Jul 23, 2008

Regulatory Placebo

Posted in Science at 1:00 pm by David Bradley -- 6 Comments; add your comment

My recent article on the subject of an unnatural approach to diabetes led to some quite intriguing comments from readers especially as I suggested that it would make sense from a safety perspective to bring herbal remedies under the same regulatory umbrella as regular pharmaceutical products.

Eric W a chemistry teacher from Minnesota who goes by the online monicker of “Chemgeek” pointed out that the US Food & Drug Administration (FDA) had attempted to do this several years ago (it’s something that has been mooted in the European Union too), but in the US at least all that happened is that products now have a warning such as: “These statements have not been evaluated by the FDA…” Which is obviously a rather weak stand to take on products that can be potentially lethal in combination with the wrong disease or other medication.

The problem as I see it, is that if any given herbal product has potent physiological activity, then it is too all intents and purposes, a medicinal drug, and should be tested and labelled as such so that consumers can be warned of contraindications. If the herbal product has no physiological activity, other than perhaps to provide some spurious antioxidants for which our needs are not known, then it is little more than a placebo.

Stef Levolger, aka Slevi, is a Dutch medical student with an interesting observation on the issue. “It’s not like [herbal is] all that different from our own basic medicine. Take for example willow bark, sold as a herbal treatment and advertised with [various] uses by the Chinese, by [several] companies and others since the ancient Greeks. And, how do you get it home? Right, you get a bottle filled with pills. I wouldn’t be surprised if it was even produced in the same pharmaceutical factory as where regular aspirin comes rolling down the line, just got a price tag twice as high slammed on it,” he says.

I think Slevi is on to something, certainly a huge number of our so-called modern pharmaceuticals have natural product origins while many so-called natural herbal products are manufactured on neighbouring production lines by a division of the pharma companies.

Canadian blogger Mina Isabella Murray of Weird Science strongly disagrees with the idea of bringing all herbal remedies under the pharma umbrella. “That’s not to say I don’t support the notion of thorough research, safety, monitoring and accountability, but to compare the vast majority of herbals to pharmaceutical preparations is misguided and excessive,” she says, “I vote stricter regulations but ones that are separate from current pharma protocol/guidelines.”

She suggests that the issue is not black-and-white. “The vast majority of herbal preparations aren’t viewed to treat disease in the way that pharmaceuticals are presented nor are they presented as ‘cure alls’, she says, “Sure, we all
know
the stories
of dangerous herbs
and dubious advertisingwe all know the stories of dangerous herbs and dubious advertising but I don’t think that warrants all mainstream herbal preparations being subject to the same testing required for pharmaceuticals. She cites cranberries as an important preventative for urinary tract infection that, of course, cannot displace antibiotics should someone contract a full-blown infection.

But, I’d argue that the efficacy of such a “natural” remedy is dubious at best, but other products, may have genuine effects and so can interfere with the metabolism of certain medications. St John’s Wort is probably a case in point. This product widely used to treat mild depression is contraindicated for anyone with thyroid problems. But, buying St John’s over the counter, off prescription as it were, does not provide the necessary warnings.

I asked chemical consultant Hamish Taylor of Shinergise Partners Ltd how he felt about regulation of yet another area of his broader industry. “I think the answer should be YES,” he affirms, “but perhaps a sensible step is part-way i.e. strong warnings on possible side-effects and a cautionary ‘there is no clinical trial which demonstrates absolute efficacy’.”

Such an approach would allow the placebo effect of “it’s natural, I believe in it, it does me good” to shine through, which is probably no bad thing. “Feeling good is pretty much proven to make people healthier and certainly happier,” Taylor adds. He says that some degree of labelling would however prevent some of the nastier side-effects that can occur.

“By going to this quasi-interim step, it may even encourage manufacturers to undertake proper clinical trials to demonstrate effectiveness and therefore encourage greater use,” Taylor says. Of course, it is not as if the manufacturers have not investigated the potential. “The problem is that if the more popular herbal remedies were indeed 100% effective the drug component would have been isolated and purified by now!” adds Taylor.

Steve Bannister, Scientific Director & Principal Consultant at Xcelience, LLC, a drug development company based in Tampa, Florida, suggests that really the question we should be asking is what level of regulatory resources can we afford?what level of regulatory resources can we afford?

“Natural products have long provided leads for drug discovery,” Banniester says, “In modern natural-product drug discovery, activity-guided fractionation (often using an isolated receptor) identifies an active molecule and a single molecular entity results from semisynthetic improvement of the phytochemical’s drug properties. The drug-regulatory process includes guidelines for determining safety, efficacy, and quality, as well as for setting acceptance criteria for each.”

However, some herbal products may have efficacy as a result of a combination of components, additionally adverse reactions to such a product may be due to a different combination. “To pass through the current drug regulatory process, a product specification, including identification of the specific active components and their requisite levels, along with identification and limits for the unsafe impurities, is needed,” adds Bannister. He further explains that this specification must be defined in terms of safety and efficacy in humans. “This is an extraordinarily difficult undertaking, and if required, would prevent herbal products from reaching approval,” he says, “This, combined with the fact that some herbals really do work, is the principal reason for a different different set of regulations.”

One has to consider what is an acceptable level of risk and how it is managed? What risks are associated with adulterated products, what are the adverse reactions, and to what extent does lack of efficacy lead consumers away from different, effective, treatments.

As it stands, the fully implemented US Good Manufacturing Practices for herbals are meant to control adulteration but can only do so if there is adequate compliance inspection. Of course, evidence of a significant incidence of adverse reactions is sufficient to lead to a product being banned but again this requires significant surveillance resources. Also, disease-treatment claims can be made only for approved drugs, so consumers may have been led to a particular herbal for their symptoms through hearsay or lifestyle magazine “evidence”. Monitoring of such claims for herbals, such as the neurochemical effects of St John’s Wort also requires surveillance resources. It all costs.

Delano Freeberg, Chief Technical Officer at API Purifications Inc, suspects that the devil is in the details. “In special cases, increased regulation may be beneficial,” he says, “I believe public health is not served by increased regulation. In fact, I believe we will benefit from the application of well-understood scientific and medical criteria for the reduction of regulation. The benefit of this approach to the public is the timely availability of lower-cost drugs. I believe this can be accomplished with no effect on safety.”

He points out that regulation is not required for extracts. “Many herbal remedies are known to have efficacy, even in a crude extract. The composition of this extract often does not differ much from that of the starting biomass (natural herb). If the herb being used is “GRAS” (generally regarded as safe), there is good scientific foundation for believing the extract will likewise be safe,” adds Freeberg, “An important caveat: “Natural” does not imply “safe.” Hemlock extract (Conium maculatum) is 100% natural but also 100% deadly.”

He also suggests that regulation should depend on potencyregulation should depend on potency. “Traditional over the counter pharmaceuticals contain a single active component. Natural remedies usually contain several compounds of known efficacy. Green tea, for instance, contains high concentrations of around a dozen different catechin antioxidants. The traditional pharmaceutical OTC preparation must be held to a higher standard of regulation because of the higher purity and potential potency of the active ingredient,” he says.

Regulation should also depend on drug type. “I feel the FDA over-regulates and does not take into consideration scientific findings that provide a basis for reduced regulation,” says Freeberg, “I provide one example. Synthetic statins have moderate to severe side effects in 5% of patients. Cholesterol can be equally reduced by the intake of policosanol (One recent study found no efficacy; however, dosage levels may not have been appropriate), a group of long-chain alcohols from beeswax. Side effects of policosanol were mild – no worse than placebo.”

There is certainly a scientific basis to demonstrate that many natural compounds have little adverse physiological effect, even in high-purity forms. This can be determined from structure-activity relationships and historical clinical and toxicological data.

Florence Leong, an Investment Director at ATP Capital Pte Ltd, believes the answer lies not in regulation but in consumer education. “Consumers need to be educated on the difference between OTC herbal remedies and pharmaceutical products,” she says, “Not all natural products are safe, the reason why OTC have fewer listed side effects as compared to pharmaceutical is because OTC products are not as thoroughly evaluated. Often the long list of side effects in pharmaceutical drugs frightens the consumer and the cursory listing of side effects gives consumer the false perception of safety.” Unfortunately, she adds, consumer education is a long and tedious process and regulation is consider the efficient ‘quick fix’.

She echoes my own earlier sentiment regarding efficacy claims where OTC products are not as robustly proven as pharmaceutical products. “This is an area where regulation should be tightened as many manufacturers of OTC products do try to push the limits by making specific efficacy claims in non-print advertisements. And often they do get away with it,” she says.

The active constituents of pharmaceuticals products are consistent, which ensures reliable efficacy and, on for established products, predictable side-effects. In contrast, efficacy of OTC herbal medications can be variable due to natural variations of the chemicals in different batches of raw materials, contamination, and manufacture unscrupulousness. This means herbal products can swing between no effects and no side-effects, via those that work and have their own side-effects to the wildly hazardous batch of mercury-laden dessicated ordure.