Field of Science

Again, drug design and airplane design are not the same

A while back I had a post about an article that compared airplane design to drug design. I discussed the challenges in drug design compared to airplane design and why the former is much less predictable than the latter, the short answer being "biological complexity".

Now the analogy surfaces again in a different context. C & EN has an interview with Kiran Mazumdar-Shaw, CEO of India's largest biopharmaceutical company Biocon. Shaw is an accomplished woman who does not hold back when she laments the current depressing state of drug development. I think many of us would commiserate with her disappointment at the increasing regulatory hurdles that new drugs have to face. But at one point she says something that I don't quite agree with:

Mazumdar-Shaw dismisses the argument that drugs create a public safety imperative mandating stricter oversight than many other regulated products. “So you think passenger safety is any less important than patient safety?” she asked. Yet aircraft makers don’t face a 12-year, all-or-nothing proposition when designing, developing, and commercializing an airplane. Nor, she added, does Boeing have to prove that it is making something fundamentally different than what Airbus already has on the market.

To which my counter-question would be, "What do you think is the probability of unforeseen problems showing up in aircraft design compared to drug design"? I see a rather clear flaw in the analogy; aircraft design is not as tightly regulated because most aircraft work as designed and the attrition rate in their development is quite low. The number of failures in aircraft development pale in comparison with the number of Phase II failures in drug development. In fact as the article quoted in my previous post described, these days you can almost completely simulate an aircraft on a computer. Regulatory agencies can thus be much more confident and insouciant about approving a new airplane.

This is far from the case for drugs. First of all there is no clear path to a drug's development and in the initial stages most people don't have a clue as to what the final product is going to look like. But more importantly, designing drugs is just so much riskier than designing aircraft that regulatory agencies have to be more circumspect. How many times do drugs show all kinds of side-effects which would never have been predicted at the beginning? How many times do drugs show side-effects that would not even have been imagined at the beginning? It's this almost complete lack of prediction driven by the sheer complexities of biology that distinguishes drugs from airplanes.

In another part of the interview Mazumdar-Shaw voices her impatience with regulators' recalcitrance to adopt new technologies. The example she gives is of Hawk-Eye, a computer that tracks a tennis ball's movement and makes it easier to call out the result of a disputed bounce. Just like sports authorities are reluctant to use these technologies to override the flaws in human judgement, Mazumdar-Shaw thinks regulators are reluctant to use new technologies to overcome the limitations of human judgement. The point is not irrelevant but the truth is that decision making in drug development is far more complex than decision making in tennis tournaments. For Hawk-Eye to track tennis balls is a simple matter of physics, and it can do this with high accuracy. Contrast this with drug development where the "event" to be analyzed is not the bounce of a ball but the efficacy of a drug in a large clinical trial as assessed by a variety of complex statistical measures. In addition, approving a drug is inherently more subjective, being based on efficacies of existing therapies, the exact numerical superiority of the extra benefits, cost and patient populations. Good luck writing a computer problem that could possibly assess this morass of sometimes conflicting information and reach an informed judgement.

I think many of us are frustrated with the increasing regulatory hurdles that new drugs face and we all wish that the process was smoother. Personally I don't think that the FDA's systems for assessing risks is as finely attuned to potential benefits as it should be. But I don't find myself following Mazumdar-Shaw in advocating for drug approvals that are as easy as aircraft approvals. The former is science and engineering. The latter is science with a healthy dose of intuition and art. And some black magic.


  1. "For Hawk-Eye to track tennis balls is a simple matter of physics..."

    ...and what is biology, of course, than a simple matter of physics? ;-)

    1. Either physics or - in Rutherford's words - stamp collecting. Given its complexities I am leaning toward the latter...

  2. I've worked in regulatory for both pharmaceuticals and research-only companies and I am aware of some of the frustrations of regulatory affairs. The concern with cost/benefit related to strict compliance with the rules sometimes results in lost business.

    While it would propel business forward to lessen the regulatory requirements in pharmaceuticals I keep thinking of medications in which safety concerns were not caught in the clinical trials. How would I feel if someone in my family were affected by Vioxx? Clearly regulatory affairs failed the market in this case- we didn't know the adverse events well enough when it was released on the market.

    I'm also aware of how sometimes regulations become out-of-date or are irrelevant to particular situations. It is frustrating to spend time tracking something on a spreadsheet that is just busywork- not relevant but required by law. This is a waste of effort and makes everybody want to ignore regulatory affairs.

    There are no easy answers here..... lessen the requirements and suffer from adverse events (with a booming business culture). Increase the requirements and thwart the progress of science....but definitely fewer risky drugs on the market!
    Hot topic to write about here Ash- thanks for your thoughts!

    1. Yes, as you indicated there are no easy answers here, but don't you feel it's difficult to contrast the heart attacks caused by Vioxx with the millions who were living a pain-free life? I am not saying that the withdrawal decision was premature, only that these issues are indeed thorny.

  3. "Cost to benefit ratio" is a subject in itself. It makes Drug Regulation (DR) a complex affair. Less predictive nature of biology makes DR more of philosophy than just a quantitative science. This can be fairly illustrated from example of drug "thalidomide" which was withdrawn as a sedative due to side-effects of inducing phocomelia. However, same molecule is used nowadays for treatment of a skin disorder called ENL. Pharmaceutical companies have witnessed several such cases in history.

    On the other hand, airplanes cannot be used for some other purpose, ones they are proved to be a failure for public safety.

  4. I'm not sure that aircraft manufacturers are actually regulated and that might be one reason that for the differences. Also I don't think we actually design drugs and that might be another reason for the differences. It is also worth remembering (and reminding the systems biology folk) that it is not generally feasible to measure physiologically-relevant concentrations of drugs in live humans unless the targets are directly exposed to blood. I looked at some of this in a blog post last year:

  5. I would be surprised if they are not regulated at all although it's clear that the differences are vast. I found it remarkable that the Boeing 777 was the first airplane to be completely designed on a computer. In 1995. You are quite right about not being able to measure drug levels in real time, a fact that may be responsible for many of our woes including complex clearance and distribution events.

  6. If Hawk-Eye misses a shot, people are unhappy and money might even change hands if it's important enough.

    If toxicological studies (for example) misassign the risk of a new drug, people could die, either from taking the drug and dying of something they would not have had otherwise or dying from a disease from which the drug which failed falsely could have saved them. There are plenty of other possible mistakes, most of which are likely to be costly.

    Risk-reward is a concept not well publicized to drug users, and is difficult for any of the many groups in the field to accurately assess. You might be able to assess the risk of a drug, but reward is probably going to be specific to each user, and dependent on emotions and other factors not predictable from first principles.

    If the key inputs to drug approval are not only highly fault-intolerant but also poorly quantifiable, people are likely to be loath to change anything for fear of what could happen. We do overestimate the cost of mistakes, though, and it is a caveat that not adopting good technology for drug development and approval also costs lives - but there is a big barrier to surmount.

    1. That's correct, the liability and reward aspects are often underemphasized. And I think it's precisely this fuzzy assessment of rewards that leads drugs to sometimes be unfairly (in my opinion) withdrawn from the market. I do think that way about Vioxx for instance.

  7. Completely agree. Although Med chem campaigns are hardly holistic in terms of the SAR they want to address, likening drug development to that of air craft is belittling the wonderful complexity of life itself. If biological systems were less complex, drug discovery would have been easier and by that token all life would have been wiped out from the planet long back. It is the complexity that helps life survive all odds, so what if it makes drug discovery tough. We'll take it.


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