“Trust, but verify” was derived from a Russian proverb and popularized by President Ronald Reagan about 30 years ago. A human study may not be the only way to verify the health benefits of foods and dietary supplements, but current regulations suggest that firms with one or more clinical studies are more likely to have adequate substantiation. However, relatively few studies fuel the large number of supplements claiming health benefits, mostly based on science of the ingredients.
A good reason for brands to shy away from a clinical study is the cost. Some firms find that the return on investments (ROIs) are slow, and others find human studies too risky. Enough reason to put off such a decision to another year. Another major reason why firms avoid doing clinical trials may be they don’t understand the process enough.
Studies, said the FTC, must be “conducted and evaluated in an objective manner by persons qualified to do so, using procedures generally accepted in the profession to yield accurate and reliable results,” per Dietary Supplements: An Advertising Guide for Industry. Clinical studies are complex. Understanding the process better may help firms limit costs, time and risks during clinical studies. Clinical trials are costly, time-consuming and risky. But not doing studies could be costlier and riskier to supplement firms.
It’s always good to have prior info about the investigational product, such as 1) the intended serving size; 2) the most prominent expected effects, but more importantly, those that will lead to differentiated claims; and 3) the minimum time required to demonstrate the health benefit. If such data is missing, then it’s best to plan an exploratory or pilot study, which is also valuable. A pilot study may also point to the likely target group of people. These data that convince an investigator and an independent review board (IRB) to approve the study is called an investigator’s brochure (IB). An investigator or contract research organization (CRO) will not move forward if a product is not ready for a human study or if study objectives are untenable. When the study synopsis is ready with agreed assumptions, such as number of volunteers to be screened, recruited and completed in a study (sample size), the number of sites, the study variables, costs and timelines, then the contract with the CRO may be signed. It may be a long discussion with the CRO to get full confidence in a large study, but some studies are running within weeks from the first email, if study goals are clear. Writing these pre-study documents like the protocol and IB is inexpensive, but critical for success.
Clinical Trial Supplies
If the draft protocol is ready, or if the requirement for the investigational product (including active supplement and matching placebo) is clear, then the sponsoring firm may start capsulation, packing and labeling the clinical trial supplies. A statistics software may generate the randomization chart and other specific labeling critical to the study. Getting the blinded randomized trial supplies right can take one or two months. An existing contract manufacturer may be trained to comply with specific clinical trial needs.
Site Selection, Essential Documents and IRB Submissions
The CRO will select the site or, in case of a multi-centric study, several sites. Every CRO has its standard operating procedures (SOPs) for selecting the most suitable investigators or study sites, checking its experience, staff, infrastructure and current interest in taking on the study. IRBs typically require the IB, protocol, case report forms (CRFs), informed consent documents (ICDs) and investigators’ resumes as the bare minimum to consider a study proposal. Typical lead times for IRB approvals is two months, but some could take much longer depending on complexity of the project and locations.
Management of multiple activities, team members and providers requires the skills of an experienced project manager. The study needs to be insured from risks of adverse events that may occur directly due to the investigational product or otherwise. Registration of the study on one of the registries like clinicaltrials.gov brings transparency and credibility in clinical research on supplements. Local and central labs are interviewed and contracted. A trial supplies management agency may be hired in the absence of inhouse pharmacist to ensure the integrity of the supplement during the study. A statistical plan is usually part of the final protocol, but a data management plan is developed and database validated using the chosen software. Monitoring and audit plans are drawn. Clinical research coordinators support the investigators at the site. Clinical monitors ensure good clinical practice (GCP), protocol and SOP compliance. Biostatisticians, clinical data managers, lab technicians, et al., support the project manager. It is the project managers at CROs that ensure complex and unpredictable studies conclude on time, on budget and deliver the objectives. An investigators’ meeting is recommended for studies when they use more than three sites, several labs or other complexities. It helps to bring all players on the same page prior to study. Otherwise site initiation visits are opportunities for site training, query resolution and motivation. The time taken for these important pre-study activities is typically three months.
Recruitment, Data Monitoring and Audits
No study is without its surprises and challenges. Despite good planning and training, sites will sometimes go wrong in the recruitment, data collection or other procedures. Some data loss is common whereas other protocol deviations are allowed and reported. Clinical studies are run by humans on humans. Errors and omissions are inevitable. Hence CROs use multiple layers of checks by site staff, monitors and auditors as per the approved plans. A well-designed study could be fully trashed without this vigilance during implementation. Study data is often captured electronically, but paper CRFs are still not out of fashion. Some firms may ignore the value of the informed consent process. It is not just a human subject protection measure, but also opportunity to motivate the volunteers leading to better retention and compliance to protocol. Compliance to the investigational product and other trial instructions remains the biggest challenge in human study conduct. Timely recruitment of volunteers into studies is another challenge that may be overcome by offshoring the study to locations that offer speed. Typical recruitment speeds vary between one volunteer per week per site to dozens, thus meeting full requirement of hundreds of volunteers in couple of months across multiple sites instead of waiting as much as a year only for recruitment. Supplement firms must seek evidence if identified CROs performed this function adequately in their previous projects. A review of their SOPs may be useful in gauging their experience in monitoring and auditing human study data.
Data Management, Statistical Analysis and Reporting
Everyone is asking the project manager by the time the last volunteers are exiting the study, “Do you know if the supplement works?” But in a blinded, controlled study that’s impossible to know until the data is carefully collected from the site(s) and analyzed. One hears at every industry meeting some talk about “p” values and other statistical terms but there is hardly a mention of best practices in clinical data management (CDM). Just like CROs, firms specialize only in CDM. Professionals make careers only in CDM. All data from the sites and the labs must be retrieved in a credible manner ensuring zero error and allowing it to be audited later. Once the database has been locked and analyzed, the firm may require either only a study report or a manuscript to be fashioned for a peer-reviewed journal. The consort statement is one of the several guidelines that help improve and standardize clinical trial reporting for easier understanding by the reader and regulatory agencies.
Much like manufacturing GMPs (good manufacturing practices) and toxicology good laboratory practices (GLPs), clinical research with its GCPs is a process-driven function in health care. But only clinical research offers the “excitement of discovering a new health benefit.”
Jayesh Chaudhary is a co-founder and CEO of Vedic Lifesciences, a “verifiable” CRO serving the nutra industry for more than 17 years. He is among the pioneers who brought good clinical practices (GCP) and other stringent standards to natural product research.