From Bench To Bedside

Medicinal professionals hear the phrase "from bench to bedside" quite often, and they're not talking about leaving the park bench to go home and sleep. In medical research, this phrase refers to the time, work, money, and intellectual fortitude necessary to take a medical treatment from concept (lab bench) to working, actionable treatment (hospital bedside). It's a tough gauntlet, and roughly 99% of concepts (hypotheses) fail to produce useful treatments; yet the pursuit continues as mankind endeavors to ease the suffering of the ill and injured.

In my discussions with people, there is a great deal of misunderstanding about how "drugs" or other medicinal treatments are conceptualized, tested, produced, re-tested, and then eventually confirmed to be functional in humans.

I am not an authority on pharmacy or medical practice, but I do have a Ph.D. in Biomedical Science that has given me a decent foundation on which to further my understanding of current and future medical treatments. 

So if you're interested, the following is a 10,000-foot view of the process by which a medical treatment moves from the minds of scientists into hospitals and drug store shelves.

Step 1: Hypothesize

This is the beginning of science. It applies to medical science, as well as any other pursuit of empirical knowledge. You must start here. Come up with a rational idea in light of current understanding and run with it.

Example: A naturally occurring plant product, resveratrol, causes a decrease in pulmonary (lung) inflammation due to pathogenic infection.

I have no idea whether that hypothesis is true or has even been tested--I just made it up.

Bear in mind, this hypothesis could be further broken down into more specific parts to determine exactly how the compound decreases inflammation; but usually it's best to see if there is any effect first, and then figure out how the effect is elicited later.

If further experimentation indicates that resveratrol does have an anti-inflammatory effect, then one could further hypothesize that...

Resveratrol decreases infection-induced inflammation by inhibiting the TGF-B signaling pathway and blocking upregulation of COX2.

Step 2: Experiment

This is undoubtedly the most difficult part of science. The physical labor is trivial compared to the daunting task of experimental design. To test the hypothesis, one needs to convince other experts that the correct model (cells or tissues) is being used to assess the question. In the case of pulmonary inflammation, it would probably be best to use a pulmonary endothelial or epithelial cell line. However, some folks won't be satisfied with that, and you'll need to use living tissue models (explants).

After choosing the correct model(s) to work with, the scientists will need to outline (and fund!) a whole series of experiments that will hopefully substantiate or refute the hypothesis clearly and definitively. This is also not easy, since even simple questions can be challenging to answer with evidence-based rigor. In fact, my experience with science has taught me there are more unprovable questions than there are provable ones. The burden of proof is very heavy, especially as it relates to medicine--so much responsibility!

As I parenthetically mentioned, funding a project is of paramount importance because even the greatest ideas will not come to fruition without money. In order to get money, the scientist must publish enough findings to convince people they are worthy of money. After obtaining money, they can hopefully purchase the supplies, the models, the facility access, and the personnel to perform the work.

Step 3: Interpretation

After spending tens or hundreds of thousands of dollars (sometimes millions) and countless hours on completing medical science experimentation, the next major step is to interpret the plethora of data that was generated.

A great deal of work must go into quality control and confirmation to insure the experiments were done properly and consistently. If an experiment is not repeatable, it was worthless. If you can convince peers and experts that the experiments were done well, then the data is worth careful consideration.

After considering the data, it can usually be interpreted several ways. The key of being a successful scientist is to do enough experiments with enough controls to leave very few interpretations from your data. It should be HD clear! High resolution. No vague or foggy data. This is when scientific misconduct is most likely to happen--scientists are tempted to ignore or even hide data that conflicts with the interpretation that best suits their career goals. We all hope this is a rare occurrence, and thankfully investigations have shown that scientific misconduct is quire rare.

Step 4: Application

In hopes that the experimental design was fantastic, the funding was adequate, the experiments were performed at a high standard, and the data points clearly to one interpretation, then the task of translating begins. In medical science, translation refers to moving a discovery in the lab into a functional, useful application in the medical field. This is how the discovery moves from lab bench to patient bedside.

Unfortunately, many discoveries in medical science are never translated into a medical application. That doesn't mean they are useless, because the discoveries advance our understanding of biology and allow us to push to boundaries of human understanding. But very few lab discoveries are "targetable", meaning the discovery can be used as leverage against a disease in the clinic.

After a treatment for a disease has been tested thoroughly in the lab, it must be tested in living creatures. Using the earlier example of resveratrol, if data supports the idea that it could be used to treat pulmonary inflammation, then scientists must test that idea in multicellular organisms that are physiologically similar to humans. Although many people aren't excited about this idea, those organisms are usually animals; many human medicines are tested first in mammals before they ever reaches humans.


If a discovery leads to a targetable treatment, then more funding and work must be poured into developing or modifying a treatment regimen. Pharmaceutical companies spend an average of $1,000,000,000 on the development of each drug. I did not mistakenly add too many zeroes! I mean one billion.

Step 5: Clinical Trials

Clinical trials are the time when the treatment is tested in the clinic. It involves several phases that begin with small groups of paid volunteers and continues to actual treatment of diseased individuals. This is likely the most expensive and dangerous part of developing any drug treatment.

The following paragraph is a quote from Wikipedia. I know, go ahead. Make fun.

"Clinical trials involving new treatments are commonly classified into four phases. Each phase of the approval process is treated as a separate clinical trial. The drug development process usually requires several years to complete. If the treatment successfully passes through Phases 0, 1, 2, and 3, it will be usually be approved by the national regulatory authority (e.g. FDA) for use in the general population."

Phase 0: Pharmacodynamics and pharmacokinetics

This is the first set of experiments in humans. Single doses of the treatment are administered to a small number of people to gather preliminary data pertaining to what the treatment does to the human body and how the body processes the treatment.

Phase 1: Safety screening

During this phase, scientists/physicians establish safe dosage ranges and identify side effects.

Phase 2: Establishing treatment efficacy compared with placebo

The experimental treatment is given to a larger group of test subjects to determine if it is effective on a variety of people. This phase will confirm or deny the findings from phase 1.

Phase 3: Confirmation of safety and efficacy

The experimental treatment is administered to an even larger group of people to confirm its effectiveness and determine its side effects in a broad population. The treatment will also be compared to the current standard of care for the targeted disease. More information will be acquired about how best to administer the treatment and what regimen works most efficiently.

Phase 4: Post-approval studies

After a treatment has been approved for sales, further studies are performed to gather additional information and assess risks, benefits, and optimal use. Occasionally treatments must be recalled, removed from the market, or have their regimens modified.

Another important aspect of these studies is determining how the treatments interact with other drugs, activities, and diets that individuals have. Everyone is different, and some treatments are not compatible with other drugs, activities, or diets. 

Conclusion:

It is each person's decision (as an adult) whether they want to be treated for a disease. I can understand why someone may decide not to accept treatment for something, especially if the treatment will diminish their quality of life. When it comes to chronic diseases, there are no easy decisions.

The hope is that the treatments will get better, just like they are better today than they were one hundred years ago. Progress is slow, and mistakes are made along the way; and alternatives are available to "standard" treatments. I am not against those things unless it is obvious quackery being sold as "alternative medicine". Then it's deceitful and wrong.

You might think drugs don't affect you, but this process applies to everything from NyQuil and Tylenol to experimental anti-cancer agents and new treatments for Parkinson's or Alzheimer's. I think it's helpful to understand how something was developed and tested before you swallow it or allow it to be injected into your bloodstream.

Image credits:
Guy with magnifying glass from http://k9coach.blog.com/2012/11/10/apdta-2012-investigate-behaviowur-like-a-crime-part-1/
Pills in money image from http://digito.me/resources/clinical-trials-are-going-digital/
Clinical trial flowchart from http://www.cancerevolution.info/cancer-therapies/main-concepts-in-therapy/108-reform-clinical-trials.html

Dr. Daniel Devine is currently serving as Senior Scientist I at St. Jude Children's GMP, LLC on the Production Team to manufacture pre-clinical and clinical-grade biological treatments. 

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