Discussion: Does evidence-based medicine come before science?

A discussion about a recent post from Dr. Vinay Prasad on rethinking medicine.

*Cover image from Premedfaq

Dr. Vinay Prasad posted an interesting article yesterday that has got me thinking:

Rethinking Medical Education: Evidence First, Biology Later

It’s a very short piece so I would argue that people take a look and see what they think.

Prasad’s perspective is a rather interesting one, with the crux of his argument suggesting that medicine has focused too much on the perspective of science such as biology rather than evidence-based medicine which may be more inclined towards hard data:

Here's the rub: when we instill a deep-seated reverence for biology before introducing the principles of evidence-based medicine, we're setting up our future doctors for cognitive dissonance. It's harder to accept that a treatment doesn't work when it "should" according to biological principles. As a result, evidence that contradicts our understanding of biology is often met with skepticism, even outright rejection. This is a disservice to our patients, who ultimately care about outcomes, not biological plausibility.

This brings us to the crux of our argument: the need to revamp the medical curriculum. Let's start with the history of medicine, the triumphs, and the pitfalls. Next, introduce the principles of clinical trials, the linchpin of evidence-based medicine. Show students examples of medical reversals, such as the Cardiac Arrhythmia Suppression Trial (CAST), where our understanding of biology was turned on its head by clinical trial data. Such an approach will underscore the importance of evidence over theory, preparing our future doctors to prioritize patient outcomes over biological dogma.

As a layperson my position on this matter will be far different than Prasad’s. A practicing physician will have far more insights that someone who worked in science (even in a clinical setting).

I’m curious what people’s thoughts on this argument are. Again, the post from Prasad is only a few paragraphs long. You can stop here and provide your own opinion, and I’ll provide my own below to add to the discussion.

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My Thoughts

Over the past few years my thoughts on medicine have changed rather dramatically. All the way back when I was in college I thought about going to medical school, although I didn’t think that would be a good fit for me and decided to pivot, eventually wanting to head towards pharmacy school and eventually turned towards research.

As is the case for all undergraduate pre-med students, there’s a ton of science prerequisites that need to be taken including some form of biochemistry, organic chemistry, and physics.

I’ve come across plenty of pre-med students and friends who made the same arguments that Prasad had- why should I take a whole year of organic chemistry if I’m going to practice medicine?

This argument, from my perspective, is a completely disjointed argument, as if to argue that medicine somehow does not relate to the field of organic chemistry in any matter.

The perspective of medicine focused on treatment may, on the surface, be an appropriate endeavor. However, at the same time such an approach focuses more on the what rather than the hows and whys of medicine.

That is, I would argue that medicine has focused far too much on dealing with symptoms without actually detailing what medications do, or describing what processes are occurring in relation to a particular disease.

Strangely, I would argue that modern medicine may be dictated by a prevailing notion that neither doctor nor patient may be informed as to how a drug works (i.e. its mechanism of action), and is one of the reasons why adverse reactions, contraindications, and long-term health complications are not known until too late.

Take, for instance, the fact that there are over 11 different classes of antihypertensive medications as noted by the American Heart Association, which each one having a different mechanism of action.

Would a clinician, with the intent of helping deal with someone’s high blood pressure, know exactly which antihypertensive to choose from this broad list? I don’t have any evidence to make such an argument at this time, but I wouldn’t be surprised if the approach is to rely on what others have used, or what the physician has prescribed in the past.

I started writing about COVID medications because I kept hearing that people were conflating Molnupiravir with Ivermectin as being similar in structure and thus mechanism. It’s quite apparent that this isn’t the case from a quick glance at these molecules, and so I found it rather strange that such remarks came about.

Molnupiravir became the first drug I covered, and although this article was very outdated it at least made note of the possible mutagenicity of Molnupiravir.

I won’t make any claim of being the first one to comment on the possibility of mutagenicity with respect to Molnupiravir, however at the same time this article was published many people were looking more closely at the clinical trials and overlooking this possibility of mutagenicity.

After several months people were focused more on the initial results from Merck’s clinical trial showing a relative hospitalization and mortality reduction rate of nearly 50%. It was only after some time that people started raising criticisms of the possible mutagenicity of Molnupiravir, even though the evidence was right there in the structure of the molecule (hint: if you mess with base-pairing in a nucleoside analogue you’re likely inducing mutagenicity. This is seen in other mutagenic nucleoside analogues as well).

As an aside, there were remarks early on as to why an antiviral for Influenza only licensed in Japan was not being examined for SARS-COV2. This drug, Favipiravir, is also a mutagen, and likely one of the reasons why the use of this medication as an antiviral was limited across the globe aside from countries such as Japan.

Some evidence has suggested¹ that Favipiravir likely operates as a mutagen for SARS-COV2, and likely raises the same concerns held with respect to Molnupiravir.

Because of this lack of understanding a drug’s mechanism, many people may rely solely on clinical trials (and generally poor ones at that) without understanding what a drug actually does.

It’s apparent that early examinations of Molnupiravir should have raised this concern, and now that Molnupiravir has been used in some regions there’s some concerns that Molnupiravir use may be inducing further mutations in SARS-COV2. This concern was even brought up when Molnupiravir was being examined by the FDA Committee Meeting.

In this regard, knowledge of Molnupiravir, and a basis of hypothetical models may provide hesitation and restraint prior to the widespread use of a drug. A quick understanding of the drug’s structure would relay some information with respect to its mechanism of action, and thus lead to some concerns with use in humans.

Rather than argue that medicine has focused far too much on science, I would argue that medicine seems to try to delineate itself from scientific principles, in much the same ways that I witnessed during my undergraduate years where pre-med students found no need to take basic scientific courses even though the drugs they will prescribe or the diseases they will diagnose will rely on both basic and complex understandings of science.

A pre-med student turned medical resident who neglects science would fall into the trap of prescribing Molnupiravir without being aware of its mutagenic properties.

In contrast to Prasad’s arguments, science provides a hypothetical model that one can build upon. It allows people the ability to falsify or verify a proposed model prior to the adoption of such a model for clinical practices. Science is not just making guesses, but providing a framework to which one can build off of. In that regard, science is an approach to truth seeking and sensemaking, while evidence-based medicine may operate under the basis that the truth or the underlying science has already been settled.

And if I were to find a crucial point of contention in Prasad’s argument I would consider this sentence:

Patients don't care about the biological mechanisms; they care about what helps them get better, regardless of the underlying science. That's the crux of our argument today.

This position is one that likely gatekeeps medicine from the patient, in that it infers that the patient may be too ignorant to understand, or even attempt to understand, the complexities of health and disease.

One may argue that patients may not care about biological mechanisms, but it’s also true that patients have been demoralized and disincentivized to care by mechanisms that try to dumb down information in a palatable manner to patients. Or put in a more crass way, patients are led to assume that they should be spoonfed information about their own health in the most simplistic forms rather than take a proactive stance that engages curiosity and critical thinking.

If COVID has taught us anything, it should have taught patients that they should be more informed self-advocates for their own health. In order to have a proper discussion with a doctor, patients need to have the knowledge base and curiosity that drives them to seek out answers.

So from my perspective it is not that doctors start from a scientific basis before evidence-based medicine, it’s that medical students aren’t properly provided the critical thinking skills to tie science in with the practice of medicine. It is almost like asking doctors to recognize patterns without providing them the tools for pattern recognition. Bret Weinstein and Heather Heying have argued that most people, including researchers, don’t understand how to formulate hypotheses, and I would argue that this does appear to be a widespread issue. Also, note that a theory and a hypothesis are not the same, even though hypothesis has been conflated to an extreme degree in much the same ways that the word literally has become synonymous with figuratively.

More doctors should have an understanding of science rather than less.

Hopefully I made my position clear, but I’d like to hear people’s thoughts on the matter. Note that some of the comments in Prasad’s post have made remarks with respect to “following the science” or arguing “what a woman is”. People are free to make any comment they choose, but I encourage people to provide more meaningful comments that add to the discussion.

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1. Zhao, L., & Zhong, W. (2021). Mechanism of action of favipiravir against SARS-CoV-2: Mutagenesis or chain termination?. Innovation (Cambridge (Mass.)), 2(4), 100165. https://doi.org/10.1016/j.xinn.2021.100165