Clinical Research: Twenty years of GCP

Historical Perspectives

The FDA adopted the Good Clinical Practice (GCP) as a standard for conducting all clinical research in April of 1996. That is just 2 years after the passage of DSHEA. The USA, along with EU and Japan, is a member of the International Conference on Harmonization (ICH), which sets mutually agreeable research quality standards for these and most other countries. Any biomedical research carried out as per the ICH standards gains instant global recognition. Thus FDA-GCP or ICH-GCP becomes the gold standard for the design, conduct and reporting of studies involving human subjects whatever be the regulatory objective – pharmaceutical, device, functional food or dietary supplement. This year we are celebrating the 20^th anniversary of GCP and for this reason it is timely to reflect and contemplate.

Why Choose to Perform a Clinical Trial under Good Clinical Practice?

GCP is a quality standard or guidance for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance

1. That the data and reported results are credible and accurate
2. The rights, integrity, and confidentiality of trial subjects are protected.

GCP serves the best interests of everyone. GCP is truly akin to GMP for product manufacturing, where GMP ensures the highest quality for consumers, reduces manufacturing errors and improves productivity and profitability for the manufacturer. Ensuring volunteer rights, safety and privacy in a clinical trial is unequivocal. No-one would argue against these protections for subjects enrolled in a study.  However, GCP's economic value to supplement companies is greatly underrated. This article explores why this is so, and makes a case for VALUE for GCP certified clinical trials within the nutraceutical industry.

Current state of GCP in the Nutraceutical Industry

Despite the 20 years of GCP, most nutritional or dietary supplement studies struggle to meet the GCP standard.  Why? Most likely it is because of several factors:

• Limited number of CRO choices. Increased competition would raise the standard of the offering
• Economics. Most nutraceutical companies who do clinical trials have a tight budget
• Ignorance.  Because they do not routinely conduct clinical trials they are unaware of the standards and regulations that surround them. GMPs are encountered daily, GCPs maybe annually, at best.

That’s such a pity because sponsoring clinical research that does not meet GCP fully, maybe a sheer waste of money. If a manufacturing facility falls short of quality standards, chances are that the product on the shelf may reveal the true story in the form of poor packaging or unstable product. There may be recalls. However, in the case of a non-GCP clinical trial, no one ever may know what happened behind the scenes. There is no physical evidence like a failed product, just an unreliable clinical study report or confusing published paper.

Publications

Most academic journals will accept data from a study that was seemingly designed and reported well. But what about actual study “conduct”? A good plan is only half the job done and it still needs perfect execution. Neither authors, nor peer review groups lay sufficient emphasis on proper trial conduct thus leaving gaping holes for the data credibility to fall through.

So what criteria do academic journals look for in clinical research papers? Most journals expect as a bare minimum - review by an Independent Review Board (IRB), registration of the protocol with a Trial Registry like clinicaltrials.gov and even adherence to CONSORT. But none of these assures quality standards in trial conduct. There can be a wide gap between study design and study conduct. There is also a growth in “lesser” journals where even these standards are lowered, and GCP is even more remote as an entry requisite. This creates some confusion. Unless a company has skilled researchers in-house these nuances may be lost. Moving down to the public it may be even less apparent.

So the better (prestigious) journals are moving in the direction of GCP as a prerequisite for publication, while the explosion of lesser journals is creating a mixed message on the quality of the publication. There are groups that scrutinize supportive research where measures like GCP, are very important, and that is the Federal Trade Commission (FTC) and to a lesser extent the FDA.

Federal Trade Commission & Food & Drug Administration

To date the Federal Trade Commission (FTC) has largely passed the buck to peer-reviewed journals for evaluations of claim substantiation and study conduct. The FTC views clinical support from publications in lesser journals as being largely inadequate.  By contrast, they readily accept results published in journals with a track record in peer review and quality. Their focus is on the quality of the work and not where the research was conducted. This is a common misunderstanding within the nutraceutical industry. However, within the system, GCP may be slip through the cracks of peer review, where the focus remains on design and data.

The FDA routinely inspects clinical trial sites all over the world for compliance to the standards, when data is submitted for drug approvals. However, since dietary supplements don’t require pre-marketing approval, any GCP inspections by FDA are ruled out.

The Marketing of Clinical Trials

The dietary supplement consumer has a limited understanding of clinical trials, either their design, results, statistical evaluation and their quality standards, but nevertheless they are the affected party. Clinical trials are largely used for marketing purposes in the nutraceutical industry, shoring up marketing claims and acting as a differentiator from the competition. There are some circumstances where they provide depth to patents but largely they are vehicles for enhanced product marketing.

There is a strong trend in recent years on improving consumer education and connectivity by increasing transparency both in terms of the product, its potency & purity, as well as sourcing. The obvious next steps are to improve transparency of product support and claims as it relates to GCP and clinical trials. If a company has made the investment to perform a clinical trial then it needs to be forward-thinking as to how that trial will be used. GCP is a gold standard that assures the trial will be well performed, with exemplary ethics and review, all of which are highly marketable attributes in the world of transparency. So the bottom line is that GCP in clinical trials has rich marketing potential.

Raising consumer awareness about GCP could become a strategic option for differentiating label claims in an otherwise crowded space. A GCP clinical study assures the consumer that the claims are truly credible and that the rights and safety of the trial subjects were fully protected during the research that was conducted on them. Overall, a GCP study ensures that frivolous research is minimized and only that data is collected which was originally planned and no more.

Clinical Trial Design: The Value Proposition of GCP

A human trial should be conducted and continued only if the anticipated benefits justify the risks. The current market perception is that all randomized controlled trials must have a placebo-control group but there are a number of examples where this is not acceptable. Case in point, it is easy to appreciate that a study assessing joint pain for example cannot maintain trial subjects on a placebo for extended periods of time if there is no rescue medication or if for example, the protocol demands that pain is induced by exercise stress. Similarly, unproductive and unsafe trials are required to be modified or terminated early so that trial subjects may switch to better options promptly. As US-based companies are increasingly looking at more favorable destinations in Europe and Asia to offshore supplement studies, ignorance of GCP requirements may mean that the interest of human subjects are not fully safeguarded by the Contract Research Organization (CRO) or medical institution involved.

Clinical Research: Potential Conflict of Interests

Why do we think that most nutritional studies are non-GCP? For the most part, trials on dietary supplements are run by doctors in medical schools or by CROs providing a turnkey solution including recruiting trial subjects. But therein lies the problem. When the institute or organization that is managing the study is also performing all the duties of the investigator, there is a potential conflict of interest.

GCP lays emphasis on the need for monitoring and auditing of all trial activities. Which means that all activities at the investigational site e.g., screening subjects, informed consent, randomization, follow-ups, etc., must be performed by a person or persons different from the monitoring and auditing teams. We find that this basic principle is often violated in most dietary supplement studies either due to lack of awareness or due to budgetary constraints. To put it simply - an investigator cannot QC his own work! The same concept is in play with GMPs.

Separating Roles & Responsibilities

Separating these roles between sponsor of the study, monitoring and auditing agency versus the investigational site(s) has numerous benefits.

• Maintaining confidentiality
• Protecting the identity of trial subjects, randomization code, proprietary information of the investigational product, etc.
• Allows for studies to be easily performed at multiple sites (multicentric), which in turn can result in an expedited trial & lowered costs.

So separating these roles and distancing the players is quite important. Multi-centric trials score much higher in terms of speed, costs, data credibility and confidentiality than single center studies. However, multiple sites are possible only when study is being managed by one centralized agency, which also oversees the whole project but is not investigator themself. This is not common in studies done for dietary supplements in the US. With all subjects coming from a singular trial site, there is no “competitive recruitment” possible and no chance to incentivize better performers. Sponsors remain at the mercy of such investigators even if they get busy or unavailable due to unforeseen reasons or if credibility of data from their site becomes questionable due to any reasons.

Protecting the R&D Investment

The ICH-GCP guidance has been around almost since DSHEA. Certainly there is a buzz around the new NDI notification draft guidance that has been released recently. However, sponsors of clinical studies have not yet recognized the value of GCP, and how it can add to their studies. For example, deviation from a study protocol, however carefully designed, is inevitable in most studies. Criteria set for screening and recruiting volunteers, allowances for deviations in their follow-up visits, allowances for consumption of investigational products and other compliances to protocol are all easy to lay down in a protocol but ground reality at the site may differ. Investigators may find some protocol stipulations too restrictive for reasonable progress of the study. In other cases, there may be urgent changes that may need to be effected without contacting the sponsor. In both cases, its only the sponsor of the study who knows their product best and which deviations to allow and which to reject. GCP sets the standard clearly regarding communication of protocol deviations by investigator to the sponsor’s representative such that there are no surprises in the end. It is not totally unexpected that a site that has been left unchecked can actually end up recruiting a completely different type of population despite the protocol specs! This may render the clinical study to be essentially worthless.

What are the Characteristics of a GCP-Compliant CRO?

ICH E6 (GCP) holds the Sponsor of the clinical trial responsible for upholding data quality and for audits to ensure that study is being done as per the standards. Most studies may take a year or longer to complete. Without standards and measures that are subject to audit, the clinical study may wander away from the objectives. So look for these features when shopping for a CRO:

• A detailed Sponsor-CRO contract. If the contract does not explicitly state roles & responsibilities it must not be assumed that the CRO is equipped to conduct a study specifically compliant to ICH-GCP (E6).
• Maintaining recruitment quality at the site(s). This is no easy task. It may entail multiple visits to the sites as recruitment happens and investigational product is dispensed.
• Site monitoring. Also a demanding task, which the study sponsor may not be qualified to handle given that it requires fair degree of training and experience. GCP requires independent confirmation that assessments of trial subjects is done as per protocol and that there was no bias or missing data. Sponsors can however delegate this work to a CRO.

GCP compliance for all human trials is the way forward for dietary supplement and ingredient-makers to protect their R&D investment and also differentiate their studies from competition. The value of GCP has been hidden from the industry for long. It is time to unlock this potential.

Mark J S Miller is the Chief Science Officer & VP, Marketing for Healthy Directions, a health and wellness company & was a Medical School Professor for 3 decades.