This post is going to veer a little off my usual topic list, but it is something I’d like to write about, and one of the glories of a blog is that I can write about whatever I want.
Several weeks ago, a friend sent my a post from Slate Star Codex about potential FDA picks. I read Slate Star Codex from time to time. I am a liberal and he is a libertarian, so I rarely agree with him, but his arguments are thoughtful enough to be worth thinking about, and I’m all for reading things that challenge my opinions. My friend sent me this post because she wondered what I think about the potential changes at the FDA. I have spent my career primarily working in biotech and pharma, and she wondered what an “insider” would think.
I should note that most of my career has been at the periphery of drug discovery. I work with drug discovery data, and I’ve even been involved in helping some project teams figure out project management. But I am not a “drug discovery scientist”- i.e., I am not someone who makes her living discovering and developing drugs. I know how the process works, though, and it is from that knowledge that I form my opinion. If you want the opinion of someone who is an actual drug discovery scientist, I recommend checking out Derek Lowe’s blog, In the Pipeline. His recent posts about the reason that the majority of drugs that enter clinical trials fail and “the flightosome” are particularly relevant.
I want to wait and see who actually gets nominated for the FDA and what that person says his or her plans will be before I weigh in on the potential candidates. But there is one thing in that Slate Star Codex piece that I strongly disagree with, and want to write about: the idea floated by Jim O’Neill (one of the names being bandied about as a potential FDA pick) that the FDA should approve solely on safety and not efficacy. I come down against it much more strongly than the author of the Slate Star Codex blog does. In short, I think that is a terrible idea. So terrible that if it comes to pass, I will start looking to the EMEA (the European equivalent of the FDA) for guidance on what drugs to take.
I am not swayed by the arguments about grandfathered in drugs like aspirin or penicillin. The efficacy of those two drugs is actually pretty easy for a consumer to judge. But what about my asthma medicines? Asthma is a complex disease. It responds to a lot of things in the environment, and the intensity of my asthma varies a lot from day to day. How would I possibly evaluate the efficacy of a new drug I tried? Did the drug make my asthma better, or was the air just cleaner today than yesterday? Did my asthma get worse when I stopped taking the drug, or did I just have lunch next to someone covered in cat hair? I have no hope of doing a proper study. Luckily, the company that makes the drug had to do a large clinical trial with sufficient statistical power to provide some indication of whether or not the drug works.
Furthermore, saying “just approve on safety” ignores the fact that in many cases, it isn’t a question of whether the drug is “safe,” but of whether the benefits outweigh the risks. Again, take my asthma drugs. If I am having an acute attack, I might be prescribed prednisone. However, prednisone has terrible side effects: irritability, insomnia, and weight gain, to name the three I hate the most. Would it be judged safe in this new regime? It, of course, would be grandfathered in. But what about a new drug with a similar activity profile? Would it be approved?
Let’s say it was, and it falls to consumers and their doctors to sort out which drugs are efficacious. With all due respect to my doctors, I don’t think they are qualified. And with no self-deprecation intended, I do not think I am qualified either. I have a PhD in biochemistry and have spent more than 15 years in the drug discovery industry. But I do not have the specialized knowledge to evaluate the efficacy data on every possible drug I might take. And frankly, neither does my doctor. This work is currently done by teams of people, drawn from a variety of scientific and medical disciplines.
Even allowing that doctors could be trained to evaluate this data, I don’t think the data would be available to evaluate, except for drugs also submitted to the EMEA. Phase III clinical trials (the ones that establish efficacy) are expensive undertakings. There is no reason to think drug companies would continue to do them if they were not required. They would do smaller studies, perhaps, to provide pretty charts to use in their marketing materials. But these studies would not necessarily have the statistical power to answer the question of whether the drug was efficacious. In effect, consumers would be part of a big, uncontrolled trial to find that out.
This is what already happens with herbal remedies and things like the zinc lozenges I take to ward off colds. There is weak data indicating the zinc works, and a plausible mechanism. But there is no definitive data, and there probably never will be, because no one has any incentive to collect it. I joke that if I’m just getting a placebo effect, that’s fine with me. And it is fine for something as low risk as zinc lozenges that may or may not help me avoid the latest cold my kids have brought home from school. If I am taking something with no value, the only harm I’ve done is that my stomach might be a little upset. It is not fine for the health decisions of higher consequence: Is the benefit provided by this asthma inhaler worth the slightly increased of an asthma-related death? (This is a real question that can be asked of one of the drugs I take.) Does this cancer treatment provide increased longevity to compensate for its toxic side effects?
The FDA forces the studies that provide the data to answer those questions, and forces honest evaluations of that data. Yes, the approval rate is low. That is in large part because we are trying to mess with a complex system that we do not understand well (our own bodies). The models and in vitro experiments that we use to try to predict which drugs will work are flawed, largely because we don’t understand the entire system we are modeling.
I have spent my entire career explaining to engineers that biology does not care what they think is logical, so I am perhaps more skeptical than most of the ability of people from Silicon Valley to come in and “fix” drug discovery. I have in fact watched prior attempts to do just that, and watched as those engineers were humbled by the complexity of the human system. This is amusing when it is just investors’ money getting wasted. It is frankly a little terrifying when it might actually be people’s lives and health on the line.
As for the other proposals in the Slate Star Codex blog post: I’m open to most of them. I have no problem with reimportation. In my opinion, that fight is just about money. But, I would caution that we should be careful what we wish for: the US market covers a lot of the R&D expenses at pharma companies. If that gets cut, research budgets will probably fall, at least until the pharma companies have a chance to renegotiate their deals with other markets. In the long run, I think that will work itself out. In the short term, I think we will see even fewer new drugs. This would be bad news for people who get diseases like pancreatic cancer, for which there is currently no good treatment. But I am not so egotistical to think I can actually predict what would happen in this situation. If we want to try it, sure, why not.
I think streamlining the approval process for drugs already approved by the EMEA is a good idea. Yes, the FDA prevented the thalidomide tragedy from happening here, but the EMEA’s requirements have gotten more stringent since those days. Last I heard, the FDA and the EMEA were already working to simplify the process of applying for approval in both jurisdictions (I think they were also working with the Japanese agency), but I haven’t had cause to check in on that in awhile. Maybe it could be sped up or improved.
I’m all for allowing more companies to make generics, but I want manufacturing QA procedures rigorously maintained, and there are some issues with doing away with the requirement to demonstrate bioequivalence that would need to be considered. Look at the Ranbaxy case from a few years ago to see why: in that case the company made up bioequivalence data, so why should I believe that the company should be trusted to “do things right” in the absence of any oversight at all?
As in any organization overseeing a complex process, there is almost certainly room to improve the FDA’s process. But I am very leery of someone coming in without a proper understanding of the realities of drug discovery and development and applying ideas borrowed from Silicon Valley. The human body is not an engineered system, and it is not a system we understand well. A lot of what looks like “inefficiency” in the current drug discovery landscape is actually just “biology is surprising.” So bring in a reformer, sure. But bring in one with the humility to know what he does not know. And if there is any proposal to do away with the requirement to demonstrate efficacy, I’ll be loud about protesting it.