Harnessing clinical data

Clinical trials are becoming increasingly complicated and expensive, and the pharma industry must accelerate efforts to improve the efficiency of its processes.

It is estimated that at the moment only around 11% of drugs that enter clinical testing will eventually be approved in the US and Europe – which is a decline from a decade ago when the success rate was 16%, according to data from the Tufts Centre for the Study of Drug Development.

Moreover, despite considerable effort to reduce testing time and bring new medicines to market faster, timelines have actually grown around 15% over that period with nearly all studies – up to 94% – needing an increase in study duration to meet patient enrolment targets.

Rising numbers of studies mean one in every 200 patients worldwide would need to be enrolled into a trial to meet the current demand, yet data from the Christensen Institute suggests only 5% of cancer patients enter studies.

Adding to the challenge, trials are also getting increasingly complex. In part that stems from pharma’s appetite for developing drugs in more challenging diseases, such as cancer and central nervous system (CNS) disorders. These need more time to show a therapeutic effect and a lot of data to be collected in terms of assessment of disease staging and progression and – increasingly – genetic and biomarker read-outs.

That means protocols are generally getting more intricate, with more procedures, tougher eligibility criteria and rising numbers of investigator sites – driving up costs so companies are striving to squeeze as much value as possible out of each trial they sponsor.

Rising numbers of combination trials and studies of advanced therapy medical products (ATMPs), as well as greater adoption of adaptive trial designs (which allow protocols to be modified depending on initial patient responses) is also driving up complexity, with the average number of endpoints doubling between 2002 and 2012.

Protocol amendments because of almost inevitable recruitment delays often require notification of regulatory authorities and ethics committees, further holding up the process.

So what can be done? It is clear there is no magic bullet, but there is hope that a combination of measures focusing on patients, investigators, standards and the adoption of new technologies could help improve matters.

There is a bright future for clinical research [in] the convergence of wearables, mobile tech and therapeutics

Patient-centricity
One topic on which all parties seem to be in agreement – including pharma companies, CROs, investigators and ethical committees – is the need to find new ways to engage the public so they become active, informed and committed trial subjects. In turn that relies on ensuring trial protocols are sensible.

Martin Robinson, executive vice president and co-founder of the International Academy of Clinical Research (IAOCR) gave an example of how poor protocol designs can wreak havoc with recruitment rates. While working a few years ago for a major CRO, his company was asked to conduct a shingles study that required patients to spend a week in hospital.

“If you’ve got shingles, the condition is uncomfortable enough without having to spend days away from home,” he said. “Sure enough, we were contracted to recruit 1,000 patients and we recruited two.” The scenario is sadly all too common, with data suggesting that 11% of studies fail to enrol a single patient.

There are signs that pharma companies and other sponsors are recognising the importance of patients. They are being integrated into the drug development process earlier – for example by asking for feedback on draft protocols and procedural schedules from advocacy groups – although adoption of these approaches remains patchy across the industry, said Robinson.

Last year, Sanofi became the first top 10 pharma company to appoint a chief patient officer appointing Anne Beal to the role. The drugmaker also ran a pilot programme called CHOICE between 2013 and 2014 designed to make its clinical trials platform “responsive to what patients value in health solutions,” according to Melva Covington, who led the project at the company.

The initiative encouraged collaboration between Sanofi and partners – including investigators, review boards, regulators, vendors/CROs and payers – with an emphasis on communication and sharing best practices, training, and measurement tools for quality and performance, along with the creation of a data repository for easy access to references, guidance and resources.

In the UK, a public-private initiative called INVOLVE – backed by the National Institute for Health Research (NIHR) – has been working on drawing up standards for public involvement in research and looking at new ways to involve the public.

The overarching aim is to encourage people to come forward and join trials, and ongoing initiatives include reaching out to the public through social media, introducing plain-English summaries as a requirement for NIHR funding of trials, and developing a database of groups that support active public involvement in research.

“No researcher or institution who applies to the NIHR for funding can expect to be successful without a plan for public involvement that lay reviewers have scrutinised,” said Simon Denegri, NIHR director for patients and the public in research, and who chairs INVOLVE, in a recently-published report on public engagement in NHS-funded research.

Both in the public and private sector more thought is now being given to the practicalities of clinical research to make sure trials work for patients as well as satisfying the scientific, ethical and logistical facets, according to Robinson.

Meanwhile, lawmakers are trying to incorporate patient involvement as a legal requirement of the regulatory process. The 21st Century Cures Act, which recently cleared one of its major hurdles by being approved by the House of Representatives in the US, includes a basket of initiatives aimed at improving access to new drugs – and puts patient engagement at the top of the agenda.

The CCA also has a number of other facets that will impact clinical trial sponsors, including the creation of a new Commission on Data Sharing for Research and Development that will be responsible for creating a resource to allow researchers to share data and develop clinical practice guidelines and best practices.

It also specifies that the FDA should develop a framework for increased use if adaptive designs and calls for closer links with the EMA and other overseas regulators on the development of a network for carrying out clinical trials in children. Meanwhile, a similar initiative is underway in the Senate suggesting legislation could be debated in both tiers of US government before the end of the year.

Technology
The advances in technology such as remote monitoring devices can be a real boon for patient engagement, for example by reducing the need for subjects in trials to attend clinics as data is sent automatically to the investigator.

“There are opportunities to make trials more patient-friendly, and the industry is starting to realise this now,” according to Robinson. Only around 30% of patients live near trial sites, and patients report inconvenience is the top reason for dropping out of a study.

In a report on the use of technology in trials, Tata Consultancy identified a range of initiatives being explored by industry. In the trial planning stages, these include social listening and big data analytics for greater understanding of patient needs that can aid patient recruitment and retention and the use of electronic platforms to get patient and physician feedback on protocol feasibility.

During trial execution, there are preliminary moves towards the integration of wearable devices and cloud-based technologies to monitor patients as well as gamification to encourage engagement, as well as the use of real-time, risk-based monitoring (RBM) of investigator sites. In future, it is expected that artificial intelligence could be harnessed to tease out more sophisticated findings from clinical trials data.

Drugmakers are however recognising that layering new technology and devices into studies is outside their core expertise, and enlisting the aid of partners to help.

“We cannot do it ourselves,” according to Any Brown, Novartis’ global programme head – trials of the future – who presented on the topic at the Clinical Innovation Congress held in London in March. “In fast moving digital technology areas we have to work with the best partners out there.”

One example of that is Novartis’ recent deal with Qualcomm for access to its 2net platform for ‘wireless health’, a cloud-based system for remote patient monitoring via the integration of sensor-embedded medical devices, smart devices and clinical data.

The drugmaker said in January that it would use 2net for observational trials, using smartphones to collect biometric data from patients with chronic lung disease, while Roche is also planning to link to the system and Walgreens Boots Alliance has signed up to use it for remote patient monitoring, transition patient care support and chronic care management.

Novartis also recently set up a $100m investment group DRx Capital – specifically to seek out opportunities in wearable, mobile and digital technologies.

The impact of Apple’s foray into healthcare – and particularly the launch of its ResearchKit – should not be underestimated, according to Glen de Vries, president of Medidata Solutions.

“The fact that Apple has chosen to make it open source is going to create benefits for patients, for academic researchers and for the whole life sciences industry [and] we expect huge numbers of apps to be created with it.”

Medidata and others are now working on ways to connect ResearchKit with their own platforms for EDC and trial management, as well as third-party laboratory and medical record data.

Meanwhile, IBM’s recent move to create Watson Health and forge partnerships around its supercomputer expertise with Apple, Johnson & Johnson (J&J) and Medtronic is a clear example of how the interests of technology and life sciences companies are converging.

It is also indicative of the importance of handling the huge amount of data coming from trials but also even larger projects such as the TrialViz collaboration in the UK between Dataline Software, the Clinical Practice Research Datalink (CPRD) and the University of Sussex, which endeavours to tap into the electronic health record (eHR) databases in the NHS.

The web platform enables users to interactively select suitable patient cohorts for trial studies by searching through billions of primary and secondary clinical events, tests and prescribing information from a cohort of 15m patients.

“In five years’ time, it will be possible to measure a full set of vitals 24 hours a day,” according to Mike Bartlett, senior enterprise architect at Lundbeck, and this will provide access to previously unavailable data such as physical activity and sleep patterns, blood and glucose levels and even social interactions. The company is hoping to start trials using wearables later this year, he said.

Data privacy issues will have to be addressed, and in the context of 24-hour monitoring there will need to be clear understanding on what data must be collected and reported to the regulators and even what constitutes and adverse event. For instance, should the latter be based on patient feedback or data, he asked, noting that it may be challenging to filter out the background ‘noise’ of daily activities.

Eventually, the industry might be able to go the regulators with the infrastructure in place to monitor patients and keep them safer than ever before, because of the sensor technology, and potentially be able to get conditional approval earlier, said Brown.

It could also potentially herald a shift away from the current system of pharma companies being paid for medicines to being paid for patient outcomes in the real world, he suggested.

Standards
This futuristic effort is being matched by a somewhat more mundane attempt to make current processes more efficient, and that is the rationale behind TransCelerate – a cross-industry pharma consortium with 13 initiatives underway (see fig 1) to agree common standards, practices and platforms.

These include guidance on RBM, a registry of investigators that can streamline recruitment and mutual recognition of Good Clinical practice (GCP) training to avoid investigators having to sit through multiple rounds run by different companies.

Keeping investigators on-board is particularly important as a CenterWatch survey in 2011 found that around a third of investigators in the US and half of those in Europe had never participated in a second study. The reasons given included the complexity of completing contract and regulatory documents, late payments, difficulties in recruiting patients and burdensome GCP training.

While less glamorous than harnessing leading edge technologies, TransCelerate is already showing that much can be achieved through collaboration and shared learning. Pilots on RBM have shown it is possible to slash costs by 19%, for example, while facilitating procurement of drugs for comparative trials slashed costs from $29m to just over $20m in 39 transactions.

“Overall, we think there is a bright future for clinical research [in] the convergence of wearable devices, mobile technologies and therapeutics,” said Brown. “We are doing this right and we think it’s the way forward.”