The tribulations of clinical trials

Targeted treatments based on whole genome sequencing and the time taken for conventional trials in the face of emergencies like the current Ebola outbreak are presenting new challenges to clinical trial designers.

Advances in whole genome sequencing have made it possible to identify unique druggable alterations in individual tumours but real-world application of this technology in diseases such as pancreatic cancer remains a challenge.

In an ongoing Australian pancreatic cancer clinical trial, the Individualised Molecular Pancreatic Cancer Therapy or ‘IMPaCT’ trial, researchers have been learning ways to bring about a new paradigm of personalised cancer care for pancreatic cancer and other aggressive cancer types. In conventional terms, the trial could be viewed as a failure, as to date it has been unable to recruit eligible patients. In reality, ways have been identified in which it can bring about a new model of personalised cancer care.

IMPaCT arose to exploit results from genome sequencing of pancreatic cancer under the auspices of the Australian Pancreatic Cancer Genome Initiative, a member of the International Cancer Genome Consortium (ICGC) in Australia. Sequencing revealed that small subsets of patients with changes in their tumour genome could benefit from existing therapies.

The pilot stage of the IMPaCT trial assessed the feasibility of acquiring suitable tumour specimens for molecular analysis and returning high-quality actionable genomic data within a clinically acceptable time frame.

Initially, the single-arm trial screened patients for three molecular targets: HER2 amplification, indicating treatment with trastuzumab/gemcitabine; KRAS wild-type, indicating treatment with erlotinib/gemcitabine; and DNA damage repair pathway defects, indicating treatment with platinum-based chemotherapy. While patients waited for the molecular analysis results, they were permitted to start standard-of-care chemotherapy treatment.

Patients in the initial cohort of the trial underwent disease resection, and 70% of patients eventually had disease recurrence. The researchers began collecting tissue for analysis in 2009; however, by the time the first trial site opened in April 2013, only eight patients with eligible molecular targets remained alive.

The researchers altered the trial design to conduct real-time screening for mutations in patients diagnosed with untreated metastatic disease. The screened mutations were expanded to include KRAS, BRCA1, BRCA2, PALB2 and ATM.

Out of 93 patients whose tumours were examined, 76 samples were of sufficient quality to be screened using next-generation genomic sequencing. Only 22 patients were deemed eligible to participate in the trial because their cancer cells contained one of the three molecules that could be treated with existing therapies.

Unfortunately, none of the eligible patients went on to receive targeted treatment. The researchers encountered many hurdles. The technology was very new; there was much scepticism about ‘genomic medicine’ to overcome; many complex administrative processes and protocols demanded by current clinical trial frameworks had to be observed in setting up the trial at three hospital sites; and they were dealing with a cancer that killed swiftly once diagnosed, so sequencing of the tumour had to be fast.

“Our data highlight just how difficult it is to do this sort of trial in a poor-prognosis cancer like pancreatic cancer,” said Lorraine Chantrill, MBBS, FRACP, medical oncology staff specialist at Macarthur Cancer Therapy Centre in Campbelltown Hospital, and a researcher at The Kinghorn Cancer Centre, Garvan Institute of Medical Research, both in Australia. “We know that, unfortunately, only about 15% of the population had molecular targets eligible for this type of treatment and that it has been very difficult to do the molecular analysis quickly enough before patients get too sick to be treated.

“It became very clear to us that patients with advanced pancreas cancer can’t afford to wait protracted periods of time for sequencing results before they start treatment, and they also don’t want to be ‘randomised’ and risk being given ‘standard-of-care’ therapy - which isn’t very effective in the case of pancreas cancer - rather than targeted therapy,” said Dr Lorraine Chantrill.

“We are now particularly aware of the need to have efficient multidisciplinary teams that can work quickly to obtain patient consents, collect high-quality tumour samples, analyse them and return the results within a month or less.”

Two amendments have been made to the trial to make it more appealing to patients and their doctors. Patients will now receive the best-known treatment available while they wait for sequencing results - which will then guide further treatment in all cases. No-one will be randomised from now on.

Professor Andrew Biankin*, MBBS, PhD, senior author of the study, observed that while the sequencing could be performed rapidly, simple logistics such as specimen access from hospital pathology departments resulted in the greatest time delays. “We can do the scientific part, but the societal and systemic parts pose the greatest hurdles,” he said.

“A disruptive approach, such as our ability to sequence cancer genomes, poses substantial problems for traditional healthcare systems, which have grown organically to accommodate other technologies and other practices.

“We now need to modify and align conventional health and research systems with new technologies and practices, interact more closely with regulators and payers, and work with government and industry partners to circumvent hurdles for the benefit of our patients.

“We have made a good start in mapping out what is necessary, the challenges that we need to overcome. Only by actually doing it will we work out the right way forward,” said Biankin.

“We have found that a non-randomised trial is more appealing to patients in this situation,” Chantrill said.

Andrew Biankin went on to say: “It highlights how current healthcare systems are not well aligned for a more personalised approach to therapy. Lessons learnt here could inform appropriate changes in healthcare systems to enable precision medicine in practice.

“It is important for the public to know how hard it is to put into practice molecularly guided treatment within the constraints of our health service delivery,” Chantrill added. “We hope that our work will help others who are planning similar studies.”

The Ebola epidemic could return with a vengeance unless lessons about medical trials are learnt

Health experts have warned that a greater flexibility must be brought to medical trials to combat diseases like Ebola to avoid facing another nightmare outbreak.

The rapidity and spread of the Ebola outbreak and the urgency of a response led to many challenges not least of which was to advise those managing people on the ground of the best way to treat the illness and which treatments might be effective.

The conventional design of medical trials may have been too time-consuming and demand recruitment of too many patients for what was a very urgent situation. The experts have urged a greater flexibility be used in future.

One of the experts, Professor Sanjeev Krishna, of St George’s University of London’s Infection and Immunity Institute, said: “The challenges posed by the current Ebola outbreak affect all types of interventions. These include difficulties in evaluating new potential drugs, vaccines and diagnostics, especially when the numbers of individuals who are infected can change quickly from day to day or week to week.

“To design really useful and informative trials that can give results to change practice in this and any future outbreaks, we suggest highly flexible, but nevertheless powerful designs that can adapt to changing patterns of infection and mortality.”

Writing in the prestigious medical journal The Lancet Infectious Diseases, the medical experts and academics said: “Even if somehow the present epidemic is eventually contained (over a time course that is currently uncertain), the world will still be largely unprepared for the next epidemic that could strike again at any time in an equally explosive manner.”

The Ebola outbreak that has devastated parts of West Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths as of 25 March 2015.

Faced with such an exceptional event and the urgent response it demands, the use of conventional randomised controlled trials (RCT) for Ebola-related research are considered by some to be both unethical and infeasible. Others suggest that potential interventions should be assessed in non-randomised studies on the basis of compassionate use - giving patients what doctors think might work. However, these non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret results. It can also waste scarce intervention-related resources by not answering fundamental questions about their value, making them unethical in some people’s eyes.

Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. They should be included in the toolkit against emerging infections.

*Professor Biankin, who is now based at the Wolfson Wohl Cancer Research Centre at the University of Glasgow in Scotland, will be undertaking parallel trials in the UK, implementing all the lessons learned through the IMPaCT trial.