Author: clinicalaccelerator

The “choice destination” of clinical trials evolves hugely as economics of competing countries fluctuate and political decisions introduce new obstructions. The popularity of the UK, for instance, fell steeply in the 21^st century, which epitomises some of the acting forces.

With an understanding of the factors that mold these changes, we can gain a position to predict or at least consider the changes ahead and, therefore, how to select optimal sites for clinical trials.

Weakened UK position

If we look at the UK, we see that its position on the global clinical trial stage declined by almost a quarter between 2000 and now. Its global share of patients in clinical trials fell from 6% to 1.4% between 2000 and 2006, and this was echoed by a 22% cut in the number of clinical trials performed in the UK between 2007 and 2011 (Parliament, 2013).

Why?

It is thought that this change was driven in part by the EU Clinical Trials Directive, which was adopted in 2001 (Parliament 2013b). The Clinical Trials Directive brought in significant challenges to the conduction of clinical trials within the whole European Union. This line of thinking is also supported by observations of a similar downward trend in other established EU countries.

Many academic organisations agree that the Clinical Trials Directive increased the cost and bureaucracy of conducting clinical trials, with no clear improvement in patient safety or the quality of trial results (ICR, 2013).The situation in the UK is particularly challenging because it has a difficult governance and regulatory landscape (Parliament, 2013).

Inquiry continues

The Science and Technology Committee is conducting an inquiry into clinical trials. In its third report, published in September 2013, the Committee stated that although it believes the government is aware of these problems, it has not yet delivered fully on its promises to address them.

Governance and regulation

Meanwhile, a discussion published by the Institute of Cancer Research (Emedcareers, 2013) discussed the future of the UK in clinical research. Marie Palmer, Director of the UK NHS R&D Forum, pointed out that research and development is not currently a core part of a Trust’s business in the UK and that R&D is barely accountable. If insufficient patients are recruited to a trial, for instance, there are no consequences, she said. Jackie Powell, Director, Joint Clinical Trials Office, Guy’s Hospital, pointed out that investigators are currently not driven to recruit patients into trials (Emedcareers, 2013). Marie Palmer (Director of the UK NHS R&D Forum) added that this weak motivation would continue unless the Government introduces “meaningful targets”.

UK future and global context

Dr Palmer proposed that a “cultural shift” is needed within the NHS that positions clinical trials as a business and makes trusts accountable. She said that they need to be made a “core activity” to make them a genuine priority. Allison Jeynes-Ellis (Medical and Innovation Director, ABPI) said that UK clinical trial champions are needed to really embrace them.

Across the world, other key players are improving their position. Areas including China, India, South Africa, Latin America and Eastern Europe can offer more cost-effective clinical trials, through less expensive medical staff and study sites. The quality of the clinical data from these ‘emerging regions’ may cause some uncertainty but, as can be judged by the results of numerous FDA inspections, at least the Eastern European data is on par with data originating in the established regions of US, Europe and Japan.

The Institute of Cancer Research discussion concluded that the UK will improve its position but not regain the 6% hold it had at the turn of the century. Alastair McDonald, Study Program Director, Astrazeneca, noted infrastructure is improving in emerging countries and that Astrazeneca has consequently closed sites in the UK and Sweden in favour of sites such as China.

The UK Government has an ongoing interest in clinical trials and recognises their economic importance, it claims in its response to the Science and Technology Committee Inquiry into Clinical Trials (Parliament, 2013b). Weighed against the less expensive, and increasingly proficient, options in other regions, the UK could see gradual, limited improvement in its position on the clinical trial stage.

References

Parliament (Sept, 2013) Science and Technology Committee Third Report: Clinical Trials: http://bit.ly/V6iVez

Parliament (2013b) Barriers to conducting trials in the UK: http://bit.ly/1mqmphu

Institute of Cancer Research (2013) Effective action needed to make the UK a more attractive location for clinical trials: http://bit.ly/1qEp8cc

Emedcareers (Sept, 2013) Do clinical trials have a future in the UK?: http://bit.ly/TsmtpX

The Lung Cancer Master Protocol (Lung-MAP) trial uses genomic profiling to match patients with experimental treatments. It is hoped that the design will reduce recruitment and infrastructure problems for researchers.

If your medication is a gene-targeted biologic for cancer, a ‘ground-breaking collaborative trial’ of investigational products in people with squamous cell lung cancer has raised hope for one method likely to facilitate patient recruitment.

A public-private collaboration between multiple US-based, cancer-focused organisations and a group of pharmaceutical companies is screening patients with advanced squamous cell lung cancer for the gene variants linked to development of the tumour, and matching them to investigational drugs designed to treat those defects.

Biologic benefit

In view of this case, researchers developing biologics to treat cancers driven by genetic defects may want to seek out companies working on gene-targeting treatments for the same tumour and discuss the options. It is always difficult and time-consuming to enrol patients with rare and specific diagnoses. This way, patients with specified gene defects would be collected automatically through the screening stage of the trial, and the infrastructure load would be shared between the collaborating organisations.

Organisations

The public side of Lung-MAP’s collaboration was composed of the National Cancer Institute, SWOG’s (formerly Southwest Oncology Group) Cancer Research, the Foundation for the National Institutes of Health, Friends of Cancer Research and Foundation Medicine Today. The private section included pharmaceutical companies Amgen, Astrazeneca, Astrazeneca’s global biologics R&D arm, Genentech, MedImmune and Pfizer.

Reference

Press release: The Wall Street Journal/Market Watch: http://www.marketwatch.com/story/groundbreaking-collaborative-clinical-trial-launched-2014-06-16

The substantial cost of clinical trials will be reduced a fraction after implementation of the EU’s updated regulations governing clinical trials. The Commission estimates an annual saving of €800 million (1,088 million euros, £643 million).

This is about 60% of the cost of taking a single pharmaceutical to market. The claim is estimated two years before the recommendations come into practice. The earliest date they will first apply is 28 May 2016.

To put this price ‘saving’ into context, a study by Cutting Edge Information found that 42% of Phase I trials run longer than planned, which compares with 31% of Phase II and 30% of Phase III trials. Each day the trial is postponed equates to losses in drug sales of up to $600,000 (440,000 euros, £357,000) for small products and up to $8 million (5.9 million euros, £4.8 million) for blockbusters. The costs of delays – which tend to carry on for months ­– are potentially a lot more than the savings expected from these updated regulations.

Recruitment challenge

Possibly the largest factor behind clinical trial delays is slow, and insufficient, patient recruitment. A shortage of patients has been reported by CentreWatch to delay 70% of clinical trials between one and six months. A postponement in bringing a blockbuster to market of a single month could cost up to $240 million (177 million euros, £143 million).

In a news piece discussing this challenge, the Los Angeles Times quoted Dr E. Ray Dorsey, a neurologist at the University of Rochester Medical Center, who has studied the problem. Dr Ray Dorsey said: “It’s a major issue. Many trials are started and never finished because they can’t complete enrollment. A lot of money is wasted.”

However, the problem of recruitment appears to vary with geography. In a multi-national breast cancer trial that planned to recruit 3500 patients, the US arm began nine months after the other countries, with an expectation of recruiting 350 patients – 10% of the original target.

The answer?

The purpose of this blog is to explore various challenges faced by clinical research organizations and clinical investigators in implementing clinical trials within reasonable timelines and at reasonable cost, and discuss strategies to overcome them.