By Deb Borfitz

December 8, 2009 | Financial conditions for investigative sites look “pretty bleak,” but top-notch sites are well positioned to benefit from growth in clinical trial volume as the economy recovers, according to industry trends data presented by Kenneth Getz, senior research fellow at the Tufts Center for the Study of Drug Development, at October’s Site Solutions Summit in Clearwater Beach, FL. At the moment, dedicated sites are being pinched by price competition from novice sites while academic institutions continue to give up market share to the private sector. Sites overall might do well to acquire the performance jitters, as currently less than 10% of them are delivering on promises made during feasibility assessments. Maintaining the status quo is not an option for trial-sponsor companies struggling to move promising compounds to market before their blockbuster products fall off the patent cliff.

Grant spending is now a nearly $9 billion market growing at a 7%-8% annual clip, “the majority of it coming from industry,” says Getz. The typical investigator today is a white MD over the age of 50 with an urban or suburban-based private practice. Surprisingly, only about 25% of the $7.3 billion in industry-funded projects were placed at sites dedicated to clinical research last year and only 28% of those were managed networks as opposed to single sites. Academia, which accounted for a 70% share in 1994, consumed only 36% of the total. Some academic institutions, including Mayo Clinic, have exited industry-funded clinical research completely.

As of 2007, 57% of all clinical research regulated by the U.S. Food and Drug Administration (FDA) was conducted domestically, says Getz. A decline in the number of U.S. investigators is being offset by increases across Central and Eastern Europe, China, India, and Latin America.

Historically, global drug development spending by sponsor companies has been growing about 11% annually by sponsor companies without a commensurate rise in productivity, says Getz. “It still takes seven years from IND [Investigational New Drug application] to market launch and regulatory review and approval times have gone up, even with PDUFA [Pharmaceutical Drug User Fee Act].” Moreover, most drug approvals now include a mandate for companies to do post-marketing studies.

The Revenue Squeeze
Industry turned out 20 novel molecular entities this year, up from 17 in 2007 but down a bit from 24 in 2008, says Getz. Sixty-one percent of promising compounds in the R&D pipeline are in the discovery/pre-clinical phase and only 16% of drugs that make it into human testing end up on the commercial market. “If the success rate improved even slightly, it would have huge implications on commercial pipeline performance.”

Companies are putting increasing focus on both the pre-clinical and first-in-man development phases to get a better, earlier read on the promise of new drug candidates, says Getz. “First-in-class drugs now have only one year of exclusivity before other drugs [start to] chip away at market share.” Companies make back their investment on only 20% of approved drugs. One-fifth of the commercial portfolio of major pharmaceutical companies is at risk of generic competition within the next five years. That represents a huge amount of revenue loss, he notes, as a product loses 80% of its market share within 18 months of patent expiration. Since companies can’t rely on blockbuster drugs to recoup expected revenue loss, they are instead quickly conducting follow-up studies for new indications.

Clinical research organizations (CROs) provide half the total capacity needed industry-wide amidst considerable downsizing and merger-and-acquisition activity, says Getz. Since the third quarter of 2008, sponsors have terminated or left unfilled over 50,000 positions—7,000 directly for R&D—and are “looking for partners to pick up that slack.” Sponsors and CROs alike are now willing to spend more to stimulate better site performance.

Focus on Performance
From sponsors’ perspective, the “real top performers” (responsible for 50% or more of enrollees) constitute only 20% of all sites year after year, says Getz. Among active INDs, 14% have at least one complaint about an investigator filed with the FDA. Turnover is problematic among both study monitors and study coordinators. “Ninety percent of all trials are delayed an average of six week,” no small matter given the $30,000-45,000 per site price tag to keep a study open a single day.

Compliance-related activities are costing companies half of their entire clinical trial budgets, says Getz. This includes Good Clinical Practice review at each investigator meeting, “which can be an insult to [experienced] study staff.” The added sting is that the number of patients per active New Drug Application is “sharply declining” at the same time the average number of investigators is rising, “making is harder for sites to be profitable.”

Sponsors have been trying to use demographic and psychographic data to predict site performance, continues Getz, when the only reportedly reliable statistic is sites’ ability to enroll their first patient within 90 days of study start. During later phases of clinical development, companies tend to use metrics from electronic data capture and clinical trial management systems to “pit sites against each other.” They also will “engage additional sites but not start them until another site fails.” One of the more positive developments is that sponsors are willing to secure “more integrated, coordinated relationships” with preferred sites, including seeking their input on protocol design. A chief challenge is that few sites are willing to accept and few sponsors want to guarantee a certain level of clinical trial work.

Shift in Study Placement
Collectively, these industry trends will drive a shakeout among “marginal” part-time and dedicated sites across the U.S. and Western Europe and be a catalyst for “more retrenchment among institutions that rely on [federal] stimulus money and NIH [National Institutes of Health] grants,” says Getz. The slowdown will extend into emerging regions, with more studies being placed in India in China in lieu of Central and Eastern Europe.

Long term, the more committed sites should be rewarded with a higher volume of research, says Getz. “We’ll see regional shifting as drug development becomes more personalized and sponsors seek a more [genetically homogenous] population. The pressure will be to…place more studies back in the U.S.” For phase I studies, sponsors are already preferentially placing studies back in North America and Western Europe, he adds.

Problematic Protocols
“Within five years, I think we’ll see a totally different relationship between sponsors, CROs, and sites,” says Getz. “Not enough attention has been paid to the fundamental problem of public trust [of clinical research] and protocol design.” Failure to adhere to the protocol is the most common non-compliance issue. Equally troubling is the huge number of seemingly unnecessary procedures that study subjects endure, which has been growing 7% annually. “Up to 30% of data collected [by industry sponsors] is never used for an FDA submission.” Coupled with an eligibility criteria list that has ballooned to include more than 45 inclusion and exclusion items, the excess procedures have helped increase the “execution burden” on sites by 11% per year. Yet compensation per procedure is down 8%.

“More complex protocols have harmed the performance of sites,” says Getz, pointing to growth in the number of case report form pages from 55 to 180 between 1999 and 2006. Cycle times are “substantially” longer and enrollment rates are worsening, with the screen to randomization rate falling from 75% to 59%. The randomization to study completion rate is likewise dropping, from 69% to 48%.