Right time, right place, right patient

pharmafile | January 17, 2006 | Feature | Research and Development |   

With patient recruitment such a key cog in the overall clinical trial machine, pharma and biotech businesses are increasing their efforts to hone and accelerate their enrollment efforts. Get recruitment right and the pay-offs can be substantial  -streamlined enrollment, expedited trial progress and lower costs to name but a few.

On the other side of the coin, difficulties in  patient recruitment can cause a multitude of problems, simultaneously jeopardising trial timelines and blowing budgets out of the water.

Patients are pivotal

In its report Accelerating Clinical Trials Cutting Edge Information (CEI) says 'Experts agree that patient recruitment is not just an issue for clinical trial managers, it is the issue.'

Pharma respondents surveyed for the CEI report complained that patient recruitment and enrollment consumed more of the total trial process than any other activity, accounting for 30% of the overall operation.

Industry players also viewed patient enrollment as the activity offering the greatest opportunity, and challenge, for accelerating clinical studies.

"One of the most critical success factors in clinical development is getting patients to participate in clinical trials, and to motivate them to stay until the end of the studies," says Dr Manuela Leone, general manager, Europe, at global CRO MDS Pharma Services.

Currently, speed, together with costs and quality, is a major issue; therefore, great focus has been shifted onto patient recruitment.

Recruitment woes

CenterWatch reports that almost 50% of trial delays result from patient enrollment problems and 86% of US clinical studies fail to recruit the required number of subjects on time.

But just what are these stumbling blocks to a fluid flow of patients into trials? According to Dr Leone, the barriers to recruitment and retention are well recognised in the industry and can be classified into four broad groups: subject-related; investigator-related; protocol-related; and other barriers. Gerard Dunne, chief executive officer of BELTAS, a CRO involved in patient recruitment, highlights some of the problems as:

• Difficulties in motivating patients to switch therapies
• Unaware patients
• Unsure patients with a lack of trust in the clinical trial process
• Too strict protocol enrollment criteria
• Competing trials at centre
• Insufficient pre-screening

"In addition, having to amend protocol entry criteria delays the process, as does poor study management in regard to study set-up," notes Dunne. "Looking for alternative ways to reach patients is another factor which slows things down."

Janet Jones, director of patient access and retention at global CRO Kendle, describes the challenges of patient recruitment as ranging from the fit of the patient population to the protocol, to selection of motivated sites, to motivation of patients to join a study and stay.

Factors contributing to a slow-down in recruitment include overcommitment by investigators and a lack of patient awareness and understanding of specific clinical trial opportunities and the clinical trial environment.

There is also hot competition between pharma companies clamouring for patient populations to fill a burgeoning number of trial programmes.

CEI notes that patient recruitment becomes an increasingly important and competitive issue in the latter stages of drug development, not just because of the significant hike in the number of patients required for phase III but also because these larger pivotal studies usually carry considerable relevance to a firm's bottom line.

Netdoctor managing director Alex Ballantyne says: "Increasing competition and new techniques in molecule discovery have required the pharma industry to undertake more and more clinical trials. In the rush to market the single most important factor leading to delays is the recruitment of suitable patients into clinical trials."

He points to management consultants McKinsey's 2002 report A Cure For Clinical Trials, which found that failure to get enough suitable patients in time accounts for 85-95% of all days lost in the clinical trial process. It estimated that 'taking a single month off a trial by improving recruitment could generate an additional $40 million in sales for an average drug'.

Striving for improvement

With so much at stake, it is hardly surprising that pharma companies and their service providers are now applying themselves vigorously to the business of patient recruitment, seeking solutions and strategies which will fulfill the population needs of planned studies and thus lubricate the overall drug development process.

Kendle's Jones believes the key to overall success lies with an integrated, yet tailored approach. "It is important to create customised solutions to patient recruitment, blending clinical and logistical knowledge with marketing expertise. The logistical challenge is to be in the right locations across the world and be able to access the right patient populations. The marketing challenge is to apply tried and tested principles to provide an individual brand for studies focused on motivating the right patients to join the study and stay," she says.

Dr Leone agrees that a variety of methods are favourable, noting that a successful plan to fulfill need for patient recruiting and retaining should be based on several approaches that integrate more scientific and traditional methodologies along with commercial and technological tools. Examples of such strategies include:

Effective feasibility process – This approach aims to increase efficiency by identifying the appropriate geographical regions and the appropriate site, and minimise impact of protocol complexity by securing the suitability of the study design to the actual medical practice and patient availability.

Effective patient awareness and information – This method strives to increase patient understanding and willingness to participate and remain in the study, supported by use of technology tools such as the internet. Key elements to such a strategy encompass:

• Dedicated units devoting time and tools to increase patient recruitment efficiency
• Efficient contingency plans to be clearly settled as a result of comprehensive upfront risk assessment evaluation
• Establishment of key criteria to assess site performance
• Implementation of incentive programmes
• Effective and continuous site comm-unication and monitoring
• Expanded geographical areas to include new emerging territories

Overall, the integrated application of such strategies across the different phases of the trial might constitute a step towards elimination, or at least limitation of the impact of the four towering barriers to patient recruitment.

While strategic thinking has spawned new techniques for tackling the recruitment issue, several progressive pharma companies such as Pfizer, Lilly and Wyeth have opted to establish dedicated patient recruitment operations. These adjuncts to the core pharma business are designed to provide clinical teams with an increased understanding of the complexities of the process.

"While promising, results of these initiatives remain mixed," notes Frank Kilpatrick, president of Healthcare Communications Group, a specialist US-based provider of professional clinical trials recruitment services.

So while certain big pharma businesses look to create their own remedies to patient problems, what can the service companies offer by means of a solution?

"Service companies can best deliver by not over-simplifying the recruitment and retention remediation processes," says Kilpatrick, "for example by providing metrics-based scenarios from which senior pharma managers may make deliberate investment decisions to ensure timely enrollment of those compounds deemed most promising as consistent with overall corporate drug development strategies."

According to Mindy Warner, senior vice president at Fleishman-Hillard's Clinical Trials Division, the industry is working towards having the right people in place at the right time.

"Maybe a pharmaceutical has typically had its CRO manage recruitment. While that might work in some instances, in others it will make sense to bring in a provider that can offer a broader array of services so recruitment efforts are highly focused."

The internet age

The patient shortfall remaining after investigator site and mass media recruitment may reach as high as 20%, forcing companies to look for alternative methods of attracting patients for participation. "Fortunately for pharma firms, the internet opens a window to millions of patients whose doctors do not refer patients to clinical trials," says CEI.

Beyond the increased audience, web-based recruiting offers several other advantages to pharma companies. For example, the audience for web recruitment is inherently more targeted than traditional advertising which can decrease recruitment costs.

According to Warner, the internet is also a tool that can help streamline the recruitment process allowing individuals to pre-screen for studies via the web, thus assessing eligibility and freeing study sites from this chore.

In the US, several commercial based clinical trial information companies have already been established. And in the last few years, the FDA has ordered that information on clinical trials of therapies for life-threatening illnesses should be made available to the public via the internet.

"There is a groundswell of interest currently in leveraging the internet for clinical trial recruitment, predominantly as a complimentary channel rather than in direct competition to traditional recruitment methodologies," says Ballantyne.

Netdoctor's own experience suggests that online recruitment can significantly reduce enrolled patient cost versus a traditional approach by better managing patients from initial interest to investigator clinic in as short a time as possible.

Therapy area variability

"While many recruitment strategies may apply across therapy areas, there is no one-size-fits-all approach," cautions Warner. Indeed, when it comes to recruiting subjects into trials for different diseases, patient power appears at the fore.

"Obviously patients are interested in trials with the fewest invasive procedures, greatest compensation, fewest placebo arms and greatest potential for an easy cure," remarks Kilpatrick.

Incredibly only 5% of cancer patients in Europe and the US participate in clinical studies, despite clear evidence that such patients have both survival and quality of life benefits. In testament to this fact, Dr Leone views oncology trials as some of the most complex and challenging trials for recruitment.

Recruitment barriers such as lack of reimbursement, an elderly population and referral pattern/site locations gaps may be particularly severe in oncology trials and studies in other chronic diseases that are life-threatening or have comparable target populations  for example chronic CNS disorders. As the recruitment readiness of patients varies across different disease states, so does the catchment approach that is adopted.

"For conditions in therapeutic areas involving mostly patient-initiated or preventative treatments – such as sexual dysfunction, sleep conditions, etc- the most efficient patient recruitment approaches include media-based programmes to educate potential subjects about new alternatives," says Kilpatrick.

"For less mobile populations, such as seniors, grassroots/community outreach and caregiver/support group initiatives may work best. For professionally diagnosed conditions  oncology, cardiovascular, etc – clinician education and site database assistance may provide the greatest return on investment."

The competitive element is a further factor which can impact on recruitment across therapy areas. Recruitment rivalry is more intense in popular drug development arenas, such as diabetes and cardiovascular disease, where interest is huge and trialists encounter similar challenges in finding and retaining patients to meet recruitment targets.

Looking further afield

Unsurprisingly, a drought of patients has spurred companies to broaden the geographical horizons of their quest for subjects to fill clinical trial programmes. China, Central and Eastern Europe, India, Latin America and Russia are all emerging as nascent clinical trial locations with the potential to furnish sufficient patients to loosen the recruitment bottleneck.

CenterWatch data shows that 20-30% of clinical trials are now being conducted in these so-called 'ascending markets'.

For an industry struggling to meet recruitment targets, the benefits of greater globalisation of the trial process appear manifold. Dr Leone outlines some of the key factors influencing the decision to extend trials to emerging territories as:

• The population numbers: a massive 40% of the global population lives in China, India, Brazil and Russia
• A large, treatment-naive subject population
• Low operating costs – lower salaries, travel and investigator fees
• Increasingly stable testing infrastructures, with regulatory reform really driving the growth
• GCP compliance (ICH E5 acceptability of foreign data)

However, as Kilpatrick cautions, there is no such thing as a free lunch. "Some locations represent great opportunity for quickly enrolling certain conditions  while in other jurisdictions, diseases may be unknown," he notes.

"Regulatory and logistical questions also emerge such that the economics, logistics and resources of each contemplated trial must be studied to determine whether such co-location is appropriate." This pragmatic approach to new, more exotic trial territories is echoed by Dr Dunne.

"Emerging clinical counties (ie, Latin America, Eastern Europe and Asia) offer access to large patient populations, the majority of which are treatment naive, however this is tempered by some quality and infrastructure concerns."

Despite the inherent challenges, developing nations are proving a powerful panacea to pharma's recruitment woes. Yet with so many barriers to be overcome, it is clear that successful patient recruitment demands a strategic, multidimensional approach, tailored to the individual trial.

"For each study, there will be a unique patient recruitment challenge requiring a unique solution," Jones concludes.

Summarising this patient recruitment predicament, CEI reveals many pharma companies have found it difficult to overcome the enrollment bottleneck and have suffered accordingly. "Top pharmas must now find new methods of attracting patients to their studies, or risk falling behind in the market," they warn.