Historically, the nutraceutical industry has relied heavily on “borrowed science,” noted Gitte Jensen, PhD, research director, NIS Labs, Klamath Falls, OR. However, more companies are conducting their own clinical studies to strengthen marketing claims and reinforce their regulatory standing.
Dr. Jensen said NIS Labs has seen sizeable growth in clinical studies over time. “We run a full-fledged immunology lab. Fifteen years ago the majority of our work (about 90%), was lab work documenting mechanisms of action in vitro and 10% clinical studies. Today, although our lab is much busier, the balance between lab work and clinical studies is 30/70 and the majority of the lab work is on samples from the clinical studies.”
Requests have also increased steadily in the past five years for Miami Research Associates, Miami, FL, a subsidiary of QPS Holdings, LLC, according to Douglas Kalman PhD, RD, CCRC, FACN, director of nutrition and applied clinical trials.
Companies might invest in clinical work for a variety of reasons, he said, including exploration and interest in potential uses of products/ingredients, regulatory concerns, intellectual property (IP) purposes and to substantiate claims and/or differentiate products.
Alexander Schauss, PhD, FACN, CFS, senior director of research, AIBMR Life Sciences, Puyallup, WA, noted two types of companies that approach research from opposing points of view. “Many companies are investing in research and claims substantiation because they have either experienced enforcement action by federal or state agencies, or have seen the cost of not doing so,” he said. “Then there are those who have spent progressively more over the years on research and sound R&D, and factored in that cost to ensure that they can withstand scrutiny.”
Dr. Jensen agreed that proactive companies are motivated to conduct research as part of a strategic marketing plan. Strong clinical data can appeal to consumers and help keep product lines relevant.
As natural products have become more mainstream, she added, consumers have gained more knowledge. “There is a certain segment who wants to understand what they are consuming and companies need to be able to address that through testing and clinical trials.”
While the number of clinical trials being conducted in the nutraceuticals industry has grown over the last several years, “it’s still actually quite low compared to the number of products on the market,” said Jay Udani, MD, CEO and medical director, Medicus Research, Northridge, CA. Overall though, “there have been significant improvements” in the quality of studies conducted in the nutraceuticals field, he added, primarily because there are more studies in the first place.
Most of the companies Dr. Udani has seen pursue research are suppliers of proprietary ingredients that are looking to differentiate their products from commodity ingredients and charge a premium. “They want to be able to give their customers (finished product manufacturers) the ability to make more specific claims, rather than generic structure/function claims.”
While many companies still only pursue clinical validation in response to regulatory challenges, others are being proactive and seeking clinical data before going to market. “That’s the biggest change in the last few years,” said Dr. Udani. “We get approached more now with pre-market materials to test, because companies know when they go into the market they need to be able to differentiate themselves.”
However, many companies still only pursue clinical research when faced with a regulatory challenge, according to Jennifer Andrews, MSc, marketing manager, Nutrasource Diagnostics, Inc., Guelph, Ontario, Canada. “Too many companies are already selling products and are getting in trouble from regulators for making drug-like claims. Completing the steps in the right order is very important.”
Companies can save substantial amounts of money and other resources if they conduct research and validate their products before going to market, she said.
Value & The CRO Advantage
Validated research is an indispensable tool, noted Joshua Baisley, HBSc, associate director clinical development, Nutrasource Diagnostics, Inc. “Clinical trials have become instrumental in substantiating claims and differentiating products in the marketplace. Recently, there has been increased interest in proof of concept studies researching potential effects in indications where there may be limited research in humans.”
Companies with research to support their products have a unique marketing positioning, he added, as formula-specific data offer significant value in a competitive marketplace. “Companies are becoming more innovative with combining active ingredients to achieve synergistic or complementary effects,” he added. Other companies are examining how their product performs as an adjunctive therapy to prescription drugs.
“There has also been recent interest in companies repositioning dietary supplements as drugs, which has driven not only clinical research, but also pre-clinical research due to the greater regulatory requirements associated with drug development,” said Mr. Baisley.
Dr. Kalman also noted greater interest from large pharmaceutical companies and consumer packaged goods companies in sponsoring original research.
Overall, continuing regulatory changes are pushing nutrition science to an increasingly higher standard, according to Christiane Alexander, PhD, business development, analyze & realize GmbH, Berlin, Germany. The EU’s Nutrition and Health Claims Regulation (NHCR) is forcing manufacturers to invest in clinical trials if they want to pursue a proprietary health claim. “This goes hand-in-hand with the fact that companies want to create USP (unique selling proposition) values for their product and to show what makes them stand out against the competitors. These USPs can be taste, health benefits, image improvement or health claims.”
Scientific and regulatory standards for foods and traditional herbal drugs have become more stringent, she added. “Today, traditional herbal drugs have to be produced according to GMP standards, which involves strict requirements for the characterization, standardization and stability of products.”
On the other hand, Dr. Alexander continued, “claims on food have to be approved by the EU commission according to the NHCR. This involves drug standards for nutrition trials wishing to demonstrate health effects. The medical food legislation is being revised and currently appears to many companies to be a black box as to what kind of products will be able to survive in this category.”
Many CROs offer specific experience in working with natural products. Efficient recruitment, quality in logistic procedures, sample and data handling, as well as statistical knowhow are all essential to a successful trial, noted Dr. Alexander. Regulatory expertise is also necessary. “Therefore, in particular for companies with limited regulatory resources, combined service providers that have in-house knowledge of clinical and regulatory aspects that work in teams to develop optimal trial designs are strongly recommended.”
As a “one-stop shop,” services may include product concept development, clinical trial planning, result generation and regulatory submission, she added. “An important aspect is guaranteed fulfillment of high-quality assurance standards including good clinical practices (GCP), and specific regulatory requirements.”
The implementation of a quality management system based on standard operating procedures is important for meeting regulatory standards. CROs have qualified procedures in place for sample and data handling, use qualified statisticians for protocol planning and data analysis, Dr. Alexander noted. “A CRO’s prime concern is meeting sponsor budgets and timelines. Therefore, CROs have adequate recruitment and operational methods in place that allow for efficient inclusion of subjects into the clinical trial and conducting the trial according to plan.”
Dr. Kalman concurred, saying the CRO advantage typically includes speed of execution compared to an academic university or teaching hospital setting. “CROs tend to be faster in start-up and execution,” he said. “Both are governed by the same FDA IRB (institutional review board) oversight rules. CROs also hold the advantage of not looking to own your data; universities typically want to own the study data and any discoverable IP, whereas CROs have no general interest in that.”
Dr. Udani noted that experts at CROs may be more familiar with regulatory requirements such as structure/function claims and investigational new drug (IND) requirements than universities. “If you run a study on a disease population, according to FDA guidance, you have to file an IND, even if you’re not going the drug development route. I’ve seen several cases where universities have run trials without knowing that or have filed INDs with or without their sponsor’s knowledge.”
Dr. Schauss said CROs like AIBMR retain highly skilled staff who understand the nutraceutical industry and its requirements. “Their guidance can save tens of thousands of dollars or more. They know what studies should cost and who best to place the studies with. They can perform important monitoring services to ensure that the client’s money is well spent and projects completed on time.”
Process & Fundamentals
Gathering existing data on the product and/or ingredients is the first step to help develop an initial claims-driven, strategic research plan, said NIS Labs’ Dr. Jensen.
“Sometimes there is enough data to jump directly into a clinical trial. In many cases though, it is prudent to start with some in vitro testing, followed by a pilot study or maybe even a very basic proof-of-concept study. Laying the proper groundwork helps maximize the chance of getting robust data that could be used for manuscript writing, marketing and regulatory purposes.”
Dr. Schauss advised companies not to take shortcuts. Unfortunately, he said, his staff has reviewed poorly conducted studies that would cost much less if performed by well-established laboratories and research sites. “It can be a painful experience for them to learn the money they thought they saved was wasted and the results don’t actually survive the scrutiny of knowledgeable scientists and regulators.”
Before going down the clinical trial path, companies must first establish the safety of a product or ingredient. “There are specific assays and in vivo studies that can be carried out to determine safety. Also, have a company such as AIBMR perform a thorough literature search to establish what is known about the ingredients. AIBMR maintains one of the largest natural products/nutraceutical research libraries in the world, managed by a full-time information services director. Sometimes a literature search performed in our library will reveal a wide range of published research that can’t be found in popular databases or search engines.”
Most often, Dr. Schauss said, his company will recommend that a pilot study be carried out before investing in more expensive controlled clinical trials. This can save companies money before deciding to proceed to randomized, double-blind, placebo-controlled clinical trials.
Nutrasource’s Mr. Baisley noticed that more companies seem to understand the importance of planning and not rushing a clinical trial. “Previously, many companies focused on timelines and budgets. While these remain important, there is more of a realization of the costs involved and that increased efforts at the outset of a clinical trial, during protocol development, including contingency plans, can increase the probability for a successful trial.”
Prior to conducting clinical research, companies should secure a few things, he said, including a realistic budget, the actual product (i.e., ensuring manufacturing plans won’t delay the trial), as well as a list of desired claims (both scientific and marketing).
“Many times we see a disconnect between the scientists and the marketing group within a company when it comes to deciding what they want to say about a product,” said Mr. Baisley. “The timeline also needs to be thought through. Is the timeline realistic and in line with when the data is needed? Typically clinical studies, depending on their length, can take close to a year or more from the time the contract is signed to the final report. This of course is dependent on the duration of the study period.”
Dr. Alexander said the right study population and group size need to be established first and foremost. Inclusion and exclusion criteria are also vital. Appropriate duration as well as the adequate choice of study parameters and endpoints need to be established. And for subject-reported outcomes, validated questionnaires must be used for trials in support of registration procedures.
Dr. Kalman noted fundamentals to study design include (and are not limited to): “understanding how to determine sample size, understanding power, having the right pre-planned statistical methodology, knowing how to ask the right question(s) that are translated into the study objectives/outcome objectives, knowing how to specify clearly just whom comprises the inclusion and study exclusion criteria, having the right grasp of what the statistical analysis means within the study design, and perhaps in the larger field of related research.”
After running more than 250 studies over 15 years, Dr. Udani has developed a “Theory of Natural Health Product Clinical Trial Design,” which includes three steps.
Step 1 involves the identification of a healthy or at-risk population—as opposed to a disease population. For example, he said, “in joint health studies you can’t enroll patients with osteoarthritis (OA). Instead you can identify people who are potentially at risk for OA. They have joint pain when you stress the joint, (running/exercise), but don’t meet criteria for OA.”
Step 2 involves reducing as many of the secondary variables as possible that could affect the primary endpoint. For example, in a joint health study, if a patient is taking fish oil, that might affect the primary outcome and researchers would need to control that or account for it in statistical analysis. In addition, researchers need to apply standardized stressors and protocols whenever possible, Dr. Udani said. In the joint health study example, an OA population will have pain at rest, while a non-OA, healthy, at-risk population will likely only experience pain when stressed.
“So we have developed and validated a standardized protocol called the Stepmill protocol in which we put people on the stair climb machine and try to induce a standard level of pain and discomfort in the knee. This is how you see the separation between active and placebo for dietary supplements in non-disease populations.”
Step 3 involves the selection of endpoints that are relevant scientifically, to regulators, and also to consumers. “If I’m looking at measuring circulating levels of inflammatory cytokines, it’s very unlikely a consumer is going to understand that on a package. But if the package instead says, ‘Patients in a clinical trial were able to run on a stepmill 15% longer after using this product,’ that is something they will understand and is relevant.”
Developing validated assessments and protocol standards has been a challenge for clinicians working in the natural products field, Dr. Udani added. For instance, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is a validated method for evaluating OA patients, but not healthy, at-risk populations. “Some questions are meaningless for an aging Boomer who gets knee pain when they exercise,” he said. “We can include standard models but we have had to come up with and validate other models as well so that we have the ability to obtain data that’s meaningful from a structure/function standpoint.”
Dr. Alexander noted that health effects of nutraceuticals are often more challenging to prove compared to drugs. Eating, smoking and exercise habits are all confounding factors that trial participants need to report and researchers need to control. “After all, nutraceuticals are contained in foods and eating is an emotional event. Therefore, attitudes and cultural differences can play a role in accepting or liking the idea of taking a certain product, which may affect recruitment.”
Defining the best outcome measure and test panel for a natural product can also be a challenge, according to Dr. Jensen. “In some cases it might be prudent to consider a pilot study before proceeding with a full randomized, controlled trial. This can help to ensure that the type of response, timing of response, and magnitude of response is defined, and can guide the study design for the full trial.”
According to Mr. Baisley, when designing and conducting clinical trials, researchers are challenged to define inclusion and exclusion criteria “that balances the need for speed of recruitment while providing a population most likely to benefit from the therapy being researched.” Additionally, clinicians must understand all the claims the sponsor wishes to make or evaluate, from both a scientific and marketing point of view.
Researchers need to understand designs and endpoints accepted by industry and regulatory authorities, he added. “Much of the published literature is often the latest and greatest science available, but may not be accepted by regulatory bodies, as they are much slower to react to industry shifts.”
What may appear to be a sound design based on recent research could in fact impede success of defending or achieving a company’s claims, Mr. Baisley said. “Conducting clinical research without regulatory insight can be financially devastating to a company. Regulators assess claims based on the body of evidence. Depending on the goal of the trial, it may be advantageous to conduct systematic reviews according to regulatory guidelines in advance of, or at the same time as, protocol design to mitigate any shortcomings or contradictory evidence in published literature.”
Ultimately, study outcomes must be objective, verifiable, valid and defendable among scientific peer-review, said Dr. Kalman. “Sponsors sometimes have beliefs about their product and the challenge is translating beliefs into a valid scientific approach to evaluate the product. Other limitations can include study budgets (not all sponsors understand the time and costs that go into running a proper clinical trial). One other challenge is that not every ingredient or product fits the standard interventional model typified by the randomized, double-blind, placebo-controlled clinical trial.”
The Future of Research
While the high cost of clinical research has traditionally been a prohibitive factor, Dr. Udani noted that technological advances are helping to bring costs down, in some cases 30-40%.
“We have been designing and running virtual, remote clinical trials for 4 years,” he said. “We use mobile applications to collect clinical trial data. It’s right in alignment with Apple’s new ResearchKit. Our platform works on IOS and Android, and we have run 25 studies using a Systematic Mobile Application system.”
Trial participants can download applications that track compliance at home, he explained. Through a patented technology system that visually records a person taking their pill, researchers can keep tabs on patients without actually seeing them in the clinic. This also allows researchers to recruit patients all over the country faster than they normally would, Dr. Udani noted.
“It lowers the overall cost structure for clinical trials in dietary supplements to a point that’s more affordable for most of our sponsors,” he said.
A weight loss study using the virtual research model, for example, was about 30-40% less expensive than an in-clinic version. “The overall cost structure is much more efficient through the use of technology.”
As for emerging areas of research, Dr. Udani said cognitive health is a significant growth area. “We have validated systems for running computerized cognitive function tests remotely where we do proctored telemedicine visits. We take over the patient’s computer and run the system on their computer with them and record the whole sequence.”
In the context of an increasingly aging population, Dr. Alexander agreed that brain health and cardiovascular health are gaining particular importance. “Innovative dietary solutions tested in a clinical environment are obviously an emerging need.”
In addition to testing new ingredients with high bioavailability, she said common nutritional products like high-quality waters and teas have demonstrated strong physiological values. “Another trend is to better understand the mode-of-action of foods or food components by which they achieve health effects.”
As a trained immunologist, Dr. Jensen said she has been excited by a large cross section of products and structure/function claims related to the immune system, which is integral to most regulating and repair functions in the body.
“A surprising number of natural products trigger physiological changes almost immediately, such as through aroma or physical contact via mucosal membranes, and responses may be measurable within .5-3 hours of exposure to the product. These responses may also lead to cumulative effects, thus providing both immediate and long-term benefits.”
She also noted emerging science behind “natural support of stem cell biology, in contrast to more invasive and artificial stem cell transplants. Stem cell nutrition is a modern term for many adaptogenic natural products with deep roots in traditional herbal medicine.”
According to Dr. Schauss, there is an emerging appreciation for the epigenetic effects of dietary supplement ingredients on gene expression. “The application of transcriptome analyses in molecular studies during clinical trials is becoming a promising tool.
Transcriptomic signatures serve as useful biomarkers in evaluating the effect of consumables in terms of both health promotion and disease prevention. Pathway analyses of expressed genes can identify changes in lipid metabolism, cell adhesion, immune function, blood glucose homeostasis, etc. that can provide insight into mechanistic pathways involved in disease prevention.”
Mr. Baisley acknowledged that probiotic research has been increasing with better understanding of the gut microbiome and its importance to gut health, where absorption and metabolism occur. “This area of research is exciting from both a scientific and regulatory standpoint, as establishing normal ranges or normal shifts in the microbiome is a science in itself due to the host’s individualized flora.”
Sean Moloughney is the editor of Nutraceuticals World. He can be reached at email@example.com.