A group of gently greying medical experts with divergent views sits around a London breakfast table, each of them avoiding a fried meal and all united by their participation in an unusual experiment.
They are part of a groundbreaking clinical trial for an experimental new drug that is in fact a combination of cheap old ones. Taken together, they believe, the ingredients in this polypill could help revolutionise the prevention of cardiovascular disease.
Yet the concept, the product of a decade-long effort, continues to meet significant hurdles from regulators, companies, public health specialists and doctors alike.
“It’s a disappointment, because the potential gain is so big with little consequences of harm or side effects and little cost,” says the polypill’s architect, Nicholas Wald, professor of environmental and preventive medicine at the Wolfson Institute at Barts and the London School of Medicine and Dentistry.
The story of the polypill shows the difficulties in challenging the dominant approach to drug development in recent decades, but also the emergence of fresh attempts to do so by both academics and companies.
By studying new uses for old drugs that are already understood and safe, they offer the prospects of leap-frogging much of the costly uncertainty of early drug development, if they can overcome commercial, regulatory and medical scepticism.
In the coming days, Plos One, an online medical journal, is set to publish their latest efforts in a paper by Prof Wald, David Wald and Joan Morris, to combat their critics and demonstrate the value of a polypill taken by everyone aged over 50 years old. While most clinical trials publish the results of drug tested in strictly anonymised groups of patients, the paper lists almost all the 86 participants by name, including the authors themselves and many other senior medical figures who support the principle of the polypill.
The idea behind the drug is simple. It combines existing drugs that are used to treat people who have already suffered from cardiovascular problems such as statins which lower cholesterol levels, and other medicines to lower blood pressure. By giving the same drugs preventatively and earlier in life to a much broader and ostensibly healthy population at risk of future heart disease, the polypill aims to safely and cheaply prevent and defer heart attacks and strokes. By combining them in a single daily tablet, it makes the treatment more user-friendly. And by using such a mixture of low cost, generic medicines, the polypill would prove cheap to health systems and patients alike, with notable benefits in the developing world where cardiovascular disease is poorly treated and the risks are growing rapidly. “The prevention of a first heart attack or stroke means that there is not a second one to prevent,” says Prof Wald.
Bringing the concept to realisation has proved considerably more difficult. The first problem is commercial. Richard Smith, the former editor of the British Medical Journal and one participant in the trial, says the fact the polypill uses existing off-patent drugs limits the commercial incentive for research-based pharmaceutical companies to become involved.
At the same time, he suggests that most generic drug companies that might have greater interest in the concept lack the regulatory and commercial skills to win approval and sell the polypill successfully as a new approach to public health.
Instead, Prof Wald, who first described the idea of the polypill in a patent filing and in a academic paper at the start of the millennium, has invested hundreds of pounds of his own money to date. He has also persuaded Cipla, a leading Indian generic drug manufacturer, to provide copies of the polypill, as well as sugar placebo versions that look identical, to run his clinical trials.
Other companies are also getting involved, including an Indian rival, Dr Reddy’s, which has focused on a polypill for secondary prevention, in those patients who have already had a heart attack or other cardiovascular problems. This, along with other versions includes aspirin and different drugs which carry greater risk of side effects – justified for those already at higher risk, but not for otherwise healthy individuals.
But a second hurdle for primary prevention drugs like Prof Wald’s polypill, is regulatory. While each of the ingredients has separately been studied in patients, it would add to the burden of proof to use them together in otherwise healthy individuals, and examine how the body copes when they interact with each other.
One regulator says: “As with any combination, you have to show that each drug is justified. The polypill is breaking interesting new ground, but there would need to be large numbers of patients in trials to test for efficacy and safety.”
Attitudes are beginning to evolve, with combinations of novel drugs to treat illnesses such as HIV and tuberculosis as well as cancer under investigation. But the large numbers of patients required to be enrolled in such clinical studies raise costs considerably.
Prof Wald believes the structure of his latest study is highly statistically significant. Mr Smith points out that its duration was still short-term, over a matter of weeks, and that its participants were unusually committed and motivated, raising concerns over how far the results can be generalised to others.
A third issue is the reaction of the wider medical establishment. A single “one-size-fits-all” polypill reduces the complexity and cost of identifying different types of patients, instead using the simple test of whether someone has reached 50 years old, when cardio-vascular risks begin to increase, but it may not work for all. Some fear it will be a substitute for improved diet, exercise and other low-tech approaches.
David Taylor, professor of pharmaceutical and public health policy at the University College of London school of pharmacy, and participant in the trial, says a polypill that people could buy over-the-counter and use without seeking doctors’ visits is a threat to their profession. “The polypill would mark a challenge to paternalistic medical assumptions with a shift away from medical control,” he explains.
While such concerns could prove difficult to overcome, a growing number of niche pharmaceutical companies are starting to examine the “repurposing” of generic medicines for new uses with less uncertainty over safety because of their well- established existing record in patients for other uses .
They are also finding ways to overcome the limits on patents and provide reassurance to investors.
The polypill itself still faces considerable challenges, but it highlights fresh efforts to challenge the traditional model of drug development.