Failed clinical trials come at a huge cost to their pharmaceutical sponsors. Many trial sites fail to enroll more than a single patient—up to 60% of oncology trials, according to Covance, for example. Yet they estimate it costs a sponsor $50,000 for a site start-up, with a loss of almost $2 billion between 2006-2010 from non-performing sites.
Did you know that only 3% of patients with cancer participate in clinical trials? Although we have an aging population and cancer rates increase with age, this dismal participation rate hasn’t budged in recent years. What factors are at play?
Perspective
I raise this issue as part of a New Year’s resolution to try to boost clinical trial participation. In part reminded of the importance of volunteering by Nina Martinez’s (@marganina) posts on her participation in HIV trials, and Lisa Bonchek Adams’ (@adamslisa) important posts detailing her experience on trials for metastatic breast cancer, I recently enrolled on an NIH clinical trial for hyperlipidemia.
I’ve volunteered for several trials over the years, beginning in college. That’s part of what boosted my interest in medicine and conducting clinical research. As an investigator, my threshold for accepting a clinical trial was whether or not I would be willing to be a participant or have a family member participate. In fact, my husband and I were both volunteers on my very first trial, Trospectomycin in the treatment of pneumonia, enrolled by a co-investigator. Unfortunately, this is no longer allowed—it was quite reassuring to patients, however.
My first visit at NIH went very smoothly, once we got through the insane security procedures. The clinical coordinator reviewed the consent form with me, then I met this friendly phlebotomist who put me right at ease. The coordinator escorted me from one study procedure to the next. Finally, at the end, I had an opportunity to ask more questions.
What are the barriers to clinical trials?
The biggest barrier in recruitment is lack of encouragement or support from the attending physician. Many physicians simply are unaware of clinical trials that might benefit their patient. Further, with the increasing pressure to see patients more and more quickly, they simply don’t have the time to engage in lengthy discussions with patients. Many are also concerned about lack of control—it is critical that the trial physician communicate regularly with the primary physician.
There is a huge lack of awareness about clinical trials. In a 2000 Harris Interactive survey, 80% of cancer patients were unaware of clinical trial options. In a 2013 Zogby survey, more than half of patients were still unaware of trials. Only a quarter learned of trials from their physician.
Many patients also don’t understand that, if there is a standard treatment available, they will not get a placebo—a new drug is always compared to the existing treatment. Others misunderstand and believe that an experimental treatment must be better than the standard. One must be careful to avoid this “therapeutic misconception” and reiterate that the proposed intervention is experimental.
Other barriers I’ve encountered include:
Unrealistically restrictive inclusion and/or exclusion criteria. Typically, I screened 10-20 patients to find one who met criteria to enroll on a trial. On one ill-fated study, it was over 150 before I found a match. This is part of why so many trials fail—per the National Cancer Institute (NCI), 40% of oncology trials failed to achieve the minimum patient enrollment, and more than three of five phase III trials failed to.
For example in a Duke review of “real-world” patients receiving targeted therapy compared to those in a Phase 3 trial, 39% of those in the Renal Cell Cancer registry cohort would even have failed to qualify for a clinical trial of the agent they were receiving, largely because of comorbidities common in the real world. This is also a huge problem in oncology trials, where there are seeming “no win” criteria—either exclusions because of too much prior chemotherapy, not being newly diagnosed, or having advanced disease. Again, Lisa Bonchek Adams walks readers through this, and much more, in her detailed posts about her experiences seeking treatment options. So at the same time as many are the most motivated to try an experimental treatment, they are the most likely to be excluded by protocol requirements. And unlike Lisa, most patients who are rejected from one trial give up, and don’t seek other ones.
Unrealistic, inconvenient protocol requirements (“You want me to do what?”).
Politics—rivalry between physicians and/or hospital administrators.
Bad publicity—unfortunately, much of what we hear about clinical trials are things that were done unethically (Markingson case at University of Minnesota) or conducted poorly (TeGenero, or “Elephant Man” case).
Physician or hospital concerns about potential liability.
Insurance or HMO policies that may preclude reimbursement for care. This is less of an issue with cancer trials than previously.
HIPAA is one thing that killed my ability to conduct trials, particularly as the infectious diseases protocols had a very narrow window for enrollment. One easy way for centers to avoid this is to have a simple statement when patients are registering for care asking, “Would you like to be informed of possible clinical trials you might participate in?” IRBs can also issue waivers for screening, since even they understand you have to know of a patient’s existence before you can approach them.
Standardized order sets for “quality” were also a major problem. Pneumonia sets typically included “Levaquin or Ceftriaxone-Azithromycin” as options. Call Dr. Stone for pneumonia study was not an option, and doctors were afraid of being chastised. Also, once a prospective patient has received an antibiotic, they become ineligible for the trial.
Lower income is also predictive of lower participation in clinical trials, surprisingly even among Medicare patients. At the same time, I had to be exceedingly careful with patients in trials whose main interest was that it would provide the only access to health care they could get.
Historically, African Americans, Asian/Pacific Islanders, Hispanics/Latinos and Native Americans are hugely underrepresented in trials, in part from the understandable legacy of mistrust. For example, although blacks have the highest incidence of cancer (593.7 cases per 100,000 people) but they have the lowest rates of participation in cancer clinical trials, only 1.3%.
Women have also been notoriously underrepresented in clinical trials. For example, of 258 cardiovascular clinical trials studied, women made up only 27% of the population. In another 196 trials which included both genders, only 33% reported gender-based outcomes, despite NIH mandates to do so. I brought up the disparities in how men and women with chest pain or cardiovascular disease were treated when I was a med student; my questions were met with disdain. Since then, it's been found that women with acute cardiovascular disease present quite differently from men with the same disease.
The exception to poor participation in clinical trials is that of pediatrics, where more than 60% of children with malignancies participate in trials, and minorities are equally represented.Kenneth Getz, founder of CISCRP and CenterWatch, has noted a new problem in conducting clinical trials. He stresses, "given the advent of social media in clinical research, study volunteers have an obligation to not divulge information about their study drug or to try to break their randomization cohort."
What are some potential solutions?
Most importantly, there needs to be more education of physicians and by them. Their administrative burden needs to be reduced, perhaps by having coordinators do more of the screening and patient education. Some sites have found brief videos to be effective for providing an overview on clinical trials, via a tool called PRE-ACT (Preparatory Education About Clinical Trials). The videos are tailored to the patient based on their responses to a survey. Imagine if the TV in doctors’ offices ran educational material, instead of Fox news!
Another promising tool, developed at Case Western Reserve University, is Trial Prospector. This computer program automatically extracts demographic, lab, and pathology results from hospital data bases and matches the patient’s information with eligibility criteria for different clinical trials. This is likely more accurate than manual screening, as well as enormously less burdensome for staff.
Finally, specific disease advocates and patient-centered research sites, like Patient-Centered Outcomes Research Institute (PCORI) and their network for conducting clinical outcomes research, PCORnet, American Association for Cancer Research, Rare Diseases Clinical Research Network (RDCRN),and alliances like the Clinical Research Forum, are important resources in educating and encouraging clinical trial participation.
Hopefully, with more engaged and vocal advocacy groups, we will see a boost in clinical trial enrollment and effective new drugs.
Credits: Images courtesy of Ken Getz, The Center for Information and Study on Clinical Research Participation (CISCRP)
