Drug regulation: still room for improvement
pharmafile | August 15, 2008 | Feature | Research and Development, Sales and Marketing |Â Â drug safety, medicines actÂ
This year is a bit of a jamboree of health-related anniversaries, with the NHS celebrating 60 years and the Medicines Act 40 years, presenting an opportunity to look back at how things have (or haven't) changed in the intervening years.
I won't attempt to give you an authoritative guide to modern drug regulation, but rather to look quizzically at how it has developed over the years and at some of its oddities. I will consider clinical research in more detail as it's where I work, and the area has received more than its fair share of new legislation recently.
Setting up modern drug regulation
The UK's Medicines Act was passed in 1968 and became law in 1971. During the preceding 40 years, an acceleration of new discoveries changed the face of medicine. Sulphonamides for the first time could treat bacterial infections, followed very rapidly by penicillins, and then tetracyclines and expanding families of other antibiotics. Hypertension became treatable, initially with rather unpleasant centrally acting compounds, then methyldopa, beta-blockers and diuretics. Psychiatric hospitals started to close when psychosis could be controlled. Cancer prognosis improved dramatically when cytotoxic drugs appeared.
This is just a small sample of the new drugs which became available to doctors to prescribe, and all without any real controls over how they were developed and used in patients. When the Medicines Act became law, all drugs on the market at the time were given licences of right, because it wasn't practical to make them all go through the process of providing evidence of efficacy, safety and quality. All new medicines of course had to provide such evidence, and have done ever since – with the notorious exception of homeopathic products which, as of September 2006, do not have to provide any evidence of efficacy.
Legislation developed in similar ways in other developed countries, although regulation started considerably earlier in the US. Indeed the Pure Food and Drugs Act of 1906 shows how far back the FDA's roots go. The US thought it held the intellectual high ground for decades, until thalidomide. Even though thalidomide was never licensed there, it emerged that around 20,000 US patients had been given it in clinical trials the FDA knew nothing about. Nor could it have known, as there was no regulation of clinical trials. The FDA dug deeper, liked less and less what it found about the conduct of trials in the US, and the result was the issue of the world's first standards for Good Clinical Practice (GCP) in 1977. It took 10 years for GCP to become a recognised term in Europe. In most countries where GCP applies, it has progressed from a voluntary set of guidelines, via de facto standards, to fully enacted national legislation.
Failure to achieve universal standards
Fast forward to the early 21st century, and the drug safety and regulation agenda in Europe is beginning to be dominated by EU legislation.
The European Clinical Trials and Good Clinical Practice Directives are key pieces of regulation, but unfortunately have failed to achieve in some areas the universal standard that was intended. Two areas are uppermost in my mind: ethics approval and study drug supplies.
The Directives do lay down time scales for ethics committees to process submissions, but the criteria for assessing submissions still seem to be quite open. How is it possible for over 40 ethics committees in eight EU countries to approve a protocol, while a single committee rejects it and refuses to accept any argument? That's what has just happened to one of my studies. It is unlikely that this committee knows something that none of the others do; it simply doesn't accept the scientific thesis for the study design, even though this has been accepted by everyone else and well used in previous studies within the same therapeutic area, and for drugs which are on the market. It would be inimical to force all committees to act the same and to forego their independence, but the regulators should expect a committee that rejects such well validated methodology to provide adequate references of published work in support of its rejection, which it has not done. Some of you might recognise this story from a previous article; the update is that we have re-submitted the protocol with all the information to answer the committee's concerns and it remains unmoved.
But maybe we are getting there. Fifteen years ago ethics committees were unregulated and could do what they liked, as I can testify to my cost! At least now they have to be trained and are overseen by national organisations. Just as tricky is the matter of getting study drugs across national borders, especially if the drugs are controlled, e.g. opiates. In this case, laws to address drug abuse can crash into those drafted separately to deal with medical research. For example, in many countries individual institutions are limited as to how much controlled drug they can store, which may not fit with your study protocol. Needless to say, such matters as storage limits, import and transport licences, and drug return and disposal requirements, will all vary widely even within the EU.
The UK: political and financial influences
Let's look at the UK as an example of a European drug regulation system, focusing on the political and financial aspects.
The MHRA is an executive agency of the Department of Health, and oversees government legislation and regulations in relation to medicines and medical devices. This means it has an enforcement role, but there are limits. The MHRA is not funded by taxation, but by fees. At present the majority of the fees come from product licence applications. There is clearly a difficulty here – The MHRA only has resources to regulate those who pay the fees, i.e. those submitting bona fide applications for authority to market medicines and other healthcare products. What if someone decides to ignore the law and sell medicines without product licences? The answer is that the MHRA has the remit and the authority to enforce the law, but not necessarily the resources.
To be fair, it has taken enforcement action against various purveyors of unlicensed and dangerous products, particularly some Chinese medicine shops, but has been obliged to confine these activities to the more extreme abuses. You might wonder why such shops can make astounding claims without providing evidence to support these. The truth is that they are effectively breaking the law, but nothing is done about it. The Medicines Act states that any substance sold with claims that it will treat any disease is a medicine, and such products fall within the remit of the MHRA and not normal consumer legislation. I have sympathy with the MHRA in this matter because the politicians decline to provide the resources to carry out the enforcement that is obviously necessary.
The other source of MHRA funding, and a growing one, is inspection fees. Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) have been around for a long time, and companies have been liable to inspections on these matters for just about as long. GCP, as I noted above, also has a long history, but inspections are a more recent development. In the UK they began on a voluntary basis about eight years ago, but are now mandatory. The relevant legislation is the UK's enactment of the EU Clinical Trials and GGP Directives, and again I have discussed these in a previous issue.
The UK is rapidly gaining a reputation as a particularly tough territory for inspections. I only have experience of MHRA inspections for GCP, so have to rely on hearsay regarding other authorities, but there does seem to be a consistent view that FDA inspections are less stressful. This view is also consistent with the various national legislations within the EU – the UK Statutory Instruments are more precise than others and have more detail. One example of this is the matter of serious breaches of protocol or GCP, which must be reported to the MHRA as soon as they are discovered. In fact this requirement is not peculiarly British and is a key requirement of the over-arching GCP guidelines from the International Conference on Harmonisation (ICH), which calls it 'serious non-compliance'. It's just that the UK defines it in more detail. Difficulties arise in dealing with overseas contractors who don't understand this demanding UK requirement.
Project planning
International drug regulation is highly complex and variable, and this has major implications for project planning in drug development. That's because an effective project plan will need to reflect not only geographical differences, but also longitudinal ones (over time). This means it is vital to have team members in the countries where you are planning to run a trial, to keep your planning templates updated with current regulatory practice. This is often not included in the budget, with the result that plans can be thrown into disarray.
A spring clean of medicines legislation
The MHRA has just announced a major review of existing medicines legislation, with the overall aim of clarifying and decluttering the laws that regulate the field.
Since the Medicines Act was passed in 1968 a number of amendments and expansions to its scope have appeared through the use of Statutory Instruments, new legislation which is not approved through parliament.
These legislative changes relate to the UK or arise from EU legislation, and the MHRA says this has now resulted in "a very complex and fragmented set of legal provisions".
The MHRA says the number of Statutory Instruments relating to medicines regulation continues to grow, making the current legislation unwieldy.
The agency says the aim of its new project is to ensure it can feel confident that the legislation which it uses is "comprehensive, supportive of its responsibilities and objectives, and is as comprehensible as possible".
The MHRA says its aim is to bring together the various provisions into a more ordered set, and use the review as an opportunity to make improvements and to simplify the provisions where possible.
The project will involve reviewing nearly 40 years' worth of legislation, and the MHRA believes this will take around two to three years to complete.
It says informal consultation with industry and external stakeholders will be held in October 2008, with views sought on which areas would benefit most from potential reform. The regulator says priorities for reform will be decided in early 2009, with the focus being on UK national legislation. It adds that there will be limits to how much can be changed, as much of the major medicines legislation is now on a European Union level.
The future is global
One very clear difference between 1968 and today is the globalisation of the industry and medicines regulation. Regulators around the world are now collaborating more than ever, and recognise the need to harmonise their approach when dealing with a truly globalised pharmaceutical industry.
The EMEA, based in London, is the counterpart to the 27 member state agencies, and provides a single point of access to the EU market. For the industry, this has its pros and cons. Centralised agreement should mean rapid approval across the continent, but the EMEA still has to call on one member state agency to act as its agent (i.e. do the legwork), and the risk is that they might select one that is hostile to your type of product. The EU remains very much a multi-cultural grouping. The alternative route is the mutual recognition procedure, whereby a submission is made to a single member state and others agree to recognise the first one – but this is not guaranteed.
Thus while national agencies like the MHRA will continue to play an important role, most of the significant changes to legislation will come from the European and indeed international level.
One of the next major milestones for industry will be the switch over to electronic-only submissions to the EMEA after 1 January 2009. The move is a significant and long-awaited step into the electronic age, which is likely to pave the way for further change in the field.
Les Rose is a freelance writer and clinical science consultant with Pharmavision Consulting. For more information e-mail:lesrose@ntlworld.com
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