CROs Look Towards Pre-Emptive Standards As FDA Guidance Looms

Some contract research organizations could install new oversight procedures in a pre-emptive move as FDA contemplates its first guidance to regulate the industry.

Doug Peddicord, executive director of the Association of Clinical Research Organizations, said CROs and study sponsors want to better define governance responsibilities for clinical trials with more scrutiny upcoming. He also said companies do not want to wait for FDA to complete the long guidance process before making changes.

"I think CROs and sponsors are starting to really look at kinds of governance models, so how best for the sponsor to in fact do its due diligence and then to be clear about what the governance structure is," Peddicord said in an interview.

"I think each of the partners (in the drug development process) is beginning to look more and more at the governance structure because the governance structure in the past often hasn't been terribly efficient."

Leslie Ball, director of the FDA Center for Drug Evaluation and Research Division of Scientific Investigations, said June 15 the agency is contemplating CRO guidance. It would likely be the first guidance specifically addressing the industry.

"I think that it is an area that we're very interested in," Ball said during the Drug Information Association annual meeting. "I'm participating in a meeting this fall that will be specifically addressing the issue of vendor oversight and I think that this is a good suggestion to publish guidance, so we'll definitely think about that."

Ball said she was surprised to learn about "virtual product development" where a drug developer sells a product to another company and "virtually everything is outsourced." Ensuring quality with an increasing number of companies involved is more difficult, she said.

As more companies joined the development process, ambiguity increased in terms of oversight responsibilities, Ball said.

"One of the things that we've noticed and we've cited in our warning letters is that there's a lot of finger-pointing when things go wrong," she said. "The sponsor will point to the CRO, the CRO will point to the third party vendor that took over some responsibilities."

Peddicord said ACRO welcomes guidance and regulatory clarity about relationships and responsibilities would be helpful.

"A real statement of what ... the agency sees in regard to regulatory responsibilities, including those that are delegated formally in writing and those that are not, and some real sort of articulation of what's the difference between those two things and how the agency would choose to address those two things (should be included)," he said.

Agency Grasping For Trial Control

FDA is under increasing pressure to gain more control over clinical trials.

House Energy and Commerce Committee members suggested in 2008 that they may write legislation to regulate CROs as well as institutional review boards following unreported investigator misconduct during clinical trials for Sanofi-Aventis' Ketek (telithromycin). Members of the Subcommittee on Oversight and Investigations indicated in their questioning they were wondering whether the situation suggested an industry problem that needed a congressional fix (¹ (Also see "Ketek Is Emerging As Lens For Wider Hill Scrutiny Of Clinical Trial Integrity" - Pink Sheet, 18 Feb, 2008.)).

Rep. Bart Stupak, D-Mich., subcommittee chairman, said it may be time to "rethink the regulatory framework for the clinical trial industry," which included IRBs and CROs (² (Also see "Legislation On CROs And IRBs Might Be One Fall-Out From Ketek Probe" - Pink Sheet, 18 Feb, 2008.)).

No legislation on the subject has been filed since then.

More attention landed on the CRO industry late last year when FDA cited Johnson & Johnson and Icon Clinical Research, a CRO that conducted a trial for J&J's investigational antibiotic ceftobiprole.

The agency determined there were several problems with the drug's clinical trial data, including faulty study blinding procedures and enrollment of ineligible patients. J&J received a "complete response" letter from FDA in December 2009 and it appeared approval was many years away, in part because of problems with data quality. Trouble with the application eventually led J&J to hand back rights to ceftobiprole to the Swiss biotech Basilea (³ (Also see "J&J and Basilea End Ceftobiprole Deal" - Pink Sheet, 22 Feb, 2010.)).

A report by the Department of Health and Human Services Inspector General also recommended increased oversight of data gathered outside the U.S. Policy changes appear imminent, FDA officials said (⁴ ).

DSI already is increasing the number of clinical trial sponsor inspections. A couple years ago, there were 20 to 30 inspections conducted, while last year, the number increased to 73, Ball said.

Peddicord said FDA is in the midst of changing its regulatory framework as CROs have become a more important link in the drug development chain. He said much of the agency's concern stems from its issues with the manufacturing side of the business.

As large pharmaceutical companies divest portions of their clinical development infrastructure, CROs are left with a more important role. Peddicord said FDA is recognizing it now and paying more attention.

"It's no longer going to be the most efficacious approach to simply regulate through the sponsor," he said. "In some ways that really has been historically the approach, but it's an approach that was very much made for sort of the large pharma side from a number of years ago. It makes much less sense with small biotechs, for instance, where the one or more CROs may have essentially all the infrastructure."

IRB Guidance May Be A Clue

The hint of upcoming CRO guidance comes months after the agency issued IRB guidance that placed the responsibility on drug developers for providing information for IRB continuing reviews.

Just like a potential CRO guidance, the IRB draft guidance was a move to better position the agency to handle the globalization of the development process.

Since multisite studies are the norm today, reviewing information should come from the study sponsor, FDA said in its guidance.

The document was not intended to shift responsibilities, but increase the efficiency of the process. But laying those ideas out on paper did not make developers happy and many wanted changes (⁵ (Also see "Adverse Event Reporting: Sponsors, FDA Disagree On Responsibilities To IRBs" - Pink Sheet, 5 Apr, 2010.)).

Peddicord said that IRB guidance could be a preview of agency thinking on CRO guidance, but when it was issued in January, the group did not see it that way.

"It's virgin territory," said John Lewis, ACRO vice president of public affairs. "It's not a question of whether they're going to go in this direction, but there's just a lot of details that need to be worked through."

- Derrick Gingery ( ⁶ [email protected] )