Part 1: The Evolution of the Clinical Trial – Is Ethnopharmacology the New Frontier?

Today’s American consumer is accustomed to the protections provided them by The Food and Drug Administration, protections that ensure the medicinal products we are exposed to are pure, safe, and effective.

However, the current model of consumer protection applied to medicinal products has been, and continues to be, a product of evolution of knowledge, attained over time.   In this two part series, we are going to look at how and why the system of testing our medicines under clinical conditions came to be (Part 1), and what the system may come to look like in the near future (Part 2).

The FD&C Act: A Brief History of Time

In 1906, Congress passed The Pure Food and Drug Act, in response to public outcry after publication of an exposé written about the meat processing industry.  For the first time Americans realized that they could not be sure that anything they purchased for consumption was what it was advertised to be, and that the manufacturing process had not contaminated the product in any way.
Until this point in time, the following was a typical advertisement for a medicinal product:
1906: Manufacturing and Purity
The Act of 1906 required that manufacturers take precautions to ensure that products contained only what they intended them to, and that the act of processing them did not introduce any foreign components.  This protection was provided largely by introducing regulatory inspections of processing and packaging plants.  Government inspectors could now enter these plants and confirm that products were purely what they said they were.
However, time passed, and the American public came to realize that something could be pure and deadly.
In 1937, there was a rash of deaths of children who ingested a legal and pure elixir of Sulfanilamide.  This product was purely what it claimed to be, and the acts of processing and packaging it had not contaminated it in any way.  Why then did 107 American children die?  Because the product contained a mixture of diethylene glycol and sulfa, a deadly combination better known today as automotive anti-freeze.
This pure substance was deadly.
1938: Clinical Testing and Safety
In response to this experience, Congress moved again, creating in 1938 The Federal Food, Drug and Cosmetic Act. This time, prior to allowing legal sale of a product, the government required that the safety of medicinal products be proven to be safe, and not just pure.
This was the birth of the Clinical Trial, but it bears little semblance of today’s version of the Clinical Trial. The methods of, and requirements regarding, clinical experiments studying the result of administering newly developed medicinal products to humans, prior to approving them for general use, has been constantly evolving since that time. In the late 1950s Americans had another infamous experience with a legal, pure, and safe product.  The horrific effects of that experience come to mind today when anyone hears a reference to “Thalidomide” babies.  Thalidomide was a product prescribed to combat nausea, and it was proven to present no danger when ingested.
What happened?  The number and nature of birth defects increased dramatically for children exposed to Thalidomide in utero.  What had that to do with Clinical Testing?
Regulations did not include limiting use of a product to a patient demographic that resembled the clinical trial subject demographic.  In short, the drug was prescribed for pregnant women experiencing morning sickness, but the safety tests had not been designed to test the effect of administering the drug to pregnant women, or to study the impact consumption may have on an unborn child.
1962: Clinical Testing and Efficacy
The government adapted our protections again in 1962, passing another act that expanded the requirements and standards applied to Clinical Trials, requiring that the trial data be used also to prove efficacy; for the first time, relating the nature of the clinical data to limitations posed on the future use of the product.
Today’s collaboration between industry and regulatory protection generally follows this path:
  •  Research begins in a laboratory, seeking to identify the physical realities of disease and condition and to identify potential synthetic (pharmaceutical) or living (biopharmaceutical) entities that could interfere (e.g., to inhibit or reverse)with those realities.
  • Once a structure shows promise, development work begins, attempting to identify formulation and delivery options.
  • Once formulation and delivery options are evaluated, they are combined into therapeutic candidates and administered to animals under controlled and strictly regulated conditions in order to establish toxicology (safety) profiles.  These are referred to as pre-clinical studies.
  • Once pre-clinical studies are complete, the manufacturer hoping to gain a license to sell the eventual product develops a clinical protocol, detailing:
    •   How participants (subjects) will be chosen
    •   What dosage will be used
    •   How the new drug will be administered
    •   How long treatment will continue
    •   How the subjects reaction to the product will be monitored
  • If the U.S. FDA agrees that the plan for clinical testing is as safe as possible (e.g., no obvious riskswere observed during the pre-clinical testing and the protocol is capable of recognizing a safety issue as early as possible in the test), then Clinical Trials, as we know them today, begin.
Clinically testing a medicinal product is a phased process:
  • Phase I: The studies test the therapy on a small number of people and focus on the identification of any indication that the product poses a safety risk, and also seek to determine the most appropriate dosage.
  • Phase II: The studies will have a longer duration and will expand the subject base to include several hundred patients, as they seek to demonstrate effectiveness of the therapy.
  • Phase III: The studies will have an even longer duration and expand again to include thousands of people in order to confirm effectiveness and monitor safety and side effects.
One of the most critical aspects of development of a Clinical Trial protocol is the determination of how subjects will be selected.  The more stringent the selection process, the more precise the results.  However, as required by the act of 1962, the criteria restrictions we choose to impose in this step, will also be imposed on the availability of the drug once it is approved for use.
Current State: Clinical Testing – Results are a Function of the Health of the Subject + the Nature of the Product
Some research studies seek participants who have the illnesses or conditions that the therapy has been developed to interfere with, while other studies use generally healthy participants in order to observe the effect of a therapy on a representative person. Regardless of how subjects are selected, the following is always true:
How a drug is metabolized, how it performs in a clinical trial, and how the bodies of people in the clinical trial respond to the drug will determine the drug’s future use.
Currently, when studies seek to include and exclude subjects based on per-determined criteria, the criteria is relevant to their condition and/or diseased state.  The assumption being, that all else is equal.  We assume that the effects observed for the study subjects will be representative of the effects realized by the entire population.
Frankly, we assume that the way in which people respond to the drug in a clinical trial is a function of the combination of the disease state and the product designed to interfere with it, or the healthy patient’s state, and the therapies ability to enhance it.
As an industry, we may be starting to challenge those assumptions.
Be sure to check in with the blog next month for the 2ndpart of series; an evaluation of what may be the next stage of evolution of the Clinical Trial System – Ethnopharmacology.
© Coda Corp USA 2013. All rights reserved.
Gina Guido-Redden, Chief Operating Office. [email protected]
Corrine R. Knight, Director of Business Initiatives, [email protected]
Coda Corp USA
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