Drowning in the Sea of Regulatory Compliance

According to clinical investigators, it's ugly out there! Investigators and site staff consistently report that managing site operations is difficult—particularly maintaining positive cash flow and profitability. Lead generation has intensified as competition for new study grants has increased. Study protocols have become more complicated and demanding. Patient recruitment and retention challenges have escalated. And the burden of regulatory compliance has become onerous and extremely frustrating.

Kenneth A. Getz

Indeed, in recent interviews with clinical investigators, regulatory compliance is one of the top burdens that sites face today. Many argue that compliance requirements place unreasonable demands on study staff time and focus, and may, ultimately, undermine study conduct performance.

"It's not clear if sponsors have even noticed the connection between mounting compliance paperwork and the low morale and steady exodus of good investigators from clinical research," lamented one New Jersey–based investigator.

The results of a recent study by the Tufts Center for the Study of Drug Development are consistent with these observations. Turnover among clinical investigators is at an all time high; and the majority of those dropping out of clinical research are experienced, community-based investigators—not novice investigators, as is commonly believed.

Interviews with clinical investigators reveal that there is much to gripe about. Top site concerns offer research sponsors insight into areas where intervention and assistance might improve study conduct performance.

Besieged by safety reports

One of the largest problems relates to the way Investigational New Drug (IND) Safety Reports are handled. Food and Drug Administration (FDA) regulations require that all investigators and institutional review boards (IRBs) involved in a clinical study be informed about any associated severe adverse event (SAE) that occurs anywhere in the world.

"That's a lot of reports," noted Jim Maloy, MD, executive vice president with Drug Research and Analysis in Montgomery, AL. "One global cardiac study for which we enrolled one patient had 400 IND Safety Reports submitted to the IRB."

"And the information isn't particularly useful. If a study is blinded, recipients have no way of knowing if the SAE was connected to the actual study drug, a comparator drug, or a placebo," added Maloy. "The reports also don't indicate how many patients experienced the SAE. I have yet to see a local IRB change a protocol or ask for a change in the consent form based on [IND] Safety Reports, and I've been involved in a thousand studies," he said. If an SAE is severe enough to warrant such changes, they're generally made before an IND Safety Report gets issued.

"The problem is compounded if a central IRB is involved," said Jed Ervin, MD, founder and president of the Center for Pharmaceutical Research in Kansas City, MO. "Central IRBs receive dozens of copies of each IND Safety Report, reviewed and signed by individual investigators."

Reconsent and disclosures

"But more time consuming and bothersome for sites," added Ervin, "is the requirement that they go back through the entire consenting process, inclusive of IRB approval, whenever an amendment is made to the study protocol." For a single study, at least two or three amendments are not unusual. "Reconsenting annoys patients and creates an ethical problem if they're asked to retroactively agree to changes once the study has ended—a disturbingly common occurrence," he explained.

"Financial disclosure forms represent another big headache, especially for private research operations that provide administrative support to subinvestigators at disparate locations around town," said Maloy. "Federal regulations require that the forms be signed by all investigators at the beginning and end of a study and a year after study completion. Yet conflicts of interest are almost solely a problem in academia where the results of government-sponsored research get commercialized."

Burdensome paperwork

"In terms of time and paperwork, I believe that regulatory compliance is most burdensome when a hospital uses its own local IRB," said Staci Gola, RN, BSN, CCRP, director of operations at Advanced Clinical Research (ACR) in Salt Lake City, UT. "Study approvals by local IRBs take an average of two months. And this is not helped by the fact that all regulatory forms, with the exception of the 1572 [Statement of Investigator Form], are different in type and format."

"The maintenance of study records represents another major burden for sites," said Gola. "Since the regulatory guidelines are so ambiguous, the investigator ends up keeping records indefinitely. ACR has records in storage that have been there more than 20 years. Replacing boxes in which records are stored every 10 to 15 years is a monumental job and storage fees run thousands of dollars annually," she added.

Suggestions for sponsors

Research and development costs, cycle times, and the scope and complexity of clinical trials are all increasing. At the same time, the volume of global clinical trial activity is rising, with an increasing proportion of active clinical projects entering the more demanding later stages of drug development. An unstable clinical investigator community does not serve growing sponsor demand for strong and sustainable study conduct performance while ensuring patient safety.

Clinical investigators believe that relieving some of the regulatory burden is a critical place to begin improving stability. Although many investigators view efforts to ease the regulatory burden as futile at this point, some remain more hopeful.

Investigators want sponsors to play a more active role in addressing several key areas. Among their suggestions:

• Take the time to closely evaluate the regulatory requirements placed on investigators and study staff. Identify those areas that are the most paper and labor intensive and look into streamlining them and/or working with FDA to streamline those that require agency assistance.

• Modify the 1572 Form so principal investigators can include financial disclosure information for themselves and for all sub-investigators. Have investigators complete traditional disclosure forms only if there is an actual conflict.

• When the protocol gets amended, require that patients reconsent only to those specific amendment changes.

• Spend more time doing up-front study planning so that investigators can deal with regulatory issues in a proactive, stepwise way rather than an emergent, reactive fashion.

• Encourage institutions to use central IRBs to reduce variation in paper-work and to assist in streamlining document-routing activity.

• Create standardized, universal IRB forms and have sponsors include preprinted general information common to all sites in submission packets.

• Send IND Safety Reports to a designated data safety monitoring board (DSMB) that is responsible for issuing periodic summaries to IRBs.

• Have the sponsor or contract research organization (CRO) submit a single document to central IRBs for each IND Safety Report that is reviewed and signed by multiple investigators.

• Assess, recognize, and remunerate the "hidden" cost of records archiving during the budgeting process.

• Establish and encourage mechanisms to receive continuous feedback from principal investigators and study staff in order to identify and tackle operating concerns.

Sending out an SOS

Many experienced investigators are seeing a more difficult operating environment and high levels of turnover. They are looking to sponsors for assistance.

"The regulatory climate has become so oppressive in the recent past that two out of three principal investigators who have worked with us for 20-some years said they don't want the responsibility anymore," warned Maloy. "They don't have time for it. They're busy seeing patients in their practice."

"It would seem completely sensible for sponsors to do all they can to make regulatory compliance less nightmarish an experience for their study sites," concluded an investigator based in New Jersey. "It's in their best interest, isn't it?"

Kenneth A. Getz ,MS, MBA, is a Senior Research Fellow at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, email: kenneth.getz@tufts.edu