Working in pharmacies where supplements are sold alongside traditional (over-the-counter) medications, I’m regularly astonished at the different perceptions consumers can have about the relative efficacy and safety of different types of products. Once, speaking with a customer about a medical condition she wanted to treat, I indicated that there were no effective non-prescription therapies — she needed to see a physician for access to an effective treatment by prescription — and I gestured behind the counter. “Back there?!” she pointed. “That’s where you keep the stuff that kills people! I want something natural!” Suggesting that my patients with heart disease or HIV had a somewhat different perspective, I tried (unsuccessfully) to talk her out of a questionable-looking supplement (Hint: avoid anything from a company with a P.O. box as a mailing address.) This appeal to nature, combined with a perception that natural products are safe, and conventional drugs are unsafe, is pervasive.
One of the responses regularly tossed at health professionals who argue for higher regulatory standards for supplements, CAM, and other natural health products is that conventional medicine kills, and prescription drugs are its preferred weapon. In contrast, they argue, supplements are safe. Any credible health professional will agree that conventional medicine can cause harms. David Gorski has examined Science-Based Medicine and patient safety before. The number of preventable adverse events from medical treatments is far too high. And even the idiosyncratic events — freak accidents, basically — mean we must always consider the rare but possible harms of the therapies we use. But as Harriet Hall, another SBM blogger, has pointed out, we cannot look at drug harms in isolation: the variable perpetually ignored by critics of mainstream medicine is the benefits associated with those drugs, which can make the risks seem quite acceptable. Both expected benefits and possible harms need to be incorporated into our decision-making process.
When it comes to drug (or supplement) safety monitoring, causality assessment is the evaluation of the odds that a particular treatment is associated with a particular adverse event. A single adverse event may have characteristics that suggest the relationship to a treatment is highly probable. But because correlation may well not equal causation, data are usually rolled up an analyzed in aggregate, by national and world-wide agencies to help identify the rare but serious adverse events. What this means is, if data are not collected, we have an incomplete picture of a product’s adverse event profile. Yet when it comes to supplements, good data on safety and efficacy are often lacking.
How Safe is the ‘Alternative’?
One of the recurrent themes of science-based medicine is that any medical intervention that can plausibly cause physiological benefit can also plausibly cause physiological harm.
— Steven Novella, Vitamin E and Stroke, Science-Based Medicine Blog
Despite the widespread perception that supplements are safe, some do have undesirable biological and pharmacological activity. There is no inherent safety to any product, natural or not. There is both anecdotal and more systematically-captured information to suggest harms can be associated with supplements. So how do we gather good data to inform decision making?
The primary challenge we face when evaluating the risk profile of supplements is the lack of good quality clinical trial evidence. When these data do exist, studies are typically of short duration with small sample sizes. Without clinical trials that systematically measure and report adverse events, there’s no harms profile, and the “Side Effects” section of the monograph stays nice and short. In contrast to supplements, new drugs undergo extensive clinical trials and adverse events are actively monitored, collated, and eventually are summarized in the product monograph. It should surprise no-one that the list of adverse events is longer, when you actually go out an systematically look for them.
As regulators worldwide generally don’t require any meaningful pre-sale testing of supplements for safety or efficacy, there’s typically little data available when any product becomes marketed. (Some regulators will approved products based on a history of “traditional use”, which offers little insight into a products safety profile, as that data have never been systematically collected.) Instead, regulators worldwide (e.g., Canada and the USA) rely almost entirely passive surveillance to monitor the safety of marketed products.
Passive surveillance depends on the spontaneous reporting of adverse events from health professionals, alternative medicine purveyors, manufacturers, and even consumers directly. Passive surveillance is the key method of collecting safety data on drugs and supplements once they have been licensed for sale.
However, passive surveillance is an imperfect means of collecting safety data. It is much more effective at identifying rare and infrequent adverse events (e.g., liver toxicity) than incremental increases in the risks of common medical conditions (e.g., heart attacks). While the true denominator cannot be know with certainty, it’s generally accepted that only a fraction of adverse events are identified, and only a fraction of these are actually reported. Despite these limitations, the Institute for Safe Medication Practices reports that in 2009, the FDA received 19,551 reports of patient deaths associated with drug therapy. Is this the smoking gun that Big Pharma is killing us? Not quite. Causation has not been established, and even then, we need to consider harms in the context of the benefits a therapy may offer. The system isn’t perfect, but it is producing data that may be helpful for decision making, and understanding the evolving risk profile of licensed products.
Despite their widespread use, surveillance of supplements reveals generally few adverse events. It could be that many products lack meaningful pharmacologic activity — either positive or negative. An adverse event is probably less likely in drugs without any meaningful beneficial effects. But beyond efficacy, there are several other factors, unique to supplement use, that may contribute to even less frequent adverse event reporting. These were identified in a series of qualitative semi-structured interviews conducted by Rishma Walji in 2010, and summarized in the paper Consumers of Natural Health Products: natural born pharmacovigilantes?:
- Consumers believe supplements are safe, because they are “natural.” Therefore they’re less likely to associate adverse events with supplement use.
- Supplements don’t require a prescription. No health professional may be involved in monitoring response to therapy, who might be able to identify adverse events as part of a monitoring plan.
- Because consumers may not involve health professionals in their decisions to take a supplement, they may feel obliged to deal with it on their own, and not involve health professionals. Perceptions about how their health professional will react to their use of supplements may come into play.
- Consumers may not know how to manage and adverse event, and who to report an adverse event to. They didn’t get it from a doctor, so they don’t report the outcome to a doctor.
- Even if they do contemplate reporting an adverse event, the process can be complex, especially for consumers.
- Users may have a distrust of “conventional” medicine which drove their initial use of the product. When adverse events were identified, there were reluctant to consult “conventional” health care providers for assistance.
- Some surveyed stated a fear of losing access to supplements, driving a reluctance to report adverse events.
From my own practice, I’d add few additional factors to the list. Supplements are commonly used for short durations, and for self-limiting conditions, in comparison to prescription drugs that may be used chronically. Prescription drug manufacturers are required by law to report to regulators any actual or potential adverse events that they learn of. This requirement was recently implemented in the USA for supplement manufacturers — however, contact information may not yet appear on supplement labels.
Disappointingly, consumers surveyed reported a preference to discuss adverse with health food store personnel, family or friends, which appears to be a factor of both comfort and convenience. Enablers to reporting adverse events included knowledge and importance of adverse event reporting, and personal comfort with their health care provider.
Real World Harms
People often ask “what’s the harm” of supplements and other forms of alternative medicine. This question can be answered, if incompletely. Considering the numerous case reports of harm helps us understand patterns, look at causality, and guide the safe use of these products. A recent case series of adverse events supports some of the observations that Walji made in her paper, and expands on the possible consequence of CAM use. The paper, Adverse events associated with the use of complementary and alternative medicine in children, is from Lim et al., and appears in the Archives of Disease in Childhood.
Monthly surveillance reports of CAM-associated adverse events in Australian children were collated over a three year period. This active surveillance program (pediatricians are asked monthly to report any rare disorders that have been observed) followed adverse event reports with detailed questionnaires, evaluating causality, severity, and whether the adverse event was potentially related to a failure to use “conventional” therapy. The program identified 39 adverse events, with 64% considered severe, life threatening, or fatal. Thirty cases (77%) were considered to be related to CAM, and 17 cases (44%) were felt to be due to a failure to use conventional medicine. Four deaths were documented, all attributed to a failure to use conventional medicine in favour of CAM. One of the deaths, from seizure, was attributed to a decision to use CAM rather than drugs, with the aim of avoiding the side effects of drugs.
The authors make the following observations on CAM use and adverse events:
- Reporting can be complicated because information on the product may not be available.
- Products can be contaminated or adulterated with therapeutic, undisclosed drugs, complicating evaluations of causality.
- Because CAM products are perceived as safe, they may not be stored properly in the home.
- CAM use may be accompanied by dietary advice that is dangerous, and not based on good evidence. Two of the fatalities associated with CAM occurred in children on marked dietary restrictions prescribed by a CAM practitioner.
It’s a small case series, and we know neither the actual numerator or denominator. Still the severity of some of the reactions is concerning, and the author’s comments point to additional factors that may influence the incidence of adverse events reported.
Information is Beautiful … But Incomplete
As a pharmacist, I constantly need to contextualize data directly for patients, translating trial results into more understandable figures like numbers needed to treat and numbers needed to harm. I’m always searching for better ways of communicating the understanding of risks and benefit. Information is Beautiful is one of my favourite blogs, as the authors highlight innovative and effective ways of graphically presenting data. So I was initially excited about their attempt to summarize the data for supplements — click on the image to view the data on the IiB website:
Clicking each bubble will link you to the supporting clinical data. But there’s a crucial element missing in their presentation: harms. You cannot evaluate the value of a treatment based on efficacy alone. For example, selenium is ranked very highly for colorectal cancer prevention based on this study. Not only is there evidence to the contrary, selenium consumption is associated with a significant increase in the risk of type 2 diabetes. The risks actually seem more compelling and relevant than the potential benefits. Or look at red yeast rice, another supplement rated highly. While RYR does seem effective, is less effective and more dangerous than drugs derived from it. I like the IiB visual approach, but it fails in communicating meaningful data on risk and benefit, both of which are essential for decision-making.
Supporting Science-Based Decision Making
Whether one is considering a “conventional” drug or a supplement, the questions we should be asking are the same:
- What benefits can I expect given my own condition? What data exist to support this? How much more effective is this treatment than a placebo?
- What harms with this treatment have been documented? Has the product been studied extensively enough to understand the potential risk profile?
- In how many patients has this product been studied? How closely do they match my situation?
- What alternatives exist, and what are their risk-benefit profiles? What are the risks of no treatment at all?
- What are the economic consequences of the treatment strategy I decide upon? How much “bang for the buck” should I expect?
Any active treatment can have harms, yet robust safety data can be hard to come by for supplements and natural health products, painting a skewed picture of their risks and benefits. Our passive system of collecting safety information isn’t likely to remedy this situation. While regulators may have created different standards for supplements and CAM, permitting sale in the absence of good safety and efficacy data, our decision-making should make no such exceptions. Evaluating what we know about efficacy and safety, and what we don’t know, and the limitations of both, are critical to science-based decision making.
Lim A, Cranswick N, & South M (2010). Adverse events associated with the use of complementary and alternative medicine in children. Archives of disease in childhood PMID: 21178176
Walji, R., Boon, H., Barnes, J., Austin, Z., Welsh, S., & Baker, G. (2010). Consumers of natural health products: natural-born pharmacovigilantes? BMC Complementary and Alternative Medicine, 10 (1) DOI: 10.1186/1472-6882-10-8