Find out how despite improvements in sponsors' compliance with clinical trial regulations last year, trial monitoring continues to be an issue, according to CDRH.
In fiscal year 2007, the violation rate for companies inspected by CDRH's division of bioresearch monitoring (BIMO) hit a 10-year high, largely due to problems found during inspections triggered by complaints (1"The Gray Sheet" Jan. 7, 2008, p. 3).
In fiscal 2008, 22% of the 57 sponsor inspections performed under the BIMO program were classified by FDA as "official action indicated" (OAI), indicating significant regulatory violations.
The compliance rate marks an improvement over the 33% OAI rate observed in fiscal 2007 (40 sponsors inspected), but is still double the 11% rate recorded in 2006 (53 sponsors inspected).
Nevertheless, failure to properly monitor the clinical trial enterprise continued to be the number one deficiency among sponsors for the fourth or fifth year in a row, according to Michael Marcarelli, director of the device center's BIMO division.
Device companies were subject to only four BIMO warning letters in 2008, down from eight in 2007.
The BIMO division, part of CDRH's Office of Compliance, is responsible for overseeing the quality and integrity of clinical trial data, and ensuring that trial subjects are protected from undue hazards and risks. The unit assigns and oversees inspections of sponsors, clinical investigators, institutional review boards (IRBs) and bench testing labs.
Of the 301 BIMO inspections conducted in fiscal 2008, significant regulatory violations were found in 15%, up slightly from 14% in 2007. Twenty-eight BIMO warning letters were issued in 2008, compared to 29 the year before.
Removing complaint-based inspections from the picture, just 5% of routine sponsor inspections were classified OAI.
"It looks like what's really causing that tremendous fluctuation in non-compliance rates are our complaint-based inspections," Marcarelli said in a Dec. 17 interview with "The Gray Sheet."
Through complaints, "we are learning about some of the questionable activities that are occurring in the device clinical trials arena."
Device firms should keep that in mind, he added. "You never know the source of complaints. They come from all areas: they come from competitors; they come from disgruntled employees; they come from just associates; they come from human subjects. They come from everywhere."
As usual, BIMO plans to conduct about 300 inspections in fiscal 2009, with no plans to increase that target in the near future.
Clinical Trials Initiative To Tackle Monitoring Issue
To help resolve the trial monitoring issues flagged by BIMO audits, FDA will cast a wider net, Marcarelli says.
A project to improve clinical trial monitoring methods is one of four initial efforts of the Clinical Trials Transformation Initiative, an endeavor formed by FDA and Duke University in November 2007 to improve the conduct of clinical trials.
The project will research alternative approaches to study monitoring, Marcarelli explains. "What we have now is less than perfect, to say the least," he said.
The Clinical Trials Transformation Initiative's 13-member executive committee is co-chaired by FDA's Rachel Behrman and Duke's Robert Califf, and includes Susan Alpert of Medtronic and CDRH's Bram Zuckerman (2"The Gray Sheet" May 19, 2008, p. 15).
The group also has a still-evolving steering committee of more than 50 members, including device makers St. Jude Medical, Johnson & Johnson Devices & Diagnostics, C.R. Bard, Biotronik and bioMerieux. The group also includes several top pharmaceutical makers.
"I think it's reflective of the overall clinical trials industry, in that pharma has the majority and device is the minority," noted Kevin Mitchell, VP of clinical studies at Biotronik. "But from our point of view, there are never enough device people."
At the most recent steering committee meeting, on Dec. 1, the group elected two co-chairs - James Ferguson III, M.D., of The Medicines Company and Briggs Morrison, M.D., of Pfizer - and began discussing the first four projects drafted by the executive committee.
Steering committee and executive committee meetings will occur quarterly, and going forward project proposals, which can be introduced by anyone, even if they are not members of the consortium, will be vetted by the steering committee.
"We expect this to be a rolling process," Alpert, Medtronic's chief quality and regulatory officer, said. "We don't want open-ended or such broad projects that they can't be done in a reasonable amount of time [or] have real outcomes."
The projects will all be focused on ways to make clinical trials "more effective and more efficient."
"The types of projects being brought forward are very focused on the areas of clinical trials execution that cause them to be hard to do, cumbersome, expensive, annoying, aggravating ... There's a real understanding that we have to get to some of the fundamentals in order to change this environment."
So far the group has discussed the trial monitoring project in the greatest detail.
"The first step in the process is to do an overall survey amongst all the types of industries or entities that do monitoring in order to see what is actually being done," Biotronik's Mitchell said. "It's not consistent from company to company, and it is certainly not consistent between different types of industries."
Mitchell and Alpert stress that device stakeholders, though a minority, are making sure their industry's perspective is considered in all the initiative's work. To date, no IRBs have signed on as members of the initiative.
Three other projects approved by the consortium focus on improving the reporting and interpretation of serious adverse events; interpreting and communicating clinical data in the public domain; and managing data collected in clinical oncology research (see sidebar: "3Trial Transformation Projects").
Marcarelli Red-Flags Institutional Review Boards
BIMO's Marcarelli says the agency is also looking for ways to deal with a relatively-high non-compliance rate among IRBs in clinical trials.
In fiscal 2008, 11% of 88 IRB inspections were classified OAI, up from 9% in 2007. IRBs received six BIMO warning letters, up from five in 2007.
Marcarelli says BIMO conducted fewer bench testing lab inspections in 2008 to put more resources into IRB inspections. The office has also begun targeting small- and medium-sized IRBs, a practice which likely explains the climbing non-compliance rate.
Smaller IRBs "don't have the supporting infrastructure" of large, academic IRBs, Marcarelli said. Most commonly, the review boards did not adequately conduct initial or continuing reviews. They also failed to keep adequate meeting records and study documentation, or failed to follow written procedures.
BIMO is developing outreach tools for IRBs to address such issues.
Pediatric Device Trials An Early Inspection Target
BIMO plans to continue improving its approach to selecting inspection sites. The group worked with the Division of Biostatistics within FDA's Office of Surveillance and Biometrics last year to develop a more scientific, risk-based algorithm for selecting sites under BIMO's PMA oversight program.
When applications come in, the algorithm is applied to the data "so that we can do a better job of possibly selecting a site that may have greater weight in the overall study."
Within its early-intervention program, BIMO is looking to the CDRH-wide matrix organization to help gather safety signals and identify which sites should be inspected earlier in the study process or during active device research, Marcarelli says.
BIMO currently uses its own "educated approach" to select early-intervention inspection sites based on compliance trends, public health concerns or areas of Congressional interest.
"For example, there's been a huge discussion regarding encouraging pediatric device development," he said. "We're going out to the sponsor sites, we're going out to the clinical sites, we're going out to the institutional review boards that oversee pediatric studies."
The idea is not to punish pediatric device developers, but to catch their mistakes well before a device application is submitted to FDA. "We know there's a public health need to have these kinds of devices available," Marcarelli said.
In November, BIMO's program enforcement branch split into two branches: one will focus on orthopedic devices and in vitro diagnostic devices, and the other will focus on cardiovascular and other products.
Following an increase in FDA funding last year, the BIMO office is now hiring five new employees for review positions.
- Jessica Bylander
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