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The price of science

The potential for research to benefit the supplements industry is beyond doubt — if it is conducted with utmost transparency, says Joseph Chang PhD. But when federal regulations limit how companies can market these studies? findings, the costs of R&D can become tough to justify

Modern medicine and the supplements industry are hardly cosy bedfellows. Mainstream medicine perceives supplements to be poorly manufactured and scoffs at the paucity of scientific data that support supplement claims, even as sound dietary supplements science floods in at an ever-increasing rate. While, at face value, this seems an admirable endeavour, science can raise issues for supplements companies that can complicate rather than eliminate negative perceptions of the industry.

R&D is an investment in a potential future stream of revenues from the sale of products. Unlike other types of investments, such as a new manufacturing plant, supplements R&D must be able to recoup not only the investment, but be compensated for the risk the company took of losing its investment altogether and for the time spent waiting for product commercialisation. Without such an expectation, it would be foolish for a company to put its money on the line. The ?expected? payoff does not, however, mean an assured return; rather, it means a minimal payoff if a supplement successfully reaches market.

Because R&D risks are so significant in capital, time and outcome, it?s no surprise many companies hesitate to fund research; instead, it would seem the supplements industry is far more inclined to take the path of least resistance to extol the benefits of a supplement. A cursory search on the Internet can easily turn up a plethora of supplements with intriguing marketing claims, suggesting that the path of least resistance is invariably associated with creating marketing claims that appeal to uninformed consumers.

This has provided fodder for industry critics who have argued the size of the US industry ($18.9 billion in 2003, according to Nutrition Business Journal) justifies research spending. But such arguments fail to take into account a significant nuance. The industry is highly fragmented; indeed, most supplements companies, unlike drug companies, exist only as marketing companies and depend on various manufacturers to supply the requisite ingredients for their products. For such companies to consider the high cost of R&D as a value proposition, fundamental changes in mindset and business strategy will be required.

Damned if you do?
The Office of Dietary Supplements (ODS) was created in 1995 as a result of the Dietary Supplement Health and Education Act. Its mission was to conduct basic and clinical studies addressing dietary supplements. Funded with approximately $1 million at its inception, the ODS budget has since expanded to just under $20 million in 2003 — still a tiny fraction of the overall National Institutes of Health appropriation of $20 billion.

Curiously, the ODS does not have granting authority, and, therefore, largely provides research funding through collaboration with NIH in support of research projects. To date, such projects have focused primarily on the effects of supplements on diseases that include cataracts, bone density loss, rheumatoid arthritis, cancer, hearing loss, dental health, cardiovascular disease, alcoholism, cognitive function, depression, diabetes and the nervous system.

The types of studies sponsored by the ODS are clearly disease focused. Based on current regulatory restrictions, the supplements industry would be hard pressed, except for a few select ingredients (eg, fish oil, calcium, folic acid and fibre), to use such data for marketing purposes without invoking the wrath of the Food and Drug Administration. Until the FDA rules on how the industry could use the results of ODS-sponsored research, the value of such studies to the supplements industry is difficult to deduce.

Clearly, the supplements industry faces a Gordian knot when it comes to leveraging such studies for marketing purposes. On the one hand, as defined by DSHEA, supplements can only be marketed with structure-function claims, not disease claims. On the other hand, a body of evidence is being created that may confirm the notion that some dietary ingredients may in fact exert a prophylactic effect on diseases.

Unlike drugs, a clear path for investigating supplements candidates does not exist and emulating the new drug application process can be disastrous
An obvious option available to most companies is to conduct its own research. The risk of capital has already been highlighted above. Even if capital is available, there are no guidelines as to the types of research that can support structure-function claims. At best, supplements companies can only guess at what is acceptable research. Unlike drugs, a clear path for investigating supplements candidates does not exist and emulating the new drug application process can be disastrous.

Studies conducted with disease populations are unlikely to be relevant, although this subtle but critical limitation is lost on most industry critics who insist supplements companies conduct drug trials. Unfortunately, the popular term ?nutraceutical,? while compelling, can be seen to promote the notion that supplements are drug-like.

Promulgation of this term will be a disservice to the industry because if, indeed, supplements are nutraceuticals, then it follows they need to be clinically tested under drug guidelines. This will create an R&D bill for the industry that it cannot possibly pay — or wish to pay. As a point of reference, Pfizer, one of the largest drug companies in the world, spent $4.4 billion, or 15 per cent of revenues, on R&D in 2003.

The supplements industry, on the other hand, is under constant attack from medical reports or editorials debunking its efficacy. For example, a recent issue of Lancet, a highly respected British medical journal, saw it fit to highlight the observation that supplementation with antioxidant vitamins (E, C and beta-carotene) does not have an impact on important measures of health and disease among individuals who are already ill. Another respected medical journal, Annals of Internal Medicine, published a meta-analysis showing that vitamin E exacerbates cardiovascular risk. Such reports are obviously very influential in the eyes of the consumer and potentially damaging to the supplements industry. In many ways it finds itself in a ?damned if you do, damned if you don?t? situation.

Rethinking research strategies
What sort of research can further the cause of the supplements industry? Unfortunately, the difference between a ?structure-function? claim and a ?disease? claim is a legal, not scientific, line in the sand. While the legal community can parse distinctions from these artificially created categories, the scientific distinction is murky at best, making it difficult to develop a commercially viable research strategy. Perhaps the best example of where science confronts legality is the ability to lower cholesterol.

It would seem logical to consider cholesterol as a structure that functions as a cellular building block, and, thus, lowering its level in the body should be viewed as a straightforward structure-function claim. Yet, under FDA regulations, cholesterol-lowering is a disease claim and supplements companies are not permitted to make this claim because the agency has defined the elevated level of cholesterol as a disease marker. This shackles the industry and penalises companies that wish to fully characterise a supplement.

Despite the vagaries that exist in the supplements industry, the industry should not ignore the basic pharmacological tenet that a dose-response relationship exists for any substance (natural or otherwise) and that the amount of an ingredient included in a product must be chosen based on pharmacological rather than economic principles. ?Fairy dusting? practices cannot be condoned since such minute doses of ingredients have no basis in science and are unlikely to provide significant health benefits. If ?fairy dusting? practices are not curbed, the inherent value of natural products will erode and compromise industry credibility.

Identifying safe and effective doses of ingredients and a better definition of the chemical nature of supplements can only lead to better products. Studies using molecular targets gleaned from the science of genomics and proteomics are also very useful. To the extent possible, correlative studies of plasma concentrations and changes in a relevant biochemical marker can be meaningful. For example, measuring oxidative stress relative to supplement dose would be interesting since most botanical ingredients are reportedly antioxidants. Such information can guide batch-to-batch manufacturing consistency of an antioxidant supplement.

In sum, botanicals research is not impossible, but it has to be driven by well-defined research objectives. Research objectives such as safety, clinical pharmacology and efficacy endpoints have different levels of difficulty. Expectations to meet several objectives in a single study are also unrealistic and can complicate interpretation.

When good science goes bad
Perhaps the single most important consideration for a company is whether it has the gumption to accept the ramifications of a negative outcome of a funded study.

One of the precepts in scientific research is the implicit understanding that all data require full disclosure. Eyebrows tend to rise when it is revealed negative data are suppressed; indeed even in the pharmaceutical industry, it has been suggested that the drug database is biased inasmuch as it is believed that not all the clinical studies conducted by the industry have been published. Certainly, the recent Vioxx issue has included allegations that Merck may not have disclosed negative data in a timely fashion.

Similar potential landmines exist for supplements companies, and if the industry views scientific research through rose-tinted glasses, it could cause angst within management ranks when research leads to unexpected findings. To embark on a flawed research strategy that satisfies neither the marketers nor the scientific community would be imprudent.

Patents spending
Most natural products cannot be patented because they are not new or inventive, and an applicant cannot describe how to manufacture them. If, however, a new molecule is discovered in a natural product that has not been previously described, it may meet the criteria for patentability, provided there is proof of biological activity. The more human intervention needed to produce the invention, the greater the chances of it being patentable. Essentially, patents can be applied for: the substance itself, the method of use, the formulation and the manufacturing process.

A brief analysis shows the majority of patents issued in the supplements industry are based on novel botanical applications. But here is the dilemma: what if a competitor incorporates your patented ingredient into a product without making any claims covered by the patent? Such practises are rife in the industry and copycat products are a dime a dozen as soon as an article is published on an ingredient.

The ?borrowed science? phenomenon is pervasive in the industry and has allowed many companies to market products without risking research dollars. Obviously, the patent holder can sue for infringement, but the pursuit of patent infringement is an expensive proposition. It can strain the financial resources of a small company, which would otherwise be spent on further research.

Lack of intellectual property protection does not need to stifle research if Congress is willing to provide tangible benefits to companies that are willing to go the extra mile in research. Notably, the birth of the biotechnology industry was assisted significantly by congressional legislation through the Orphan Drug Act. This legislation grants companies the exclusivity to market unpatented drugs for rare diseases.

While biotechnology companies still need to adhere to the drug approval process, they at least do so with the confidence that if their research is successful, competitors will not purloin their data. Here, the FDA provides a safe haven, which has served to foster and reward research for the public good

while providing the biotechnology industry with a protective umbrella to market products.

If one considers the criticisms directed at the supplements industry such as unsubstantiated claims, lack of safety data and minimal quality controls, it would seem a variant of the Orphan Drug Act may motivate a supplements company to consider R&D as a growth platform, and to believe that its investment can be recouped without fear of exhausting its resources on patent fights.

Reliable, relevant research
The supplements industry has reaped the largesse of DSHEA for the past 10 years in the US. Globally, interest in health and wellness is growing due to rising living standards, resulting in ageing consumers seeking options to improve quality of life by delaying disease onset. Undoubtedly, supplements will continue to be of interest to these consumers. But in order for research to buttress and maintain this interest, companies should recognize and acknowledge certain scientific realities to be self-evident.

A negative outcome of an expensive study can be hard to swallow, especially if it is not consistent with marketing needs. This, unfortunately, is the price exacted by science
Most importantly, scientific research is uncertain and outcomes cannot be predicted. A negative outcome of an expensive study can be hard to swallow, especially if it is not consistent with marketing needs. This, unfortunately, is the price exacted by science, and unless the industry is willing to accept the good with the bad, we must be careful for what we wish for.

Joseph Chang, PhD, is president of Pharmanex. He would like to thank his colleagues for their advice and ideas for this article.
All correspondence will be forwarded to the author.

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