Contract Research Organizations (CROs) are invaluable partners for dietary supplement and functional food companies looking to make their business a lasting one by continuing to invest in research-whether it consists of preclinical or clinical trials, assessing toxicity and safety aspects of products, identifying new compounds, nutrition label generation, or supporting new product development, including overcoming technical and regulatory hurdles. Just as research organizations are diverse, so too are the sponsors seeking their services-varying in size from large multinational nutraceutical companies to small startups in search of high quality research in such therapeutic areas as immunity, cognition, obesity and cardiovascular and bone health.

According to Darryl Sullivan, senior technical manager, Food and Nutraceutical Analysis, Covance Laboratories, Madison, WI, while large companies with established "name brands" perform a great deal of contract research in order to protect the reputation of their products, companies that are in a "growth mode" through new product development are also conducting large contract research programs in order to accelerate their new product launches.

Further, both large and small companies continue to feel the weight of current and impending regulations, which Kristen Reynolds, associate director, Marketing & Sales, KGK Synergize Inc., London, Ontario, claims has led to an increase in the demand for research in the form of toxicity studies and human clinical trials during the past two years. Looking ahead, she doesn't expect this growth to diminish thanks to the dynamic global regulatory environment.

Commenting on the importance of more in-depth research in the nutra-ceuticals market, Alwine Kardinaal, PhD, senior advisor of health claim support and regulations, TNO Quality of Life, The Netherlands, says better insight into the working mechanisms of dietary compounds and the reasons for individual variation will help predict a product's efficacy and develop targeted approaches. "The continual development of new, validated re-search tools (biomarkers, computer models, humanized animal models, etc.) will help us elucidate the pathways that lead to obesity, diabetes or inflammatory diseases, which in turn will help prevent these conditions and diseases," he said.

Investigating 'Borrowed Science'

Those companies that decide to work with a CRO often face the question of "borrowed science," meaning if a company invests in a clinical trial for its product, the results of that study can be "borrowed" to support a claim for a-nother company or product. But "borrowers" beware: it is the whole/specific profile that establishes identity. Simply using one or two marker compounds that were proven to be bioavailable in the research does not mean the same health benefits will occur.

"Scientifically you cannot assert with any confidence that the outcomes of any study will be replicable for any other product even if the ingredient profile appears similar," confirms Jay Udani, MD, CPI, CEO and medical director, Medicus Research, Northridge, CA. "As we know in this industry, every plant has many different domains including soil characteristics, preparation, standardization, stability and purity, which cause a great deal of variability. Each ingredient or formula needs to be tested itself in order to prove (or disprove) its efficacy."

Some companies are beginning to get the message that "pirated" science is not in their best interest in the long run. However, as Andrew Shao, PhD, vice president, Scientific and Regulatory Affairs, Council for Responsible Nutrition (CRN), Washington, D.C., points out, companies still face an uphill battle against the fierce powers of commoditization. "In most cases, the incentive is still not there for a commitment to invest in R&D," he said. "Take for example the quality and research-focused ingredient supplier that takes years to develop an ingredient backed by safety and efficacy data. After that work is done, they bring their ideas to a few potential manufacturer customers who then go and source a similar version of the ingredient-which the consumer cannot differentiate-from some other supplier who has not done the due diligence, but who is willing to sell the ingredient for less."

For those companies who are skeptical to put research funding behind their products because they are fearful that competitors will benefit from their final data, KGK's Ms. Reynolds advises companies to complete their clinical study on the final branded product and publish the data under this branded name, rather than on one single ingredient. While she doesn't doubt the significance of research conducted on single ingredients, she does feel it is more important to substantiate finished products. "Once you add that single ingredient to any others, you do not know if that ingredient will have the same positive effect," she said.

Despite the challenges, Douglas Kalman PhD, RD, CCRC, FACN, director, Nutrition & Applied Clinical Research, Miami Research Associates, Miami, FL, believes there are solutions. "The government can help spur more research by coordinating an effort between companies, the IRS and the U.S. Patent and Trademark Office," he said. "This could trigger innovation and allow companies who sponsor research on finished products to have a set period of exclusivity in the marketplace, so that they can reap some return on investment, while helping improve the science foundation in the industry at the same time."

A New Gold Standard?

Another topic for discussion in the research community is evaluating the most efficient method to conduct nutritional research. In May, CRN brought up this topic at their scientific symposium, The Workshop, where it challenged the scientific community to consider a broader spectrum of research beyond randomized controlled trials (RCTs)-considered by many to be the "gold standard" for demonstrating the benefits of nutrients. But some scientists feel observational studies may be a better method for collecting data on dietary and nutritional supplements because they represent typical populations, typical behaviors, and how food and supplements are, in reality, used.

"We recognize the scientific rigor of RCTs, and they are certainly an important piece of the research puzzle," said Steve Mister, president and CEO of CRN, in his opening remarks at The Workshop. "But we cannot ignore all the other research-case-control and cohort studies, and other epidemiological data-as these studies often point us in the direction indicating where further research should be focused and may be just as rigorous for proving hypotheses as well as developing them. If observational studies show a benefit not confirmed by a clinical trial, that does not discount the importance of the initial studies. The totality of the evidence should not be dismissed."

Dr. Kardinaal also brought up other alternatives that can offer mechanistic insight into nutrition compared to RCTs due to ethical constraints-i.e., it's not ethical to deprive a subject of a vital nutrient just to determine which tissues are affected and how. "One example of these alternatives is the TIM model," said Dr. Kardinaal. "'Evidence-based' is the path ahead for nutrition. Part of that approach is the evaluation of the body of evidence, in which RCTs have a strong relative weight, but evidence from other type of studies may also have an important contribution."

Offered by TNO, the TIM system is a gastrointestinal model that mimics most of the physical and biochemical mechanisms of the human gut. Introduced several years ago, TIM has been improved and validated. "Recently efforts have been undertaken to make TIM a relevant predictable nutrition tool by combining it with cell-lines and in silico kinetic modelling in order to realistically predict blood plasma levels after ingestion of a bioactive," said Dr. Kardinaal.

But ultimately, Miami Research's Dr. Kalman says that it's in the nutraceuticals industry's best interest to become more familiar with the research community. "Get involved with the Association of Clinical Research Professionals (ARCP) and attend real scientific conferences such as Experimental Biology to see various forms and levels of science that you can use to grow your company," he said.

Pursuing a Research Project with a CRO

Once companies have their intellectual property (IP) protected, they should first define the main objectives of their proposed research projects before beginning a search for a CRO.

"You must understand the mechanism of action of your product and design your study so that it can test the product appropriately," said Dr. Udani. "Using an 'off the shelf' protocol may save you time and money up front, but will cost you dearly at the end when your study doesn't show the results you were hoping for."

According to Dr. Udani, it is this unclear mechanism of action that causes some products to fail. "Commonly the product was not given in a high enough dose or there was a flaw in the assumptions that were used in the study design," he said.

Once you define as best as possible what it is you need, you can then begin your search for a CRO, which as Mr. Sullivan points out, is not always straightforward. "It would be wonderful if research could be standardized at some level," he commented. "There is a huge spectrum of CROs around, ranging from very good to questionable. Many laboratories rely on ISO accreditation. While the ISO 17025 program assures that the laboratory keeps good records, it does nothing to assure the quality of their data."

Dr. Kardinaal's advises sponsors to look at the CRO's track record to determine the organization's quality of science. "You can get a sense of a company's track record by looking for publications by the company's scientists, but be aware that they may not publish all their work as some is confidential," he said. "Another way to estimate a company's scientific strength is to learn about the group leader: is the group leader/senior scientist well known and knowledgeable? Lastly, ask if a company has its own research platforms and if it invests in cutting edge research. This shows the CRO is committed to technological innovations and that the scientists know particular research areas very well." He said further that when a CRO has this deep commitment to science and extensive knowledge of the field, it is in a good position to provide the best scientific applications for a sponsor's research question.

Be sure to choose a firm that is well versed in your area of interest, as some CROs specialize in weight loss studies, others in cosmetic studies, and so on. Once you find a CRO that seems to match your needs, make plans to visit the CRO's facility. "You need to see their capabilities, including staff and equipment (i.e., If you intend to study the effects of your product on lean body mass, then be sure the firm has a DEXA machine, or some other reliable means to measure LBM)," said CRN's Dr. Shao. This is an investment after all, so it's a good idea to actually see what you are paying for.

"When it comes time to review the contract, be sure all the deliverables are spelled out clearly, including data capture and analysis and timeline," continued Dr. Shao. "Also, the contract must include a confidentiality agreement. For example, if the company wants to maintain control of the data and not publish it, this should be spelled out explicitly." For a relatively new product with little data generated thus far, companies may choose the conservative route of not publishing.
Sponsors also need to share known process information, according to Robert Morgan, president and CEO, POS Pilot Plant Corp., Saskatoon, Saskatchewan. "There is no need to repeat mistakes. It is better to build on existing knowledge and experiences," he offered.

Another issue that should be ad-dressed is speed. Quality studies take time so be aware of timelines and plan research accordingly. "One of the biggest obstacles in completing a human trial is recruitment," said KGK's Ms. Reynolds. "If you are looking for a population with very narrow criteria, this can take a very long time. Your CRO will be able to give you an idea of timelines to recruit for a study, but sometimes generating patient interest and locating those you need for a study takes longer than anticipated."

Considering all of these factors, Mr. Kalman wants companies to keep in mind that studies are never guaranteed to obtain the results hoped for, but they do offer the greatest vantage point to demonstrate the safety and efficacy of a product in the context of FDA and FTC regulations.

Money Matters

Sponsors must be realistic when it comes to monetary expectations-this especially holds true when the price of working with a CRO comes into play. Instead of viewing research as a cost, research should be seen as an investment that will hopefully lead to some sort of pay-off or return.

"Currently many companies do not blink at spending anywhere from $5000 to $150,000 in one month for advertising, yet they balk on a $40,000 or $60,000 study," Dr. Kalman commented. "The conundrum is that they need the science to defend their products and claim uniqueness to the product. They also need it to obtain IP and defend against any regulatory or litigation issues. Often the fines for not following the general rules as they now exist far exceed the costs of a few studies." Dr. Kalman recommends companies devote a minimum of 5-10% of their annual marketing budget to sponsoring studies.

Frank Jaksch, president and CEO, ChromaDex, Inc., Irvine, CA, discussed the considerable gap between what companies want to accomplish during the research process and the actual budget necessary to accomplish the goal. "Most of the time we find ourselves providing guidance to our customers to help them move a project from the 'blue sky' category to a more manageable, step wise program," he said.

Studies are priced based on their design and the complexity of the procedures and tests involved, ranging from a few thousand to hundreds of thousands of dollars, so companies need to have a clear understanding of what their budget is for working with a CRO.

According to KGK's Ms. Reynolds, a human trial can have companies paying between $1000 and $5000 per subject depending upon the parameters of the study. "The more specific testing involved (e.g., x-rays, DEXA, ultrasounds, etc.) in the study, the more expensive the per-subject fees will be," she said.

For smaller companies, the cost of human trials is simply not feasible. "For more complicated research, smaller companies tend to try to do less focused studies in collaborative efforts with research groups from universities," said Ronald Korstanje, MSc, vice president business development, TNO Life Sciences, Inc., Cambridge, MA. "This may lead to trade-offs like longer timelines and/or less research focus. This is taken for granted because of the lower price."

Ms. Reynolds points out that there are other ways a company can conduct research without investing a lot of research dollars immediately. "There are very cost effective in vitro tests and in vivo models that will give a company a good indication of how a product will perform in humans," she said. "Companies can also opt to begin with a smaller, pilot clinical trial in a limited number of subjects. While this data may not be published or considered 'statistically significant,' it may give them important preliminary information on which to base a larger significant clinical trial."

"What is most important," Mr. Sullivan said, "is what kind of value are you getting for the money you are spending. At Covance, I am often asked to repeat an analytical research project because the original work was performed by the 'low cost' laboratory, and the data were rejected."

Since cost seems to be one of the biggest roadblocks in research projects, companies should be aware that there are various funding sources available. "Companies who are looking for investors or funding avenues could consider the Nutrition Capital Network, Small Business Innovation Research (SBIR) grants, or reaching out for a joint venture with the military (DARPA)," said Dr. Kalman. "But first, a company should meet with a well-versed accountant to restructure their company to include R&D, thus making it easier to take advantage of the IRS allowable tax credits (IRS 41 and 174)."

An Outlook on Nutraceuticals Research

Due to the tremendous amount of growth in the functional food and beverage markets, a great deal of time and money is being spent on researching new and innovative ingredients. In that vein, CROs continue to receive more requests for toxicity studies, which are required to obtain food and beverage GRAS (generally recognized as safe) approval. Miami Research's Dr. Kalman has even noticed an increase in the amount of studies being sponsored by the mainstream food industry. "These studies include functional foods, specialized waters and meal plans, with Glac�au/Coca-Cola and Kraft Foods leading the charge," he said.

Mr. Jaksch of Chromadex said it is great to see the industry spending more research dollars on clinical trials, but he said there also needs to be an increase in the amount being spent on the chemistry before a product goes into a clinical trial.

It's clear that the dietary supplement and functional food industries are quickly moving toward an era in which solid scientific backing for claims will be essential. Many experts feel research will no longer be an option in the future, but rather an obligation prior to putting a new product on the shelf. As a matter of fact, Dr. Kalman feels that industry regulation will become tighter and more stringent over time and at the very minimum, companies will soon be required to conduct safety studies on their finished products.

Medicus' Dr. Udani feels the future of nutraceutical research lies in larger studies, resulting from the collaboration between sponsors and research organizations. "These studies will provide the basis from which to convince physicians to use these products alongside their pharmaceuticals in improving the health of our aging population," he said.

For the future, TNO is developing relevant analytical nutrigenomic platforms that will contribute to the understanding of the relevant physiological processes and regulatory pathways related to nutrition and the effect they have on chronic physiological developments. "Nutrition science is developing a more holistic (systems biology) approach, which will help us develop a fundamental understanding of how bioactive compounds affect physiological processes and health outcomes," said TNO's Dr. Kardinaal. "There has been very significant progress in analytical developments in this area. The current focus is on data analysis and the biological interpretation of the data from these new techniques."