You’ve probably heard the saying, “Let food be thy medicine and medicine be thy food” that’s attributed to the Greek physician Hippocrates, who is often called the father of medicine. But have you ever thought about what it really means?
A couple of articles I read this week caused me to reflect more deeply on this well-worn adage.
The first was a report issued by the US Food & Drug Administration (FDA) (roughly the equivalent of the Therapeutic Goods Administration [TGA] in Australia), entitled 22 Case Studies Where Phase 2 and Phase 3 Trials had Divergent Results.
As background, a phase 2 trial typically tests out a new drug (or an old drug on a different condition than it’s approved for use in) on a couple of hundred human volunteers who have the particular condition that the drug’s sponsor (e.g. the pharmaceutical company that developed the drug) wishes to have it approved for the treatment of, but no other diseases. A range of dosages are used, short-term side-effects are identified, and biomarkers such as laboratory values are measured to identify whether the drug has the potential to treat the target condition. (There are some differences in trial design for medical devices such as stents, but for convenience, the FDA chose to use the same terminology in the report for medical devices as for drugs.)
If the results of the phase 2 trial are promising, the drug’s sponsor will organise a phase 3 trial. Phase trials typically involve giving the drug to 300-3000 people with the target condition, over a longer time period than phase 2 trials, and measuring clinical outcomes (such as participants’ function, survival and disease complication rate) rather than just biomarkers. The purpose of a phase 3 trial is supposed to be to determine whether the benefits of the drug outweigh its risks, and whether those benefits are clinically relevant – that is, whether they actually improve patients’ lives rather than just giving them better ‘numbers’, be that blood pressure readings, cholesterol levels or any other biomarker.
That said, the FDA has a long and ignominious history of approving drugs that offer no meaningful benefit to patients, such as Addyi, the so-called ‘female Viagra’, which in phase 3 clinical trials demonstrated an earth-shattering increase of 0.5-1 ‘satisfying sexual events’ per month in women with ‘hypoactive sexual desire disorder’ – a drug company-invented diagnostic label for a ‘condition’ defined by reduced sexual fantasies and desire for sexual activity in women. (Hmm, is there a possibility their partners might need to be a bit more creative in the bedroom, or perhaps these women have underlying health conditions that reduce their sex drive?)
The trade-off for this rather underwhelming ‘improvement’ in their sex lives is an increased risk of developing hypotension (low blood pressure) which may lead to syncope (fainting), dizziness, vertigo (spinning sensation), central nervous system depression (resulting in somnolence, or day-time sleepiness), nausea, fatigue, insomnia, anxiety, constipation, abdominal pain, rash and dry mouth, especially if the user also drinks alcohol or uses other medications including blood pressure lowering drugs, antibiotics, fluconazole (an antifungal medication commonly used to treat thrush), or antiretroviral drugs. Still keen to try Addyi?
In fact, the FDA’s approval rate for new drugs now stands at 89% (or 96% if you count multiple uses of the same drug), up from 44% in 2009. In writing the report, the FDA drew on cases stretching back to 1999, and it’s possible that some of the drugs, vaccines and medical devices included in this report may have gained approval if they’d been submitted more recently under the FDA’s apparently less stringent criteria.
To summarise the report, in 14 out of the 22 cases, phase 3 studies did not confirm phase 2 findings of effectiveness; in 1 case, the phase 3 trial uncovered major safety issues that the phase 2 trial had missed; and in 7 cases, phase 3 trials found that the treatment was neither safe nor effective. Shockingly, in 2 cases, phase 3 studies showed that the experimental product increased the frequency of the problem it was intended to prevent: a drug-eluting stent increased the risk of heart disease patients’ arteries blocking up again, causing heart attacks; and a drug intended to reduce heart attack risk by raising HDL (‘good’) cholesterol raised the risk of suffering a major adverse cardiac event (including heart attack) by 25%, and the risk of dying from any cause by 58%.
If you’re heaving a sigh of relief at the fact that all these ineffective and/or dangerous drugs and devices didn’t make it onto the market, not so fast. Many serious adverse effects are not detected until a product is approved, released into the medical marketplace, and used by thousands of patients for much longer periods of time than in phase 3 trials. Vioxx – the anti-inflammatory drug that was withdrawn from the market in 2004 after it was found to cause heart attacks, strokes and death – and Avandia, the world’s most popular diabetes drug until it was found to have caused tens of thousands of heart attacks, strokes and heart failures – are the unwilling poster children for the dangers of assuming that a drug that has passed the approval process is safe and effective.
When making decisions about whether to approve a drug, vaccine or medical device, the FDA and other regulatory agencies rely on clinical trial data provided to them by the medical product’s sponsor; they don’t conduct safety studies of their own. And that’s where the second article I read this week, titled Reporting of Adverse Events in Published and Unpublished Studies of Health Care Interventions: A Systematic Review, comes in. This paper delved into the differences between reporting of adverse events (‘side effects’) of medical treatment in published vs unpublished documents. Published documents were mostly studies published in medical journals, while unpublished documents were obtained from websites, conferences, and industry-held data.
Of the 28 studies included in their analysis, the researchers found that only 46% of published documents contained information on adverse events, compared to 95% of corresponding unpublished documents. Furthermore, published documents reported lower rates and a smaller range of side effects than unpublished studies.
Their conclusions are sobering:
“These findings suggest that researchers should search beyond journal publications for information on side effects of treatments.
These findings also support the need for the drug industry to release full data on side effects so that a complete picture can be given to health professionals, policy makers, and patients.”
My conclusion: ask your doctor if he or she has gone to this much trouble to research the true risks and benefits of a drug before prescribing it to you.
Back to our friend Hippocrates. When we choose to use drugs as medicine, we’re buying into a reductionist way of viewing disease, which is that disease is comprised of biological mechanisms that can be targeted by drugs in order to alter the body’s function in a way that benefits health. For example, a common type of blood pressure drug called angiotensin receptor blockers, or ARBs (common brands include Atacand, Micardis and Avapro), stop a protein that the body makes, called angiotensin, from acting on blood vessels. As a result of interfering with angiotensin’s activity, ARBs dilate the blood vessels, which lowers blood pressure.
Unfortunately, it’s not possible for a drug to produce a desired effect without also producing undesired effects – usually called ‘side effects’, although it’s more accurate to describe everything a drug does, desired or undesired, as simply ‘effects’ – which in the case of ARBs include persistent cough, dizziness, headache, drowsiness, diarrhoea, fatigue, indigestion, upper respiratory tract infection (colds and flu), sexual dysfunction, and kidney and liver failure.
The real kicker is that ARBs actually increase the risk of heart attack when compared to either placebo (an inert ‘sugar pill’) or to another type of blood pressure medication called ACE inhibitors, and they don’t help people with high blood pressure live any longer.
Compare this to the approach of using food as medicine: whole or minimally processed plant foods such as fruits, vegetables, whole grains, legumes, nuts and seeds contain a host of biologically active compounds including vitamins, minerals, antioxidants and phytochemicals, which interact with multiple targets in the human body to produce a host of actions that result in multiple health benefits, simultaneously.
This is what Professor T. Colin Campbell refers to as wholism – the recognition that most chronic diseases – and even many acute ones – share similar biological pathways, and adopting a whole food plant-based diet may result in improvement, and even complete resolution, of multiple health conditions at the same time.
For example, ‘treating’ obesity with a wholefood plant-based diet may result in ‘side effects’ such as lowering high blood pressure, reversing type 2 diabetes and coronary heart disease, reducing asthma attacks and preventing cancer.
Of course, some drugs are useful in some circumstances – I would take antibiotics if I had bacterial meningitis – but at the end of the day, the reductionist idea of targeting a single disease mechanism to effect a cure, without adversely affecting any other body process is a fantasy. The authors of the FDA report acknowledged this:
“Many medical conditions are complex; targeting a single component of a condition cannot be presumed to have a positive effect on the patient unless there is objective clinical evidence. This array of unexpected results from phase 3 studies demonstrates the complexity of the interaction between a medical product and the patient, and how logical presumptions without corroborating clinical evidence can be unreliable… While biomarkers have many important uses in clinical practice and product testing, most have not been shown to reliably predict clinical outcomes. As several of these case studies illustrate, promising biomarker data in phase 2 do not necessarily translate into effective product performance.”
On the other hand, whole plant foods are native to the human body, and when we construct our diet from them, we blur the line between ‘food’ – substances which provide fuel for us – and ‘medicine’ – substances which help us overcome disease and restore health.
And we enact another saying attributed to Hippocrates:
“Make a habit of two things: to help; or at least to do no harm.”
The same cannot be said for much of what goes on in modern medicine, and most of its treatment approaches to chronic disease.