UPenn creates integrated clinical research program

The extra effort results in much better system

For the University of Pennsylvania School of Medicine in Philadelphia, there was no question that the only acceptable solution to the problems in human subjects research was to establish a comprehensive program that included all areas, including investigators, IRBs, and the institution’s leadership.

While the university’s human subject research program received intense scrutiny after Jesse Gelsinger died in 1999 during the course of a gene therapy trial, the research oversight deficiencies experienced by the University of Pennsylvania were no different from any other noncommercial research setting, says Deborah Waltz, MS, CIP, director of Research Compliance and Quality Improvement Office for Human Research at the university.

"I think the problem with some institutions is they don’t look for problems, and if you don’t have a feedback mechanism and don’t sample what’s going on, you’re under a delusion that everything is fine," she says.

"What happened from the perspective of the research industry is that investigators in academic centers truly believed that the FDA laws and regulations did not apply to them," Waltz explains. "I came to this university after 20 years in the pharmaceutical industry and with experience in quality assurance and regulatory compliance."

Starting a comprehensive compliance and oversight program from scratch is very difficult, but it’s been well worth the effort, she notes.

"The visibility that Penn has allowed us to have for speaking and talking about problems and solutions has helped make a difference in how research has been conducted across the country," Waltz says. "It’s safer for the research participant, we have better data and more reliable results, and everybody wins."

Institution, researchers benefit

Waltz offers these details on how the university’s compliance and quality improvement program is designed:

• The focus primarily is on protecting human subjects. While human subject protection is the chief goal, the program’s role also includes protecting the institution and the investigator, and these additional responsibilities are in harmony with the primary focus, she says.

For example, when investigators make mistakes and otherwise show they lack the necessary understanding of human subjects protection, they are rehabilitated rather than punished through a denial of research privileges, Waltz notes.

"If we see that an investigator needs a better understanding of how to conduct compliant research, then we teach him," she explains. "We stop enrollment in his studies and show him how to do it properly. As he goes forward, we monitor closely, side-by-side, so that we ensure sustained compliance."

Compliance staff may attend informed consent sessions, providing instruction on how to improve the process, Waltz says.

"We may continue on close oversight for two to three years," she adds. "Those investigators will be our best investigators going forward; whereas, at other institutions where they banned researchers for three to five years, what happens is the investigators eventually return and will do research with no better understanding of human subjects protection."

• Recognize personal incentives to conducting higher quantities of research. In the academic community, one of the major motivators for staff to produce volumes of research is the tenure track that rewards those who publish, Waltz says.

"Investigators graduate from medical school; and in the past, they had zero segments of their curriculum about clinical research," she explains. "So then they’re told to go forth and publish, and there are no resources to teach them how to do this."

Their instructors and mentors also may lack adequate training in human subjects protection, and so the problem is compounded, Waltz says.

This is why investigators need proper training and monitoring, Waltz says.

"At first, investigators didn’t exactly embrace the concept of having someone monitor their research, but now it gives them a comfort level that shows they’re doing better."

• Start a compliance and quality improvement program that begins with the top management. "We say that you need strong top-down support from the highest levels of the institution because the first time you offend one of the renowned investigators, that person will head to the dean’s office," Waltz says. "This will set the tone for the success of the program because if the dean tells the monitoring group to back off, then it undermines the whole program."

Waltz says she used to tell institutions to buckle up because once they start this program, the first visits will be bumpy.

• Use monitors and stop relying solely on the IRB for all human subject protection. Institutions often forget that the IRB is not enough protection against research abuses and problems.

"Pharmaceutical companies monitor every single study with people dedicated to going out and verifying what’s happening," Waltz says.

Monitors check a variety of areas, including:

— Where is the money going?
— Are there really X number of patients enrolled as reported in the protocol?
— Are the data accurate?
— Is the study conducted according to the protocol?

"So one of the important notions to get across to investigators is how important it is to have strict protocol adherence," Waltz says.

"When I was in the pharmaceutical industry, I would come to academic centers across the country, and the investigator would tell us that, We don’t really have to follow the protocol because we’re academia,’" she recalls. "But this places the subject more at risk, because once you deviate from the known, you enter the unknown."

• Pay close attention to investigational new drugs (INDs). "The No. 1 mistake that people make in noncommercial settings is a failure to recognize that they need an IND for their research," Waltz says.

Investigators often confuse federal agencies and their responsibilities and may think that they’ve met federal regulations once their study has been approved for funding from the National Institutes of Health, when they may not be in compliance with the Food and Drug Administration (FDA) or the Office for Human Research Protections, she adds.

This contributes to what Waltz calls the phenomenon of IND avoidance, in which investigators may avoid applying for an IND because they fear they would have to follow good clinical practices if they do.

"Educating investigators about the need to follow good clinical practices regardless of IND status goes a long way to correcting that situation," she says.

"One problem is that many investigators in the country have never sat down and read the regulations, and many are not well versed in interpreting the law," Waltz explains.

This is why institutions, through a compliance or regulatory office, ought to centralize the responsibility for deciding whether an IND is needed, she suggests.

At the University of Pennsylvania, all investigators are required to present an IND number on a protocol that’s submitted to the IRB, or they must present an exemption in the form of a letter from the compliance office stating that this protocol does not require an IND or an FDA letter of exemption, Waltz says.

"There are a number of physiological and metabolism studies that may not require an IND, but most other studies do," she says. "As soon as you start to use a drug outside of the approved labeling, you go into the unknown as far as the FDA is concerned."

The institution has an IND tool, which must be completed by investigators and is used to decide whether an IND is needed, Waltz says.

"In filling out the IND form it drives the investigator to make his own conclusion that he needs an IND," she says. "It forces him to do something he otherwise would not have known how to do."

• Require education and certification of investigators. The University of Pennsylvania has an on-line certification program, and when investigators submit protocols they must include their certificate to show that they’ve completed the required training, Waltz says.

The certificates last three years before they must be renewed, and investigators are sent notices when it is time to renew their certification, she notes.

Developing the certification program was time-consuming and cost about $100,000 initially, reports Waltz.

"It takes a certain amount of ongoing resources to keep the certifications up to date and manage systems that track investigator certification and to let them know when it’s about to expire," she adds.