Letters to the Editor
Editor ’ s Corner
I
Solving the Contract Research Agonization Problem
The content of the Editor ’ s Corner is the opinion of the authors 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 ACNEditor @ hematology . org .
N 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 epitome of high-quality data collection and trial standardization , over time they have devoloped 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 more than 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 .
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 CLIAcertified 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
14 ASH Clinical News December 2017
December 2017 Editor ’ s Corner
The CRO Agony Continues …
In the December 2017 issue , ASH Clinical News Editor-in-Chief Mikkael A . Sekeres , MD , MS , and the members of the Editorial Board ( with insight from research nurses , coordinators , and colleagues at various institutions ) offered several proposed solutions to “ the CRO problem ,”
ADYNOVATE ® is FDA approved for patients of all ages with Hemophilia A expressing concerns about the questionable practices of contract research organizations . The missive struck a chord with readers , several of whom wrote in to share their frustrations with this segment of the clinical research enterprise .
PROVEN PROPHYLAXIS + SIMPLE ,* TWICE-WEEKLY
DOSING SCHEDULE = moments
Y OSING SCHEDULE =
THEIR WAY
* ADYNOVATE allows patients to infuse on the same 2 days every week .
ADYNOVATE [ Antihemophilic Factor ( Recombinant ), PEGylated ] Important Information
6 ASH Clinical News
Indications
ADYNOVATE , Antihemophilic Factor ( Recombinant ), PEGylated , is a human antihemophilic factor indicated in children and adults with hemophilia A ( congenital factor VIII deficiency ) for :
• On-demand treatment and control of bleeding episodes
• Perioperative management
• Routine prophylaxis to reduce the frequency of bleeding episodes
Limitation of Use ADYNOVATE is not indicated for the treatment of von Willebrand disease .
DETAILED IMPORTANT RISK INFORMATION
CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ( ADVATE [ Antihemophilic Factor ( Recombinant )]), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).
WARNINGS & PRECAUTIONS Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .