Does Faster Drug Approval Lead To Better Medicine?
Between 2009 and 2013, the FDA accelerated approval for 22 drugs that could be used to treat rare and life-threatening conditions. The drugs are approved based on bioindicators and different laboratory research, and manufacturers are required to have post-approval clinical trials to confirm the safety and efficacy of these medications. Many patients with rare diseases that don’t have treatments are willing to take a risk on these fast-tracked drugs.
But according to a group of researchers, these post-approval studies for the drugs are often not happening in a timely way. Their results were published this week in Journal of the American Medical Association. Dr. Aaron Kesselheim, an author on that study, and Dr. Robert Califf, professor of medicine at Duke University, discuss how the fast-track approval process could be improved to create more effective medications and safer guidelines.
Aaron Kesselheim, M.D., is an associate professor of medicine at Harvard Medical School in Boston, Massachusetts.
Robert Califf, M.D., is an advisor with Verily Life Science. He’s also a professor of medicine and vice chancellor for health data science at Duke University. He’s based in Durham, North Carolina.
JOHN DANKOSKY: This is Science Friday. I’m John Dankosky. Ira Flatow is away. Getting a drug to market can take years of testing and clinical trials. But some patients with rare or life-threatening diseases don’t have the time to wait. The FDA has created a system of accelerated approvals for drugs that might provide promising treatments for these patients. A group of researchers studied some of these fast track drugs and found that they weren’t being properly evaluated or followed up on with clinical trials. Their results were published this week in the Journal of the American Medical Association.
So here’s the question, how can we quickly bring potentially promising new drugs to the market, but also ensure that they’re safe and effective? Let me bring in our guests. Aaron Kesselheim is one of the authors of the study. He’s also an associate professor of medicine at Harvard Medical School and director of the program on regulation, therapeutics, and law at Brigham and Women’s Hospital in Boston. Aaron Kesselheim, welcome to Science Friday.
AARON KESSELHEIM: Thanks for having me. It’s a pleasure to be here.
JOHN DANKOSKY: Robert Califf is a Professor of Medicine and Vice Chancellor for Health Data Science at Duke University and the adviser for Verily Life Science. He’s also the former FDA commissioner. Robert Califf, welcome to the show.
ROBERT CALIFF: Howdy, thanks. Good to be here.
JOHN DANKOSKY: Well, let’s start with Aaron Kesselheim. And maybe you can explain first of all, how a drug gets this accelerated approval, the thing we call fast track. What are the conditions that need to be met for it to get on this track?
AARON KESSELHEIM: Sure. Well, this is intended for drugs that treat serious or life-threatening conditions, or maybe address an unmet medical need. And it’s part of a kind of a grand bargain where the FDA will be more flexible in terms of the amount of data these drugs require, or the endpoints that the trials will be testing prior to approval.
In exchange, the companies will be required to do confirmatory trials after approval. And the goal is to try to get these drugs, if they show promise, to patients as quickly as possible, but then also make sure that they’re followed up with conformatory studies done in a timely fashion.
JOHN DANKOSKY: So Robert Califf, are these fast track drugs, if they’re skipping a part of this important process, are there more stringent regulations, or are they more scrutinized more heavily than other drugs?
ROBERT CALIFF: Well, and first of all, let me just comment on your premise here. You said, FDA created this pathway. It wasn’t FDA, Congress through law created a pathway, our elected officials. And the bargain here that you talk about is rarely with patients. And patients have been very clear that they are willing to take more risk if they have a serious or life-threatening disease for which there’s no other effective treatment.
But I do think the important issue here that we’re talking about is what to do after one of these products has gotten on the market, and how to ensure that the right data comes in to demonstrate for sure whether the benefits and risks are where you’d like them to be.
JOHN DANKOSKY: Well, let’s look at what’s in the study. So Aaron Kesselheim, you looked at 23 different drugs. Where do you see that the evaluation process fell short?
AARON KESSELHEIM: Well, one of the things that we found, for example, is that a lot of these drugs, which were tested on surrogate measures, which is changes in blood tests or radiological studies, endpoints short of real clinical endpoints, mortality, morbidity, change in patient symptoms, a lot of those surrogate measures were used in the preapproval studies. And so one would think that after approval, a lot of these same drugs would then be tested on these more real clinical measures. And what we found was that actually, a lot of these drugs are still being tested in surrogate measures.
And another point that we found is that now a number of years out after these trials were instituted, a lot of the trials remain to be completed. And I think that again, the goal here should be to try to complete these studies in as timely a fashion as possible to try to get more information to patients and physicians so that when they’re making decisions about these products, they can make them with this full information as possible.
And we can learn more about them, so that even patients with life-threatening diseases shouldn’t be at risk for taking drugs that don’t work or could make them suffer or die quicker. So I think that that’s also part of what we might expect in these post-approval studies that we didn’t find as often as I feel like we should have.
JOHN DANKOSKY: Were you surprised by these findings?
AARON KESSELHEIM: Well, I think again, I think part of the deal here with patients is that again, we’re going to try to get these drugs that show promise as quickly to patients as possible. And then we want these kind of rigorous confirmatory studies. And I think we weren’t finding them as often as we had hoped we would or expected that we would.
JOHN DANKOSKY: How about you, Robert Califf? Were you surprised at what Aaron found?
ROBERT CALIFF: No, not at all. These things are carefully monitored by FDA. And Aaron wasn’t surprised either, this is not a secret. But it was good to have the documentation of the facts so that we can think about how to do it better. But you can easily sound cup half empty here, like things are terrible.
But put yourself in a patient’s shoes. You’ve got a drug, for you have a disease with a very high mortality, there’s no effective treatment. And something comes along that looks pretty darn good, doesn’t meet the usual standard, but you’re a very high risk of dying and I think it’s clear from what patients have said, what advocates have said, and ongoing surveys that people are willing to take more risk in that situation. Then the drug gets on the market.
Would you take a placebo in that situation, for example? Would you be willing to wait to get the drug if you were in a clinical trial until the mortality results were in, which might take a long period of time. So I think this is a little more complicated than just let’s design better studies, and it’s very straightforward. Each case is different. But I’m not arguing that things need to be done better, we need a better post-market system. I’m just saying it’s not quite so simple as people aren’t doing the job.
JOHN DANKOSKY: should something about the scrutiny of the drugs that get approved for fast track, is there something about that that could change, do you think, Dr. Califf?
ROBERT CALIFF: I think the system right now is actually working pretty well on the front end. It’s tuned to those at most risk, those with the most at stake, what patients want. And it’s difficult. And another point I always make is thank goodness we have civil servants at FDA who by definition, cannot have a conflict of interest. That is, their full time jobs are in government.
So they make these decisions, which are very hard because as Dr. Kesselheim’s group pointed out, and the same for devices in a complimentary study, you don’t have all the data you’d like to have in the best of all circumstances. So you have to make a hard judgment. I think the place where the work is needed is in the post-market phase.
JOHN DANKOSKY: I’m wondering, Aaron Kesselheim, what you feel about this risk reward that we’re talking about here, this idea that for patients who really do want access to these drugs, this can be lifesaving certainly can give a bit of hope. Do you think that the system is working pretty well right now?
ROBERT CALIFF: Well, I do. I do think the system is working well in a lot of different ways. And I would agree with Commissioner Califf that we’re indebted to the scientists and experts who work at FDA, and have to make these hard decisions.
I also think that even patients who are dying and who are facing unmet medical need, I think that even they deserve to have drugs that they can count on where there’s some chance that the drugs will work, and that we have as good of knowledge as we can about the safety of the products. In part also because a lot of these drugs will invariably be very expensive.
And people are going to need to be making choices about whether or not these are drugs that they’re going to want to take. So I would agree with Commissioner Califf that a lot the work here needs to be done on the post-market side. And I think that policymakers need to think about giving FDA more authorities and more resources to make sure that that kind of monitoring can be going on. And in circumstances where trials are delayed for one reason or other, or where the trials actually end up coming out negative, that the FDA can then take relatively quick action.
JOHN DANKOSKY: Commissioner Califf, where exactly is the responsibility to run these post-approval clinical trials? Is this in the hands of the companies? Who exactly is in charge here?
ROBERT CALIFF: Well, the companies have the legal responsibility to make sure the trials are done. That’s a commitment that’s made. The FDA has a responsibility to monitor. And if the trials are really not being done, it is possible for the FDA to pull the product off the market. But remember the complexity there. If you are a patient, and you thought the drug was working for you just because the company hadn’t gotten a study done, would you think it’s a good idea to pull the product off the market?
So that’s why in the editorial that I wrote, the big deal here to me is that doctors and patients need to be aware of this and really need to work together. Remember that the way clinical trials get done, the companies pay for the trials. But they’re actually done by doctors giving consent to patients who agree to be in a clinical trial. So if doctors don’t step up to the plate and demand that the trials get done, and if patients don’t participate, we’ll never get this information. It will be in the imperfect state that Dr. Kesselheim is lamenting here, I think appropriately.
JOHN DANKOSKY: Dr. Kesselheim, you mentioned pricing before. And this is, of course, an important piece of this. What about the idea that companies that fast track drugs should be subject to some kind of price restrictions?
JOHN DANKOSKY: Well actually, that is an idea that we’ve proposed in a different article. And this is obviously, now we’re kind of outside the scope of the FDA and what the FDA can or can’t impose. But I do think that we need to be thinking about whether a drug company that gets a drug to market based on less rigorous data on a faster process should be allowed to set the price at the same level as another drug company that does a longer, more rigorous clinical trial.
In just a few seconds, Dr. Califf, I’m wondering if you agree with that assessment about pricing and price restrictions.
ROBERT CALIFF: I love my FDA job and I’m delighted to be free to comment. Yes, I completely agree. We should pay for drugs based on the value they bring, which is the extent to which they save lives and improve quality of life. If you haven’t demonstrated that in the clinical trials, you have no way of knowing. So I’m in complete agreement there.
JOHN DANKOSKY: We’re glad you’re freed up to speak as well. Robert Califf, professor of medicine and Vice Chancellor for Health Data Science at Duke University. And adviser for Verily Life Science, a former FDA commissioner. Thank you sir for joining us. I appreciate it.
ROBERT CALIFF: Thank you.
JOHN DANKOSKY: Thanks also to Aaron Kesselheim, associate professor of medicine at Harvard Medical School, director of the program on regulation therapeutics and law at Brigham and Women’s Hospital in Boston. Thank you, Aaron.
AARON KESSELHEIM: My pleasure, thank you.