How many useful drugs are approved in the other industrialized countries, but not in the US? The answer to that question has changed over the years, as this Council on Foreign Relations article notes. It’s from 2001, so it’s not about recent history, but its points about the 1960s and 1970s are that the US regulatory authorities were definitely more cautious than Europe’s during that period. Some of this was surely due to the late-1950s thalidomide disaster, where several European countries had approved a drug that the FDA rejected. The latter agency’s caution (as personified by Frances Kelsey) was terribly confirmed, but it’s quite possible that the agency erred on that side for some time afterwards for fear of something similar.
These days, the differences are (fortunately) not so stark. But there have been calls for reciprocity – automatic approval of drugs that have been approved by other well-regarded regulatory agencies – as a way to save both time and effort in the US regulatory process. A bill has been introduced in the US Senate to this effect by Ted Cruz and Mike Lee, the RESULT act. It would require that the FDA approve any drug, device, or biologic that (1) is approved by one of the countries on its list (the EU, Canada, Japan, Israel, Australia, etc.), (2) addresses a medical need, and (3) is not already banned by the FDA for other reasons. There are other provisions that I’ll return to, but first, some comments on reciprocity itself. (Similar bills have been introduced before in the House).
The idea has some well-regarded backers – economist Alex Tabarrok of George Mason has been an advocate for many years (and is name-checked by Cruz in his comments on the bill). Here’s another brief for the idea, and its title sums up the argument: “If a Drug is Good Enough for Europeans, It’s Good Enough For Us”. The first objection is usually a worry about a “race to the bottom”, as companies try to pile into the least strict agency on the list as a lever to get all the others to accept it.
I do have a concern about this, though (see below), but even before that comes Japan. There are a number of drugs that are available in Japan that are not available here, and that, to a very good approximation, is because they don’t really do much of anything. The Japanese authorities are strict on safety, but not so much on efficacy, so there are putative Alzheimer’s drugs on the market there that don’t actually do anything for Alzheimer’s, but primum non nocere, they at least don’t make things any worse. Unfortunately, a lot of things fall into that category; you might as well give people a potato to chew on. Won’t help – won’t hurt. Potatoes do tend to be cheaper than prescription drugs, though. (I should note that it’s not like the Alzheimer’s drugs approved here, all of which are also available in Japan, do all that much good, either).
So Japan is one potential problem with this idea, but even stipulating that we find a way to deal with this, the question has to be asked from back in the first paragraph: how many effective drugs are there that haven’t yet been approved in the US? I think that some people have more of a 1970 mental picture here, that there are all sorts of great therapies that our slow, cautious FDA has not stirred itself to deal with yet. But the main ones I can think of are mifamurtide, for osteosarcoma and the EU’s willingness to consider biosimilars more readily than the FDA. That last one, though, falls more into the cost-saving category than the new-lifesaving-drug one, since the whole idea is to come up with mimics of existing biologic agents. I’d welcome examples in the comments, but overall, I’m having trouble coming up with any dramatic examples of a high-impact drug that’s available in Europe right now but not in the US. (Novartis’ Bexsero meningitis vaccine should still count as an example, though – it was approved in January of this year, two years after its European approval. Novartis didn’t even file for US approval until the previous June, although that delay in filing probably represents their estimate of the FDA’s willingness to approve).
There have, though, been a number of recent studies comparing speeds of regulatory approval in different regions. Here’s one looking at 100 recent “priority review” drugs (so designated at the FDA) that have eventually been approved both by them and by the European Medicines Agency. 87 of those 100 were approved by the FDA first, and the FDA review time was, on average, shorter than the EMA’s. In recent years, the great majority of FDA approvals each year are for drugs that have been approved first in the US. (Medical devices are another area entirely, though – the US and the EU diverge more there, which is why I’m covering only drug substances in this post). Here’s a comprehensive look at drug approvals in the US, EU, and Japan in the 2004-2013 period. What’s clear is that the FDA’s median time to approval is the shortest of the the three, likely due to the priority review processes, although it’s also the most variable. Of the five new active substances approved by all three agencies in 2012-2013, three of the five were first submitted to the FDA, and all five were first approved by the FDA.
I should say something about generics here, since I would assume that this bill applies to their approval as well. What most people don’t realize is that while prescription drugs are more expensive in the US, generic medications have actually tended to be much cheaper than in Europe. Recent years, though, have seen a number of cracks in this system, but most of these are due to FDA regulations or incentives themselves, not so much, I believe, to generics being approved in other countries and not in the US. If we want to address climbing generic drug prices, and I think that we do, this is probably not the place to start in with the hammer.
So overall, I don’t see a big wave of non-FDA-approved drugs out there that will finally wash over us if a reciprocity bill is passed. Other countries, in fact, would benefit more from deciding to follow the lead of the FDA instead. That doesn’t mean the reciprocity is a bad idea per se – it just means that if someone is selling it as a way to break through to a world of lifesaving drugs that are being held back, they’re (at the very least) not well informed. There are, though, other provisions of the Cruz/Lee bill that I’m not so sure about.
The FDA would be given a thirty-day time frame to approve or deny all reciprocity requests. The agency is no doubt going to have a fit about this, sensing (as is likely) that they would not get the funds necessary to actually do that. And it would cost more – one reason that the agency has been moving faster in recent years is that they are able to collect fees from the companies that are putting in the applications (PDUFA). As mentioned above, I’m not sure just how many drugs would be coming in under these provisions, but if there really are quite a few, it’s going to bog things down under current conditions.
And here’s another one: “If a promising application for a life-saving drug is declined Congress is granted the authority to disapprove of a denied application and override an FDA decision with a majority vote via a joint resolution”. Now that’s a first. And it’s a really bad idea. I really, really, do not want the legislative bodies deciding these things. You can argue about the FDA’s decisions, but this would instantly make things worse, because it invites – encourages – political grandstanding to reverse drug rejections. Any Senator or Representative who votes against such a resolution, well, they just want people to die, right? Won’t that be the campaign ad that their opponents will run in the next election cycle? And if you worry about industry lobbying now, wait until you give Congress a veto over the FDA. No, this provision is a flat-out moral hazard, even applying just to reciprocity requests. Why doesn’t the legislature just make cancer and Alzheimer’s disease illegal, while they’re at it?
I think that it’s the “life-saving” part of the language that tries to give everyone an out here. If the patients involved are going to die anyway, then you don’t have quite as many safety worries. That’s been the argument in several therapeutic areas for accelerated approval, and there’s something to it. (And even as things stand, safety concerns are, in fact, much less of a factor in oncology as opposed to, say, diabetes drug approvals). But the language of the bill isn’t just for “life-saving” therapies. It just says that it applies to drugs or devices approved in the other countries on the list, for which there is an unmet medical need.
And there’s one more potential problem with the whole reciprocity idea. The country list is that found in section 802(b)(1) of the FDA Export Reform and Enhancement Act:
. . .Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or any member nation in the European Union or the European Economic Area. As of July, 2007, the EU countries are: Austria, Belgium, Bulgaria, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, and the United Kingdom. The EEA countries are the EU countries, Iceland, Liechtenstein, and Norway. The number of “listed countries” expands automatically as countries become members of the EU or the EEA.
One can imagine the regulatory authorities of one or more countries on this list being (or becoming) a weak link – thus the “race to the bottom” worries. I’m not saying that this is likely, but it is possible, if one of the smaller or more impoverished ones suddenly finds itself as a potential window for access to the largest drug market in the world. The Secretary of HHS has the discretion to add countries to the list, as I read things, but I’m not sure what the process is for taking one off, or how long that might require.
So, to sum up: I don’t have any overarching objections to drug approval reciprocity. But some of the arguments made for it (such as it speeding up drug approvals in the US, and leading to new drugs showing up here in general) don’t seem to me to be accurate. And there are some potential unintended consequences that need to be thought about as well. The Cruz/Lee bill in particular has that Congressional override provision in it, which to me is by far the worst idea in the whole thing.