allows use of surrogate endpoints and post-approval studies. This was not in previous versions of Cures and should not be rushed through without adequate discussion.
This is basically warmed-over language from the REGROW Act (Reliable and Effective Growth for Regenerative Health Options that Improve Wellness), introduced by Sen. Mark Kirk (R-Ill.) and co-sponsored by Sens. Susan Collins (R-Maine) and Joe Manchin (D-W.Va.). The language is different, but the idea is the same: To speed up the delivery of adult stem cell therapies to patients by cutting back on testing and letting them go to market before they have been demonstrated to be efficacious and safe. REGROW is backed by a wealthy Texas entrepreneur, Ed Bosarge, who runs the stem-cell firm Bosarge Life Sciences and has been—shall we say?—quite generous with campaign contributions to key legislators. Bosarge didn’t get everything he wanted, but this provision will basically allow the approval of all sorts of dubious stem cell “therapies” at a much lower standard of evidence.
The bill also changes course compared to current law and allows pharmaceutical companies to promote “off-label” uses of their drugs:
SEC. 3037. Health Care Economic Information (page 188 et seq): Allows pharmaceutical companies to promote off-label uses to insurance providers, allowing them to dramatically expand their markets while evading the requirement of FDA approval for new indications.
As I said at the time (and have been quoted saying again), a homeopath would love this provision, and, I’m sure, so would drug companies. Why bother with the time, bother, and expense of those pesky clinical trials to get your drug approved for additional indications, when you can rely on clinical experiences based on therapeutic use, uncontrolled observational studies, or registries instead? If I were the CEO of a pharmaceutical company, I’d love it. Indeed, the one thing this provision most definitely does not do is to speed effective treatments to patients. Rather, it smacks of being a payoff to pharmaceutical companies.
No, strike that. It is a payoff to pharmaceutical companies:
But the debate surrounding the 21st Century Cures Act came to embody a larger dispute about how government can and should operate. Some 1,455 lobbyists, acting on behalf of more than 400 companies and other organizations, lobbied on the legislation, according to the Center for Responsive Politics. Over the past year and a half, companies known to have lobbied on the Cures Act spent half a billion dollars to influence Congress. The resulting bill was packed with politicians’ pet projects and sops to industry.
Basically, the way the antiregulatory pro-industry contingent got this bill passed was to offer “something for everyone.” There’s an increase in funding to the NIH, although, again, like the funding for opioid addiction programs, it’s not guaranteed for long. Basically, the bill represented a “Hobson’s choice”:
The bill would make billions of dollars available for medical research. It would fund lofty goals, such as precision medicine, a White House initiative to map the human brain and Vice President Joe Biden’s “Cancer Moonshot.” It would save lives. But it would also undermine regulations that patient advocacy groups say are essential for making sure medical and drug research is conducted ethically and safely — meaning it could cost lives, too.
There’s no “could” about it.
Basically, the pharmaceutical industry and its lackeys in Congress bought off biomedical research advocates with the promise of more funding to the NIH and to efforts to combat the opioid crisis in the US. The price was a hole host of industry-friendly provisions weakening the FDA and producing new expedited pathways for drug approval, as well as permission to promote off-label drug use. True, a few of the more onerous provisions were removed, but one truly pernicious provision (the watered down REGROW Act language) was added. It’s not as bad as REGROW, but you can be sure that Bosarge will be back for more.
Expect more Vioxx disasters, now that the 21st Century Cures Act threatens to turn the FDA into a puppet of the pharmaceutical and medical device industry and Donald Trump is considering a libertarian with zero medical or scientific background who thinks FDA regulations kill people to be FDA director. Also expect pharmaceutical company profits to soar. I hope ASCO and the other medical groups that pushed for this bill think it was worth it.