15 May, 14 | by BMJ
“I’m outraged,” said Robert Beaglehole, former director at WHO responsible for non communicable disease, at the end of the second polypill summit in Melbourne recently. He’s outraged because the world is failing to respond adequately to the “global public health crisis” of non communicable disease (NCD) that is destroying lives in low and middle income countries as people die from preventable diseases. In particular, said Salim Yusuf, incoming president of the World Heart Federation, only about 3% of people in the world with established cardiovascular disease are getting the four evidence based treatments of aspirin, beta-blockers, an ACE inhibitor, and a statin. We have it in our power to change that dramatically, particularly through the use of the polypill, and yet regulatory, commercial, and cultural barriers are blocking progress.
Many people at the meeting drew parallels with vaccines and HIV. It has been possible to rush to market vaccines combining multiple vaccines, to license rapidly polypills for HIV, and to find huge sums of money to combat AIDS. Why can nothing like the same commitment be found for combating NCD?
The concept of the polypill has now been around for more than 10 years, and several have been manufactured. But getting polypills licensed and finding funds to conduct the necessary research and market the polypill has proved difficult. So many of those invited to the polypill summit entered the meeting frustrated with the lack of progress, although by the end of the meeting there was more optimism.
Anthony Rodgers, a researcher from the George Institute for Global Health and the organiser of the meeting, reminded people at the end of the meeting of the classic graph of how new technologies are eventually implemented. First comes the peak of inflated expectations, which with the polypill was probably marked by the papers published in The BMJ in 2003 claiming that if everybody began to take the polypill at age 55 then 80% of heart attacks and strokes could be prevented. I wrote an extravagant editor’s choice suggesting that that issue of The BMJ might be the most important for 50 years. (In a discussion over dinner we agreed that it still wasn’t clear whether the suggestion was right or wrong.) After the peak comes the trough of disillusionment followed by the upward slope of enlightenment leading to the plateau of productivity. Rodgers thinks that the polypill has finally arrived at the plateau of productivity.
Certainly there begin to be a lot of research studies. Ferrer, a Spanish pharmaceutical company, has a polypill with three components (aspirin, simvastatin, and ramipril) for secondary prevention that it has got licensed in 10 countries, including Spain, Sweden, Mexico, and many of the countries of Central America. A public-private partnership with Ferrer and CNIC (Centro Nacional de Investigaciones Cardiovasculares) has conducted an observational study with 2164 patients looking at factors affecting adherence and is now beginning an open randomised trial of the polypill against usual treatment with outcomes of adherence, blood pressure, lipid levels, safety, and tolerability. Results are expected in September 2014.
The UMPIRE trial, which has already been published in JAMA, was conducted in Europe and India, compared the polypill with usual care in 2004 patients with established disease, and showed an improvement in adherence of 33% (86% with the polypill against 65% with usual care). The biggest benefits were seen in those not being treated and those who were non-adherent at the beginning of the trial.
The Kanyini-GAP trial used the same design as the UMPIRE trial in 623 Australians, half of them indigenous, and found a 49% improvement in adherence in those taking the polypill (70% in the polypill arm versus 47% for usual care). This trial has just been published in the European Journal of Preventive Cardiology. Again the biggest benefit was in those not being treated or who were not adherent at the start of the trial. An economic evaluation of this study, the first economic study based on individual patient data from a trial rather than modelling, showed savings with the polypill. (A review of six modelling studies from low and middle income countries and two from high income countries showed all studies found use of the polypill to be cost effective.)
A third trial using the same design, the IMPACT trial, was conducted among 513 people in New Zealand, half of them indigenous, and it too found an improvement in adherence. This study has been accepted by The BMJ and should be published soon.
These three trials were designed to allow an individual patient meta-analysis (www.spacecollaboration.org), which overall found a 43% improvement in adherence in those taking the polypill. Blood pressure was lowered by 2 mm Hg in the polypill arm, which was statistically significant, and LDL cholesterol also showed significant improvement. The key finding was that treatment was as good as “very good usual care.” The biggest benefits were seen in those who at baseline were not treated, partially treated, or non-adherent. In other words, the polypill increases equity, bringing most benefit to those who need it the most.
One other important finding suggests we can put to bed the oft-expressed concern that high-risk patients may adopt less healthy lifestyles after taking a polypill. The data show that those in the polypill arm did not at the end of the trial have less healthy lifestyles than those receiving usual treatment. Another important, but perhaps not surprising, finding was that people taking the polypill were about 30% more likely than those on usual treatment to achieve all the targets of blood pressure, lipids, and aspirin adherence.
A crossover trial from Utrecht of 81 patients asked whether it was best to take the polypill in the morning or evening and found slightly more benefits from taking it in the evening. (I take mine at night, accepting that sometimes the diuretic will mean that I have to get up in the middle of the night to pee.) The study, which also included an arm of usual treatment, found better adherence with the polypill, and that 92% preferred the polypill, 8% expressed no preference, and no patients preferred usual care.
A large study is underway in northern Iran, with its origins in a cohort study of 50 000 patients looking at gastrointestinal disease that showed many deaths from cardiovascular disease, prompting the researchers to think about what could be done to prevent such deaths. The Iranians have now manufactured their own polypills, and two different polypills are being tested in two different arms against “minimal care,” which is largely lifestyle advice, including text messages, in a trial with 8410 participants. Early results seem to be very promising, and Iran is contemplating using its network of non-physician health providers to offer the polypill to all those over 50 with one risk factor (smoking, raised blood pressure, hyperlipdaemia, or raised blood glucose). It looks as if Iran, with its strong tradition of primary care, might be the first country to use the polypill on a substantial scale.
Cardio Pharma Inc, a start-up company in the US, has been talking to regulators at the FDA (Food and Drug Administration) and is confident that it can get a polypill onto the market with a series of pharmacokinetic and pharmacodynamic studies.
A series of large trials coordinated by McMaster University in Canada are under way or about to start, and TIPS3 is a trial of the polypill in primary prevention in some 5000 people in several countries. The polypill without a way of getting it to people is useless, and Yusuf described how he begins to think of the polypill as a “vehicle rather than a drug” and has devised a trial where community health workers will identify those at risk, and offer the polypill and lifestyle advice together with a treatment supporter who will encourage adherence to both lifestyle advice and the drug; patients will also be supported by text messages.
Finally, a study using data from many countries showed that only a third of people in low income countries (excluding India, which has wide availability of generic drugs) had local access to all four drugs that are needed for secondary prevention of cardiovascular disease (aspirin, an ACE inhibitor, a beta-blocker, and a statin). Using the definition that if a person had to spend more than 20% of his or her income on drugs then they were unaffordable then the four drugs are unaffordable to two thirds of those in low income countries (again excluding India). So for most people in low income countries the drugs are unavailable and unaffordable.
The meeting thus began with a growing body of research showing how the polypill was badly needed, particularly in low income countries, and how its use could lead to better care compared with taking individual drugs even for well treated patients in high income countries. So surely it is time for regulators to license the pill.
Drug regulators, particularly those in high income countries, operate within a tight legal framework that is mostly designed to deal with large pharmaceutical companies registering new drugs that cost around a billion dollars to bring to market and then another billion to market. These companies know how to work their way through the systems, compiling huge dossiers of information and translating patient information into 25 languages in the case of Europe; and in the context of a two billion dollar expenditure the cost, probably in the low millions, of registering the drug is affordable. But the generic companies who manufacture polypills have neither the experience of licensing drugs nor the funds to meet the costs.
So this system is almost insurmountable when the aim is to register a low cost drug. But licensing the polypill in high income countries like those in Europe will be important for the companies who make the polypills in order to be able to charge low prices in poorer countries by charging higher prices in high income countries.
People at the summit made the point that European health systems are under increasing financial pressure, and innovations like the polypill that seem to lead to both better treatment and lower costs are badly needed. It works against the interests of European citizens if their licensing system allows onto the market highly expensive drugs aimed at a few, but blocks low cost drugs that could help millions.
One other critical issue is that the approach from regulators to date has focused on straight substitution (i.e. switching people from a polypill only once they have been stabilised on the same drugs at the same doses). However, this almost by definition excludes patients most in need i.e. those with adherence and access problems, and the data emerging from clinical trials shows that straight substitution has the least to offer in terms of clinical benefits, certainly compared to “step-up” substitution.
Despite the problems, Ferrer has managed to get its polypill licensed in Spain and Sweden. The cost has, however, been high, and it now needs to spend large sums marketing the drug. Inevitably the price of the drug may have to be high, although below the cost of the individual components.
During the discussion, somebody pointed out the irony that between 20% and 40% of adults in high income countries take drugs like vitamins and calcium every day, many of which do no good and some of which actually increase the risk of heart disease.
The kinds of trials that will be needed to get polypills approved cost millions of dollars. Where might the money come from? Not from venture capitalists, it seems. A venture capitalist explained how they decided on which products to back and told the audience that the polypill was unattractive. The need for relatively long term trials works against the short term time frames of venture capitalists. The inflexibility of the regulators puts them off. They are more attracted by products with high margins, which are protected in a “regulated monopoly” by chemical composition patents. The cost of marketing the polypill will be high. There is a lack of clarity around patents and intellectual property rights, and they can’t see themselves being able to sell any business to a large company within a few years, which is the way that venture capitalists recoup their investment.
Some in the audience challenged the analysis of the venture capitalist, but it’s clear that it may be difficult to persuade them to invest in companies making polypills.
The Wellcome Trust, which is interested in converting scientific innovations into products and services that benefit the public health, was more sympathetic and has already funded a large trial of the polypill in primary prevention. Government funders of research from Australia and the US warned of pressure on their budgets, but realised how the polypill could bring benefits to their health systems. Nobody has, however, devised a system that allows future savings in health systems to be used to fund research and development. Indeed, government funders warned that it was increasingly hard for them to invest in research that will produce benefits in the distant future; politicians want faster returns.
Getting the polypill used
We didn’t hear much from businesses at this summit, but we know that once polypills are made available the next challenge is to get doctors to use them. One presentation illustrated how doctors (like everybody else) have “mindlines,” which means they tend to go on doing what they have always done even until well after evidence has shown what they are doing to be dangerous. We were told the story of diclofenac, which a systematic review showed to be harmful. The review, published in The BMJ, had no impact on prescribing in Britain, nor did a letter from the regulatory authorities. It was only when the information was packaged in a simple form and delivered to doctors by people who went to see them (as drug company representatives have done for years) that prescriptions began to drop, although at very different rates in different areas. And it was only when a financial incentive was introduced that prescriptions dropped away to nothing.
The message for polypill proponents was that encouraging the use of the polypill will not be easy, but it may be easier in places, like many low income countries, where there are few doctors and new systems, using community health workers, will be needed to provide access to the polypill.
Beaglehole, although outraged by the failure of global authorities to recognise how the polypill could help with the global emergency around NCD, was optimistic. Governments have signed up to reducing deaths from NCD in those under 70 by 25% by 2025, and the polypill could be very helpful in achieving that target. We now have much more supportive research, and some polypills have been licensed in some markets. He was encouraged by the message from regulators of the need to work together, and he’s optimistic that his own small country, New Zealand, might be able to get a polypill licensed, providing a company was interested. He took heart as well from the achievements of those who promoted treatment for HIV and thought that they should be part of the next summit.
He concluded, however, that polypill proponents need to “get serious, get organised, run a campaign, and work out a strategy for the next five years.”
By the time of the next meeting, in Mexico in 2016, we aim to be well into the plateau of productivity.
Competing interest: RS works for UnitedHealth, which was one of the sponsors of the meeting, and the company paid his expenses to attend the meeting. UnitedHealth has no direct financial interest in the polypill. RS is a longstanding enthusiast for the polypill, has been in a trial of a polypill, and has been taking it for about five years.
Richard Smith was the editor of the BMJ until 2004 and is now chair of the board of trustees of icddr,b [formerly International Centre for Diarrhoeal Disease Research, Bangladesh] and chair of the board of Patients Know Best.