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Nine Explanations For Why The FDA Is Approving Almost Every New Drug Application

This article is more than 8 years old.

Last week I wrote a post about new data from BioMedTracker that show that the Food and Drug Administration, which once approved as few as 40% of new drugs submitted by industry, has been on a green-light-almost-everything jag, approving 89% of drug applications.

What’s more, a closer look showed an even higher approval rate. This year so far, 96% of new molecular entities– industry jargon for drugs that have never been approved for any use before – that have been submitted to the FDA have reached the market. For anyone who was watching the FDA a decade ago, that’s just shocking. Good or bad, it’s a radical change.

The story generated a lot of smart discussion on Twitter and a post from PhRMA, a drug industry trade group. I think the PhRMA post was badly thought out – more on that in a bit -- but I take seriously the comments of people like David Miller, director at Alpine BioVentures, Alexander Gaffney at PwCHealth, and Peter Pitts, from the Center for Medicine in the Public Interest. The thrust of their arguments: it’s facile of me to argue that the FDA is simply going easier on companies. “Is the FDA getting ‘easy’ or are they finally doing their job?,” Miller tweeted at me. When I said that was a matter of perspective, he replied: “Not a matter of perspective. FDA is there to approve drugs. New guidance programs are a big part of that job.”

My answer is a number: 96%. The FDA is still the gold standard when it comes to drug regulation. It generally requires huge amounts of efficacy and safety data to be collected before new drugs can reach patients. When it doesn’t, it is because a disease is rare and terrible. The FDA insists that companies give it raw data, which it then picks apart in a massive public service. But the agency also goes through cycles, sometimes approving too little, sometimes too much. If 96% of applications for brand new drugs are getting through, it’s hard not to suspect that we’re getting close to the “too much” end of the pendulum.

But it’s certainly true that there are a lot of factors that explain why the FDA approval rate is suddenly so high, and I only gave them a few paragraphs in the last piece. So here I’ll list nine, and give them a lot more space.

1. The approval rate is much lower, because only 12% of drugs that enter clinical trials reach the market. This is the weakest explanation for the approval trend that I’ve heard, and I’m including it only because PhRMA decided to retreat back to it. The trade group first insisted that approval rates are low if you include all the years of research it takes to develop a drug, pointing out that the failure rate of Alzheimer’s drugs is 97% over the past 16 years. (Over the past decade, actually, the failure rate in Alzheimer’s is essentially 100%.)

It’s certainly a fair point that the FDA doesn’t just let any drug onto the market. I should have made that point more strongly. But medicines that are clearly unsafe or don’t work should not be given to patients. The process of developing a new medicine is expensive and arduous, but the fact that many drugs fail in clinical trials doesn’t have much bearing on the FDA, except that the FDA helps set the definition of “failure.”

Many of the approvals coming through this current year are clearly not resulting from higher quality research and drugs that are targeted to specific patient populations. There are big steps forward, like Novartis’ Entresto for treating heart failure or Bristol-Myers Squibb’s anti-cancer drug Opdivo, but there are also incremental steps like Rexulti, the umpteenth antipsychotic and Sayvasa, the third in a new class of stroke-preventing medicines. Medically important? Yes. Evidence of a new paradigm? No.

2. Drug companies are better at research, and they are simply producing better drugs.

The past 20 months have seen the approval of 61 new medicines, including cancer drugs that work by boosting the immune system and pills that cure hepatitis C in most patients. It’s a pharma renaissance. For decades, the cost of inventing a new drug has been increasing exponentially. Though it’s too soon to say for sure, now it may be leveling out or even decreasing. But improving research productivity does not explain why the rate of new drug applications that are approved would go up. That would require that companies decide not to push marginal drugs, even though they might get approved. That doesn’t seem likely. If it’s happening, investors should complain, because these marginal drugs might sell too.

Remember: so far this year, there seems to be only one new molecular entity that’s been rejected. Oddly, it is Merck’s Bridion, which medical journals initially proclaimed a breakthrough anesthesia antidote but which the FDA worries could cause allergic reactions.

3. Drug companies are picking areas where the chances of approval are higher.

This is certainly true. The odds of approval vary dramatically by disease. According to BioMedTracker, in 2012, cancer drugs were approved 75% of the time, and cardiovascular drugs were approved just 50% of the time. Half the drugs in development are now cancer drugs, and many of the new molecular entity approvals this year so far are for rare diseases, which, because patients are so sick, require smaller clinical trials and less proof of benefit.

4. The FDA is doing a better job communicating with companies.

The FDA is doing a better job clearly telling companies what they need to do to get a drug approved, which means fewer applications that fail because t’s needed to be crossed. It is also telling companies when a drug is unlikely to be approved based on current data. This occurred with the biotechnology company Celldex recently, when it decided, based on FDA guidance, not to file for approval of its cancer immunotherapy, Rintega, for recurrent brain tumors. That means that more companies who might previously have filed decide not to push it.

This was the argument from Peter Pitts, at the Center for Medicine in the Public Interest. “More agency/sponsor meetings earlier in the process not only result in better submissions (more likely to be approved because of higher quality science and more sophisticated protocols),” he writes, adding that one FDA official told him "We’re seeing fewer dogs.”

5. The FDA has more power to restrict the use of an approved drug than it used to. When Merck’s Vioxx and Pfizer’s related Bextra were pulled from the market, a lot of the discussion at FDA meetings had to do with the fact that patients and doctors didn’t seem to heed warnings on drugs. If a drug was being widely used and was causing harm, there was nothing to do but yank it.

When worries that GlaxoSmithKline’s Avandia emerged, the FDA had another option: what’s called a Risk Evaluation and Mitigation System, or REMS. This can include making doctors and patients fill out paperwork to be sure they understand a drug’s risk, or even using a special pharmacy. Both steps, in fact, are being taken with Sprout Pharmaceuticals’ Addyi, for treating low libido in pre-menopausal women. Because a REMS allows the FDA to control how a medicine is used, it allows the FDA to approve drugs that it previously would have rejected.

6. The FDA is taking a risk by taking strong stands against drug approvals right now. The legal climate has not been friendly to the FDA lately. Take the case of Amarin Pharmaceuticals, which on August 7 won a case in the Southern District of New York allowing it to tell doctors about unapproved uses of its drug Vascepa, which is used to treat high triglycerides.

Vascepa is only approved for patients with very high triglycerides, which can cause inflammation of the pancreas. The FDA had initially told Amarin that Vascepa, which is purified from fish oil, could be approved for triglyceride-lowering in heart patients before a study to prove the drug prevents heart attacks and strokes could be completed. The agency changed its mind because several studies of triglyceride-lowering agents, including fish oil, failed to show a benefit. The ruling may not have helped Amarin shares, which are down 15% since, but it puts the FDA in the position of potentially losing some of its authority, which is almost all related to regulating the claims that drug companies make. That could have a chilling effect on the agency’s decisions to reject drugs.

7. The FDA is without a permanent commissioner. The communication initiatives that have improved drug approval rates were started by Margaret Hamburg, who stepped down in May. Hamburg did an amazing job shepherding the FDA through a shifting political environment. Early in her tenure we were still facing widespread worries about drug safety in the wake of Vioxx and Avandia. By the end, the climate had completely changed. Not having a dynamic individual fully in charge of the agency means that it is more likely to sway in the political wind.

8. It’s just random chance. This is always possible. Drug approval rates go up and down. Am I certain that the current spate of approvals aren’t just the result of things going remarkably well for a while? Of course not. That would, however, argue that the approval rate is going to come down on its own. And I do think there’s more going on here. But anything – from which drug company’s research labs are most productive to who makes the best stock picks – can just be luck.

9. In the current political environment, the agency is approving drugs it shouldn’t. Even with all the other factors listed above, can we be certain that some drugs the agency should reject aren’t getting through? I’m not convinced we can.

The risks to both public health and industry are high. I’ve seen how fast the regulatory climate around new medicines can change. I think industry is asking for a lot in terms of how fast medicines should be approved, especially given what it already appears to have. In its post complaining about my last article, PhRMA puts up a chart that shows the draconian winnowing that is drug development. In that chart, which is a cartoon meant to get a point across, the drug development process comes to a point during FDA review, when the last winnowing happens. That was the standard model we all had in our heads. Except right now, almost every drug that enters that process comes out the other end.

We’ve seen how fast the winds can change when it comes to the regulatory environment for the pharmaceutical industry. It will only take one bad example – one withdrawn drug like Vioxx, Seldane, or Baycol – to quickly tip things back in the other direction. The pharmaceutical industry, living in what may be the best of times, should be very worried about what happens if it pushes its luck too far.

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