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In a quest to bring new medical products to Americans, Congress is considering a grand bargain.

Legislation passed last year by the House would provide billions more dollars for medical research and encourage faster approval of prescription drugs and devices. The Senate, meanwhile, is currently working on a set of companion bills in hopes of crafting a compromise measure.


“If we succeed, this will be the most important bill signed into law this year,” Senate health committee chairman Lamar Alexander, a Tennessee Republican, said at a committee meeting last month.

This sounds promising. After all, adding $9 billion to the National Institutes of Health’s budget over the next five years to underwrite new cures is a good idea. And in an era when desperately ill patients are clamoring for new medicines, giving the Food and Drug Administration extra tools also makes sense.

But there’s a catch. By linking the extra funds to speedier approvals, Congress appears ready to undermine regulatory standards. And this is a misguided notion that, unfortunately, is more likely to help companies than patients.


For instance, the House bill, which is known as the 21st Century Cures Act, would allow the FDA to approve added uses for a drug without relying on a randomized clinical trial — the gold standard for determining whether a medicine can benefit patients and the extent to which there are serious side effects. Instead, the bill would permit the agency to base such decisions on “clinical experience,” a loosely defined term that means, essentially, anecdotal observations from physicians and patients.

To be fair, the FDA would not have to consider such information. And the Senate has, so far, not adopted this notion. But this is hardly the sort of rigorous scientific data that should be used to establish whether a drug is safe and effective.

“This is a harsh way of putting it, but this is why I call it the 19th Century Fraud Act,” said Harvard University political scientist Daniel Carpenter, who studies the FDA. “This is a part of the bill that threatens to take us back more than a century.”

“I call it the 19th Century Fraud Act.”

Daniel Carpenter, Harvard University

The final details of the Senate bill remain uncertain, but some proposals are also prompting objections. As an example, one suggestion for speeding approvals of medical devices is to label certain products as “breakthroughs,” a designation that would offer an expedited review pathway. To qualify as a breakthrough, though, a company need only argue its product is either a significant advance over existing devices or is in the best interest of patients.

The use of the word “or” is problematic, because it creates wiggle room for unproven claims. “It’s very vague and only encourages companies to seek breakthrough status,” said Diana Zuckerman, who heads the National Center for Health Research, a nonprofit think tank.

There are other portions of the House and Senate proposals that merit criticism, but one doesn’t need to be a Washington insider to have concerns.

A new poll from STAT and the Harvard T.H. Chan School of Public Health found that 58 percent of Americans oppose changing safety and effectiveness standards to allow for faster approvals of new medicines, and half of the public also objects to regulatory changes to accelerate approvals of new medical devices.

Dr. Robert Califf, the FDA commissioner, may not have participated in the survey, but he expressed similar sentiments earlier this month. In a speech at an industry conference, he said that, if the legislation is not “carefully crafted, [it] could pose significant risks for FDA and American patients.”

“Innovative therapies are not helpful to patients if they don’t work, or worse, cause harm,” Califf told the gathering.

The Republicans in Congress know what they are doing. By bundling NIH funding with faster FDA approvals, the lawmakers are making it easier to win support from universities and small biotech companies, which rely on government research grants. (In a pointed blog post last fall, University of Pennsylvania President Amy Gutmann wrote that Congress can “change the course of history” by approving the measures.)

They are also appealing to many patients and their families — an increasingly large and vocal group of Americans — who want the FDA to approve more medicines for unmet medical needs.

There is no question that more research funding is necessary and that finding legitimate ways to get medicines to patients faster is crucial. But Congress ought to separate the debate over research funding from the rest of the legislation. Loosening regulatory standards would only create problems for which real cures will be needed.

This weekly column offers opinions on the latest pharmaceutical industry news.

  • I think it’s important to note that even if, theoretically, regulatory standards were loosened — safety concerns for many of the patients 21st Century Cures would benefit are obsolete. If a patient is terminally ill or has a rare or orphan disease with no FDA approved treatment, safety is a lesser concern. When the option is either death or try, patients deserve the right to try. The name of this legislation may be “21st Century Cures,” and although it aims to cure eventually, a great deal of what it aims to do is give patients with no treatment options the ability to try and save their quality of life or life itself.

    Emily Muller.
    Seventeen year old activist and patient. Founder, Emily’s Fight. Director of Communications, We Are More.

  • I would bet that most of the people surveyed have no idea how the government regulates drugs and devices, how long it takes or how much it costs. The language in the survey, “Government standards should be changed to make prescription drug development faster”, connotes a relaxation of existing rigor, when that is not the intention of either proposal. And, the current clinical trial system is the “Gold Standard” simply because that is what we’ve done for the past 5o years. We have no data to judge that the proposed changes would create a less than gold standard, but it would be different, less costly and result in more treatments getting to desperate patients faster.

    A good counter balance survey would be one that asks afflicted cancer patients (ALD, Alzheimers, MS and all the other deadly and intractable diseases) whether the FDA should make changes to the way it approves drugs to significantly reduce the 10 year time frame from lab to their doctors.

  • Thought provoking, Ed. I believe the important distinction here is Congress providing the FDA with increased regulatory flexibility versus a dictate for a lessened standard for approval. At present, the likelihood of a drug being approved for a new indication based only on real-world, or clinical, evidence is very slim. Clinical trials would likely still be required. But in the future, with more and better data, who knows?

  • Dear Sir,
    This column seriously mischaracterizes the 21st Century Cures Act, which would do nothing to change the evidentiary standards of safety and efficacy that the FDA must apply in approving new drugs. The current standards require “substantial evidence” from “adequate and well-controlled investigations” to support efficacy. The FDA already has broad authority to determine what evidence meets that standard in the case of each individual application. Nothing in current law precludes FDA from including real world evidence, collected after a drug is approved, from subsequent regulatory decisions about that drug, including potential new indications. And, as you note, nothing in the 21st Century Cures Act would compel them to do so, either.
    What the Act does do is make note of the fact that real world evidence, inaccurately derided here as “anecdotal observations,” provides an increasing quantity and quality of data on how real patients respond to treatments once they are on the market, and that FDA may make use of that evidence in their decision making processes. We don’t stop learning about a drug once it is approved and has a label. In fact, the FDA currently makes systematic use of real world evidence to monitor the safety of approved drugs through its Sentinel Initiative, which enables them to search for adverse events in electronic health record systems and insurance claims databases – a far larger dataset to identify potential safety issues than is possible even in the largest of Phase III trials.

    As researchers – and regulators – gain access to more and more sources of real-world data about treatments, and better tools for scientifically assessing that data, it only makes sense for FDA to pay attention to that data when it provides meaningful information about the products they regulate. The suggestion that the FDA would begin approving new indications for drugs based upon “anecdotal observations” is base fear mongering and frankly, insulting to the hardworking and scrupulous staff of FDA.
    Count me among the 58% of Americans who don’t want the FDA to change their safety and efficacy standards. Contrary to the misinformation peddled in this column, the 21st Century Cures Act does nothing of the sort.

    Thomas P. Mathers
    President and CEO
    CoLucid Pharmaceuticals, Inc.
    222 Third Street
    Cambridge, MA 02142

    • Thanks for your note, Mr. Mathers. I appreciate the time you took to write and the views you shared.

      I understand your points, and agree that clinical experience can and should be considered, but not used wholly as a substitute. And yes, the Sentinel project will hopefully provide further needed insights into risks, but it’s also an ‘after-the-fact’ effort and not designed for approvals.

      In any event, I’m not trying to generate fear. I’m hoping to further discussion. If there is still room for improvement in the legislation, why not?

      All best,

  • This article is based on an unfortunate assumption that the FDA’s regulatory model, now more than 50 years old, should not be updated to reflect the current state of knowledge regarding the biology of disease and our greatly expanded ability to create new, targeted treatments that work. The author also falls into the trap of accepting that the randomized controlled trial is the only way to determine whether a drug is safe and effective, but in fact the opposite is now obviously true. The randomized controlled trial design is more than 50 years old, selected in the early 1960s based on the medical ignorance existing at the time. It was the best we could do then, but we can do a lot better now. Ed Silverman usually writes less biased, more factual articles. The reality is that FDA has been scientifically stagnant for decades, mostly failing to adjust to the continuous and enormous scientific advances occurring in the way we medically innovate. Congress supported by the patient community began trying to drag FDA into this century about 4 years ago, and the current legislative effort is a second try, because FDA, as it always does, fought to remain stagnant. The choice of Drs. Zuckerman and Carpenter as sources, both well-known luddites when it comes to the FDA, belies the bias of this article. Ed, why not also include some input from the very large and more expert community of stakeholders who support modernizing our hopelessly outdated FDA?

    • Not to put too fine a point on it, this is not an article but it is labeled as an opinion piece. One can observe that the FDA has been approving more rapidly since the advent of User Fees and the number of damage suits has also been increasing. I would applaud a faster approval process but this piece of legislation does not seem to be the vehicle. It has the flavor of ‘first to be reimbursed’ rather than ‘a race for the cure.’

    • Hi Steve,

      Good to hear from you and thanks for writing.
      First, you should know that, unlike my usual blog posts, this was an opinion column, unlike my columns at The Wall Street Journal. This is marked as ‘The Pharmalot View’ for that reason, although I gather that may not be clear to everyone.
      So I was not attempting to display bias, simply offer my own thoughts.
      As to your points, I agree that there is room for improvement at the FDA. The agency is not a sacred cow. And the recent example of the Duchenne muscular dystrophy drug from Sarepta is a good illustration of how thorny the approval process can become.
      But I do think standards, of some sort, are a good thing. Is everything in the 21st Century Cures Act a bad idea? No. But I pointed to a couple of places where the language could swing the pendulum quite far in the other direction. That could be risky. Perhaps the Senate version will aim for a mid-ground that balances concerns.
      Not sure if this helps, Steve, but I do want to hear from you and others who seek reform. And I will continue to seek out those voices as I do my work here.
      All best

    • Good point about the article being an op ed. I knew that and perhaps overstepped a little with the comment about your articles not usually being so biased (which as you mention is why we write op eds.) Moving to better trial designs is not in any way an abandonment of standards, and to my knowledge, no well-informed stakeholder is advocating that we abandon standards, but the ones we have now which are almost universally based on demonstrating a statistically significant difference between the median outcome in a treatment arm versus the median outcome in a control arm of a randomized trial is far too simplistic an approach, and is holding us back. The evidence that it is the wrong approach is everywhere, but the well-learned mantra is – the randomized controlled trial is the gold standard. Why? The population-based, simplistic comparison approach provided by RCTs is not only too crude to be very useful, it is ridiculously expensive, fraught with ethical problems, repulsive to patients and their physicians and in almost every pragmatic way, unsustainable. Most importantly, in diseases where our knowledge is advancing rapidly, for example in many cancers, we now know beyond any real doubt that it is just the wrong design. The uniform populations that are the primary basis of “controlling” a randomized trial just don’t exist, thus the validity of randomization and the outcome data that flows from them, is also not valid, or even very useful for the practice of medicine, but the blind faith in RCTs drives an awful lot of bad medicine where patients are given drugs found to effective based on the results of an RCT but will not benefit from them because the information we get from RCTs is crudely probabilistic, not medical, and definitely not targeted. The information regarding how to target drugs is not coming from the randomization, it is coming from the direct correlation of the presence of the biomarker, treatment with the drug, and observance of the associated beneficial effect. No control arm is needed see these relationships, yet FDA and some others continue to insist that the randomized trials be conducted anyway, even when it is clear they are ethical, not needed, and will only delay the delivery of medical progress to countless people who can’t wait. Defending the need for standards is fine, but continuing to defend the randomized controlled trial as the basis for defining those standards, and for measuring regulatory compliance with them, is an enormous problem for medical progress and for patients. I appreciate your mention of the Sarepta situation, which is a classic case where running a traditional randomized clinical trial is close to impossible, if not actually impossible, given the size of the population. Perhaps worse is that an RCT is scientifically just the wrong trial. It doesn’t fit the characteristics of the disease or the highly variable manner in which the disease progresses in the population of boys that suffer from it. The right questions for this disease cannot be asked with an RCT, consequently, an RCT cannot produce the answers we need. So should our FDA be using its considerable power to force sponsors to run the wrong clinical trials just satisfy a now 50-plus year old convention? The drug clearly has benefits, and it so far has shown virtually no significant risks, yet FDA’s neurology products division is doggedly trying to force its convention of a large, double-blind, placebo-controlled randomized trial on virtually every neurology drug candidate that comes before it, because, as was mentioned during the adcomm, FDA has interpreted the statutory standard as evidence from a randomized controlled trial based on language written into the statute in 1962. So standards? Of course. But trial designs, endpoints and standards that are consistent with the state of medical knowledge today, written in a way that allows them to evolve tomorrow, and next week and next year, to fit the knowledge we will have then, instead of – as the FDA’s Division of Neurology Products would obviously prefer, the knowledge we had in 1962. For the life of me, I do not understand why so many people think that the randomized controlled trial is some deep, inviolable scientific truth handed down by some mythical god of medicine. An objective, closer look at how it ended up becoming the backbone of FDA regulation and a faith-based tenet of clinical research reveals a very different, and not nearly as faith-worthy story of how that happened. It is an absolutely awful way to test new medicines to try to find out if they are safe and effective. A lot of people know this, including physicians and other experts, but uttering it is medical blasphemy, and they know better than to utter it publicly. Locking in to the RCT as the backbone of regulation and clinical research for as long as we have will eventually be recognized as one of the big wrong turns in modern science. The proposed legislation, therefore, does not go far enough. Congress should change the approval standards in the Food, Drug and Cosmetic Act to not only allow alternate trial designs, endpoints and approval standards, they need to write the new requirements in text that will allow those standards to continue to evolve in real time, because the science of medical innovation is evolving rapidly in real time. The RCT is actually the equivalent of a 1962 landline phone with a rotary dial and an actual metal bell in it, and our FDA that still insists that the RCT is the gold standard is the phone company as it existed in 1962. One ringy dingy, two ringy dingies….

  • One can only hope that CDER heeds this quote when deciding on the Sarepta product:
    “Innovative therapies are not helpful to patients if they don’t work, or worse, cause harm,” Califf told the gathering.

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