January 1, 2012 (Vol. 32, No. 1)

Josh P. Roberts

Cancer drug development is perhaps the most arduous task faced by the drug industry today with technically difficult, time-consuming, and expensive clinical trials constituting the lion’s share of that challenge.

Merely handling the logistics of the trials—how and where they should be conducted, recruiting patients, and monitoring the sites—can be daunting for cost-sensitive pharmas, which is why more and more turn to contract research organizations with oncology expertise to help tap the lucrative cancer therapeutics market.

Researchers from several of these CROs shared their thoughts at “Oncology Trials Outsourcing”, a virtual conference hosted by Outsourcing-Pharma.com.

Oncology clinical trials increasingly require the assessment of biomarkers, molecular and genetic profiles, and complex pharmacokinetics, often involving the services of a central laboratory, pointed out Julie Gargano, therapeutic area director, oncology, for Novotech.

The total number of unique procedures performed per protocol has increased by more than one-third in the past decade, said Roberto Lara, manager, business development for Scimega Research. This, in turn, has led to a huge rise in the administrative burden sites are saddled with.

At the same time the total number of trials being conducted is increasing—there are nearly 10,000 oncology compounds under evaluation, more than half of which are being tested in patients—and many sites in the West are becoming saturated. The result has been poor recruitment and extended study timelines.

“It’s no secret that patent life is an issue,” observed Lara. “The faster we become at concluding our trials, the more we’ll be able to maximize our return on investment.”

CROs are providing a viable option for many biotech and pharma companies that have decided to outsource clinical trials designed to test novel approaches to the treatment [sturti-iStockphoto]

Site Selection

An overarching theme of the virtual conference was that a key to successful patient recruitment to clinical trials is the recruitment and selection of participating investigators and sites.

CROs are perhaps in a unique position to assist in the assessment and enlistment of the facilities and infrastructure associated with a trial site, especially for pharma and biotech companies not intimately familiar with regulatory requirements, local customs, and demographics.

Many CROs specializing in navigating the clinical trial landscape may even have pre-established relationships with institutions amenable to hosting clinical trials.

With Scimega’s “Reverse Feasibility” program, for example, the CRO engages in ongoing dialog with a network of oncology investigators to identify their study needs. Sites can thus be prequalified, contractual provisions prevetted, and confidentiality agreements set in place.

“This allows us to match studies to sites that are motivated to recruit patients and get trials up and running as soon as possible,” Lara said.

Oncology trials are a little bit different from other trials—in aspects ranging from the complexity and regulations surrounding procedures, to how sick the patients may be, to physicians’ motivation for being involved—said Tom Ruane, senior director, patient recruitment, Quintiles.

He sees a need for collaboration not just with pharma but also with the investigators running studies at the site level “to get an understanding from their perspective before we just send out studies to be done.”

And while pre-eminent sites with key opinion leaders are highly regarded in the industry, they may not see everyday patients in everyday settings. So Quintiles tries to complement high-profile centers with smaller district hospitals that may have less opportunity to take part in clinical trials.

Especially when dealing with non-Western sites, a host of other considerations come in to play as well, and sponsors should not assume that every willing site is actually able to conduct a given clinical trial. Many may need added assistance when it comes to following protocol, for example, and in differentiating between medical practice and clinical research, Gargano said.

Novotech—which operates in eight countries across the Asia-Pacific region—has developed a profile that it looks for in the ideal target site, and uses a comprehensive questionnaire to assess a site’s capabilities in terms of recruitment potential, experience, interest in a trial, and understanding of the protocol.

Potential competing trials, previous experience in conducting trials, and investigator commitments should also be looked at.

U.S.? EU? ROW?

Regulatory and infrastructure differences between the West and the rest of the world may be off-putting, and language and cultural barriers can seem a bit daunting as well. But there are many reasons sponsors might consider conducting all or part of a trial on other shores.

About 80% of trials are behind schedule. This, said Lara, is due principally to patient recruitment, which, in turn, is driven by appropriate site selection.

There are certainly plenty of cancer patients in North America, yet fewer than five percent will ever access a clinical trial. Whatever the reason for this—whether willingness, access, other therapy, geography, or lack of knowledge—“you’re actually ending up in a very narrow funnel of trying to find those patients,” pointed out Nicholas Kenny, Ph.D., evp, oncology, INC Research.

INC will “pressure test” a drug and study design to determine if it will be acceptable to the physicians and the patients that the sponsor is trying to access, and then look into where to best conduct the trial.

For example, because the North American landscape for lung cancer trials is very competitive, with a lot of very good drugs in development for the same indication, “trying to place a new lung cancer study in North America can be quite difficult,” explained Kenny.

“Whereas if you look at some of the emerging regions, or even Eastern Europe, there are still a large number of patients there that might be naïve to clinical trials, or have not been accessed to the same extent. We would look very strongly at alternative geographies.”

There can be substantial cost savings overseas as well. Investigator and site fees in Asia are about half of those in the U.S., pointed out Gargano, while the costs of providing trial-related medications, investigations, and hospitalizations can drop to as low as 30%.

Similarly, labor costs in general are substantially less, and the fact that the region’s more than four billion people are concentrated around major urban areas makes for lower travel expenses for monitoring the sites as well.

Asia-Pacific hosts many specialty care centers with state-of-the-art facilities, and most of the specialists received post-graduate training in the U.S. or U.K. Nonetheless, she cautioned that to insure that the quality of the data collected is up to international standards, it’s still important to assure that staff training and support systems are in place, or that provisions have been made to invest in such infrastructure.

In emerging regions, constraints tend to be centered around “having enough facility with the institutions—whether it’s the community oncology setting or a large academic center—as well as enough physicians and support staff that have been trained in the execution of the clinical trial,” concurred Kenny.

First in Man

Kenny believes that it’s useful to distinguish between first-in-man trials and later phase studies. Patients in the former are usually very sick, and may be grasping at their last opportunity to get some sort of interventional therapy.

The trials tend to be quite complex in design, and often require a highly specialized group used to dealing with that complexity, and to putting a drug into a patient for the first time without knowledge of what can be expected.

INC places 95% of such trials in academic medical centers in the West “because the infrastructure is in place; we know the centers; we know they know how to deal with it and get through,” he said.

In contrast, there is a different set of issues “once you’ve got a drug through that proof of concept into a global trial,” Kenny noted.

For example, North America treats with multiple lines of therapy for a variety of tumor types, yet other therapies may be too expensive, may not be reimbursed, or may not be available at all in other regions—“so if you have trials looking to develop a complex, targeted therapy, it may not be possible to put that in an emerging region.”

Trialing biosimilars—which the participants pointed to as an emerging trend in the field—flips the cost and availability equation on its head. Most biosimilar trials are conducted in Eastern Europe, Latin America, and other emerging regions where the drug may simply be too expensive or not reimbursed, he said.

“In that setting, the opportunity that is presented to both the patient and physician to go into a trial where they have an even chance of getting a biosimilar drug or the innovator drug to help treat that disease is actually quite attractive.”

There is no one-size-fits-all. “If it’s an area we know will do well in North America, we’ll continue to do the trials here as long as the cost is appropriate,” Kenny concluded. “If it’s an area where we know North America is saturated, we’ll do feasibility analyses and market analyses to figure out where else we can take it.”

Colored ultrasound scan of a section through the pelvis of a 52-year-old man with an adenoma of the prostate gland (pink). Adenoma is a benign tumor that is most common in men over 50 years of age. Prostate problems, including cancer, are expected to increase as the male cohort of the baby boom generation grows older. [Zephyr/Photo Researchers]

Personalized Medicine

There is a trend toward catering patients’ treatments to their individual genetic and epigenetic makeup, in order “to give the treatment only to those patients that should benefit from that treatment,” said Scimega’s director of scientific affairs and strategic project manager Luc Daigneault, Ph.D.

Sponsors are looking for sites that know exactly what kind of mutation patients have, placing an onus on the sponsor or CRO to inform and instruct sites how to screen based on the trials they are participating in. There may even be a requirement to develop a companion diagnostic to pick out the targeted tumor subtype.

One benefit of this trend toward personalized medicine is that far fewer patients are required to achieve sufficient statistical power to demonstrate efficacy. “For Phase III in oncology it used to be 2,000–3,000 patients per trial. For melanoma with the BRAF mutation, they were able to obtain an approval with 300 patients worldwide,” recalled Dr. Daigneault.

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