Re: Rachel F. Dear, Kevin McGeechan, Megan B. Barnet, et al. “Standard Care” in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials. J Natl Compr Canc Netw 2017;15(9):1131–1139.

I believe the study by Dear et al¹ in the September issue highlights the complexity of how to define “standard care” for the control arm of phase III clinical trials. In reviewing this study, I am assured that analysis of trials within the United States suggests a significantly lower deviation rate than trials conducted outside of the United States. This suggests that we are doing something right with our efforts in developing guidelines and standards, in addition to the vast regulatory oversight placed on clinical trials conducted in our country. Using the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer at only one specific point in time as the “gold standard” may not be the most precise way to measure deviations of standard care, although certainly it provides us with a good starting point.

The authors note that 13% of trials in the United States deviated from standard (11 of 83 trials), but I would have to think that the clinically significant deviations from standard care are probably less, because the definition of “standard care” is a moving target and very complex, particularly if taking into account the extensive knowledge bases of the experts writing these protocols and the amount of time it takes for one protocol to be written, approved, and instituted for accrual. For example, the authors include one US trial in metastatic breast cancer as deviant because the control arm was 75 mg/m² of intravenous docetaxel every 21 days, when the corresponding NCCN Guideline at the time (v1.2004) recommended 80 to 100 mg/m² every 21 days. However, when we look at the current NCCN Guidelines for Breast Cancer (v2.2017), the recommended dosage is now 60 to 100 mg/m² every 21 days. Therefore, the dosage delivered in the control arm was, in fact, what we would currently consider completely acceptable.

This highlights the point that although the NCCN Guidelines for Breast Cancer are updated on average 1 or 2 times per year, there are always new fluxes of information, such that no clinical practice guidelines can ever truly reflect available data in real time. Keeping this in mind, I am encouraged by the findings within the US trial cohort.

On the other end of the spectrum are the debates and controversies surrounding trials conducted outside of the United States. In these, the authors report 39% of trials (49 of 127) deviated from standard care (NCCN Guidelines or German Gynecological Oncology Group [AGO] guidelines). One major issue relates to international outsourcing of clinical trials by more Westernized, affluent countries and/or large lucrative pharmaceutical companies to low- or middle-income countries in order to reduce costs and avoid the “red tape” regulatory checks we have in place in the United States. This may, in part, be a factor. One could also discuss the interpretation of “best proven intervention” for the control arm mandated by the Declaration of Helsinki and whether it refers to best care available worldwide or the best care available locally. One could discuss whether guidelines developed in Western countries can even be applicable to countries with limited resources.

So, although the discussion is complex, ultimately probably a little of all of the above apply, we must consider all of these factors and include geographic variations and preferences in practices. Nevertheless, this body of work allows for a starting point for identifying deviations from “standard care” in clinical trials, and with further investigation into practice patterns over time and regional/geographic practice differences, it may be possible to identify clinically significant deviations that may be detrimental for patients.