Create a formal initiation process and SOPs for IND clinical trials

Research office monitors educate

When a research institution is its own sponsor of investigational new drugs (INDs), there often aren't solid standard operating procedures (SOPs) for investigators.

This is an oversight that the University of Texas M.D. Anderson Cancer Center in Houston, TX, sought to rectify when a formal IND initiation process was established a few years ago.

"As our department grew, we wanted to standardize the process," says Cathy Henceroth, RN, BSN, manager of the office of research education and regulatory management at M.D. Anderson Cancer Center.

"We developed an SOP and working timelines and different source documents," Henceroth says. "It's been an ongoing process since 2005."

The institution's clinical trial monitors identified some of the issues that often occurred with IND trials and these experiences helped the regulatory office develop the SOP content, says Christina Amos, RN, CCRC, a senior clinical research monitor.

Research institutions sometimes do not have formal processes for handling IND trials, notes Joyce E. Brown, RN, BSN, CCRP, a senior clinical research monitor.

At the Dec. 1-4, 2007 Annual Human Research Protection Program (HRPP) Conference, sponsored by Public Responsibility in Medicine and Research (PRIM&R), the M.D. Anderson group discussed the importance of a comprehensive initiation process for INDs. It was clear from audience questions that quite a few people don't have handbooks, SOPs, or standard policies on initiation, Brown says.

A team of about five people worked on improving the IND process and revamping an existing initiation handbook, Henceroth says.

"We developed some additional SOPs and approaches to our monitoring process, and we beefed up the initiation handbook to incorporate all of those additions," Henceroth says. "It's a multifaceted, printed, spiral notebook with tabs."

The institution has about 85 open trials and has about 20-25 new INDs per year, Henceroth says.

New investigators and their teams have reported that the IND initiation SOPs have been very helpful, Amos notes.

Investigators work with different sponsors, and each sponsor has different expectations, so investigators say it's very helpful to have these expectations written out in a 100-page handbook, Amos adds.

Here are some examples of how the institution has improved its initiation process for IND trials:

• Make the initiation handbook a comprehensive resource: The office of research education and regulatory management beefed up the original initiation handbook to include comprehensive instructions on how to handle data collection, general monitoring, deviations and violations, protocol revisions, and other CR items.

"We have a section to talk about the study drug, and we included SOPs on how we talk about drug accountability," Henceroth says. "We share a sample patient diary so they have that to review as well."

The handbook discusses source documentation, providing guidance on how to write a note to file, and it includes samples of institutional forms used for tracking and utilization of source document, she adds.

"We have a section on informed consent that has all the current SOPs for obtaining informed consent, and we go over that process in detail," Henceroth says. "We have a section that talks about the cohort summary and an interim analysis, and we have one section that deals with adverse event reporting and recording and what the expectations are for tracking SAEs at M.D. Anderson."

The handbook is updated periodically.

Also, the handbook's information is used for educating clinical trial staff and investigators.

They bring the handbook to initiation meetings with the research staff, she notes.

Also, copies are given to the PI and research coordinator, Henceroth says.

"My senior monitors are taking this one step further and are developing a PowerPoint presentation that is [like] the handbook," Henceroth says. "But instead of didactic reading, it will be a presentation that mirrors the handbook."

• Create a clarification list: "We do a complete review of the protocol and informed consent, and then we create a clarification list," Amos says. "We identify any inconsistencies or issues that might need attention from the principal investigator or research team."

The clarification list is an Excel spreadsheet with a column for clarification and questions, Henceroth says.

It clearly demonstrates where the protocol specified one particular procedure and where the informed consent document did not agree.

"The final column is a place for discussion or remarks from the principal investigator," Henceroth says. "The PI can put in a response of 'We'll amend the informed consent to match the protocol.'"

Then the clarification list with all of the questions and responses as agreed by the research team and monitoring team are attached to the initiation report, Henceroth says.

Monitors send those issues to investigators so they can be prepared to address them before or during the initiation meeting, Amos adds.

"Sometimes we'll uncover small things that prevent them from opening their trial," Henceroth says. "For example, the language may not be correct between the informed consent and the protocol."

Both Henceroth and the monitor assigned to the protocol will review it, Amos notes.

"We'll have two sets of eyes looking at it, and then we'll meet to discuss any issues with it," she adds.

"One common issue is the documentation of birth control," Amos says. "The protocol will say that patients need to be on a formal birth control method, and so I'll ask what type of birth control the patient will be using."

Other common red flags involve whether the eligibility requirements make sense and how they will be documented, Henceroth says.

"We review the abstract, informed consent document, and the protocol to make sure they all say the same thing," she adds.

Any problems identified in the protocol will be noted on a statement that is given to investigators before initiation of the trial, Amos says.

"We like to send the information to them ahead of time so they can make the necessary revisions," she says. "We try to give them enough time to have that done so they can start enrolling patients."

• Focus on time frames: "One thing we've found that's common when physicians write a protocol is that the protocols are usually concrete," Amos says. "There are no parameters, such as time frames for conducting diagnostic tests, and there are no parameters for evaluations and follow-up."

So monitors will remind investigators that protocols should not be so exact because patients will not always come in on precisely the correct day for a visit or procedure, she says.

"We ask the CR team to include parameters so that as long as the visit is made within the time frame, allowing some variance, then they won't be constantly writing deviation reports," Amos says.

It's also a wise idea to provide more flexibility on the time frames listed for the visits. Instead of saying a visit won't take longer than 60 minutes, the protocol should provide safe time parameters. This will help prevent the CR staff from writing up numerous violations, she adds.

When investigators hear these suggestions, they typically agree, Henceroth says.

"They don't want to violate their protocol," she says. "With some things you can have a sizeable variance, and with others you can't."

• Educate investigators about some common problems: One of the common issues that occurs with investigator protocols involves adverse events, Amos says.

"We try to have physicians identify in the protocol how they are going to track adverse events," she says. "Because we have a lot of leukemia protocols, there may be expected AEs that PIs won't need to track."

The monitors don't want them to report all toxicities that occur when many of these are common and expected.

"An investigator will say he'll record all toxicities per National Cancer Institute criteria, but he's not thinking about it closely," Henceroth explains. "So we'll say, 'Then, we'd expect every single toxicity recorded and tracked.'"

But this isn't always possible because some AEs, like anemia, are so common that investigators really don't want to track these, she adds.

"The way we scrutinize a protocol is with a monitor's eyes, which is totally different than other eyes," Henceroth says. "The protocol has to be very practical, and it has to work."