Features

Contract Research Organizations: Partners in Science

By Sean Moloughney, Editor | June 3, 2013

With more nutraceutical companies realizing the value of conducting clinical trials, CROs can help navigate rough regulatory terrain.

If taste is king, directly influencing the fate of foods and beverages in today’s nutraceuticals marketplace, then research may be the knight in shining armor, escorting dietary supplements down the road to success.

Traditionally, cost has been a prohibitive factor for many companies that simply can’t spare the resources to conduct research in-house. Today, more companies are realizing the value of supporting their products, and business, through science. Due in part to new regulatory requirements, increased scrutiny from government agencies—and industry self-regulators—along with other pressures, the research landscape has shifted substantially in recent years. Increasingly, contract research organizations (CROs) have stepped up as capable partners.

The Value Proposition
The quality and volume of research conducted in the nutraceuticals industry continues to improve, according to Bibiane Zakaria, director of sales and client services, KGK Synergize Inc., London, Ontario, Canada.  “The majority of the research I see today can be characterized as high-quality research. We have seen an improvement in the quality of research because it is held at a higher level of scrutiny and regulatory requirements than it was 15 years ago. We are now expected to have randomized, controlled trials to substantiate claims.”

Although dietary supplement manufacturers and ingredient suppliers still need to conduct more research overall, the volume of clinical trials is increasing, according to Robert Patton, vice president of business development, Clinical Research, SPRIM America, San Francisco, CA.

And while companies face legitimate challenges in attempting to validate their products through science, there is great value to having supporting research. “Companies many times still see clinical research as a necessary evil or a huge cost and don’t see the marketing and regulatory power to performing such,” Mr. Patton noted. “Clinical research protects the company from unnecessary liability and provides marketing fire power to aggressively penetrate the market, increase sales and provide key insights to the product to fuel new intelligent innovation.”

Clinical research shouldn’t be viewed as a “necessary evil,” but rather a “cornerstone” to future success, he added. “There is a direct relationship between the level of research performed and a company’s success on many levels.”

Dr. Kevin Maki, chief scientific officer, Biofortis USA, Addison, IL, said he doesn’t believe the cost of research has been preventing companies recently from moving forward with their scientific agendas. “In the past six months, there seems to be renewed interest in clinical research—or at least a higher level of confidence in the economic environment—that is allowing for research studies that might have been on hold to be given the green light.”

Additionally, he noted that dietary supplement sales have continued to grow in the area of 5-7% over the past several years while the economy was in a recession, perhaps giving companies the confidence to move forward with strategic research plans. “Spending money to continue building a growing business is a pretty good bet.”

In terms of quality, Gitte Jensen, research director, NIS Labs, Klamath Falls, OR, pointed to an improvement in scientific tools and methods, which has allowed research in general to expand into increased understanding of biological and physiological functions.

“This increased ability to answer questions about specific mechanisms of action extends to the studies of dietary supplements. In contrast, the increased demand from regulatory agencies for clinical studies is pushing research dollars toward simplified clinical studies to back claims, and less money is spent on innovative exploration to understand underlying mechanisms of action.”

Increased demand for clinical trials has led some companies, eager to substantiate an existing product claim, to “bypass a logical plan for how to build a solid research portfolio,” Dr. Jensen continued. “Some companies feel pressured to conduct clinical trials to back existing claims without necessarily doing pre-clinical due-diligence work, or to take the time to conduct exploratory pilot studies in humans. This is unfortunate, because pre-clinical data and exploratory clinical pilot studies can help design a successful placebo-controlled trial.”

Still, regulations that require greater clinical validation to prove safety and support health claims have helped spur a trend toward more advanced research, said Jennifer Andrews, manager of corporate branding, Nutrasource Diagnostics, Guelph, Ontario, Canada. “While there is currently a large collective body of research for many dietary ingredients to support their overall safety and efficacy profile, many products contain new or novel ingredients, or a combination of several ingredients, that have not yet been researched. Products like these often require higher standards of evidence with product-specific, randomized, double-blind, placebo-controlled clinical trials.”

Mr. Patton said he expects more companies will get on board with the trend toward more research not only because of regulations but also a “growing understanding and acceptance of the tremendous value of clinical research.”

The CRO Advantage
The benefits to working with a CRO are plentiful, and outnumber the costs, according to KGK’s Ms. Zakaria. “Within a CRO, you are gaining the experience and expertise from a number of individuals within a team. CROs are experienced in working with a number of indications, regulatory agencies, products and markets. This experience allows them to incorporate the sponsor’s needs and to design and execute a high standard clinical study.”

CROs base recommendations on collective expertise, she added. “As a result, the sponsor does not have to hire experts in every area of the trial process, which has a great impact on the overall cost. It is also important to keep in mind that the CRO is dedicated to the sponsor, and the study. Often a CRO will dedicate a project manager, a clinical study coordinator, a clinical trial monitor and numerous support staff to ensure the study is completed on time and budget. This in turn allows a faster approach to marketing the product.”

Pam Coleman, president of Biofortis USA, said CROs fulfill a variety of needs. “In some cases, the speed of our service is a primary driver. I like to say we have scientific rigor at the speed of business. We can get studies started quickly—usually in half the time that it would take at an academic center.”

Other clients are more concerned about confidentiality, she added. “Since we are a private organization, we highly value confidentiality as well. We don’t have any qualms about agreeing to intellectual property requirements, which can be an issue with university-based research. Finally, our track record of completed studies and scientific publications garners respect and credibility. This would not be possible without our highly skilled scientists and clinical research staff.”

NIS Labs’ Ms. Jensen said the major advantage to using a CRO is ownership of data. “It can be difficult to get a contract with a university while protecting intellectual property rights. One drawback used to be that independent CROs without university affiliations were seen as less credible; this is no longer a major stumbling block, in part because many CROs are actively publishing good studies in the medical literature.”

Most CROs are able to move projects ahead in a focused and efficient manner, without a lot of bureaucracy, she added. “When shopping for a site to conduct a study, evaluate previous studies performed by that CRO, and review their publication record. A site visit is a good idea to ensure that you understand the onsite laboratory and clinical capacity, to ensure that you feel confident that your study is in good hands, and that your data are being collected in an optimal study environment.”

Ms. Zakaria said that sponsors sometimes shy away from working with a CRO thinking that the cost is higher than working with an academic institution. “One of the major drivers for a sponsor to partner with an academic institution is the association with an expert in the field at that particular institution. One way to address that would be to have the expert from the academic institution consult on the protocol and publication of the study. This allows the expert to advise on the study and provides for the study to be conducted efficiently and in a timely manner.”

SPRIM’s Mr. Patton said CROs gain economies of scale to keep costs low by performing many studies for multiple clients throughout the year. “Given the volume of research at a typical CRO, it allows them to attract and retain very high quality clinical research professionals who coordinate and perform the research, as the work is varied and very stimulating to the professionals. This provides for very high quality data from a team that is not distracted, like many academic centers are with multiple priorities, but is focused on your product and the protocol at hand.”

CROs exist as an objective third-party, for the most part free from bias, Mr. Patton added. “They are contracted to perform the research, which they do very well with high scientific integrity. They usually don’t have a financial interest in the product or sponsor, so they can remain unbiased as to the results the research produces. Bottom-line: CROs are able to provide very high quality research, delivering a pristine set of data results at the conclusion of the study, in a very cost competitive manner.”

Regulatory Pressures
The European Health Claims regulation that took effect in December 2012 limits the statements marketers can make about their products. However, companies can still apply for individual health claims, the Article 13.5 and 14 claims, which require at least one European Food Safety Authority (EFSA) approved, product-specific study substantiating the claimed effect.

Joerg Gruenwald, president of analyze & realize ag, a Germany-based CRO and business consulting company, said working with an experienced team focused on clinical research can help manufacturers overcome regulatory hurdles while also developing mid- and long-term strategies to protect their brands.

“Solid research will help companies differentiate their products from the rest of the crowd,” he said, as going through the process of conducting clinical trials communicates to the public that the company is invested and focused on developing high-quality, high-value products.

“Obviously the claims requirements in Europe are very high, as EFSA standards are fairly stringent.” So if a company wants to make the investment to obtain a stronger claim for its product it makes sense to partner with an expert in the field.

Industry has run into roadblocks with EFSA, which has rejected the vast majority of health claims applications. However, over the course of time, Mr. Gruenwald predicted the relationship between EFSA and industry will improve. “With more applications and trials going on we will better understand what EFSA wants and they will understand what is feasible. It can be done, and it will progress.”

Regarding the progression of research, Mr. Gruenwald noted a change in the type of companies looking to validate their produts. “We’ve been working with more ingredient suppliers than finished product manufacturers lately, which has been a shift in the past few years.”

Acknowledging the growing need for well-conducted research in Europe, two clinical research companies, Foodfiles and Naturalpha recently signed a strategic alliance to establish CRENnet (Clinical Research Experts in Nutrition Network), which claims to be the first pan-European network for running clinical trials specifically dedicated to nutrition and health products.

CRENnet will perform nutrition studies in its three clinics located in Sweden, France and Finland, using high quality standards and procedures. “This collaboration opens a great opportunity for both of us to set up multicenter studies using professional sites in Europe and top level regulatory know-how,” said Johan Olsson, CEO of Foodfiles.

The groups intend to carry out studies in a cost-effective, quick and efficient manner due to a deep understanding of national and European regulations, including dossier requirements; recruitment capacities with more than 12,000 volunteers; and accumulated experience over the past two decades. With 200 studies already conducted between the groups, the companies have particular expertise in major health areas such as gut health and metabolic disorders.

“We are very excited about the idea of building up this new network with Foodfiles, which will further improve the visibility of our companies in Europe,” said Stéphane Postic, CEO of Naturalpha. “Combining our expertise will allow our industrial partners to get the best from their innovative products.”

According to KGK’s Ms. Zakaria, increased regulation in Europe and increased oversight in the U.S. has impacted research both negatively and positively. “On one hand, the regulatory agencies have limited our industry to using healthy populations for all studies. The positive impact though, is that there is now a higher recognition of the need for research. As a result, nutraceutical companies are now conducting clinical trials to substantiate the claims being made on their products.”

However, more companies need to follow suit, she added. “Unfortunately, there are still many products on the shelf that do not have the scientific evidence to substantiate the claims being made.”

Cheryl Dicks, associate director of quality assurance, Nutrasource Diagnostics, said enlisting a CRO can help eliminate issues with interpreting regulatory guidelines, choosing the right regulatory pathway, liaising with the appropriate government divisions and executing a successful plan for market launch. “Experienced regulatory professionals know how to best navigate the R&D and regulatory pathways smoothly from beginning to end and can work through the inevitable (and often unanticipated) bumps in the road to get your product on the shelf quickly and successfully.”

In the U.S., the dietary supplement industry has seen an increase in regulatory scrutiny for product-specific clinical research tied to health claim substantiation by the FDA and FTC, leading to high-profile class action lawsuits and an increasing number of Warning Letters, noted Rodney Butt, director of project management and quality systems, Nutrasource Diagnostics.

“The goal of this enforcement,” added Nutrasource’s Ms. Andrews, “is to ensure that all marketing, advertising and promotional initiatives for a product or brand (including company websites and social media) are not misleading to the public. As a result, companies both large and small are now looking to gain high quality, product-specific clinical trial data to support their product’s efficacy and marketing claims.”

Big Pharma’s Entrance
Increasingly, large pharmaceutical companies have been entering the nutraceuticals industry through acquisitions of dietary supplement companies. So what impact will this entrance have on the state of research?

KGK’s Ms. Zakaria said the effect will be positive. “They will bring into the nutraceutical industry higher standards when conducting clinical research on nutraceuticals. In order for pharmaceutical companies to market and sell their products, they are required to prove both their safety and efficacy. They will conduct the necessary clinical research to substantiate the claims being made, and in order for their product to stand out from the competition. In order to compete, nutraceutical companies will need to invest in quality clinical research.”

The quality bar is being raised, according to SPRIM’s Mr. Patton. “These (pharmaceutical) companies look at clinical research as standard operating procedure, and they have the budgets to conduct the RCTs that help them reach their desired end points.”

NIS Labs’ Ms. Jensen cautioned “if true thinkers and innovators are involved this may be an interesting and positive merge. Meanwhile, I fear that cookie-cutter study designs that shape research behind pharmaceuticals may invade the nutraceutical market. Distinctly different study designs are needed to document whether a blood pressure lowering drug works in a hypertensive population, compared to a nutraceutical product that is to be tested in a non-diseased population, and often has multi-faceted and highly complex mechanisms of action. Complex nutraceuticals and blends thereof are not drugs.”

As pharmaceutical companies expand their portfolio to include dietary supplements, a new hybrid model has begun to emerge, according to Nutrasource’s Mr. Butt.

“The standards in place in the pharma world are significantly different from the dietary supplement world in all aspects—from manufacturing through to clinical research. As such, there is confusion in the operating infrastructure for human clinical trials, from manufacturing specifications, labeling and release of clinical trial supplies through the design and interpretation of clinical trials and trial data.”

The pharma industry has many defined standards for working with new medicines that simply don’t apply to dietary supplements, he added, and dietary supplement companies often cannot meet the minimum specifications required by an increasingly tough regulatory environment. “A true hybrid model embracing the best practices from pharma and the dietary supplement world to meet the regulatory requirements is still evolving.”

For the Future...
The significance and value of research will continue to increase, according to KGK’s Ms. Zakaria. “As consumers demand transparency, nutraceutical companies will notice an increase in scrutiny not only from regulatory agencies but their customers as well.”

In the future, she predicted clinical research will be completed prior to marketing a product and developing a health claim, “which historically has not been the case.”

Moving forward, NIS Labs’ Ms. Jensen said the blending of food, nutraceuticals, medicinal food and pharmaceuticals will accelerate; additionally, “increased regulatory demand for transparency (such as registering clinical trials and disclosure of data) is a challenge since this may compromise intellectual property rights.