Month: July 2014

As I cast my eyes over the news that everolimus (Afinitor) failed to slip smoothly through Phase III trials for treatment of advanced liver cancer – as it has for advanced kidney cancer, certain cases of advanced breast cancer and specific tumours of the pancreas – I was struck by the discordance of this result.

In addition to its proven benefits in advanced tumours at these other sites, everolimus was shown to prevent tumour progression and improve survival in preclinical models. This led me to consider the many flaws of clinical trial design that may, or may not, lead to the ‘right’ answer.

Study flaws that may mislead

Professor Pal Czobor, Senior Scientific Advisor Semmelweis University, Budapest, Hungary, and Dr Phil Skolnick, National Institute of Drug Abuse, authored a thought-provoking article about compliance (Mol Interv, 2011). They suggest the extent to which patient non-compliance has damaged the results of clinical trials ­– and I extrapolate this to their consequent conclusions, licenses and approvals – has been underestimated.

They propose: “One step to improving the design of clinical trials may lie in better attempts to analyze patient compliance during drug testing and clinical development.” Hear here!

Borderline results

On closer inspection of the trial results I see that it did not only “not (significantly) improve overall survival in patients with advanced liver cancer”, the difference was borderline or actually worse for everolimus (JAMA, 2014a). The investigators reported death rates of 83.7% in the everolimus group, compared with 82.1% with placebo. Median overall survival was marginally better with everolimus than placebo at 7.6 versus 7.3 months.

Lead author Dr Andrew X. Zhu, from the Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, pointed towards other possible deficiencies. He admitted to the news website Medscape that the Phase I/II findings may not have been as positive as people had thought (Medscape, 2014).

Phase II weakness

He said: “I think the early phase I/II data with everolimus in advanced HCC were perhaps somewhat weak, in the sense that we only performed a single-arm trial. We do not have a randomized trial to tell us the extent to which the efficacy observed was really due to the drug-induced benefit or just because of some selection bias in patients.”

In the published paper itself, the research team suggest several possible explanations (JAMA, 2014b). The failure could be simply another failed trial for a drug for this notoriously difficult-to-treat cancer, they propose. More usefully, however, they reflect on the difficulty of assessing efficacy signals from phase II trials.

Surrogate inconsistency

They note that surrogate endpoints such as time to progression, progression-free survival, and response rate, for instance, inconsistently predict overall survival in phase 3 trials.

Further to this general concern, they note some of the added complications associated with assessing the safety and efficacy of targeted therapies for hepatocellular carcinoma.

They write: “In the absence of well-characterized and validated predictive bio-markers, targeted agents will likely continue to have a high risk of failure if Phase III trials are conducted in unselected populations.”

The quandary continues…

This sounds very sensible to me. On closer study of the method of action, everolimus specifically inhibits mTOR (mammalian target of rapamycin) – an enzyme with a central role in cell proliferation. It does not, however, appear to be a pharmaceutical specifically targeted to a specific genetic difference, or a cumulative change specific to cancerous cells within the tumour, treatments that act in limited populations. The quandary continues…

There remain a host of bumps at the Phase II selection point that will become unearthed with time. Their eventual management will make the journey to approval a great deal smoother.

References

JAMA (2014a) Drug everolimus does not improve overall survival in patients with advanced liver cancer. http://media.jamanetwork.com/news-item/drug-everolimus-does-not-improve-overall-survival-in-patients-with-advanced-liver-cancer/

JAMA (2014b) Effect of Everolimus on survival in Advanced Hepatocellular Carcinoma After Failure of Sorafenib: The EVOLVE-1 Randomized Controlled Trial. http://jama.jamanetwork.com/article.aspx?articleid=1884577

Medscape (2014) Everolimus fails to improve overall survival in advanced HCC. http://www.medscape.com/viewarticle/827651#2

Mol Interv (2011) The secrets of a successful clinical trial: Compliance, compliance and compliance. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109858/pdf/0110107.pdf

Let’s look at the greatest failures of last year’s clinical trials and consider where better processes could reduce the chances of defeat or of how much is written-down.

The ten clinical trials conducted in 2013 that resulted in most financial damage incurred costs of between $1.7 million (£1.0 million or 1.25 million euros by Ziopharm Oncology) and $525 million (£309 million or 385 million euros by Sanofi).

The findings, which were reported in Genetic Engineering and Biotechnology News, highlight that half (five) of the failed studies had been for cancer indications and that four were conducted after the licensing of a drug to a biopharma giant. Indications of the other products whose trials failed included rheumatoid arthritis, heart disease, depression and asthma.

So what went wrong?

In the majority of cases, the projects failed because the data did not meet the study’s primary endpoint. In the most devastating example, Sanofi measured the ability of benzamide (4-iodo-3-nitrobenzamide) to treat newly diagnosed, metastic (phase IV) squamous, non-small-cell lung cancer and platinum-resistant ovarian cancer when added to gemcitabine / carboplatin chemotherapy, compared with gemcitabine/carboplatin alone, in the Phase III ECLIPSE trial.

The top four Failure List of sponsors and products in order of increasing write-downs reads:

Client		Product	Therapeutic area	Write-down
Sanofi		Benzamide (4-iodo-3-nitrobenzamide)	Newly diagnosed, metastatic (stage IV) squamous non-small-cell lung cancer and platinum-resistant ovarian cancer and platinum-resistant ovarian cancer	$525 million (£309 million or 385 million euros)
GSK	Phase III STABILITY	Oral inhibitor of lipoprotein-associated phospholipase A2	Major adverse cardiovascular event from composite of MI, stroke and cardiovascular death	Postulated$255.7 million (£150 million or 187.6 million euros)
Merck & Co.		Adenosine A2A receptor antagonist	Parkinson’s disease	Second quarter impairment charge: $181 million (132.8 million euros or £106.2 million).
AZ and Rigel	Phase III OSKIRA-3	Fostamitinib plus methotrexate oral spleen tyrosine kinase inhibitor	Rheumatoid arthritis	$136 million pre-tax impairment (£79.8 million or 99.8 million euros

Clearly, the cost of supporting these trials is vast and informed prevention would be invaluable.

Rescue / survival measures

Two product protection strategies reported include development of a compound in another indication and evaluation of the long-term maintenance effects of a treatment that fails to demonstrate strong improvements in priority endpoints.

Reflecting on the huge losses at stake, we wonder what the best survival strategies are that clinical trial specialists have employed to salvage investment after disappointing Phase III and Phase IV findings.

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.