Human subject protection gets a boost with research advocates

RSAs act as liaisons between researchers and IRBs

The National Center for Research Resources (NCRR) of Bethesda, MD, established several years ago the role of research subject advocates (RSAs) for the purpose of providing an additional level of monitoring for research projects involving human subjects.

The NCRR laid out the groundwork for the RSA model, which enhances, but does not duplicate the IRB’s role. Equally important, the NCRR made provisions for the National Institutes of Health (NIH) to fund RSA positions at institutions with General Clinical Research Centers (GCRCs).

Then the NCRR took a hands-off approach, which has allowed institutions and GCRCs to create priorities of their own for the more than 100 RSAs nationwide.

Given this flexibility, some RSAs and GCRCs have created very structured and thorough processes for monitoring human subject studies, especially with regard to informed consent and data safety monitoring plans.

"Some RSAs spend a lot of time in the clinic observing the informed consent process and interviewing participants to determine if they understand what it means to be in a GCRC research protocol and answering their questions," says Susan Margitic, MS, GCRC research subject advocate at Wake Forest University Medical Center in Winston-Salem, NC.

Margitic explains how she endeavors to complement the IRB’s work in assuring that human subject research maintains high standards for safety and integrity. Here are some examples of the RSA’s oversight activities:

1. Assist principal investigators (PIs) with developing data safety monitoring plans.

Margitic offers to meet early on with PIs to discuss their data safety monitoring plans (DSMPs).

"Every GCRC study has to have a DSMP, no matter what level of risk," she says. "I spend a lot of time looking at the DSMP in conjunction with reviewing the protocol and the consent form."

Margitic makes sure PIs understand what their DSMPs should include and how to determine a study’s risks, which could fall into the categories of minimal risk, low risk, moderate risk, and high risk.

"There will be gray areas," she says. "For example, we have occasionally seen observational studies where there are no interventions, such as drugs, medical procedures, or devices, but which may involve tests done to measure study outcomes, and those tests could be risky."

An example would be an observational study involving a bronchoscopy being done as a research procedure in otherwise healthy asthma patients, she explains.

"Whenever you take relatively healthy volunteers and expose them to a risky research procedure or to an intervention of significant risk for which they are not going to benefit, most RSAs would say that’s a high-risk study," Margitic says.

"Sometimes investigators need guidance concerning the level of safety monitoring that is needed," she adds. "The RSA can help them determine the physical, emotional, psychological, and other risks that may be involved in study participation."

Here are some of the questions that RSAs typically ask when working with investigators to develop a DSMP:

  • What are the expected risks/adverse events (all of which should be included in the consent form)?
  • How will risks/adverse events be minimized?
  • How will subjects be treated if an adverse event occurs?
  • Who is going to be monitoring the safety data for each individual subject?
  • Who is going to be monitoring the accumulating safety and efficacy data across all subjects, and how often will this be done?
  • Is there any conflict of interest for investigators or co-investigators?
  • What specific lab alert values or clinical criteria will be formulated to determine when an intervention should be discontinued or changed?

"For example, if you are conducting a clinical trial in which you are giving a drug that causes renal problems, you want to monitor the blood for kidney function," Margitic explains. "And if the blood test indicates a certain level of renal toxicity, then it’s essential to have plans in place to discontinue the drug or decrease the dose, depending on the specifics of the study, and these kinds of alert values must be pre-specified as part of the study DSMP."

  • When adverse events are reported, what kind of scale will be used to describe how severe the adverse event is and what the presumed level of association is between the intervention and the event?
  • What is the adverse event reporting plan [i.e., to which offices or agencies will adverse events be reported, such as the IRB, the sponsor, the Food and Drug Administration (FDA), NIH]?

2. Provide a thorough safety review of the proposed study protocol, DSMP, and adverse events.

At Wake Forest University Medical Center, the RSA presents her safety review to the GCRC protocol review committee, which reviews all GCRC protocols and approves them before they are sent to the IRB for approval.

This two-step approval process was set up this way at the IRB’s request, but it may be handled as simultaneous protocol submissions at other institutions, Margitic reports.

"I think that many RSAs review ongoing GCRC local adverse event reports that are sent to their IRBs," she says. "If a GCRC investigator reports an adverse event, I receive a copy of what was sent to the IRB."

Also, Margitic keeps her own longitudinal record of IRB-reported local adverse events, since some studies may not have a safety monitoring committee.

"This is an extra pair of eyes to look at safety," she explains. "We also review all data safety monitoring board reports and continuing annual renewal reports sent to the IRB for our studies."

The annual progress report includes details on how many people have been enrolled in the study; whether there have been any protocol deviations, study dropouts, subject complaints; discussion of unexpected complications or serious adverse events; and discussion of any new information that could affect the conduct of the study, Margitic says.

Guidance in the informed consent process

3. Offer hands-on informed consent guidance.

"We want to make sure that our GCRC consent forms have all the mandatory elements," Margitic says. "For example, subjects need to understand that they are being asked to be part of a research study with a standardized research protocol, as opposed to receiving individualized medical care or treatment."

Other mandatory elements include:

  • Purpose of the study.
  • Description of study interventions and procedures.
  • Alternatives to study participation.
  • Risks and benefits.
  • Steps taken to ensure confidentiality.
  • Whether there is financial compensation.
  • What treatment is available and who provides it if a research-related injury occurs.
  • Name and number of the study’s contact person who can answer questions or to whom an adverse event can be reported.
  • Name of the office and phone number where subjects can report any concerns they have related to their being a research subject, such as if they feel their rights are being violated.
  • Section that tells subjects that they have the right to refuse to participate in the study or to leave the study at any time and that this will not influence their care at the institution.
  • Discussion of possible unforeseeable risks, (i.e., in an investigational or Phase I drug study).
  • Advising subjects that they will be informed if there are any significant findings that may affect their participation, such as results from ongoing trials testing a similar intervention.
  • Circumstances under which the subject’s participation may be discontinued, such as if the physician believes it’s in the best interest of the individual to not be in the study any longer.
  • Whether there will be any cost to the subject for participating in the study.
  • Consequences of early withdrawal from the study (i.e., a subject who drops out may have to gradually decrease the dose of study drug rather than discontinuing it suddenly).
  • Number of subjects in a study.
  • Explanation that if a drug or device is investigational and has not yet approved by the FDA then its safety and efficacy track record have not yet been proven.
  • If the study involves a blind comparison arm, then subjects need to be informed that they may not know which treatment they are on until the end of the study, but that in an emergency situation, their treatment assignment could be revealed.
  • If genetic or biological samples are involved, the informed consent form should include what will be done with samples, how confidentiality will be protected, and whether subjects can request to have their samples discarded at a later date.

In addition to guiding investigators when they design their informed consent forms, Margitic will observe how they or their staff handle the one-on-one informed consent process.

4. Educate investigators and others working in research.

Many RSAs also serve as educators, and Margitic is no exception. At Wake Forest, she recently put together two half-day workshops called "Topics in Clinical Trials Research Studies," which covered 10 different topics.

The workshops cost $20 each, and they were open to the entire institution. About 75 people enrolled for each, she reports. "The turnout was gratifying."

The GCRC, the medical center’s office of research, and the department of public health sciences sponsored the workshops. Margitic designed the program and found speakers, and made some presentations herself.

Topics included an overview of clinical trials, explaining good clinical practices, processing IRB documents, reporting adverse events, recruiting for studies, describing the informed consent process, encouraging adherence and retention of study participants, auditing by the FDA, and budgeting for clinical trials.