Why Bother Offering That Clinical Trial? An Internal Dialogue

Why Bother Offering That Clinical Trial? An Internal Dialogue

Guest Commentary

Sep 09, 2013
   

By William M. Sikov, MD, FACP

This editorial originally appeared in the Breast Cancer Symposium 2013 Daily News; please visit for complete coverage.

You’ve completed your patient’s history and physical, and have stepped out of the room to let her get dressed while preparing to sit down with her and her partner to discuss her diagnosis, stage, prognosis, and treatment recommendations. With their permission, a 2nd-year medical resident will sit in on this discussion. As you wait, you run through what you’re planning to say—especially about her standard treatment options and about a clinical trial for which she appears to be eligible—a randomized study that should answer important questions about the treatment of her disease. You know that this part of the conversation can be disconcerting for patients; she was referred to you because of your knowledge and experience, not to have such an important decision made by a computer, by a flip of a virtual coin. 

Why bother? Why open that can of worms? You’re already 40 minutes behind schedule, and the study discussion is bound to add at least a half hour to this visit. It’s certainly not for the money; with the exception of a few well-funded pharmaceutical company-sponsored trials, your protocol office actually loses money on a per accrual basis. It’s not for the “glory”— there’s no way you’ll enroll enough patients on this national study to be a named author when the results are published, and in the academic scheme of things clinical research is a poor relation. You know the statistics, which you share with the resident—how few patients are candidates for available trials despite efforts to streamline eligibility criteria, how few are offered the chance to be part of a trial, and how few agree to participate—less than 5% of adult patients with cancer enroll in clinical trials, in contrast to more than 60% of children with cancer.1  

Challenging Accrual Numbers

Too many seemingly well-designed studies fail to meet their accrual goals; in the past, up to 40% of National Cancer Institute (NCI)-sponsored trials failed to complete accrual, although recent data suggest that that percentage should fall going forward, at least for the most vital phase III studies.2 How do you explain to a patient who agreed to participate in a study that the questions it was supposed to address won’t be answered because the study wasn’t completed? Fortunately, that same analysis projected that only 2% of adult patients with cancer enrolled on ongoing phase III studies will be entered onto studies that will close as a result of inadequate accrual.2 Even so, many trials that eventually fully accrue take much longer than planned to do so. How many axillae were unnecessarily dissected because enrollment to ACOSOG Z0011 was so slow?

The numbers are worse for minorities, young adults, and the elderly. Close to 90% of patients who enroll on NCI-sponsored clinical trials are white, of whom less than 6% are Hispanics/Latinos.3 How can we be sure that the results of our studies are broadly applicable, that there aren’t important differences in disease behavior or treatment effects (good and bad) determined by genetic traits that vary between ethnic groups, if the study population isn’t representative of the U.S. population? In addition, there may be the added challenge of overcoming suspicions as to the beneficence of the clinical trials process based on a few infamous historical precedents, such as the Tuskegee syphilis study, which monitored the progression of untreated syphilis in young African American men who were not told that they had the disease and were led to believe that they were receiving free health care from the U.S. government.

Addressing Patient Fears

You know that this patient and those closest to her simply want to know what’s best for her, not necessarily for some faceless patient in the future. You know that random selection, fear of receiving a placebo, and fear of developing any of the long list of potential side effects listed in the consent form (even if the list of side effects for the standard treatment is just as long) are among the greatest barriers to clinical trial participation.4 If you come across as too enthusiastic about the experimental approach, the patient may believe that she would be getting inferior treatment if she is randomly assigned to the standard treatment arm, so why don’t you just give her the “better” treatment? You remind yourself of how often what some experts were sure was a major advance proved to be no better and only more toxic when the randomized trial was finally completed. How many patients with advanced-stage or high-risk breast cancer were subjected to the toxicities of high-dose chemotherapy with stem cell rescue before the studies were completed that demonstrated the lack of benefit of that approach? At least when they ask you “What would you do if this were your wife or partner,” you can honestly answer that you would support participating in the study.  

You dread being told “I don’t want to be a guinea pig” when you suggest a clinical trial—it makes you want to say (maybe a little too emphatically) that none of your patients are guinea pigs (you aren’t a veterinarian, after all), and that what would really make her a guinea pig would be to give her the experimental treatment outside of the clinical trial (sometimes referred to as an “n of 1 study”). But you won’t; instead, you’ll tell her that it is only because patients like her agreed to participate in prior studies that we have been able to define our current, although admittedly imperfect, standard treatments. 

You will also have to explain that participating in the study requires additional office visits, blood tests, scans, and questionnaires. You may have to ask for blood and tissue samples, maybe even an extra biopsy, for correlative research studies. New ways of analyzing patients and their cancers—next-generation sequencing, proteomics, and pharmacogenomics—promise to revolutionize our understanding of and, eventually, the treatment for her cancer, offering the hope of truly personalized oncology, but only if studies are completed that demonstrate a correlation between these findings and patient outcomes. Fortunately, you work in a state that mandates insurance coverage of the costs of routine medical care in patients who participate in clinical trials (a requirement that is supposed to extend nationwide with implementation of the Affordable Care Act).    

Maybe we should make it easier to enroll in studies, or harder to refuse. In some countries the only way to get standard treatment covered is to participate in a study, but fortunately that’s (usually) not the situation in the United States. Of course it’s easier to accrue if the only way to get a promising treatment is on trial, such as the studies of adjuvant trastuzumab. Wouldn’t it be easier if the consent forms weren’t 20 pages long, with four pages of potential (if rare) side effects? Can we expect most (or any) of our patients to read and truly comprehend such a lengthy document, even if it is (supposedly) written at an eighth grade level? Over the past few years, the NCI has initiated efforts to streamline the clinical trials development process5,6 and to simplify its model consent.  

You explain to the resident that the doctor’s role in suggesting and explaining a study to a patient is vital, even though your research nurse will do most of the work—confirming eligibility and completing the consent process—if the patient agrees to consider the study. But you can only succeed if you try. Albrecht and colleagues7 studied interactions between oncologists and patients and their families at two comprehensive cancer centers. They found that clinical trials were offered to patients only 20% of the time, but, when offered, 75% of patients agreed to participate. In a telephone survey of 1,000 adults, 32% of responders said they would be very willing to participate in a cancer clinical trial if asked, and another 38% indicated that they would be inclined to do so.8

So, in the end it boils down to knowing the importance of your role as her physician—even if it’s the first time you’ve met. You truly believe that the study is her best option. And perhaps the most important reason why you want to contribute to, and want your patients to be part of, studies like this one is so that when you—or that resident—sit down with another patient like her in 5, 10, or 20 years you can confidently say that treatment A is better than, equivalent to, inferior to, or less or more toxic than treatment B in patients like her because this patient and thousands like her took part in clinical trials. In the end, when the results of this study are presented and then published (and of course you always inform your patients when this occurs), you’ll both be proud to have been part of the process.


Dr. Sikov is an associate professor of medicine at the Alpert Medical School of Brown University and Co-Chair of the 2013 Breast Cancer Symposium. He will moderate the General Session III: Local Tumor Board today at 1:00 PM (PDT) and Chair the Welcome and General Session IX: Evolving Strategies in Early Stage Breast Cancer on Monday at 8:30 AM (PDT).

References:

 

  1. American Cancer Society: Clinical trials: What you need to know. Available at cancer.org. Accessed July 9, 2013.
  2. Korn EL, Friedlin B, Mooney M, et al. Accrual experience of National Cancer Institute cooperative group phase III trials activated from 2000 to 2007. J Clin Oncol. 2010;28:5197-5201. Epub 2010 Nov 8. PMID:  21060029.
  3. Greenwood A. Taking action to diversify clinical cancer research. NCI Cancer Bulletin. 2010;7(10). cancer.gov/ncicancerbulletin/051810/page7. Accessed July 8, 2013.
  4. Meropol NJ, Buzaglo JS, Millard J, et al. Barriers to clinical trial participation as perceived by oncologists and patients. J Natl Compr Canc Netw. 2007;5:655-664. PMID:  17927923.
  5. National Research Council. A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Washington, DC: The National Academies Press, 2010.    
  6. National Research Council. Implementing a National Cancer Clinical Trials System for the 21st Century: Workshop Summary. Washington, DC: The National Academies Press, 2011.
  7. Albrecht TL, Eggly SS, Gleason ME, et al. Influence of clinical communication on patients' decision making on participation in clinical trials. J Clin Oncol. 2008;26:2666-2673. PMID:  18509178.
  8. Comis RL, Miller JD, Aldigé C, et al. Public attitudes toward participation in cancer clinical trials. J Clin Oncol. 2003;21:830-835. PMID: 12610181.

 

 

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Comments

Mehmet Sitki Copur, MD, FACP

Sep, 16 2013 12:36 AM

Why bother ? An embrassing 3-5% national clinical trial participation rate in adult oncology! Dr. Sikov nicely summarizes the issues with a great case vignette in the academic setting. However, 85% of adult oncology patients are diagnosed and treated in the community. This brings additional obstacles for clinical trial enrollment from extensive regulatory burden, to lack of infrastructure, to lack of insurance coverage, to lack of medial oncologists training/interest/enthusiasm for clinical trials in the community setting.

There has to be a huge cooperation and effort among the high stake holders such as ASCO, FDA, NCI,Industry, and Academia to come up with a creative, universal, standardized, minimal regulatory burden infrastructure establishment to enable conduct of clinical trials in the community setting with much less barriers.

My dream model is; Any community oncologist  becomes a member of a National Clinical Trial Network system (similar to CTSU) then any trial that is through this network accepts a one and only central IRB (similar to Central NCI-IRB), ASCO comes up with an Exemplary Community Clinical Trial Site Certification, applicable to all community sites with minimal regulatory burden (this will requrie huge coordination among above mentioned high stake holders, i.e. NCI,FDA, Industry, Academia) and  sites that  accomplish this catgory  can participate in all clinical trials as long as they achieve and maintain pre-determined minimal exemplary site attributes through their certification. Oncology fellows are given extra education and training during their fellowship and graduate thinking clinical trials first not the last choice.

This is my dream I am not sure how realistic that is why I cal it my dream.


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