In the June 2017 issue of ASH Clinical News, we published an editorial calling into question some of the purposes and practices of contract research organizations (CROs), which came into existence in the 1980s and are used by much of the pharmaceutical industry to outsource research regulatory requirements. Although CROs – considered specialists in the day-to-day minutiae of clinical trial conduct – should be the epitomes of high-quality data collection and trial standardization, over time they have developed a checkered reputation among clinical trials investigators.
In fairness, the cumbersomeness of conducting contemporary clinical trials does not fall entirely on the shoulders of CROs. They are, after all, frequently responding to Byzantine regulatory requirements, as well as well-intentioned but poorly executed incentives to maximize trial efficiency from the groups with whom they contract – their pharmaceutical partners. To put this in plain English, the more they nag and threaten researchers for data, the more they get paid.
Reaction to the editorial was extreme. One letter, penned by Steven Le Gouill, MD, PhD, from Nantes Medical University in France, Simon Rule, MD, from Plymouth University in the United Kingdom, and more than 80 hematologists/oncologists across Europe, called for medical societies and cooperative groups involved in clinical research to “challenge this pernicious culture and produce recommendations for good practice.” Another supportive Letter From the Editor, by Brad Kahl, MD, appeared in Clinical Advances in Hematology & Oncology.
The editorial has been the most read Editor’s Corner this year, with 20,000 views, and it was even the subject of a meme shared widely on Facebook . Referencing the editorial, former U.S. Food and Drug Administration (FDA) Commissioner Robert Califf, MD, commented that it is “critical for us to figure out how to do clinical trials efficiently. Docs are frustrated with growing bureaucracy.”
In a positive step, anecdotally, some CROs are now using the essay as part of their training materials to onboard new employees. Kudos to them.
When a single 1,200-word essay generates this much interest, then Houston (and by Houston, we don’t mean MD Anderson), we have a problem.
We, the editors of ASH Clinical News, propose the following solutions to the CRO problem. Some will need to be embraced by CROs themselves, some by pharmaceutical sponsors, and some by regulatory agencies – to be clear, this is not just a CRO problem. Our suggestions come from experienced clinical trialists, research nurses, and research coordinators, and thus reflect both a global view of clinical trial conduct and “boots on the ground” experiences.
Until these fixes are adopted, hematology and cancer clinical trial administration will continue to be a scourge on our ability to deliver new treatments to our patients.
“Until these fixes are adopted, hematology and cancer clinical trial administration will continue to be a scourge on our ability to deliver new treatments to our patients.”
Pharmaceutical sponsors need to take more responsibility for their own studies.
Someone from the sponsor must be present at the site initiation visit (SIV). Ninety percent of success in life is just showing up. If a sponsor doesn’t feel a trial is important enough to adequately staff the first visit, sites will similarly devalue the study; that will be reflected by low prioritization of patient accrual and a lack of responsiveness to queries. Given the incredible amount of turnover that occurs among CRO monitors, a supervisor should be present at the SIV and throughout the trial’s conduct to ensure “continuity of care” for the site’s trial. Otherwise, it often falls to our nurses, coordinators, and doctors to onboard new monitors with information we have provided to their predecessors.
Similarly, an institutional study investigator should have direct access to pharmaceutical sponsor trial leadership. A “talk to my people” approach of directing investigators to a CRO for all communication is both dismissive and insulting. Research is often nuanced and the specifics of a question, particularly if it involves patient eligibility for a trial, can be lost through the “telephone game” of going through a third party. And remember, communication is bidirectional. If a sponsor trial leader is unavailable, as investigators, we are more likely to instruct a sponsor to “talk to our people.” And by “our people,” we mean our email spam folders.
Accept the legitimacy of our facilities, equipment, and test results.
We get it. Theoretically, there is a medical clinic in a heretofore undiscovered area of rural America called Lem’s Doctor’s Cabin, where the motto is “I’ll cure your disease or I’ll eat a bug!” And Lem, who isn’t really a doctor but knows a thing or two, has a blood tester that he built himself by cobbling together a few sticks, some string, and an old lamp. Lem fancies himself a forward-thinking guy, and he likes to participate in clinical trials. In this instance, we agree, it’s probably a good idea to provide Lem with some standardized equipment and the opportunity to send his patients’ blood samples to a central laboratory.
For the rest of the medical community, who work in institutions with CLIA-certified laboratories and have carefully adjusted machines, this practice borders on insanity. Even if you argue that some lab-to-lab variability in machine calibration and population distributions may cause one site to report a test result that differs slightly from another (say, a total bilirubin of 0.7 vs. 0.9 mg/dL), this will occur in clinical practice anyway if the drug in question happens to be approved by the FDA.
The institution where one of us practices even had to dedicate a large room to the 70 distinct electrocardiogram (ECG) machines required for use in different clinical trials.
Seventy ECG machines? What do you think the machines do when nobody is looking, compare whose QTc interval is longest?
And here’s the ugly truth about clinical trial–mandated test standardization: We don’t use the results. Central laboratory findings return days after they have been collected, at which point we have already reacted to results obtained at our own institutions, and ECGs in the absence of cardiac symptoms have limited clinical utility.
Why not have an independent entity certify our facilities, equipment, and laboratory results once per year for all clinical research, or accept the findings from agencies that already certify them regularly? It would save us all time.
“When signatures become an exercise in futility, we should stop the exercise. Let’s limit required signatures to serious AEs occurring on the clinical trial in which we are participating.”
Recognize that our signatures are meaningless.
Yes, there are days we wish we were famous athletes, or rock stars, or even reality TV stars, and that our signatures were collectible and fetched a high price. But the hard fact – and we have to face this daily when we stare in the mirror and see ourselves for the hematologists we are – is that our signatures are worthless.
Having us sign central laboratory results, or worse still, indicate whether those results are clinically meaningful (By whose standard? What gives “meaning” to a lab result?) becomes almost existential. Worse yet, requiring our signature on blank reports from central labs for specimens never received or for failed tests transports us from existential to the realm of crazy.
We can place into the latter category the practice of sending us emails with forms we must print out, sign, scan, and email back to confirm our email address.
Here’s another ugly truth: We don’t always read what we sign. Because when we are asked to sign and date the signatures of the 20 people from our site working on the study, 50 pages of lab results, or adverse events (AEs) that occurred in clinical trials being conducted for other cancers, at a certain point, we can’t assimilate the information we are reading, and we just sign papers to get through them.
When signatures become an exercise in futility, we should stop the exercise. Let’s limit required signatures to serious AEs occurring on the clinical trial in which we are participating (because this is important information as we counsel patients about risks and benefits and recognize toxicity trends) and to just one investigator acknowledging responsibility for trial conduct. All of the others just waste ink and time.
Please, don’t make us make your life easier.
Your electronic data-capture (EDC) systems are bulky, counterintuitive, and time-consuming. We never remember the instructions on how to navigate them – if we ever remember our usernames or passwords to access them. These systems send URGENT emails inviting us to the “CTP Portal” or to another training session on “Firecrest” and demand IMMEDIATE ACTION (your words and caps, not ours), inundating our inboxes.
While electronic trial management systems enhance your efficiency, their structure and automated emails suck the will to work out of us. And we recognize that you are trading your time for ours. Nobody likes to be told that his or her time is less valuable than someone else’s.
We suggest you take ownership of your EDC systems, meaning that an accessible employee from the sponsor or the CRO can troubleshoot problems and answer questions. On visits or in emails, prioritize what is truly URGENT. We will provide one online signature covering all activities, to be performed either on a single and centralized site all CROs agree to use or with a clinical research associate to walk us through logging onto the website and to show us which buttons to click.
Stop the incentives for obnoxious behavior.
We know “time is money.” We are just as anxious to open trials and enroll desperate patients as you are. We recognize the importance of notifying you about AEs quickly. We hold our research employees accountable for their efficiency.
Emailing us daily, or multiple times per day, doesn’t make any of this happen faster. In fact it takes time away from opening a trial or entering data. The introduction of perverse incentives, such as “pay by query” models or bonuses for meeting data deadlines, has paradoxically slowed us down in delivering what you’re asking for.
We propose setting reasonable deadlines for data – and “EOB tomorrow” is not reasonable, unless you’re treating acute leukemia. Don’t escalate issues to the principal investigator unless one of our research personnel truly is not doing his or her job. Eliminate the incentives that created this environment of animus between CROs and trial sites – and for which downstream consequences were utterly predictable.
All of our suggestions boil down to issues of trust and mutual respect. If you trust and respect us, we will provide you the information you need.
And we will actually respect you a lot more.
Mikkael A. Sekeres, MD, MS
On behalf of the ASH Clinical News Editorial Board:
Beth Faiman, PhD, CNP
Alice Ma, MD
David Steensma, MD
Keith Stewart, MBChB, MBA
The editorial board of ASH Clinical News thanks the research nurses, coordinators, and colleagues who provided input for this editorial.
The content of the Editor’s Corner is the opinion of the author and does not represent the official position of the American Society of Hematology unless so stated.
Have a comment about this editorial? Let us know what you think; we welcome your feedback. Email the editor at [email protected].