Clinical trials are crucial to developing lifesaving drugs and procedures, but medical researchers today are frustrated: Often benefits from the proposed advances are so subtle that they require increasingly complex and incredibly expensive studies involving thousands of patients to show whether or not there is some small benefit. At the same time, patients are pressing for access to promising treatments as soon as possible, sometimes before the trials are even done.
Evidence from clinical trials is crucial to delivering quality healthcare and to reining in expenditures wasted on what does not work. But this evidence is mostly lacking, said Robert M. Califf, the vice president for clinical research at Duke University, who noted that only 15% of current medical practice is supported by good clinical trials.
“Our clinical trials system is falling behind the needs of society and we have to figure out a way to do it more efficiently and better,” said Califf, speaking at a 6-7 June conference co-sponsored by AAAS.
Mark S. Frankel, director of the Scientific Responsibility, Human Rights and Law Program at AAAS, struck a similar note: “It is critical that we consider how the developments under consideration at the conference—and at medical research centers across the country—will affect the more traditional ways that clinical research has been done, and what that will mean for translating findings into treatments.”
Those were predominant themes at “Clinical Trials: Present Challenges and Future Opportunities,” a meeting that drew more than 200 medical research leaders to the campus of the National Institutes of Health in Bethesda, Maryland. The National Library of Medicine (NLM) and the Friends of the National Library of Medicine joined AAAS as co-sponsors.
The consensus among researchers, government leaders, patient advocates, and others at the conference was that the clinical trials of the past must be adapted to the demands of 21st century medicine. Their discussions ranged from harmonizing and standardizing the conduct of those trials to engaging patients as partners in the research process.
Califf argued in his keynote address that doing more of the same types of clinical trials will not solve the problem of limited evidence. That’s because the drugs and devices being tested often propose so modest an improvement over what already is used that they require increasingly larger and costlier trials to show any effect at all.
The emerging “-omics” fields—genomics, proteomics, metabolomics—are contributing to a better understanding of the mechanisms and signaling pathways of specific diseases at the body, organ, cellular, and molecular levels.
Incorporating these advances into clinical trials should produce answers quickly, using fewer patients. It should advance the science at a more rapid pace and more affordable cost, said Califf.
The overarching framework for these activities is the public data repository and Web site ClinicalTrials.gov, run by the NLM. It started with the goal of “no secret trials and no secret results,” said Library director Donald A. B. Lindberg.
The Web site was launched in 2000 as a way to give patients access to information and increase their participation in clinical trials. A big boost came in 2004 when editors of the leading biomedical journals decided that they would not publish the results of a trial unless it had been registered from the start with the site. Then in 2007, Congress passed a law requiring that data from specific types of trials of drugs and devices be deposited at the site on public view.
“A lot of good comes from having open access to the full details of the trial,” said Deborah A. Zarin, director of the ClinicalTrials.gov program. People can see whether or not the researchers tried to hide some of the data or “cherry-picked good results” when they wrote up a paper for publication, she said.
Knowing about failure is important so that researchers do not duplicate failed studies or lines of investigation and unnecessarily put patients at risk, Zarin said. In the past, pharmaceutical companies have suppressed some unfavorable studies, even the fact of their existence, arguing they were trade secrets they did not want to share with rivals.
Zarin said ClinicalTrials.gov has opened “a window to the sausage factory” of clinical trials, greatly adding to the transparency of the research process. Today the site contains information on over 108,000 trials in the United States and around the world.
AIDS activism in the 1980s accelerated the movement for patient empowerment, serving as an example for breast cancer and other patient advocacy communities to build upon. Today the Internet and social media offer unparalleled opportunities for patients and the public to become informed, organized participants in managing their own health.
PatientsLikeMe is a technologically innovative Web site that offers a series of Web tools for patients to record and share detailed information about their medical conditions and care. The privately owned company finances its operations in part by selling aggregated and de-identified patient data to industry.
Paul Wicks, the site’s research and development director, described how a group of patients with amyotrophic lateral sclerosis greeted initial reports that low doses of the drug lithium carbonate slowed progression of the disease. One patient located a paper abstract in Italian, used Google software to translate it into English, and shared it online.
“Before it was even published [in English], there were more patients in our system taking lithium prescribed for them by their doctors than were in the [Italian] clinical trial,” Wicks said. He wrote up the strengths and weaknesses of this exercise in “systematically studying patients’ self-experimentation” in the journal Nature Biotechnology.
However, a subsequent clinical trial of lithium carbonate, organized by Massachusetts General Hospital, was stopped early at the first interim analysis when it showed no potential for a beneficial outcome, and perhaps an increase of side effects.
Califf saw the exercise in self-experimentation as more of a cautionary tale than a path for future activity. “Given the fact that patients and families are constantly online, there is a risk that they will adopt treatments based on preliminary reports when subsequent trials will show the treatment to be ineffective or risky,” he said. “Better to turn that energy into working together to get the definitive answers more quickly through better participation in clinical trials.”
One major reason why people do not participate in clinical trials is simply the hassle of it; the time and effort required to go back and forth to a site location multiple times on a fixed schedule. Patients are more willing to do so if they face a life-threatening condition and there are no or poor treatment options, but they are not as willing to do it when the situation is less dire.
That is why trials invest significant resources into creating multiple locations, add inducements such as daycare, and sometimes even compensate participants.
Freda Lewis-Hall, chief medical officer at the pharmaceutical company Pfizer, believes that a “virtual” clinical trial structure might reduce some of these barriers to participation, and also reduce the time and money needed to get results.
The company launched the REMOTE trial, which she described at the conference, as an operational study to test concepts and tools, using an already approved drug for bladder control.
Web-based and mobile phone apps are being used to manage recruitment, enrollment, data entry, and monitoring. Blood draws can be scheduled online at a fixed location or from a visiting nurse, and the drug is shipped directly to the patient. Physician assistance is available 24/7 by phone.
Lewis-Hall said some types of studies “are amenable to [this approach] because a lot of it is patient self-reports. And this is a disease that is managed primarily by the patients within their own environment. So, we thought it was a good therapeutic area” to test the concept. The U.S. Food and Drug Administration agreed and signed off on it.
It may prove to be one effective adaptation to conducting clinical trials in the 21st century.
Learn more about AAAS’s Scientific Responsibility, Human Rights and Law Program.