What Is Reasonably Foreseeable Lessons L

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COMMENTARY

What Is Reasonably Foreseeable? Lessons Learned

From the SUPPORT Trial

Daniel M. Trifiletti, MD,* Timothy N. Showalter, MD, MPH,*

and Lois Shepherd, JD

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*Department of Radiation Oncology andyCenter for Biomedical Ethics and Humanities, University of Virginia, Charlottesville, Virginia

Received Feb 23, 2015, and in revised form Feb 23, 2015. Accepted for publication Mar 8, 2015.

An Unanswered Question

There are many seemingly straightforward and yet unan-swered questions in clinical cancer care. As an example, consider that for intact prostate cancer the radiation dose that would optimize the therapeutic ratio is unknown. Current national expert consensus guidelines recommend a dose of 75.6-81 Gy, and this range could be regarded as our current “standard of care”(1). However, if 76 Gy is suffi-cient for cancer control, then why increase the risk of toxicity, length of treatment, and cost by treating to 81 Gy? Would it not it be better if we knew the lowest effective dose rather than subject patients to the subjective prefer-ences of individual physicians?

Let us envision a simple, prospective clinical trial randomizing patients with prostate cancer to 76 Gy or 81 Gy. Patients would be informed of a multi-institutional trial they were eligible for, and recruitment from a physi-cian might sound something like this: “Right now we don’t know what the best dose is, but both of these doses have been shown effective in previous trials. Nobody knows which is better.” If common practice is followed, patients might then sign an essentially unreadable consent form. The study goes forward, and let us assume one dose “wins.” Were study participants adequately informed that the higher-dose arm could increase the risk of toxicity? Or conversely, that the lower-dose arm could reduce local control? By enrolling in this study, patients volunteered to

risk toxicity and local failure. But wait just a second: both arms are within the “standard of care.” How can we say there were any increased or different risks at all? If the patient-subjects were not on the protocol they still would have received therapy in this range.

Comparative effectiveness research and quality improvement projects in cancer care are on a rapid rise and taking place against the backdrop of a national debate about what sorts of research risks must be disclosed and how. If subjects will receive treatment they might receive outside the trial, why would participation in the trial alone increase a patient’s risk? According to regulatory requirements, when might researchers be responsible for failing to disclose “reasonably foreseeable risks” in comparative effectiveness research? These questions are the subject of an anticipated federal guidance (2) prompted by a recent trial of neonatal oxygenation.

The SUPPORT Trial

The Surfactant, Positive Pressure, and Oxygenation Ran-domized Trial (SUPPORT) was a recent investigation that has led to a national debate that will have implications on trials that allocate patients to alternatives within a range of standard practice options for the purpose of determining which approach is preferred. SUPPORT was a multi-institutional trial that began accrual in 2005 (3) and is

Reprint requests to: Daniel M. Trifiletti, MD, Department Radiation Oncology, University of Virginia Health System, PO Box 800383,

Charlottesville, VA 22908. Tel: (434) 924-5191; E-mail:daniel.trifiletti@ gmail.com

Conflict of interest: none.

http://dx.doi.org/10.1016/j.ijrobp.2015.03.006

Radiation Oncology

International Journal of

biology physics

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sometimes described as a comparative effectiveness trial. At the time the study took place, the “standard of care” target oxygen saturation of extremely premature infants was from 85% to 95%. A more precise range did not have general acceptance, but some neonatologists believed that the lower end of that general range could safely be used and reduce the risk of retinopathy caused by excess oxygena-tion. The central controversy arose from a randomization between target oxygen saturations of 85%-89% and 91%-95%. The primary endpoint was a composite of retinopathy or death.

Institutional review boards (IRBs) from the 20-plus participating sites approved an informed consent document. Although the forms varied by institution, in general they explained the randomization to the higher or lower oxygenation arm and stated there were no increased risks to babies in the study because the treatments provided would be within the “standard of care”(4). Ultimately the study revealed that patients in the lower oxygenation arm (85%-89%) had a decreased risk of retinopathy but an increased risk of death compared with the higher oxygenation arm

(3).

After the results were published, the Office for Human Research Protections (OHRP) began an investigation and issued a letter in 2013 to the lead site that the informed consent documents used in the SUPPORT trial were inad-equate (5). The letter noted that “the IRB-approved informed consent documents for this study failed to include or adequately address . . . a description of any reasonably foreseeable risks and discomforts,” namely blindness, neurologic injury, and death (5). Of particular concern was the fact that subjects (or more precisely their parents) were not informed “that there may be a greater or lesser risk of death depending on whether the infant is in the lower or upper range group.” The researchers have countered that this disclosure would have been impossible because they did not know the results of the study at its onset(6). The OHRP’s decision led to a firestorm of pub-lished commentary(7-9).

Critics of the OHRP’s decision believed that the in-vestigators were being reprimanded for not knowing the results of the trial during its design(7). Supporters of the OHRP’s decision stated that although the results of the SUPPORT trial were not known ahead of time, a potential differential in the risks that were being studied (which included increased mortality) was reasonably foreseeable and that subjects should have been informed of such risks at study onset(9).

Implications

The OHRP’s decision has led many clinical researchers to throw their hands in the air, seeing this as another obstacle between patients and meaningful improvements in clinical care. There is a prevailing concern that an informed consent

document must include all theoreticalside effects and re-sults, making these documents even lengthier and more unreadable.

However, although the concern regarding the never-ending consent form prevails, it is not valid. The OHRP states, “it is not necessary to disclose all theoretical risks present at the outset of every study”(10). At the same time, however, “If researchers design and conduct a study for the purpose of evaluating a particular risk, then that risk is significant enough that it should be disclosed to the pro-spective subjects who are actually exposed to it”(2). One reason that the consent form in SUPPORT was considered lacking was that it did not identify death as a risk despite the fact that differences in mortality between the arms of the trial were being studied.

The SUPPORT controversy arises, in part, from differing perspectives by which people view clinical trials. A widely held belief among cancer patients and clinical researchers is that participation in a “clinical trial”dwhich sounds a lot like “clinical care”dactually provides the best treatment available to date. Conversely, the law views any significant alteration in patient care for the purposes of research to carry potential risk. It sees clinician-researchers as having inherently conflicting interests between patient care and scienceda divided loyalty that is only acceptable when independent oversight and informed consent are present.

In our example of prostate radiation therapy dose, pa-tients should not be led to believe that there is no difference between the doses. They should be informed that there may be a trade-off between local control and toxicity, or there may not be. They should at least recognize that this po-tential trade-off is the subject of the trialdsomething that was not disclosed in the SUPPORT trial with respect to the risks and benefits associated with higher or lower levels of oxygen.

The advancement of our knowledge in the field of cancer is critical to the care of our patients. In light of the common uncertainty regarding which treatment alterna-tive is superior, the variability of clinic practice is a po-tential target for improving cure rates and reducing medical costs. With hundreds of trials opening annually, we as researchers are charged with ensuring not just that the design is ethical but that the conduct of the trial is ethical, which means making sure subjects are adequately informed. The developing complexity of informed consent forms has made it easy to miss this point. Participants (subjects) should first and foremost know why you are doing the study and what you hope to show. They should understand how their care and results could be different as a result of participation.

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versus photons. Which side of the fence you fall on in the SUPPORT controversy should be of little consequence in regard to the trials that your institution is participating in. We should all strive to be above reproach. When designing clinical trials and informed consent documents, it is critical that researchers attempt to see things from the vantage point of a patient and potential research subject. We cannot assume that even our most astute and educated patients will know the questions to askdinstead, we should tell them the answers to the questions theyshould

ask, make our thinking about research studies transparent, and help them focus on the things they need to think carefully about before enrolling in a study. We should be able to answer “why are you doing this study?” with something more thoughtful than “because we don’t know what’s best.”

References

1. National Comprehensive Cancer Network Guidelines: Prostate Cancer Version 1.2015. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/prostate.pdf. Accessed February 5, 2015.

2. US Department of Health and Human Services. Draft guidance on disclosing reasonably foreseeable risks in research evaluating stan-dards of care. Available at: www.hhs.gov/ohrp/newsroom/rfc/ comstdofcare.html. Accessed February 10, 2015.

3. Carlo WA, Finer NN, Walsh MC, et al. Target ranges of oxygen saturation in extremely preterm infants.N Engl J Med 2010;362:1959-1969.

4. Macklin R, Shepherd L. Informed consent and standard of care: What must be disclosed.Am J Bioeth2013;13:9-13.

5. Buchanan LR, US Department of Health and Human Services. Office for Human Research Protections. Letter to the University of Alabama at Birmingham. Available at: www.hhs.gov/ohrp/detrm_letrs/YR13/ mar13a.pdf. Accessed February 5, 2015.

6. Tyson JE, Walsh M, D’Angio CT. Comparative effectiveness trials: Generic misassumptions underlying the support controversy. Pediat-rics2014;134:651-654.

7. Carlo WA, Bell EF, Walsh MC. Oxygen-saturation targets in extremely preterm infants.N Engl J Med2013;368:1949-1950. 8. Wilfond BS, Magnus D, Antommaria AH, et al. The OHRP and

SUPPORT.N Engl J Med2013;368:e36.

9. Macklin R, Shepherd L, Dreger A, et al. The OHRP and SUP-PORdanother view.N Engl J Med2013;369:e3.

10. Buchanan LR, US Department of Health and Human Services. Re: Human research protections under federalwide assurance (FWA) 5960. Available at:www.hhs.gov/ohrp/detrm_letrs/YR13/jun13a.pdf. Accessed February 5, 2015.