Although the concept of botanical quality has existed for a very long time, the word “pharmacognosy” (the name for the scientific discipline related to the study of medicinal plants) was not coined until the early 19th century. Both the concept and the science originally revolved around commerce as local collection of fresh plant-derived medicines yielded to trade in dried and otherwise processed plant materials from distant lands.
 
An article by Douglas Kalman in the June issue of Nutraceuticals World (“Research Process: Research at Your Own Risk”) got me thinking about the role of research in the world of dietary supplements. Because I work at the world’s largest funder of basic biomedical research, the U.S. National Institutes of Health (NIH), I had some difficulty wrapping my mind around the concept that well-conducted clinical research might not be in the best interest of the supplement industry.
 
Dr. Kalman raised some interesting and thought-provoking points about regulatory and philosophical issues surrounding supplement science, but I won’t talk about any of those here because this column is called “Quality Focus” and I am a pharmacognosist, and not a clinical researcher or regulator. I will briefly discuss the Investigational New Drug Application (IND) process, but even that will be in the context of the science of quality.
 
Before I begin, I’ll provide a bit of background. As we read about the results of the latest herbal studies, it’s difficult to imagine that clinical trials are a relatively recent invention. James Lind is considered the first investigator to use control groups in his work on scurvy in British sailors in the mid-18th century. The word “placebo” was first used in 1863 and the idea of randomization was first introduced in the 1920s. All of these concepts came together for the first time in 1948, when streptomycin was evaluated for the treatment of tuberculosis using a randomized, placebo-controlled, double-blind trial (RCT) design. What these bits of trivia tell us is that concerns about botanical quality are older than the accepted norm for the conduct of modern clinical trials (RCT), even if we only start counting from when the word “pharmacognosy” was coined.
 
It’s ironic, then, that reviews of the methodological quality of herbal clinical trials have concluded there are often major deficiencies in the reporting of quality descriptors in the materials and methods sections of clinical trial publications (i.e., the pharmacognosy bits). Among the first researchers to take a systematic look at the issue were Dr. Peter Wolsko and colleagues in 2005 (Am. J. Med. 118:1087). In addition to other findings, they reported that only about 49% of the 81 studies they reviewed provided the Latin name of the plant used for the study, only 10% reported the plant part used, only 15% performed any kind of chemical analysis on the herbal product and only 28% gave any information about the extraction or other processing methods used to make the finished product. Other investigators have found similar shortcomings. Despite the omissions noted by Wolsko and others, the design of the clinical portions of many of the publications they cited were very good as judged against standard scales for rating trial reports.
 
Fortunately, both clinical trial design and pharmacognosy fall within that field of human endeavor called “science,” which by definition is evolutionary. Thus, Newton is supplanted by Einstein, microscopy by plant metabolomics, and poorly-designed trials by well-designed trials. An informal, non-systematic literature review I conducted in preparation for a lecture I gave this year found that descriptions of interventions do seem to be improving, especially in the top-tier medical journals.
 
What INDs Require
 
Now that I’ve provided a bit of background, I can loop back around to INDs. I won’t talk about the regulatory or other controversies surrounding INDs. Instead, I will focus on just one small part of what IND’s require. Yes, as Dr. Kalman noted, IND submissions are laborious and do require a lot of paperwork. Most of the IND documentation is about safety and preliminary evidence of efficacy and mechanisms, but much of the labor and paperwork are related to documentation of the quality of the material to be studied.
 
The purpose of an IND is to assure the FDA you know as much as possible about the material that will be studied before giving it to humans—healthy or otherwise. The FDA requires extensive CMC (chemistry, manufacturing, control) information prior to approval of the IND. This is the part of the application that requires you to document specifications for identity, plant part, extraction and processing techniques, approach to standardization, assurance that there aren’t undeclared drug or hazardous contaminants (lead, aflatoxin, DDT), etc. You also have to tell FDA in detail how all these specifications are evaluated and about how you make your finished clinical product, so the agency is reassured that when it approves your new drug you will be able to make your product the same way every time. For complex natural products, I’d argue that this last concept is pretty important. It would be bad to have a product that sometimes doesn’t work as expected because it’s too weak, is sometimes over-potent, and is just right other times. In essence, the CMC section of an IND application can serve to lay the groundwork for future GMP when the drug is approved and goes into production.
 
I’ll break out of my botanical bias for just a second and note that in the world of pure synthetic drugs, FDA requires that IND applicants investigate whether or not reagents and byproducts used in the synthesis of the new chemical drug may carry over into the finished drug substance. The toxicology of these impurities, as well as their identity and quantity, are just as important to the “chemistry” part of the CMC documentation as are those of the target drug substance. The ability to understand exactly what is important to safety and efficacy of the product is rightly deemed critical by FDA. Just as important is the ability to control those critical factors during production and across time, thus chemistry, manufacturing and control.
 
Regular readers of this column (and I am one of those) should find some of this information familiar. While FDA might require considerable detail in the CMC section of an IND submission, elements such as raw material identification, finished product testing, purity, master manufacturing records, etc., are all elements of dietary supplement GMP. What’s more, the National Center for Complementary and Alternative Medicine (NCCAM), our sister organization at NIH, has developed and published a product integrity guideline http://nccam.nih.gov/research/policies/naturalproduct.htm, which investigators must follow if they wish to get botanical research funding from NCCAM. These guidelines, too, will be familiar to readers, as they essentially ensure that investigators know as much as possible about the nature and characteristics of the material they wish to study and to assure NCCAM that the investigators know as much as they claim to know.
 
Summary
 
I’ve touched on several themes here, but all eventually come back to one point: The principles that define quality are pretty much universal. There are some key elements of natural products that must be known, evaluated and controlled in order to guarantee consistency and overall quality. Identity, purity, strength and composition are all there. So are specification setting, evaluation against specifications, master manufacturing records (although they may be called something different in each setting), validation, “scientifically valid,” fitness for purpose, process controls and “Great Mountains of Paperwork.”