Dietary Supplement and Ingredient companies as well as regulators have long considered double-blind randomized controlled trials (DBRCTs) as the gold standard for clinical trials. While DBRCTs clearly can produce high quality data, it is important to question the quality of the trial design, the quality of trial conduct, and finally the quality of the clinical data management, statistical analysis, and interpretation.
Clinical Trial Sponsor, Investigators, and even the US regulators often miss critical points of evaluation of Trial Data quality. There is over-emphasis on peer review and number of studies. Acceptance of clinical trial data in a peer reviewed journal is still considered as proof enough of good quality clinical data. Out of 3 pillars on which a good clinical trial stands – Design, Conduct, Analysis – the one that is often the weakest is the quality of Trial Conduct or Trial Management. Sadly, journals also focus more on the robustness of the trial design and the interpretation of the results but do not ask enough pointed questions on the Conduct. Independent Review Board (IRB) approval is only approval of design and is grossly inadequate control over trial conduct.
Look beyond US Regulations and Markets
Clinical research in the US dietary supplement and ingredient industry is expected to meet the standards of claim substantiation and truthful advertising set by the Federal Trade Commission (FTC). Unfortunately, the regulatory control by FTC of such clinical research is limited and guidelines inadequate. The FTC states that all label claims must be substantiated with Competent and Reliable Scientific Evidence from studies that are designed, conducted, and evaluated
- With Professional Expertise
- In an Objective manner
- By Qualified persons
- Using Accurate and Reliable Procedures
While the FDA or FTC do not lay down further specifications for the above requirement, we need to consider each term used there carefully and may be draw from the other guidelines for drug clinical trials available from the divisions such as the Center for Drug Evaluation & Research (CDER). FDA's Center for Food Safety and Applied Nutrition (CFSAN) in its latest document of Dec 2008 “Substantiation for Dietary Supplement Claims Made Under Section 403(r) (6) of the Federal Food, Drug, and Cosmetic Act”, stops short of what we would call adequate guidance.
But why go the extra mile when FTC is satisfied with the current level of science behind our ingredients and products? Research sponsors can best answer this individually based on their international sales aspirations. The companies that will survive the ongoing consolidation in the dietary supplement industry will be forced to become more global, suggests Jeremy Zhou, a senior analyst and director of healthcare at market research firm Revere Data, San Francisco, CA. “Sales for a successful company will have to be geographically diversified,” he said. “Herbalife, as a good example of this, derives 27% of its sales from the EU and the Middle-East/North Africa markets, 18% from Mexico and Central America, 20% from North America, 14% from South America and 21% from Asia-Pacific.”
If US companies wish to make health claims and compete in the international markets, then their supporting evidence for safety and efficacy needs to stand tall in front of tougher regulators like Health Canada, EFSA (EU) and TGA (Australia). Health authorities across the world are now concerned with the credibility of clinical evidence that is being presented to them for making health claims for foods and supplements.
Whatever the global business and regulatory plans of a firm, before investing in costly national marketing and communication programs for the brand, brand managers and top management need to be assured that they have high quality due diligence in place. A well-conducted, well-powered GCP clinical trial is the best assurance that can be offered on the probable market success of a new Nutraceutical brand. Nobody can deny this common business sense.
Once a clinical trial sponsor has decided to invest only in high quality clinical trials, the next obvious question is what this good quality is. In the rest of this article, we shall be previewing the definition of the terms GCP, good trial design, good conduct, good reporting, etc., a detailed review of this subject being beyond the scope of this paper.
Good Clinical Practices (GCP) is GXP for Clinical Trials
If one is told that a trial was compliant to GCPs by International Conference of Harmonization (ICH) and was audited by an independent group, then there is not much more to be asked about the quality of the trial. ICH-GCP encompasses various requirements from design to reporting of human trial data. The US, EU, and Japan are signatories to this universally accepted guideline for clinical trials. While GCP compliance requires dedication and discipline across the entire study team, the approach is simple and logical to a person skilled in the science. Basic tenets of GCP include trial subject rights, ethics, documentation, maintaining an audit trail, and independent monitoring of data. The largest number of audit findings FDA has when they audit drug trials are related to lapses in ethical conduct of the trials. One may wrongly conclude that since dietary supplements are safe and don’t pose the kind of risks that drug trials do to the trial subjects, it is all right to have slightly lower standards of ethical review of trial conduct. In the eyes of the regulators or experienced auditors, even minor concerns regarding the ethical treatment of trial subjects may completely jeopardize the entire study or at least data coming out of the specific study site. Such is the importance laid on subject safety, rights, and confidentiality by GCP and by the Declaration of Helsinki.
Regulations can help in Clinical Trial Design
A good start is a job half done. ICH-GCP elaborates on the roles of the Independent Ethics Committee (IEC), the Investigator, and the study team of the Contract Research Organization (CRO). However, the study protocol and related documents actually can sometimes decide how well the study has been designed and eventually the probable fate of the study. Some clinical trials are doomed to fail from start due to faulty or over-ambitious protocols. There is a wealth of information, regulation and guidance available from FDA, EMEA, ICH, etc that can help in study design. Sample size calculations, selection of subject population, treatments assignment, dose selection, efficacy outcomes, statistical planning and analysis, data management, and report writing are just some of the areas that sponsors need to be concerned about when designing trials that will stand up to the scrutiny of the authorities.
Registration of the Clinical Trial makes Research Transparent and Credible
Clinical Trial Registry is as critical a prerequisite to clinical data acceptance by the scientific community as is IRB approvals and GCP. However, trial registration is still not widely prevalent in the supplement industry. Some sponsors obviously fear adverse publicity of potentially negative trial outcomes. Others are simply unaware about trial registration as an important credibility and transparency tool.
A CRO brings in “Objectivity” that is required by FTC
Going back to the FTC statement on clinical study quality, the element that is prominently missing is “objectivity” in trial design and conduct. Our observation of clinical trials for Nutraceuticals over the last one decade confirms our view that sponsor firms are unaware of the importance of a statistical plan set forth upfront in a study protocol, the criticality of a robust informed consent process, clinical trial site monitoring by personnel independent of the site, source data verification, third party audits, compliant data management, statistical analysis using Good Statistical Practices by a third party, and trained biostatistician, and finally the evaluation of the tables and graphs by a person with no conflict of interest in the product being studied. Objective trial conduct assumes greater significance in the light of the fact that most supplement studies measure the quality of life of the human subjects in the trial. If studies are not fully objective then errors or even intentional manipulations are likely to affect credibility of data. A CRO independent of the investigator’s site adds great value here. All these factors, if taken care of, can add enormously to the objectivity and transparency of clinical trial data. If trial conduct and evaluation lack this objectivity, then none of the other conditions listed by FTC (qualified and competent persons using accurate and reliable methods) matter much.
Clinical Research is a Marathon not a 100m Sprint
It must be noted here also that some sponsors do not understand their product fully, know little about its pharmacology or mode of action, dose-response relationship, possible side effects, etc., yet want to straightway embark on full blown “publishable” clinical trials. It doesn’t work that way. Clinical research is a set of experiments conducted in series, each one with a specific purpose that the other cannot serve. To expect one single clinical study to meet all the expected objectives may be unreasonable from a biological study involving human beings. Such expectations will only lead to a sponsor poorer in terms of R&D dollars and time/opportunity, and a frustrated CRO/Investigator. Clinical Development Strategy is a specialized subject, but it would suffice to say here that supplement brand-owners should consider clinical research for their brands as a marathon rather than a short sprint.
Globalize Your Clinical Trials
Quality costs, but it pays back. In fact good quality research does not necessarily require millions of dollars but a little bit of specialized training and mostly plain common sense. It’s best for supplement companies to focus on their core strengths of marketing and sales, and leave the R&D to experts like CROs. Clinical research in North America and Europe is expensive due to large number of on-going drug trials here. In contrast, Eastern Europe, Russia, China, and India offer the advantage of lower cost clinical research due to larger drug naïve patient pools and trained investigators. The drug industry has for long managed larger trials either partially or completely outside of the USA. Recognizing the need to offshore clinical research, the FDA has always allowed foreign clinical data to be submitted towards a New Drug Application as long as the data meets certain simple criteria. (FDA Guidance for Industry on Acceptance of Foreign Clinical Studies, March 2001)
When top players are facing pricing pressures and consumer losing faith in unproven commodity offerings, the worst decision that an industry can take is to curtail its innovation programs. Consumer confidence can be regained only by offering something that is novel but more importantly proven to be effective. Consumer can no longer be misled season after season with “clinically proven” labels using half-baked clinical research. It does not pay in the long run and the industry is now paying a price. It’s a wake up call.
In conclusion, a message for the industry: Raise the standards of Clinical Trial Conduct. Limit the cost of Innovation, but not Innovation itself. Build Credible Evidence and then build Brands. Offshore if needed.
Jayesh Chaudhary is Founder & CEO of Vedic Lifesciences, a CRO with offices in Redwood Shores, CA and Mumbai. He can be reached at jayesh.chaudhary@vediclifesciences.com
