Could it be that there are scientific limitations to drug development?
That the FDA is increasingly strict is incontrovertible. To take one recent example, after diabetes drug Avandia from GlaxoSmithkline was linked to cardiovascular safety risks in 2007, the FDA began requiring all sponsors of new diabetes drugs to conduct large cardiovascular safety trials. These trials cost hundreds of millions of dollars each, costs that will be borne by ordinary people: either through higher insurance premiums and higher Medicare and Medicaid taxes (because of increased drug costs), or because companies decide to abandon development of these drugs as the rewards are outweighed by the risks.
Megan McArdle of The Atlantic Monthy has an article out this month on the drug pipeline slowdown. Most of what she discusses will be familiar to regular readers of this blog. She does make an interesting argument: that, while there is something to the complaint that the FDA is getting more stringent, and that companies often eschew innovation for me-too approaches, the real problem is that drug development is getting technically harder:
When you’re up against nothing, it’s relatively easy to show that you’re more effective than the alternative. But when you’re up against already-state-of-the-art treatments, you’re looking for small improvements. That means you need huge numbers of patients to generate a statistically significant result. And since good treatments already exist, the safety hurdles are also higher—the FDA is less likely to approve a statin that causes internal bleeding than a pancreatic-cancer drug that does the same.It is true that generic drugs for heart disease, diabetes, high blood pressure, etc., along with more aggressive cost-control from insurers, has made it difficult to develop new, first-line drugs for those diseases. But there remain tens of millions of people in the U.S. for whom those first-line drugs are not sufficient. Hence, the markets for new drugs remain massive.
Meanwhile, in the areas where we don’t have good drugs, we don’t have so many easy targets, either. The great hopes for finding drug prospects by decoding the human genome have largely faltered; so far, reading our DNA seems mostly to have taught us how little we still understand about our own biology. So researchers are left with complex problems like cancer, which is really not one disease at all, but several thousand different ways that a human cell can go wrong.
And while it may seem today, as McArdle writes, that “the big fat targets like angiotensin” are sewn up, but it’s worth remembering that those big fat targets were once hypothetical, just like those of today’s emerging drugs. The targets only seem big and fat in retrospect. While the first angiotensin converting enzyme inhibitors were being developed, nobody knew if they would succeed. Hindsight is 20/20, and we often forget this when we think about drug development.
One technical challenge for small-molecule drug development today is the revolution spawned by combinatorial chemistry. Combinatorial chemistry is the high-tech process by which companies can rapidly synthesize large numbers of variations to a core molecular backbone. While combinatorial chemistry has so far led to few new drugs (Nexavar is a notable exception), these novel compounds are often patented, limiting the maneuvering room for new players. Antibodies are one way around this problem in some instances, especially now that human gene patents have been invalidated.
At the end of the day, though, drug development isn’t getting inherently harder. The obstacles posed by generic drugs and patent barriers are compensated for by new scientific insights and technologies. The biggest issues for the industry remain: (1) the massively increased strictness of the FDA, as discussed above; and (2) how the way we pay for drugs distorts industry’s priorities.
The way insurers pay for new drugs is highly politicized. If a new cancer drug extends life by three months, and the drug company charges $100,000 for it, insurers feel forced to pay up, because if they don’t, patient advocates will paint them as the bad guys. Patient advocates have less sway with the big cardiovascular and metabolic diseases, because we don’t feel as sorry for people with clogged arteries.
Because of these phenomena, nearly every drug company today focuses on “specialty” opportunities: ones where they know the FDA will be more lenient, and where insurers will have no leverage. Overall, the effect is a gradual migration away from those diseases that affect the most people. It’s not obvious that this is a good thing.