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The regulation of clinical trials

The great advances of modern medicine came out of a much lighter and less bureaucratic regulatory system for clinical trials. The current system, however well-intentioned, is causing deaths
Denis Mitchison
30 November 2009

The past 50 years have seen huge improvements in our ability to treat diseases, particularly infections.  Look at the local graveyard to see how many young men and women died before the age of 30 years.  We now expect there to be effective treatment for any infection and are shocked if it does not work.  This increase in efficacy has arisen from the use of randomised clinical trials (RCTs) to build up “evidence based medicine” that provides us with a guarantee for the new methods in diagnosis and treatment.   But the increasing burden of regulation that has accompanied the use of RCTs  now threatens the further development of improved technology.

RCTs were first used in medicine in the 1940s, mainly due to the pioneering work of Philip D’Arcy Hart and Archie Cochrane.  The essential concept is a comparison between two or more procedures allocated at random to the patients who are taking part.  This allocation must be done at random and “blind”, so that neither the patient nor the doctors running the trial know which patient has been allocated to a particular procedure.   The first RCT with a random allocation and blinded treatment was the trial of streptomycin for the treatment of tuberculosis (TB) by a UK Medical Research Council (MRC)Committee led by D’Arcy Hart, with Bradford Hill designing the randomisation procedure.  The further development of treatment for TB depended on a steady series of RCTs carried out world-wide over a 40-year period in an MRC program led by Wallace Fox.  A disease that used to kill half of the patients changed to one which could reliably be cured if the treatment was taken regularly for 6 months.  There has also been a steady and increasing number of RCTs in all branches of medicine, so that the technique is now fundamental to progress for all diseases. Indeed, such is their success that the procedure has now been imported to the social sciences, for example in the work on effective development aid by Esther Duflo.

At the time of the initial streptomycin trial in 1946-8, there was little regulation either in the step from production of the new antibiotic streptomycin to its use in human disease or in the conduct of the trial.  As a result, streptomycin produced experimentally by Merk in New York was tried out in patients only a few months later. As the MRC trials progressed and showed ability to cure, Merk was signalled to increase their production of the first drug treatment that had been demonstrated to work. This trial was cheap to run as the collaborating staff and hospitals did not get payment for their participation and there was little cost outside the MRC Units. Nowadays, there would be a long gap stretching out for 15 years or longer with expenditure in the region of $100 million to complete the three phases of clinical trials now considered standard practice before a drug can be licensed for human treatment.  Why has the cost and the lead time in development increased so radically?

The process of development of drugs for treatment currently goes through stages. Once a hopeful molecule has been identified, there has to be a series of preclinical tests for efficacy and for toxicity, with an important part of them in animal models of the disease. Then there are four stages of clinical testing, which are the most lengthy and expensive side of drug development.  These are phase 1, initial exploration of toxicity and drug pharmacology in volunteers; phase 2, proof of principle in patients; phase 3, licensing; phase 4 post-licensing exploration.  The development of a single drug is usually done by large pharmaceutical firms (Pharma) with the aim of getting it licensed in phase 3 by a national or international licensing organisation, such as the American FDA, for use in a specified manner for a specified disease.  In the case of tuberculosis, treatment is usually with multiple licensed drugs, to avoid the development of drug resistance; the experience with TB has also led to successful multi-drug treatment for HIV and cancer.   The RCTs to develop these complex regimens may be carried out by professional medical organisations, such as the world-wide trials for TB led by Wallace Fox for the MRC, in which I played a part.  Nowadays,  Pharma is more likely to collaborate or head the process and to provide some finance.  As compared to the original streptomycin trial, in which only about 100 patients took part over 18 months, a current TB phase 3 licensing trial may end up with 600-1800 patients and take 10 years or more to complete.   A current phase 3 licensing trial for the fluoroquinolone moxifloxacin has taken 10 years from the start of its design, and is still far from complete.

Then we come to the regulations in running RCTs.  Currently, the performance of an RCT has to be licensed by a national medicines control committee in a protocol containing every aspect of the trial procedures.  This contains details of the rationale for the trial, the patients to be admitted, the treatments to be compared, the drug toxicity expected and its treatment, the end-points to be used and how they are to be analysed.  Statisticians then make a formal guess as to the number of patients required.  Such a protocol may easily occupy 100 pages as compared to about 6 pages for the early TB trials, and there is also a laboratory protocol of similar length.  If any change is made in it, a fresh version has to be issued and, if more than a very minor change, it would have to go through the control committee again.  There is a separate control committee in every country and each passage through a committee usually takes 4-20 months.  A lesser problem is regulation by ethical committees, which have to agree every manoeuvre, however minor, that involves a patient.  Again there are ethical committees in every country and often more than one.

Finally we come to the most serious aspect of regulation, the existence of ICH (international conference on harmonisation) guidelines, which assure what is called “good medical practice” (GMP) and “good laboratory practice”(GLP).  These insist that every observation, and even communications between participants, be recorded in such a way as to make it impossible to change them.  They also insist that the practices in the clinical centres be monitored during the running of the trial to see whether detailed protocol regulations are carried out.   Monitoring has become an industry with billion dollar turnarounds and monitors are seldom capable of understanding the legitimate reasons for “protocol violations”.  What is the worst aspect of this regime is that it destroys the trust that used to exist between the organisers of RCTs and the centres doing the clinical work and replaces it by a system that is always trying to find fault with the centres and creates an atmosphere where everyone watches their backs and only does the work because it is a source of income.   Clinical trials have too often become cash cows necessary for financing the local health service.  Good laboratory practice tends to insist on American laboratory systems which concentrate (at least for tuberculosis) on expensive techniques often of dubious value:  an example is the needless insistence on keeping sputum ice-cold until examined in laboratory tests.

When we look at the whole picture, we see the increase in regulation as responsible for the rapidly accelerating cost of RCTs.  This also tends to cause the loss of good motivation in the clinical centres, often in developing countries, and the use of political rather than scientific reasons for running a large RCT in particular centres.  On the other hand, the regulations are designed to protect the patient in the RCT and also to assure the scientific value of the information coming out.  We need to strike a balance between these needs and the situation where rising costs and complexity are threatening to halt or at least seriously delay progress.   We need to bring together those who might carry out clinical trials, but are increasingly giving up the struggle to run them  and the licensing authorities, who too often sincerely believe that there are no problems to worry about.  If we do not find ways of reducing regulation and their associated costs we will find a huge slowing of medical progress, and consequent loss of lives.   We need to set slowing of progress against a possible slight increase in malpractice (if this is a real risk).  Is it possible to justify the current situation?

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