NIH creates roadmap for clinical research

Focus on ethics is 21st century goal

The National Institutes of Health (NIH) in the early fall announced plans to transform the nation’s medical research enterprises and expedite turning research discoveries into practical improvements.

Calling its goals the NIH Roadmap for Medical Research, the agency’s vision coincides with shifts in public attitudes about research and with some transformations that already are under way.

"NIH’s leadership now challenges all of us to think how research enterprise needs to be re-engineered," says Debra R. Lappin, JD, president of Princeton Partners Ltd. in Englewood, CO. Lappin also is an adjunct professor in the graduate program of clinical sciences at the University of Colorado Health Sciences Center in Denver, and she is the past national chair of the Arthritis Foundation, based in Atlanta.

The NIH has developed this new vision for clinical research, partly out of necessity as clinical research has gradually shifted away from the traditional setting in academic medical centers, Lappin says.

More than two-thirds of today’s clinical trials research can be found in places other than academic medical centers, and these other places often are small clinical practices in which research and ethical training and experience are limited, she notes.

"What NIH is trying to suggest for the nation is a new clinical research network in which investigators in these new settings have been trained, " says Lappin. "This is a huge challenge and it allows us to rethink the enterprise and the system."

Lappin is an inaugural and four-year member of the NIH Director’s Council of Public Representatives and had chaired the working group on human research protections, an assignment that ended in April. She will speak about this new paradigm for clinical research at a conference called Contemporary Issues in Human Research Protections, Nov. 17, 2003, at Iowa Methodist Medical Center in Des Moines.

The NIH roadmap, which can be found on the NIH web site at, has a theme of Re-engineering the Clinical Research Enterprise. It will promote better integration of clinical research networks, and NIH has established implementation groups in these areas:

• Harmonization of clinical research regulatory requirements.

• Integration of clinical research networks.

• Enhance clinical research work force training.

• Clinical research informatics: National Electronic Clinical Trials and Research Network.

• Translational research core services.

• Regional translational research centers.

• Enabling technologies for improved assessment of clinical outcomes.

As NIH pushes for recognition of the changes that have taken place in clinical research and works to provide its roadmap for future courses, there are some important ethical questions that should be examined under the lens of a new public partnership, Lappin suggests.

These include the following:

• Therapeutic misconception: "The public partnership is based on the evolution of relationships with science, and it has moved from paternalism to an era of autonomy," Lappin says.

As such, the therapeutic misconception that has both investigators and subjects viewing clinical trials as therapeutic and falling under the physician-patient relationship should be acknowledged as an ethical distortion, she says.

Surveys have shown that more than half the people who participate in a clinical trial believe they are going to be finding some relief from their medical problem, Lappin adds.

"We’re all a part of this misconception," she says. "Clinicians who recruit for trials do so with the honest thought that patients will find some relief; and we all have hope, and no one wants to remove hope from a patient’s life."

Confronting this therapeutic misconception head-on might require changes to the informed consent process and viewing research from a participant’s point of view.

"Make sure differences from the standard of care treatment are well expressed in the informed consent," Lappin says. "These differences need to be suggested with ethical clarity about randomization, flexibility in dosing levels, and measuring outcomes that we don’t normally use."

The NIH roadmap promotes the idea of expediting the clinical research trial process and moving trials into new communities where investigators can find clients, and this will create more challenges in educating research participants, she notes.

"Most clients are not going to be going to academic medical centers," Lappin says. "They’ll be participating in private practices."

The fraternal approach of treating human subjects as though the physician/investigator knows what’s best for them will no longer work, and researchers will have to adapt to the new approach that views research in the light of what best serves the public, she says.

"We need to conduct more practical or pragmatic clinical trials," Lappin says. "We must promise the public in the new partnership that if they participate in trials not only will we gain new treatments, but we’ll gain answers to policy questions of what works in a real practice setting and what works with people with multiple chronic diseases."

• Generalizable knowledge: Investigators and IRBs need to consider their obligations in promising generalizable knowledge to research participants, as well as to the public, she says.

"I want to challenge all of us to think about how to draft industry relationships that do not compromise the promise of generalizable knowledge," Lappin says. "If we are asking a participant to give us tissue samples that will go to an industry partner and may be used in a way over which we have no control, what is our ethical responsibility?"

Questions to consider include, she adds:

— Do we have any control over the study design in our industry contract?

— What have you promised me as a member of the public?

— Do I presume that you have access to all the data-sites vs. the single data-sites of where the study is being conducted, if it’s a multisite study?

— Do I presume that if there are negative findings that these will be published and that they will be of obvious value so that this science is not repeated in the future, if it in fact has rendered negative results?

"The failure of a system to publish negative trial results is a very big issue," Lappin says.

This is a big issue that could significantly impact an institution’s reputation, she adds. "If you are an institution that has a valuable patient base with a particular disease, this has very valuable data but it may be a question of disclosure."

For example, the ethical way to handle this situation may be to disclose to participants that the investigators are requesting tissue samples that will be given to an industry partner, who may use it. But the investigator has no control over whether there will be any generalizable knowledge gained from its use, Lappin says.

• Cultural and translational blocks across agencies: "I think the public is holding clinical research enterprise and the federal government and agencies conducting clinical research to a new level of responsibility for addressing translational blocks," Lappin says.

Clinical research needs to move through the system with an effective translation from NIH to proof-of-concept clinical trials, Lappin says.

If clinical trials in very early stages do not show any biological signal of success, then bring that information into clinical practice and translate what has been learned, Lappin says.

This information could help inform public policy with regard to health care reimbursement, for instance.

"If we’re going to have a Medicare reimbursement policy, then what do we reimburse?" Lappin says. "We need comparative clinical trials that compare old standards with far more expensive new drugs, and these trials are ones that the industry has no motivation to conduct."

There have been examples of where these types of comparisons were conducted and researchers discovered that the inexpensive, old treatment works best, Lappin says.

"It’s so easy to believe the newest and most expensive [drug/device/procedure] is dramatically better, and therefore the public may feel that they’ve been let down by reimbursement policies and not getting the newest and latest medication," Lappin explains. "Whereas, there have been a couple of very recent areas in which we’ve seen that what we demanded and thought we needed as the public was in fact not the best treatment — hormone replacement therapy comes to mind."

• Informed consent and conflicts of interest: Investigators and IRBs need to keep in mind that informed consent should be informed participation, and it’s a process — not an event, Lappin says.

"Perhaps we need new technology that allows informed participation to continue throughout the trial," she suggests. "It’s not a static event."

Also, it would be advisable to have a third-party advocate who has access to clinical trial information and can advise participants, Lappin urges.

"The most important point is that there should be a layered approach that allows the participant to get increasingly important information," she says. "And the participant in the trial should know the outcome of the study irrespective of publication."

A good question for investigators and IRBs to consider is at which point they disclose recruitment bonuses. Major medical associations have suggested that the IRB has the responsibility of knowing this information, Lappin says.

IRBs will have to decide whether this information should be in an informed consent, she adds.

"I honestly think there is a way to disclose the financial underpinnings of the trial in a way that does not overwhelm a participant, but gives a participant the rationale sense that trials cost money," Lappin says. "Institutions will have to look long and hard at how it will look if participants aren’t advised and something goes wrong."

Institutions and investigators should ask themselves, "Will this pass the 60 Minutes [television show] test?" she says.