The Urgent Need to Reform the Present System of Medicines’ Regulation
It has been abundantly clear for many years that the current regimen for the licensing of medicines is not fit for purpose. The process has become increasingly lengthy so that it may now take up to twelve years to take a new medicine to market. It has become extraordinarily expensive so that figures over a billion pounds are quoted for taking a drug to market. The claimed benefits that accrue from this prolonged and expensive set of procedures – that they identify rare side-effects and provide better evidence for efficacy - do not justify either the delay in making an effective medicine available to patients nor the exorbitant price that the medicines then cost. This issue of RRCT is devoted to looking into the background of the problem and to considering from a variety of points of view what safeguards medicines regulation should provide and how the present situation can be reformed.
At the outset of an issue devoted to the reform of medicines regulation, it must be emphasised that no rational person would deny that some system of medicines regulation is essential to protect the public from being sold valueless and/or dangerous, products by charlatans or snake oil salesmen or those whose enthusiasm has obscured their judgment.
It is also curious and anomalous that in the UK, the Medicines Act of 1968 excluded from its remit herbal medicines and foods with vague medicinal claims; and there is still little or no regulation for such products. There is not even a requirement that their composition is fully determined, or is reproducible from batch to batch, nor it is always clear whether such remedies are free of substances that are subjected to medicines regulation. The use of these alternative medications in the UK is very considerable and a figure of £1.6 billion per annum is estimated to be spent on alternative therapies. It would certainly seem appropriate that when an efficient and proportionate procedure for licensing medicines is put in place this should be extended to alternative medicines. However, in this issue, we are exclusively concerned with the licensing of medicines that are subjected to the Medicines Act (1968).
I have taken a keen, albeit outsider’s, interest in this subject for many years. In 2011, I was invited to give the Ver Heyden de Lancey lecture to the Cambridge Law Faculty on this topic, an edited version of which was published.
However ten years earlier Michael Hanlon wrote an article (New Statesman of 23 July 2001) based on an interview with me. This is quoted below because he writes so well and so little has changed in the interim!
How the law keeps us ill
Michael Hanlon – New Statesman 23 July 2001(reproduced with Michael Hanlon’s permission)
If anybody finds a cure for cancer, it probably won't be used. Our obsession with safety keeps effective drugs out of the surgery.
Gene therapies, the human genome project, amazing new molecules that can zap the blood supply to cancerous tumours - it seems as if medical science is advancing in leaps and bounds. Surely it can be a matter of only a few years before cancer, Alzheimer's, Aids and the rest are consigned to the same dustbin as smallpox and the plague?
Well, maybe not. Sadly, a paradox is emerging in medicine. While scientific advances are taking place at an unprecedented rate, progress in the doctor's surgery is rather slower - in many instances, slower than it has been for much of the past century. And the reason often has little to do with funding or expertise, but more with our newfound obsession with "100 per cent" safety and the growing role of lawyers and litigation in modern medicine.
Nowadays, any new drug must be tested, and tested again. Many experts believe that the testing regimens now insisted upon by the licensing authorities have resulted in unnecessary costs and delays. According to Professor Peter Lachmann, the president of the Academy of Medical Sciences, our legally enforced desire that all drugs are completely free of dangerous side effects has, in many instances, gone too far. "The regulatory regimen for drug approvals imposes very high costs for the few lives saved," he says.
Saving lives costs a lot these days. Firstly, the drug needs to be created, and tested for efficacy. Then, after a long process of testing on animals, the procedure moves to clinical trials on human beings. Then, and only then, can a licence be applied for.
In Britain, this is the responsibility of the Medicines Control Agency; in America, it is the job of the Food and Drug Administration. The administration's concern for safety knows no bounds. Mindful of the Thalidomide disaster in the 1960s, it now insists on tests so rigorous that the introduction of a new product can take a dozen years or more, and cost tens of millions of dollars.
Even after the clinical trials have been completed, drug firms must usually undertake costly post-release surveillance to detect rare complications that might occur. And even after all this, problems can crop up to deny thousands of people an effective treatment for their disease because a few have come to harm. In the late 1970s, the drug Opren was withdrawn after it caused the deaths of a number of elderly patients. The drug was - and is - one of the most effective treatments for the agonising pain of rheumatoid arthritis. But because it was ill-advisedly licensed as a general painkiller, rather than a drug specific to this disease, it had to be taken off the market entirely, rather than being relicensed for use only by specialist physicians.
Fuelling all this precaution is the fear of litigation. Already, patients who willingly took part in trials of drugs to combat Aids have started to sue over the side effects. When the lawyers start to circle, disclaimer signatures are worth far, far less than the paper they are scrawled on. In the 1970s and 1980s, thanks to the threat of litigation, the number of firms willing to produce vaccines dropped to nearly zero. Eventually, governments had to step in and underwrite the drug firms. Experts acknowledge that there is a problem with litigation, and admit that, when it comes to medicine, logic often takes a back seat. "We can all agree that it is better to see a few people dying than a lot of people dying, but when it is their mother who might be one of the few, people don't see it like that," one Department of Health bureaucrat told me.
The matter was addressed in a much more formal setting by Sir David Cooksey in his Report to the Government of 2006 where he points out that the present system or drug regulation is not sustainable and recommends that it needs change. Quite extraordinarily, this aspect of the Cooksey Report was completely ignored by the government of the day.
However, as will become apparent from the papers in this issue, this log jam has finally started to break up and a number of steps, albeit rather small steps, are now coming into use, both in the United Kingdom and in the European Union and in the United States. Although, in my opinion, none of these solutions takes us very far since they leave the essentially faulty system intact, albeit subject to exemptions, nevertheless this is likely to be the start of an unstoppable process and, the present system will gradually, and probably at an increasing rate, be replaced. What is attempted by the papers in this issue is to point the way that things are going, what the regulatory procedures should be based on, and analyses some of the important road blocks.
John Harris, who is the Professor of Bioethics, at Manchester, writes on “Access to medicines and the safety of people” with a well-argued exposition of the philosophical situation and offers a moral basis for achieving appropriate access to medicines. What he says should certainly guide all the other arguments.
Dr. Brian Davis, who has many years of experience as a regulator of clinical trials with the Department of Health and belongs to that admirable class of regulators who solve problems rather than create them, gives an account of the “Genesis of the changes that now regulate clinical trials”, beginning from the earliest forms of regulation to the situation as it is now and this sets our background.
Peter Feldschreiber and Sir Alasdair Breckenridge discuss the consequences of the thalidomide disaster in the late 1950s, which I have also described elsewhere, and conclude that the balance between public health and intellectual property is no longer appropriate. Peter Feldschreiber is a barrister with considerable experience in medical law and Sir Alasdair Breckenridge was Chairman of the regulatory authority, the Medicines and Healthcare Produces Regulatory Agency (MRHA); so their views on this subject carry considerable authority.
The changes that are now coming into place are discussed by Professor Richard Barker and Professor Sarah Garner, who give an account of the initiatives on adaptive licensing and early access to medicines. Professor Barker is a founder director of Centre for the Advancement of Sustainable Medical Innovation (CASMI) and he and Professor Garner probably are better informed on this aspect than almost anyone else.
My chapter describes the problems and a possible solution seen from someone whose has not been a successful entrepreneur and has had involvement with pharma only as a member of scientific advisory boards. My suggested changes are much more radical than anything currently being proposed but which I nevertheless have the temerity to suppose are in the mid-to longterm inevitable. They aim to address a further major problem with the current arrangements; that it is impossible for small biotech companies, or indeed academic departments, to take a medicine to market because of the huge expense involved. For this reason alone there are certainly a substantial number of highly promising medicines and approaches to treatment that have been subjected to initial preclinical studies and found to be promising, and may even have gone through the early stages of clinical trial, but which no major pharma company has finally taken through Phase 3 trials and the termination of the regulatory process. This problem must be addressed if we, as a population of patients, are to get anything like appropriate value from the biomedical research which is currently going through a golden age at the same time as the rate of production of new drugs is rapidly falling off.
One of the formidably important factors in drug development is not primarily, or solely, concerned with safety and efficacy but is concerned with the financial aspects of drug development. Since throughout the world the great majority of drug development is done by private companies, this is a hugely important aspect of the problem which many of us who come to it from the point of view of biological scientists are not sufficiently aware of.
We are therefore very fortunate in having an extensive analysis of this aspect by Dr. Jack Scannell, Dr. S. Hynes and Dr. R. Evans which lays this difficult problem and its consequences out in great detail. It is very unlikely that any really radical solution to the financial aspect such as taking drug development out of the hands of companies and into the public sector is remotely feasible and therefore the conclusions of Dr. Scannell and his colleagues are absolutely central to achieving the proper reform.
As he points out, not only are these reimbursement models very expensive but they also add a considerable period of time between the completion of clinical trials and the final licensing of the drug.They also occasionally give rise to rather bizarre events. One example is the recent introduction of Alemtuzumab (antiCD52) as a therapy for multiple sclerosis. This monoclonal antibody had already previously been licensed for the treatment of lymphomas where the dosing was rather different. The company that owns the patents on this monoclonal antibody then withdrew it from use in order to be able to relicense it for use in multiple sclerosis at a very considerably enhanced price. This has given rise to considerable disquiet in many circles and adds urgency to the problems of devising reimbursement systems that are fair to all parties including the health services that eventually pay for the drugs and the patients who wish to benefit from them.
Finally, it is of course difficult to persuade people to produce change and this requires expertise, money and devotion. The final paper by Jennifer Bryant-Pearson and James Hargrave describes the work of Empower: Access to Medicine, a charity set up in 2011 by Les Halpin, a biotech entrepreneur, who developed and subsequently died of motor neurone disease. He became acutely aware of the paucity of new drugs and the great difficulty of getting novel drugs to market and started this charity whose lobbying role was taken over by Jennifer Bryant-Pearson and who are making an excellent job of it. They give an account of how they set about trying to achieve change done in the United Kingdom.
This article was orginially published in Bentham Science