Should ICH GCP be reviewed and revised?

ICH guideline E6 (ICH-GCP) is, along with the Declaration of Helsinki, arguably the most important document in clinical research. Although neither has any direct status in the legislation of most countries where clinical research is conducted, their principles (and in many cases more substantive details) set the tone for how pretty much everyone conducts clinical research. Since its adoption in 1996 (in Europe; 1997 in the USA and Japan), ICH GCP has been the ‘bible’ for CRAs, auditors and other clinical research professionals worldwide.

Since 1996…

The world of clinical research has moved on quite some way in the past 13 years, and even more so when you consider the period of several years that was taken for the drafting, consulting, reviewing and negotiating prior to the guideline’s finalisation. Other guidelines (most notably the Declaration of Helsinki) have been updated several times in the past decades, and have a timeline for regular review every few years.

So, following a remark made by a speaker at the ICR Annual Conference earlier this year, we wondered whether ICH E6 should be reviewed and potentially revised. We put a poll on the front page of the ICR website, and were rather surprised by the result: over 80% thought that it should be reviewed (although from an admittedly small sample). We are currently undertaking a qualitative survey, asking what elements of the guideline should be updated and/or what should be added that did not exist in 1996. We hope to publish this in September’s issue of CRfocus magazine. If you would like to share your thoughts on this, and contribute to our article, please send your comments to andrew.smith@crfocus.org no later than August 10th 2009.

Of course, this is to an extent a purely academic exercise: many of the assorted national legislations, EU Directive etc. are subtly different, and the feasibility of renegotiating such a complex document with so many stakeholders (not least the more recently research-active countries that are outside the formal ICH process) is highly questionable. Indeed, some contend that the national legal arrangements have become so much more formal and sophisticated than they were in the 1990s that any thought of change to a founding guideline like ICH GCP is futile.

Still, it is useful to consider what aspects of contemporary clinical research are poorly served by the current fragmented global network of regulation and guidelines, and how different ICH GCP would look if it were being created in 2009. I’m interested to hear what you think…

End of term reports?

You can tell it’s summer! In the latter part of July, large parts of the clinical research establishment evidently winds down for a summer recess. In the past few days, three substantial and (to a greater or lesser extent) significant reports have thudded onto my desk (metaphorically, of course – I read them as PDFs…)

• Life Sciences Blueprint – A Statement from the Office for Life Sciences (July 14th)
• The Case for Globalisation: Ethical and Business Considerations in Clinical Research (July 21st)
• Appraising the Value of Innovation and Other Benefits: A Short Study for NICE (July 22nd)

I would like to be able to give a detailed analysis of each of these documents, discussing which of their many recommendations seem to be the most feasible and/or helpful. However, arriving so close together (and as we’re getting the August issue of CRfocus to print) I have only had time to skim them so far, so the best I can do is suggest that you take a look at them yourself.

As one early aside, it might be worth considering the OLS Blueprint (an action plan to re-energise and optimise the UK’s innovative pharmaceutical industry) in the context of PICTf, which was a series of reports, workstreams and metrics that ran in the first half of this decade. Much of what has made UK clinical research what it is today had its source in the PICTf work programmes, so it remains to be seen how much of the Blueprint builds on those developments, and how much re-addresses topics that PICTf initiatives didn’t quite manage to resolve. Also, with a UK General Election less than a year away, and a change of government certainly not beyond the realms of possibility, it might be interesting to wonder how many of the report’s 12 key action points would withstand a shift from Labour to Conservative.

Perhaps more likely to maintain its relevance should the Conservatives win power next year is the report by Professor Sir Iain Kennedy’s report on how NICE might better handle the valuing of innovation in its analysis of the economic impact of new health technologies. Although it sticks with the basic ICER/QALY framework, it makes some strong recommendations on what further research is needed and on a pilot scheme for  innovation might be rewarded. This chimes with the “Innovation Pass” idea in the OLS Blueprint, which was initially portrayed in the media as something of a snub to NICE, but is perhaps more an anomoly of publication timings.

If these two reports are quite UK-specific, the middle one is definitely global in scope. Commissioned by the ACRO (the US trade body for CROs, representing the head offices of many of the world’s major contract research organisations) the report aims to demonstrate that clinical research in the “pharmerging” countries is of a comparable standard of safety and ethics of the traditional countries (ie, USA, western Europe etc.) and speed, scale and reduced cost present a compelling case for embracing the shift of larger clinical trials to these new regions rather than railing against it. From my initial reading of the report, this seems something of a tautology: because the studies are commissioned by western sponsors, often conducted by local affiliates of western CROs and designed to collect data to support western registration with the FDA, EMEA etc. is it really surprising that the standards achieved are broadly similar. Still, it’s important for the rest of society to recognise this if they hadn’t already (much of our industry realised this some years ago).

For all three reports, there is then the question of momentum. By the time the world starts getting back to speed in September, we might have had time to ponder some of their more complex recommendations, but others might have forgotten about them entirely! So, let’s make the effort and read them now…

EFGCP workshop on a single clinical trial application for pan-national studies

I’ve just worked out how long it’s been since I posted something here that hadn’t already been published elsewhere (ie, reportage or fresh comment rather than the Table of Contents of the current issue of Clinical Research focus). Things have been a bit manic here in the CRfocus office, with CRfocus and other ICR tasks (mostly related to our website and our 2010 conference) taking priority over blog-only posts. Hopefully, as the summer holiday season gets into full swing, I’ll be able to blog a bit more…

Ironically, today’s the day when I really would have preferred to reporting from Brussels on the EFGCP’s latest workshop, building on the ICREL workshop in December 2008 to discuss possible routes towards a single clinical trial application for multinational clinical studies. This could be of huge benefit to the efficiency of setting up large-scale clinical trials in Europe, and some of the contenders (eg, the “Voluntary Harmonisation Procedure” currently being piloted by the Clinical Trials Facilitation Group (CTFG) of the Heads of Medical Agencies) are very exciting indeed.

Unfortunately, my schedule is such that I couldn’t make it there without some incredibly long-winded travel plans that would have doubtless resulted in substandard reporting anyway…

I’m very supportive of this event, and this project overall. While I’m not able to report on it first-hand, I’m hoping to publish a brief report from someone else who is there today, and possibly arrange an interview or two with key participants over the coming weeks. This is too important a project not to do everything we can to engage everyone in the process.

Take part in our CRfocus reader survey

We’re always looking to make CRfocus better and more relevant to your work in clinical research. To help us with this, we’d be very grateful if you could take a short survey to tell us what you think. The survey is here and at the end of October we’ll draw a lucky winner from all those who complete the survey to receive a prize!

Comment on CRfocus editorial themes for 2009

This is the time of year when we draw up the main editorial themes that CRfocus plans to look at in the coming year. This year, we’re looking to open up this process for comments and suggestions, so please let me know what you think of these topics. Of course, if you’d like to submit an article for any of these issues, please take a look at the “Write for CRfocus” page on the CRfocus website.

So, without further ado, our proposed editorial themes for 2009 are:

• January – Career development supplement
• February – Enabling technologies (EDC, CTMS etc)
• March – Patient recruitment/retention
• April – Getting the most out of labs
• May – Quality matters
• June – Annual Conference reports
• July – Outsourcing/Insourcing
• August – Career development supplement
• September – Therapeutic updates
• October – Multinational studies
• November – Improve your performance metrics
• December – Future of Clinical Research

If you’d like to comment, please add a comment here, or email me directly on comment@crfocus.org.

Have you had a regulatory inspection? Share your thoughts…

I haven’t posted to this blog for a couple of weeks, but I thought it might be useful to add a note about an article I’m working on for a future issue of CRfocus on experiences of routine regulatory inspections. I’m interested in the different styles of inspection used either by different regulators (MHRA, FDA, BfArM etc.), or by regulators inspecting different kinds of company (eg, big pharma, small pharma, biotech, CRO, freelance consultant etc.) What do you think is proportionate and constructive to maintaining appropriate quality while optimising productivity?

I’m also interested in learning about the indirect costs of being inspected, particularly in terms of diverting staff and resources from their regular activity to prepare, take part in, and follow up on the inspection. How do you think this cost (plus the direct cost in terms of inspection fees) matches up to the value that being able to say you’ve passed a regulatory inspection add to your business.

If you have been inspected by your national regulator, or are an inspector who’d like to share their thoughts on this matter, I’d very much like to hear from you, and possibly set up an interview.

Are you going to ICPM next week?

I’m still juggling my diary and travel plans, but I’m hoping to make it along to at least part of the 15th International Conference on Pharmaceutical Medicine (ICPM), held in Amsterdam in the first part of next week.

In a packed 3 day programme, the International Federation of Associations of Pharmaceutical Physicians (IFAPP) and it’s Dutch association the Nederlandse Vereniging voor Farmaceutische Geneeskunde (NVFG) will be mapping out the current state of the art in areas including:

• Translational medicine
• Trial design
• Post-marketing research
• Off-label pharmacotherapy
• Outsourcing
• The evolving system for getting new drugs to market

The meeting will also see the formal launch of the Dutch Medicines for Children Research Network.

For more information, and to book a last-minute delegate place, visit www.icpm2008.org. If you are there next week, please do look out for me…

NICE approves Lucentis but remains in the eye of the storm

Earlier today, the National Institute for Health and Clinical Excellence (NICE) announced its final guidance, approving reimbursement for the use of ranibizumab (Lucentis) and pegaptanib (Macugen) for the treatment of age-related macular degeneration (AMD). This will please many (ie, patients, prescribers, pharma companies and, it seems, the press and the public).

But the decision will also irritate others (ie, the payers), because a course of treatment will cost NHS Trusts up to £10,000 per eye. This is particularly hard to swallow because it will indirectly end the possibility to treat AMD patients with a related drug, Avastin, that is significantly cheaper. Avastin is approved for colorectal cancer, but has been used off-label to treat AMD. The company that developed both Avastin and Lucentis has announced that it has no intention to register AMD as an indication for Avastin, on the basis that Lucentis has been modified in a number of ways that make it more a appropriate treatment. Clearly, delivering more value justifies an increased price, but many observers consider the price increase in this case to be unduly high.

Surely feeding into this decision was the innovative compromise negotiated with Novartis, who markets Lucentis in the UK, for the supplier to meet the cost of any injections required by a patient beyond the 14 specified in the guidance. This is an example of risk-sharing and value-based pricing that I, for one, applaud, and hope to see more frequently.

But despite NICE pleasing many with this announcement, they remain in the centre of a media storm following its recent decisions not to approve a number of drugs for patients with advanced kidney cancer. A few days ago, a number of eminent cancer specialists wrote of their dismay in a letter to The Times. They argued that the UK spends less than two-thirds of the European average on cancer drugs and that the models used by NICE need to be radically changed.

These are two separate points, and agreeing with one doesn’t necessarily extend to the other. The UK is widely regarded as a world leader in the field of health economics, so while I’m sure even NICE would agree that there is room to improve on their modelling, one should not assume that more sophisticated models would bring the UK into line with the rest of the EU; in fact, the models used elsewhere in the EU are likely to become more similar to those of the UK.

The one thing that does differ, though, is public attitude to value, and this is where the question becomes more one of politics than of science or economics. If a society decides to place more value on treating cancer, recognising that this would mean spending less on other conditions, perhaps without such an active patient advocacy group, then the parameters of the health economic model would change and reimbursement decisions might be different.

If a sophisticated analysis is carried out in a timely, efficient way but arrives at an answer we don’t like, the first place to look is the public values used to underpin the analysis. If these are accurate, maybe it isn’t NICE that should be criticised, but society in general.

Ask Suzanne Watt about stem cell research…

Next week I’ll be interviewing Suzanne Watt, Head of Stem Cell & Immunotherapies at the UK National Blood Service. We’ll be talking about the issues around collecting and using stem cells and their implications for clinical research. The interview will be posted as an mp3 on the CRfocus website (www.crfocus.org) and selected portions published in a forthcoming issue of Clinical Research focus.

If you’d like to suggest a question or topic for discussion, please let me know by lunchtime on Monday, August 11th.

CCRA reception at the House of Lords

I have my invitation in my hand, to attend a reception organised on behalf of the Clinical Contract Research Association (CCRA) at the House of Lords. This is becoming a highlight of my summer, and I’m really looking forward to it, as last year’s event was a great success, with many interesting conversations with new people. That was despite being held in something of a monsoon!

I doubt that I will be posting a report on the event per se, but there will probably be some nuggets of insight that will feed into future postings and articles in CRfocus.

However, I am also working on a report from a conference held by the CCRA earlier this year, entitled “Is clinical research in the UK in crisis?” “Crisis” is a word that works far better in headlines than in practice, as it tends to polarise people’s emotional response to a situation. However, the meeting did identify a number of new areas that need to be addressed to improve the position of UK clinical research, and I hope to publish a summary (based on a huge transcript) in September’s issue of CRfocus.