From The Lab To You: Drug Discovery, Clinical Trials & The Pharmaceutical Industry

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From The Lab To You: Drug Discovery, Clinical Trials & The Pharmaceutical Industry

 Drugs have been part of human life since the beginning of recorded history. It started with the discovery of the various medicinal properties of plants. Plants, as we all know, are capable of containing and synthesizing countless chemical compounds, from powerful stimulants such as cocaine and caffeine, to the deadly neurotoxins like curare. Today, plants still yield many valuable compounds and a large portion of the drugs on the market today are variants of naturally occurring chemicals. Over the past 100 or so years, drugs are more commonly invented rather than discovered. Drug discovery in the past mostly consisted of observations of a plants effects (or a chemicals effect) when administered to a person or animal. The effects were noted and recorded with no knowledge as to how exactly that drug was working. Today, the opposite approach is taken in most cases. Instead of simply observing effects, modern drug development relies on knowledge as to how an alteration in a protein or pathway in the body could be effective against a disease. For example, if we wanted to come up with a medication to lower blood glucose levels, we wouldn’t have someone ingest a multitude of chemicals to find out which one works. Using our knowledge of the human body, we may want to find a chemical that alters a protein that regulates insulin release which will therefore help blood sugars.This description of the drug development process is of course a generalization but it gives a good idea of our current thinking behind the process. Even in disease states in which we don’t know everything about the pathophysiology (cancer for example), researchers hypothesize how an alteration in something can bring about a positive effect.  As new drugs are being developed, there are a variety of critical questions that must be answered through the course of clinical research to produce an effective drug.

 Questions That Must Be Answered When Researching New Drugs
  • Can we find a drug that has the desired effect on our intended target?
  • Does this effect on the target have the desired outcome on the disease we are attempting to treat?
  • Does it make economic sense to pursue this drug?
  • Can this drug be administered in a feasible way and is it a stable compound?

    Step 1: Finding A Suitable Chemical Compound



Most commonly, the first step of drug research is to screen millions of chemical compounds for their ability to interact with a specific molecular target or produce a specific biological response. This screening is mostly done by robotic systems that can process hundreds of thousands of chemicals. Chemicals that fit what is being searched for, or at least somewhat closely fit, are called “hits”.


It’s quite rare for a “hit” to actually become a future pharmaceutical drug. Most initial drug hits lack the absolute properties that are being looked for. In the majority of cases, chemists and pharmaceutical scientists have to synthesize derivatives of their “hit” chemical and optimize it so it interacts with its’ target and alters its’ function in the desired fashion. This of course comes with its’ own set of challenges.  The newly synthesized drug must have a high attraction to its target, it must be able to be easily administered and easily absorbed in the body, it must be metabolized safely and it must be free from major side effects.  The chemical must also be able to be produced on a large scale and have the appropriate properties in terms of stability.  Many times a chemical may have a deficiency in one area which prevents it from being realized into a marketable drug.


Step 2: Pre-Clinical & Toxicity Testing 


After our new chemical comes from the lab, it goes through general toxicity testing in two or more species of animals for a considerable amount of time. When possible, the toxicity testing is not performed in animals but very often it is necessary. The chemical will be particularly tested for its’ carcinogenicity and reproductive toxicity. If toxicity is observed, the researchers need to determine if the toxicity is due to how the drug works mechanistically in the body or if the toxicity is due to drug acting upon an unpredicted part of the body.


Step 3: Investigation New Drug Approval & Clinical Trial Testing 



At this stage in the process, the chemical that is being researched has been in process on average of 3-5 years. Only at this point can the drug company submit what is known as an Investigational New Drug application (IND) to the FDA. The IND is a request to the FDA for permission to test the drug in human subjects. The FDA has 30 days to review the application. The FDA can either approve it or disapprove it and request more data about initial safety and toxicity results. After the IND is approved, we finally move to the clinical trials. Clinical trials take place in four phases, the last of which is after the drug has already been approved by the FDA and can be marketed to patients. Below is a chart of the different phases of drug trials:



FDA Investigational New Drug Trial Phases
Phase I Phase II Phase III Phase IV
# Of Participants 10-200 50-500 Thousands Thousands-Millions
Subjects Healthy Volunteers Patients with disease being researched Patients with disease being researched Patients with disease being researched
Type Of Study Open Randomized & Controlled (Usually Blinded) Randomized & Controlled (Usually Blinded) Open
Purpose Of Phase Safety & Tolerability Effectiveness & Dosing Effectiveness In Large Populations & Side Effects Side Effects & Adherence
Length Of Phase < 1 Year 1-2 Years 3-5 Years No Fixed Duration
Cost (In $) ~$5-10 Million ~$20 Million ~$50-10 Million
Success Rate In Proceeding To Next Phase ~50% ~25-30% ~25-40%



Phase I: Phase I clinical trials are typically conducted in healthy volunteers. The purpose of this part of the clinical trial is solely to get safety and tolerability data in the human population for the first time. This phase of the clinical trial is not intended to determine efficacy, or how well a drug works.



Phase II: This is the phase of the clinical trial where things really begin to pickup and the  efficacy of the drug is trying to be established. Acceptable dosing ranges for safety and efficacy are beginning to be determined here as well. Phase II is the first time in a clinical trial that the drug in question is being tested in those in which the drug is intended for. If the medication is going to be used to lower blood pressure, it would be tested on those with high blood pressure. Phase II clinical trials are very small compared to phase III clinical trials.


Phase III: Phase III is the bread and butter of the drug testing process. It is where the most money is invested and it typically takes the longest amount of time to complete. Large scale statistical analysis is completed in this phase, typically with thousands of patients in different locations around the world. In order for FDA approval, a drug company must perform, in the words of the FDA, “adequate and well-controlled investigations”. Currently, the gold standard for clinical trials are randomized, placebo-controlled, double blind studies.


Even though the Phase III clinical trials are quite comprehensive, the requirements set forth for FDA approval has some severe disadvantages.


Disadvantage: What is a proper control?

Are placebos the best control? In many cases they are, especially if the drug being tested is a novel treatment for a disease. However, it can be somewhat misleading if an alternative treatment is available for comparison. Trials for new drugs very rarely are tested against an existing treatment for multiple reasons and unfortunately, they are often times in the best interest of the drug company. The main reason for testing against a placebo instead of an existing treatment is that the results are much more impactful. For example, let’s say a new drug was being tested for blood pressure and a study found it lowered systolic blood pressure by an average of 14 points. This would be great news for a drug company, as it shows efficacy versus a placebo, which we assume would not lower blood pressure (or would only slightly lower it due to a placebo effect). However, if the drug company tested their new drug against an existing treatment, the results would be much less remarkable. Let’s again assume our new drug lowers blood pressure on average 14 points. Let’s also say an existing treatment lowered blood pressure an average of 12 points. The trial in this case would only show a very slight improvement vs. an old treatment. Older medicatons tend to be drastically less expensive than newer medications. The fact that our new drug is only slightly more effective would spell bad news as the newer medication may very well be seen as not cost effective. Older drugs too have more safety data and physicians are sometimes unwilling or hesitant to prescribe newer drugs. Drug companies don’t want to pour in millions upon millons of dollars to a drug trial to determine their drug is only slightly better (or perhaps worse!) than an existing treatment. Again, it is very rare to see a comparative trial when a new drug is testing for FDA approval.
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