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July/August 2014 Issue
Last Updated Monday, September 1 2014
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CROs: Driving Research Forward



The uptick in business for CROs is a positive indication that dietary supplement and functional food companies are doing more research on their products.



By Rebecca Wright



Published May 3, 2010
Related Searches: Omega 3s GRAS Performance Regulatory
Research has been a big question mark for nutraceutical companies during the last decade for a variety of reasons—no financial incentives, no market protection, borrowing data is easier, etc. But finally, according to many experts, the industry is making progress, largely through the assistance of Contract Research Organizations (CROs).
 
Offering a bright view of the industry’s evolution, Gitte Jensen, research director, NIS Labs, Inc., Klamath Falls, OR, said today’s companies are dedicated to developing a serious research portfolio. And, despite increased regulatory action, she said, “Our clients are not afraid of exploring new concepts and I see a number of them setting new trends.”

As far as the industry report card goes, Ms. Jensen added, “I would give the industry an ‘A’ for progress, but a ‘B+’ to ‘B ’for where things stand right now. We need to protect the niche for complex foods and natural products and spend the extra money to get research designed specifically for this industry.”

Going into more detail on some of the recent hurdles, Andrew Shao, PhD, senior vice president, Scientific & Regulatory Affairs, Council for Responsible Nutrition (CRN), Washington, D.C., explained, “Some companies are beginning to get the message that ‘borrowed’ or ‘pirated’ science is not in their best interest. However, in most cases, the incentive is still not there for a commitment to invest in R&D.”

Dr. Shao also believes the narrow focus on price at the expense of quality and science continues to pervade in many circles, further undermining the long-term health of the industry.

Kelly Nichols, communications coordinator, NSF International, Ann Arbor, MI, said some of the confusion stems from label claims and terminology. “One of the major issues that the industry is dealing with is the confusion over health and label claims; over what is a dietary supplement and what is a functional food (FDA has no definition for a functional food),” she said. “These issues can be prevented by performing double-blind clinical trials on the dietary ingredient for which the health or structure-function claim is made.”

Najla Guthrie, president and CEO, KGK Synergize, London, Ontario, Canada, offered a similar view. “The biggest deterrent for conducting research in our industry is that the competition may benefit from the science our clients are paying to conduct. We advise our clients to conduct research on their finished branded products so they can limit competitors from borrowing their science,” she said.

But the reality is, according to Jillian Capodice, vice president, Nutraceutical Medical Research (NMR), White Plains, NY, research will always be necessary in order for novel, safe and effective products to be developed and delivered to the marketplace. With regard to both the dietary supplement and functional food markets specifically, Ms. Capodice believes conducting prospective, evidence-based research will likely become a crucial industry standard.

However, the tricky part with clinical work, said Doug Kalman, RD, director of nutrition research, Miami Research Associates (MRA), Miami, FL, is making sure the objective doesn’t cross the line into disease. “When you do a clinical trial on a dietary supplement that is evaluating its effects on a disease or condition, it makes that study into a drug study. Therefore, you need to file an investigational new drug (IND) application with FDA,” he said, adding, “And lately, FDA has been saying that unless you are talking about quality of life or performance enhancement, you need to file an IND.”

But before a company even gets to the clinical trial stage, it must understand how its material or products behave from a chemistry standpoint. “When planning clinicals, some companies overlook how the substance is characterized,” said Frank Jaksch, CEO, ChromaDex, Irvine, CA. “This is where there is a surprising amount of failure.”

These aren’t the only areas nutraceutical companies are coming up short. The R&D department, where research begins, is, by most accounts, understaffed and underfunded. Allocating the appropriate resources could alleviate many of the pressures companies face in today’s competitive, highly scrutinized business environment.

Skimpy R&D Budgets

R&D is a crucial part of any company’s business, whatever the industry. For one thing, it helps secure plans for the future generation of products. Unfortunately, to some degree, the importance of R&D is lost on many nutraceutical companies. Mr. Jaksch of ChromaDex explained. “There is still a fairly large disconnect in terms of what needs to be done on the research end to get products to market. And one of the reasons is that research is often improperly integrated into the R&D process.”

Currently, Mr. Jaksch estimates that nutraceuticals companies dedicate about 1-2% of revenues to R&D—which is on the high end. However, he said, “If you take the average supplement company, worth between $100-150 million, and it is making the standard commitment of 5-10% toward R&D, it should be setting aside $10-15 million per year. But I don’t know many companies that spend $5, $10 or $15 million on R&D.”

On the bright side, he said, there is a paradigm shift going on and money is coming into the industry. “Private equity companies are integrating change and reallocating budgets and putting money where it belongs.”

Another problem, said Dr. Sidney Sudberg, laboratory director, Alkemists Pharmaceuticals, Costa Mesa, CA, is that many companies are still driven by marketing, as opposed to science. “While there are some innovative companies seeking out the design and development of new compounds or products, most are just reformulating their products to get them to market faster,” he said. “The mindset of the dietary supplement industry at large is still being driven by marketing and less so by efficacy or safety. That said, cost is probably the number one barrier to moving forward on a true research project.”

Despite the money needed for clinical trials, it is essential to get these studies done, said CRN’s Dr. Shao. “Too often these studies are cut back or cut out in favor of placing resources toward marketing efforts,” he said. “What some companies fail to realize is that these trials become the marketing.”

Speaking of cost, Joerg Gruenwald, president, analyze & realize ag, a CRO based in Berlin, Germany, discussed the price range for certain types of research. “In vitro studies are the cheapest to see some first effects ($5000-$20,000 and more); in vivo animal studies are in the middle ($20,000-$50,000 and more); and clinical trials are the most expensive but offer the most value for the money ($100,000-$500,000 and more, depending on the number of participants, length of the study, parameters, etc.).”

Due to the limiting effects of price, most companies are conducting smaller studies. In fact, Darryl Sullivan, scientific director, Covance, Madison, WI, said most of the companies he works with are looking to differentiate their products in terms of quality or superiority, instead of pursuing large efficacy studies.

However, he doesn’t believe conducting a large efficacy trial would translate into wasted dollars. On the contrary, he thinks a company would actually stand in very high regard with consumers if it chose to substantiate the health benefits of its products.

Another option, according to Mr. Sullivan, is getting the industry to work together on conducting studies. “I think if there was enough investment from industry to support various product families (e.g., probiotics, omega 3s, ginseng, etc.), there would be a lot of benefit in that,” he said.

MRA’s Mr. Kalman believes the major reason companies are reluctant to sponsor direct research on their products or ingredients is that the claims they are typically pursuing are too expensive.
 
Also, he said, right now there is more reactive research going on, rather than proactive research. “I think there is a low percentage of companies looking to do studies and develop IP (intellectual property) for the purity of science. Most companies are compelled to do the research after the fact, in response to letters from attorneys or FDA and FTC.”

Where the Action is

Dr. Gruenwald of analyze & realize said there’s a broad range of companies performing clinical trials today, from ingredient companies aiming for proprietary claims, to supplement, functional food and herbal companies looking to substantiate claims. He said many are also interested in safety studies.
 
However, many experts see an increase in research activity as it pertains to functional foods. “I think there is a lot of momentum behind food becoming more functional. That train has left the station and everyone wants to be on board. And companies are throwing a lot of dollars into researching that category,” said Mr. Jaksch of ChromaDex.
 
But, he warned, “Regulators might soon make sweeping changes as far as functional food products are concerned, because they don’t seem to like the ‘tweener’ category of functional foods.”

For Alex Schauss, PhD, FACN, senior research director, Natural and Medicinal Products Research, AIBMR Life Sciences, Inc., Puyallup, WA, there is no question that a dramatic increase in R&D has shifted to the functional food sector. As a result, he said, “This places emphasis on substantiating the safety of the ingredients that go into food. In this vein, GRAS (Generally Recognized as Safe) self-affirmation will continue to be a critical milestone for companies.”
 
Offering some specifics on functional food research, Covance’s Mr. Sullivan said, “There is a lot of effort going toward changing the composition of food products with some of the designer fibers. There is also a lot of research looking into the stability of vitamins in functional foods and the wide use of pre/probiotics in cereals and yogurts.”

“There will be a lot of interesting products coming out in the next several months,” Mr. Sullivan added.
 
According to MRA’s Mr. Kalman, companies that enlist his research services are interested in probiotics, omega 3s and products that modulate stress response, followed by ingredients for anti-inflammatory applications or exercise recovery effects. And most of the studies, he said, are designed to substantiate marketing.

On the horizon, Dr. Schauss said, are new biotechnologies, or as he likes to call them, “tools that we can use to understand how components in foods favorably affect human health.”
 
For example, he said, “The field of epigenetics (i.e., nutritional genomics) is helping us to understand how genes influence ‘youth proteins’ when exposed to a food or ingredient. We’ve used these technologies to unravel the mechanisms of action on how they work in terms of genes, cell signaling, etc. This helps us understand why a functional food works and provides us information on which markers to measure in clinical trials.”
 
Finding the Right Protection


The best way a company can protect itself in the market is to know as much as possible before entering into a relationship with a CRO. CRN’s Dr. Shao explained, “First, define as best as possible what it is you need—the more well defined, the more likely you will be to avoid some of the problems mentioned previously. Also, determine the company’s stance on publication of results. For a relatively new product with little data generated thus far, companies may want to choose the conservative route of not publishing.”
 
Next, Dr. Shao said, begin the search for a CRO by using referrals from other companies and trade associations. “Choose the CRO based on your needs and the firm’s area of expertise,” he said. “Some CROs specialize in weight loss studies, others in cosmetic studies, and so on. Be sure to choose a firm that is well versed in your area of interest.”

Dr. Shao also says never go with a CRO you don’t know without visiting the facility first. “You need to see their capabilities, including staff and equipment. For example, if you intend to study the effects of your product on lean body mass, or LBM, then be sure the firm has a DEXA machine, or some other reliable means to measure LBM,” he said.

Finally, when it comes time to review the contract, Dr. Shao said be sure all the deliverables are spelled out clearly, including data capture and analysis and timeline. Also, the contract must include a confidentiality agreement, and if the company wants to keep control of the data and not publish, this should be spelled out explicitly.

Fortunately, Dr. Shao said most CROs are in business to do contract work—analogous to a contract laboratory that does analytical or quality control work for companies—and have little interest in either IP or profiting from the products on which they perform studies. In other words, patents and claims are not an issue for them.

The more important message for companies, Dr. Shao said, is that they have their IP insulated and protected as quickly and thoroughly as possible, no matter whom they are dealing with on the outside.
 
It is also important to determine why a CRO is needed. Is the need a follow-up clinical trial to validate previous results on an established product? Or is the product in an earlier stage of the R&D process, for which more developmental work is needed?
 
And what about the right to publish data—whatever the outcome—from a clinical trial? Dr. Shao says some firms include a clause in their standard contract that gives them the right to publish the results of the research. “This is often a problem for companies researching new products, where the proper form, dose, duration of use and characterization of the product have yet to be optimized. So publicizing the research findings from early versions of products can have a stimulating or stigmatizing effect (depending on the outcome) on future commercial success,” he explained. “The downside of companies keeping sole control of the data, is that studies tend to be published only when they are positive, which skews the evidence base (also referred to as ‘publication bias’).”

Where Does the Industry Go From Here?


For the future, MRA’s Mr. Kalman believes the nutraceuticals industry is headed for mandated research in the form of human clinical trials and product-specific studies.

According to Dr. Gruenwald of analyze & realize, this is already the case in Europe. “Research will be needed for product differentiation and claim support, specifically placebo-controlled, double-blind studies in humans. In Europe this is already happening and only clinically supported claims will be permitted in the future.”

The good news is many companies are realizing the importance of research, regardless of the regulatory environment. “Ten years ago there were only a handful of companies conducting research,” commented Covance’s Mr. Sullivan. “Now most large and many mid-sized companies are exploring or doing some level of research because the value is more recognized.

“The other positive,” Mr. Sullivan continued, “is that the industry is working more closely. A decade ago they wouldn’t even talk to each other.”

Mr. Jaksch of ChromaDex, who calls his company “the CRO for the CRO,” said, “The goal at the end of the day is to make a more consistent product, especially now since that is what we are getting beaten up about in the press. What you will be able to say about research in this industry in five years depends on how hard FDA cracks down and how far companies push the envelope.”

Sharing a different perspective, CRN’s Dr. Shao said, “The promise of supplements is in health maintenance and prevention. These outcomes are very difficult—in some cases impossible—to demonstrate in clinical trials. The biggest key to the future of product claims, and the industry’s ability to demonstrate the benefits of its products is biomarkers. Biomarkers as indicators of wellness and surrogate endpoints of disease are desperately needed to allow smaller and shorter (i.e., more affordable) human trials to be conducted.”

Dr. Shao feels biomarkers represent intermediate or short-term measurements of a product’s effect or benefit. Without these, he says trials are too costly and too complex. Adding to the problem is that there are currently no validated biomarkers for wellness, and there are only a handful of validated biomarkers as surrogate endpoints for chronic disease. This, according to Dr. Shao, is where the government can lend a hand.

“The government can help the process by funding the development and validation of more biomarkers. FDA is actually doing this by funding an IOM (Institute of Medicine) expert committee, whose report is due out this month; they are charged with developing a scientific framework FDA can use to validate more biomarkers. It will be a while (several years) before more biomarkers are validated, but at least this is a start.
 
“The government can also assist by developing a research paradigm that is better designed to assess the effects of nutrients and bioactives in humans,” Dr. Shao added. “Today we rely on evidence-based medicine, which was developed to assess the effects of drugs. Clearly this is not the best approach to use for nutrients and bioactives.”            



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