So, me-too drugs, knock-offs, copycats: what say you? If you're a critic of the industry, you generally say quite a bit, and it's about lack of innovation, seeking easy profits and playing it safe, putting marketing over science, and so on. But what if that's not true?
We've talked about this here before, but now we can put some numbers on the topic, thanks to this article in Nature Reviews Drug Discovery. The authors have covered a lot of ground, looking at first-in-class drugs approved from the early 1960s up to 2003, with later entrants in the same areas accepted up to 2007. There are 94 of those different therapeutic classes over that period, with a total of 287 follow-on drugs coming after the pioneer compounds in each. So there you have it - case closed, eh?
Not so fast. Look at the timing. For one thing, over that nearly 50-year period, the time it takes for a second entry into a therapeutic area has declined steeply. Back in the 1970s, it took over nine years (on average) for another drug to come in and compete, but that's gone down to 1.7 years. (The same sort of speed-up has taken place for third and later entries as well). Here's what that implies:
Implicit in some of the criticism of the development of me-too drugs has been the assumption that their development occurs following the demonstration of clinical and commercial success by the first-in-class drug. However, given assessments of the length of time that is typically required for drug development — estimated at between 10 to 15 years — the data on the timing of entry of follow-on drugs in a particular class, in this study and in our previous study, suggest that much of the development of what turn out to be follow-on drugs must occur before the approval of the breakthrough drug.
That it does, and the overlap has been increasing. I've been in the drug industry since 1989, and for every drug class that's been introduced during my career, at least one of the eventual follow-on drugs has already been synthesized before the first one's been approved by the FDA. In fact, since the early 1990s, it's been the case 90% of the time that a second drug has already filed to go into clinical trials before the first one has been approved, and 64% of the time another compound has, in fact, already started Phase III testing. Patent filings tell the story even more graphically, as is often the case in this industry. For new drug classes approved since the 1970s, 90% have had at least one of the eventual follow-on drugs showing its first worldwide patent filing before the first-in-class compound was approved.
So the mental picture you'd get from some quarters, of drug companies sitting around and thinking "Hmmm. . .that's a big seller. Let's hang a methyl off it now that those guys have done the work and rake in the cash" is. . .inaccurate. As this paper shows (and as has been the case in my own experience), what happens is that a new therapeutic idea becomes possible or plausible, and everyone takes off at roughly the same time. At most, the later entrants jump in when they've heard that Company X is working in the same area, but that's a long time before Company X's drug (or anyone's) has shown that it's going to really work.
If you wait that long, you'd be better off waiting even longer to see what shortcomings the first drug has out in the real marketplace, and seeing if you can overcome them. Otherwise, you're too late to go in blind (like the first wave does). And blind it is - I can't count the number of times I've been working on a project where we know that some other company is in the same area, and wondering just how good their compound is versus ours. If you know what the structure is (and you don't always), then you'll make it yourself and check your lead structure out head-to-head in all the preclinical models you care about. But when it comes to the clinical trials, well, you just have to hold your breath and cross your fingers.
I'll let the authors sum things up:
Overall, these results indicate that new drug development is better characterized as a race to market among drugs in a new therapeutic class, rather than a lower risk imitation of a proven breakthrough. . .a race in which several firms pursue investigational drugs with similar chemical structures or with the same mechanism of action before any drug in the class obtains regulatory marketing approval. So, the distinctions that are often drawn between the relative innovative value of the development of the first-in-class and the me-too drugs in the same class may be misguided. . .
Over to you, Marcia Angell and the rest.