Mikkael A . Sekeres , MD , MS , is director of the Leukemia Program at the Cleveland Clinic in Cleveland , OH .
Mikkael Sekeres , MD , MS Editor-in-Chief
8 ASH Clinical News June 2017
Letters to the Editor
CROs and Cons
In his June 2017 Editor ’ s Corner (“ Contract Research Agonizations ”), ASH Clinical News ’ Editor-in-Chief Mikkael Sekeres , MD , MS , called for an end to the bureaucratic madness that contract research organizations ( CROs ) have introduced to the clinical trials process . The article inspired an impassioned response from our readers , with several writing in to express solidarity and share their own experiences with site initiation visits .
information ]. See Dosage and Administration ( 2.1 ) in the full prescribing information for dosing recommendations for pediatric patients 1 year and older . The safety and efficacy of PROMACTA in pediatric patients younger than 1 year with ITP have not yet been established .
The safety and efficacy of PROMACTA in pediatric patients with thrombo - cytopenia associated with chronic hepatitis C and severe aplastic anemia have not been established .
8.5 Geriatric Use Of the 106 patients in two randomized clinical trials of PROMACTA 50 mg in chronic ITP , 22 % were 65 years of age and over , while 9 % were 75 years of age and over . In the two randomized clinical trials of PROMACTA in patients with chronic hepatitis C and thrombocytopenia , 7 % were 65 years of age and over , while fewer than 1 % were 75 years of age and over . No overall differences in safety or effectiveness were observed between these patients and younger patients in the placebocontrolled trials , but greater sensitivity of some older individuals cannot be ruled out .
8.6 Hepatic Impairment Hepatic impairment influences the exposure of PROMACTA [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
Reduce the initial dose of PROMACTA in patients with chronic ITP ( adult and pediatric patients 6 years and older only ) or severe aplastic anemia who also have hepatic impairment ( Child-Pugh Class A , B , C ) [ see Dosage and Administration ( 2.1 , 2.3 ) in the full prescribing information , Warnings and Precautions ( 5.2 )]. No dosage adjustment is necessary for patients with chronic hepatitis C and hepatic impairment [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
8.7 Renal Impairment No adjustment in the initial dose of PROMACTA is needed for patients with renal impairment [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ]. Closely monitor patients with impaired renal function when administering PROMACTA .
8.8 Ethnicity Patients of East Asian ethnicity ( i . e ., Japanese , Chinese , Taiwanese , and Korean ) exhibit higher eltrombopag exposures . A reduction in the initial dose of PROMACTA is recommended for patients of East Asian ancestry with ITP ( adult and pediatric patients 6 years and older only ) or severe aplastic anemia [ see Dosage and Administration ( 2.1 , 2.3 ) in the full prescribing information ]. No dose reduction is needed in patients of East Asian ethnicity with chronic hepatitis C [ see Clinical Pharmacology ( 12.3 ) in the full prescribing information ].
10 OVERDOSAGE In the event of overdose , platelet counts may increase excessively and result in thrombotic / thromboembolic complications .
In one report , a subject who ingested 5,000 mg of PROMACTA had a platelet count increase to a maximum of 929 x 10 9 / L at 13 days following the ingestion . The patient also experienced rash , bradycardia , ALT / AST elevations , and fatigue . The patient was treated with gastric lavage , oral lactulose , intravenous fluids , omeprazole , atropine , furosemide , calcium , dexamethasone , and plasmapheresis ; however , the abnormal platelet count and liver test abnormalities persisted for 3 weeks . After 2 months ’ follow-up , all events had resolved without sequelae .
In case of an overdose , consider oral administration of a metal cationcontaining preparation , such as calcium , aluminum , or magnesium preparations to chelate eltrombopag and thus limit absorption . Closely monitor platelet counts . Reinitiate treatment with PROMACTA in accordance with dosing and administration recommendations [ see Dosage and Administration ( 2.1 , 2.2 ) in the full prescribing information ].
The following are registered trademarks of their respective owners : PEGASYS / Hoffmann-La Roche Inc .; PEGINTRON / Schering Corporation .
Distributed by : Novartis Pharmaceuticals Corporation East Hanover , New Jersey 07936
© Novartis
T2017-32 March 2017
Thank you for your article ; it is decades overdue and a hot theme of mine in presentations . I am not a physician , but I train and educate Clinical and Medical Science Liaison teams throughout the pharmaceutical industry – mostly in oncology and hematology , always on communication issues .
There is a covert , risk-averse culture within the clinical research “ industry ” that prevents common-sense communication . Everyone is either afraid of getting sued , fired , or receiving a “ needs improvement ” on their performance review . You have eloquently described what I call a “ value event ,” or lack thereof .
This should be a topic at every National Cancer Institute – Designated Cancer Center and at every Cooperative Group meeting , and with the chief executive officer of every CRO required to attend . For 6 – no , make that 10 – hours . Including signed documentation that records their presence and agreement to cease this madness .
Improvement always begins with the question , “ Have you ever been on the receiving end of yourself ?”
Best of luck , let me know how I can help .
— George Mooney 2Pario , LLC
Spokane , WA
Editor ’ s Corner
A
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 ACNEditor @ hematology . org .
Contract Research Agonizations
FTER YEARS SPENT as an investigator on countless hematology and cancer clinical trials , all initiated with the noble intent of improving my patients ’ lives through what we all hoped would be better therapies , I have finally arrived at one conclusion that I believe to be virtually unassailable : Contract research organizations ( CROs ) are an invasive weed – an administrative kudzu – that infests the clinical trial process .
Perhaps I am being a bit dramatic in my declaration . CROs , which came into existence in the 1980s to outsource research regulatory requirements , have the potential to improve the quality of data collection and trial standardization . These are , after all , specialists in the day-to-day minutiae of clinical trial conduct – the kings of compliance ! The sultans of Serious Adverse Events ! The lotharios of labs out of range ! The foremen of Form U . S . Food and Drug Administration 1572 ! Why , then , do those of us who have dedicated our careers to exploring novel therapeutics view the Quintiles , Parexels , PRAs , and Covances of the world more as the troglodytes of trial torture ?
Recently , members of our study team ( nurses , pharmacists , research coordinators , and other physicians ) and I met with the CRO representative who would be monitoring our cancer center to start the site initiation visit ( SIV ) for a clinical trial we were opening at our cancer center . This takes the majority of a day as we review the trial ’ s “ instruction manual ” – the protocol – and our responsibilities as investigators , and as the CRO monitor tours the cancer center to see our base of operations . ( The SIV is distinguished from the “ pre-SIV ,” a visit that occurred a couple of months earlier and accomplished the same tasks – only it didn ’ t count .)
I went to take a seat , but before my tush could meet the welcome embrace of the chair ’ s cushion , the CRO monitor shoved a piece of paper and a pen toward me . “ You need to sign this ,” she said . “ What is it ?” I asked . “ It shows that you attended the SIV ,” she answered . “ But you can see that I ’ m here . What does my signature add to that fact ?” I asked .
“ We need it for our records ,” she said , confidently . This was a frequent refrain throughout the day , as the CRO ’ s records are apparently tantamount to Holy Scripture . I signed the paper .
“ Here ,” she said , shoving three more pieces of paper in front of me . I looked down at my team members ’ signatures . “ You need to initial and date next to everyone ’ s signature .” “ Why do I need to do that ?” I asked . “ It ’ s the site delegation log ,” she answered . “ But why can ’ t I just initial and date once for everyone ?” I asked . “ I can even initial and date once at the top of the page and make arrows going down to indicate it applies to everyone ,” I offered , helpfully .
“ Because it ’ s the site delegation log ,” she answered , confidently . “ We need it for our records .”
I quickly calculated whether it would take less time to argue with her or to sign and date the paper 17 times , and opted for the latter .
“ Here ,” she said again , shoving another paper toward me . “ I need you to sign this , write your initials , and write the numbers 0 through 9 in the box where it says to do that .” “ Do I dare ask why ?” I dared to ask . “ We need this so that when we are going through the medical records , we will know which handwriting is yours ,” she answered .
“ But we have electronic medical records . I don ’ t sign or date anything manually anymore . My signature and initials and numbers look like those of everyone else who uses the Calibri font on the computer . How does this help you ?” I asked .
She maintained her composure . “ We need it for our records .” I reviewed my previous mental calculation , then filled out the form .
“ Let ’ s get started ,” she said . We all turned to the screen on which her
June 2017 Editor ’ s Corner
slides were displayed . “ This is a phase II study in patients with acute mya … mya … mya …” “ Myelogenous ,” I offered . “ Myelogenous loo … loo …” “ Leukemia ,” I said . “ Right , leukemia .” She continued reading her slides , one after the next , verbatim , pronouncing some of the words correctly , some phonetically . I looked around at my team members ’ faces and saw the dreamy looks of people who had drifted off to their happy places . It was clear that nobody was paying attention , because we had all read the protocol cover-to-cover already . This may seem painful , but I had experienced worse . One monitor started our SIV by playing a recording of her own voice reading the slides off her iPhone , as she sat quietly , pushing the “ slide advance ” button on her remote . I stopped that meeting after a few minutes , incensed that she would waste my team ’ s time with this laziness .
Another monitor insisted on a repeat SIV when our cancer center moved from one building to another , claiming that he couldn ’ t be sure of the sanctity of the study ’ s conduct because we were in a completely new building . He even threatened putting the trial on hold , which would have prevented one of our patients from receiving his treatment , until we complied . “ Any questions ?” our current monitor asked . “ No ,” I answered quickly , as my team recovered from their reveries . “ Now I ’ m going to review with you your responsibilities as an investigator ,” she said to me , pointedly .
“ I ’ m aware of them already , thanks ,” I said . “ I ’ ve been an investigator on a bunch of trials over the past decade and a half , and we undergo training every three years , in which we review our responsibilities as an investigator .” I smiled at her .
She smiled back at me , nonplussed , and advanced to the “ investigator responsibilities ” slide . “ As the primary investigator …” she started , but I didn ’ t hear much after that . I was in my happy place , somewhere on a beach on Sanibel Island , sipping a fruity drink .
Over the coming years , I would often hear from our CRO monitor – or her replacement , or his replacement – with reminders about upcoming monitor visits , letters about prior monitor visits , and entreaties to log into the CRO ’ s website to create a unique username and password and sign off on a number of forms electronically so I could save the CRO time and money . Oh , and there were the many queries about adverse events , their causes , and their attributions , with the ever-so-subtle implication that we were assigning more blame for toxicities than we should to the study drug . One colleague of mine got so incensed about the banality of these queries that when a monitor continued to question him about the cause of his patient ’ s coronary artery disease , he photocopied the entire chapter on the subject from Braunwald ’ s Heart Disease textbook and faxed it to her .
Careful monitoring of therapeutic clinical trials , particularly for hematologic and cancer indications , is necessary to ensure patient safety and assess drug efficacy . But the self-righteous zeal with which CROs have introduced bureaucratic nonsense to the administrative requirements of these trials – delivered at the hands of poorly trained emissaries – is insulting to highly skilled research teams , adds substantial costs to the conduct of these studies , and impedes progress in the war on cancer .
Can somebody please stop the madness ? For the records .
... And you didn ’ t talk about the urgent emails that give no indication to which trial the urgent matter is referring . Or the trial website where you have to e-sign even more forms but that won ’ t let you log in – no matter what you do and regardless of the urgent need to do something within the 24 hours before the “ data lock ” for a study whose last patient you accrued 7 years ago goes into effect . And so on .
It ’ s a nightmare in every direction .
— Jeffrey Szer , BMedSci , MBBS Peter MacCallum Cancer Centre
Victoria , Australia
July 2017 Bonus Mid-Year Edition