CRfocus: Table of Contents of May issue

This is the Table of Contents of Clinical Research focus 20(05) for May 2009. Members of The Institute of Clinical Research can click on the links to read the full text of each article.

Features

Strengthening Protection of Research Subjects: The 2008 Revision of the Declaration of Helsinki

John Poland FTOPRA

The Declaration of Helsinki was developed to underpin the ethical conduct of human clinical research. Eight years after its previous major update, which prompted two clarifications on contentious points, the Declaration was revised late in 2008 after a process lasting nearly 2 years. John Poland provides a detailed view of the latest revisions, which have provoked mixed responses from regulatory, ethics and clinical communities.

Lost in Translation? Challenges in Preparing Participant Information for Multilingual Studies

Nicky Dodsworth MICR CSci & Efraim Roe

An increasing number of studies are being performed in parts of the world whose first language is not English. There are challenges in translation and communicating science in a multilingual world dominated by the de facto language of English. Nicky and Efraim look at the issues surrounding translation of the patient information and informed consent forms.

People

A Career Championing UK Clinical Research: An Interview

Richard Tiner

Richard Tiner steps down as Medical Director of the Association of the British Pharmaceutical Industry (ABPI) at the end of May, after nearly 13 years in the post. Over that time, he has been a prominent speaker at ICR events, and was the first person we interviewed for CRfocus. As he prepares to move on, he reflects on the changes in the UK clinical trials landscape since the mid-1990s, in which he has been instrumental.

National update

Local & National Perspectives on Streamlining R&D: ICR Scottish Forum

Mary Mumford RICR

Mary reports on the October 2008 meeting of the ICR Scottish Forum. At the meeting, Dr Janet Messer, Deputy Director of the NHS R&D Forum, gave an overview of the initiatives to integrate and streamline R&D activities throughout the NHS, while Brian Rae, R&D Manager of the Greater Glasgow & Clyde NHS Trust, spoke about the successes and challenges in developing world-class clinical research structures in one of the most health-challenged regions of the UK.

Professional development

Spice Up Your Interview Technique

Shanoo Singh

Being interviewed can be a nightmare. Interviewing skills have been rapidly and continuously changing over the past decade. Having been both a candidate and an interviewer on many occasions, Shanoo reaches out to everyone, particularly those seeking their next strategic positions, and offers some tips on how to perform at your best in an interview situation.

Viewpoint

Always Compete on Value; Never on Cost

Andrew Smith

When the economic upturn comes, the individuals, organisations and indeed countries that will be best placed to succeed will be those that have continued developing through the lean times. As an industry, we’ve become very good at working costs out of our processes. However, focusing solely on this risks neglecting importance of creating additional value for companies, shareholders and society as a whole. The relative risk of trying to leap ahead through strategic innovation is actually lower now than in ‘boom’ years, those that innovate and survive will secure their place at the forefront of the industry for a generation.

Devices, Drugs, Directives & Directors

John Kolthammer HonFICR

To recognise that our new Chair of the ICR Board of Directors has a background in medical device development, John Kolthammer, former CEO of ICR, offers a respectful and somewhat light-hearted reminiscence to draw attention to the some of the interesting issues that have always been present at the interface between pharmaceuticals and medical devices.

Regular update

Uncertainty & Opportunity: Message from the Chair

Janette Benaddi MICR Csci

Janette inspires us to remain optimistic and look harder than we have ever done for opportunities, despite any current financial insecurities or media-fuelled gloom. To add personal despondency to this will surely reduce our individual ability to cope, and will probably also make the wider recession both longer and deeper. It’s challenging to look on the bright side, but she believes that there is a bright side for many of us, if we care to search for it.

It’s Not All Work, Work, Work…

Compiled by Andrew Smith

Our regular look at the lighter side of clinical research, including “Ten innovations that won’t add value to sponsors, shareholders or society” and engaging with patients in language that is a bit more “street”…

Stopping oncology studies early for benefit

This is my Editorial column for the forthcoming May 2008 issue of Clinical Research focus 19(5).

A recent review (Trotta et al, see citation below) has found that a growing number of oncology studies have been stopped early for benefit, with the data being used to support marketing applications. The authors analysed all studies on anticancer drugs published in the past 11 years, which included an interim analysis and were stopped early for benefit. The authors contend that this has the potential to overstate the benefit of the treatment.

The case for using interim analysis to test for harm is a strong one, tied in with safety reporting throughout the study. There is also a strong ethical and commercial argument to stop a study if it becomes apparent that the drug has no notable effect (‘failure’) or no conclusive outcome will be reached (‘futility’). However, there have been a small number of studies where interim decisions to ‘press on’ despite unfavourable results have been borne out by a significant shift in the evidence base in the latter part of the study.

The real ethical dilemma, though, occurs when a pre-registration study appears to show significant benefit on interim analysis, particularly in such an emotionally charged therapeutic area as cancer. By stopping the study early and moving on through the development programme, a sponsor is widening the group of patients who could benefit from this (presumed-effective) treatment while reducing total study costs and accelerating the drug to market. This appears both ethical and commercially sound, and is often accompanied by an immediate impact on the sponsor’s share price.

However, just as some studies ‘come good’ late on, others can ‘turn bad’ as later data emerges. This could be simple statistical chance related to the specific individuals being treated, or perhaps due to a ‘tailing off’ of treatment effect with longer-term exposure. These are the possibilities warned against by Trotta et al. If the ‘true’ treatment effect is actually smaller than reported, are regulators, doctors and patients being misled (albeit unknowingly) by the sponsor? If post-marketing studies reveal this lower treatment effect once a compound has been on the market for a few years, will the company’s sales, reputation and share price be hit worse than if a smaller, but still significant, treatment effect had been reported in the first place?

Although a protocol might be sufficiently powered if continued to completion, how much is that power reduced if only half the patient-events are recorded? How much of a treatment effect would you need to see at this reduced power to be confident that it equates with a clinically significant effect across the full duration of the study? How significant an effect do you need to demonstrate to progress to the next study in the programme, or even to apply for a marketing authorisation? This is the minefield in which Independent Data Monitoring Committees (IDMCs) operate, with experienced statisticians on hand to make judgements about interim study power and the potential for the picture to change as more data emerges. Their watchword is caution, and this is often the best route to take when faced by temptingly-good interim data; for ethical and commercial reasons, my advice is, to quote Michael Jackson, “don’t stop… til you get enough”!

References

1 Trotta F, Apolone G et al (2008): “Stopping a trial early in oncology: For patients or for industry?” Annals of Oncology Advance Access first published online on February 27, 2008, available via http://annonc.oxfordjournals.org/cgi/content/abstract/mdn042v4 [Accessed April 15th 2008]