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ASHClinicalNews . org
UCH HAS BEEN WRITTEN in ASH Clinical News about the Orwellian nature of modern clinical trials , and for good reason : Almost all our readers have some experience with clinical research – it ’ s what we do . Consequently , I hope my story will resonate . To protect the innocent , the names and dates of the events herein have been changed and bear no resemblance to any real or living person , organization , time , or place ( sort of ). This is a reenactment of creeping awareness , acceptance , and ultimately … well for that , you have to read on .
I have , by now , participated in 53 clinical trials resulting in 89 publications over 24 years . And they used to be fun . Then one sunny Friday morning , a not-so-long time ago , they stopped being fun .
I arrived at my office to find an ominous-looking stack of EKGs , each stamped with an automated report of normality to which I dutifully signed NCS – not clinically significant , adding my initials and the date 23 times . Rather proud of myself for having expeditiously dealt with this “ nuisance ” before clinic started , I launched into the first emails of the day .
Two overnight messages requiring attention greeted me . The first reprimanded me for my overdue review of Investigator ’ s Brochure version 5.0 , to determine if , somewhere in its 129 pages , there were any new safety data that might require a revision to the trial ’ s informed-consent form . The email had , quite rightly , a vaguely threatening tone . I punted that delicious task for the weekend . The second request related to e-signing case-report forms in a system I didn ’ t recognize , never fully understood , and for which my password had long ago expired . I gave up and moved that one to Monday .
Then , by unfortunate coincidence , at a quarterly finance meeting with our research office later that day , I learned that one of my clinical trials was losing money , in quite large amounts . The loss was not because of bad budgeting , but because opening and activating the study took more effort and time than anyone reasonably expected . That was compounded by the realization that this early-stage trial had 11 active sites competing every six weeks for three slots and enough eligibility criteria to enter the Guinness Book of World Records for the most reasons patients are unqualified for a trial . In summary , accrual was low and slow , yet the paperwork was relentless and the expenses outpaced potential revenue . I left the meeting feeling discouraged .
Clinic ended a little early that day and , before quitting time , I replied “ yes to all ” with respect to my contributions to a trialabstract submission to a major medical conference . A quick read of said abstract awakened my dislike for using the words “ acceptable ” and “ manageable ” to describe an agent ’ s evident toxicities . So , in a Friday afternoon act of defiance , I sharpened my figurative pencil and composed an objection to both that wording and the claim that the agent would be a “ new standard of care ” for patients with an “ unmet need .” I am sure I upset the medical writer a little and the marketing team a lot , but I felt better – though I recognized that my solitary act of rebellion would change little .
Monday morning brought news that one of the trials in which I was engaged was being closed for “ business reasons .” No appeals would be allowed , but the medical team at the sponsoring company offered apologies . What would I tell my patient who had just enrolled in the study ? “ So sorry , but your contribution to the future of bloodcancer treatment was just cancelled without notice . Why don ’ t you keep volunteering to take the drug with unknown side effects or potential for benefit anyway ?”
I guess that was the last straw , the thousandth cut , the culmination , the end of the road .
I had an epiphany of sorts that day : Everything I was experiencing – an increase in cynicism , apathy about the tasks at hand , irritability with people tasked with their required jobs , lack of satisfaction , and general disillusionment with the trial system – equated to what we now recognize as the dreaded “ burnout .”
I decided then and there to quit Keith Stewart , MBChB , MBA , engaging in clinical trials . I had is the Carlson and Nelson
Endowed Director of the Center plenty of other more rewarding for Individualized Medicine and things to focus on , and , working the Vasek and Anna Maria Polak with a motivated team , I was refreshed daily by a sense of commu- at Mayo Clinic in Scottsdale ,
Professor of Cancer Research
Arizona . nity and visible progress towards a shared vision . In other words , the very opposite of the recent clinical trial experience .
I felt immediate and palpable relief . My colleagues were less than thrilled , but graciously agreed to take over the thankless , ceaseless , mundane clinical trial – related tasks . The conscientious clinical research staff reluctantly accepted my decision , though I suspect they also were secretly pleased that I would not be the one asking for eligibility review of three patients at once . The sponsoring companies were mute , but I can imagine they weren ’ t pleased either .
Meanwhile , I was jubilant . No more mandatory meetings with monitors lecturing on our failings as collators and custodians of the precious data ; no more investigator responsibility slideshows , mandatory Institutional Review Board videos , financial disclosures , case report form signoffs , investigator calls , slow-accrual guilt , toxicity attributions , tense discussions about pre-presentation press releases , or lawyerly monitoring of slides for compliance . No more lab signoffs , site initiation visits , site closing visits , budget reviews , market creep monitoring , or requests for conflict-of-interest disclosures .
Finally , released from the clinical trials club , I could be the one to ask the pointed questions at the end of a trial presentation . I could wax lyrical at journal club about poor design and biased reporting . An expanded universe of conflict-free consulting awaited me .
It took months , and repeated requests , to slowly reassign ownership or close each trial . ( For any readers considering the same path , be aware that like a romance documented on social media , a speeding ticket , or an inferior vena cava filter , participating in an industry-supported clinical trial is difficult to extricate yourself from .
Then , just as I cleared the last hurdle and was poised to skip merrily towards my new trial-free and resilient existence , the siren ’ s call arrived . The phone rang and a voice said , “ Dr . Stewart , would you like to participate in our CAR T-cell trial for myeloma ?” Five seconds passed before I answered : “ Yes .” Go ahead , judge me ! You may wonder why , with the goal line in sight , my resolve collapsed . I am still not entirely sure myself , but concluded that , at the end of the day , when there is still real unmet need , conducting trials of drugs with manageable toxicity and encouraging activity are what we do – burnout be damned .
Keith Stewart , MBChB , MBA
ASH Clinical News 9
You Make the Call : Readers ’ Response
We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”
For the full description of the clinical dilemma , and to see how the expert responded , turn to page 42 .
Clinical Dilemma :
A 35-year-old woman with hemoglobin ( Hb ) H disease has average long-term numbers ( Hb about 7.5 g / dL , reticulocytes about 7 %, bilirubin about 2.5 mg / dL ). She does not need transfusions but accumulates iron and needs long-term deferasirox to prevent her ferritin from rising above 1,000 μg / mL . Would a splenectomy be a good option to improve her Hb , reduce iron overload , and improve quality of life ?
Usually splenectomy does not help with the hemolysis . It marginally improves anemia at best . You have to deal with the increased risk of pneumococcal infection , possible pulmonary hypertension , and thromboembolism .
Kulumani Sivarajan , MD Joliet Oncology-Hematology Associates
Joliet , IL
Yes , I would recommend a splenectomy in this patient to prevent the ongoing hemolysis that is resulting in increasing iron deposition in her body .
Marion Koerper , MD UCSF School of Medicine
San Francisco , CA
My opinion is that she does not require a splenectomy . It is not indicated in the scenario whether the patient does have troublesome splenomegaly . That she is transfusion independent means that her erythropoiesis can compensate for the ongoing ineffective erythropoiesis . Therefore , splenectomy would not be very helpful to improve the degree of anemia to which the patient is now very well accustomed .
Her iron overload is from the increased absorption of iron rather than from ongoing transfusional hemosiderosis , which splenectomy would not halt . In addition , splenectomy might increase the risk of overwhelming pneumococcal sepsis .
Taking into account that this patient is well chelated with deferasirox , I would continue to use it rather than going for a splenectomy .
Thamudika Pushpakumari , MBBS Colombo , Sri Lanka
I would not do a splenectomy . It will significantly increase the risk of venothrombosis problems . I doubt that it will decrease iron absorption to any significant extent .
Edwin Forman , MD Icahn School of Medicine at Mount Sinai
New York , NY
I don ’ t see any indication for splenectomy .
Geoffrey K . Sherwood , MD Boston , MA
Nope . Well , maybe yes . I don ’ t like the temptation that most physicians have toward higher levels of Hb . Higher Hb does not necessarily mean better quality of life ( QoL ). HB H is a pro coagulant . A higher HB level may lead to higher incidence of thrombotic episodes , like portal vein thrombosis , and more pulmonary hypertension . These two are definitely not associated with better QoL .
So , when to remove the spleen in patients with HbH ? My usual answer is when it ’ s becoming harmful , when it causes unbearable pain , when it is large enough to affect stomach size and cause cachexia .
Splenectomy certainly is not on my list when tackling iron overload . Keep in mind , in thalassemia intermedia , an example of which is HbH , serum ferritin underestimates total body iron . I would consider a lower ferritin level as target to my deferasirox therapy , or I would rely on MRI assessment of liver iron concentration .
Ahmed Hamandi , MD , MRCP Al Kafeel Specialty Hospital
Karbala , Iraq
Letters to the Editor
A Slow Burn
In our July 2018 issue , ASH
Editor ’ s Corner
Clinical News Associate Editor
Burnout ? What Burnout ?
Keith Stewart , MBChB , MBA , walked us through his valiant
M efforts to step away from the clinical research enterprise – from recognizing his increasing cynicism and apathy as the dreaded burnout , to the moment he broke his resolve to lead a trial-free existence – in “ Burnout ? What Burnout ?”
The article hit home with many readers who expressed
July 2018 Editor ’ s Corner their own disillusionment with the clinical trials system . Below , one reader shares his thoughts on the trials process and the role that trial sponsors can play in alleviating some of this burden to protect trialists from burnout .
To the Editor : I read with interest and empathy Dr . Stewart ’ s views as he described his trials and tribulations of being a clinical trials investigator .
We all value the chance to try new drugs and agents for the patients referred to us – especially when there is a lack of effective standard therapies . At the same time , though , Big Pharma and clinical trial sponsors should value our participation , since we assist them in the process of readying their products for commercial use .
However , since pharmaceutical sponsors have handed the management process to contract research organizations – who take the easy way out by collecting untoward effect data and letting investigators wallow in the mess – they have taken away valuable time for other academic interests and delivering good patient care .
Have a comment about an article ? Let us know what you think ; we welcome your feedback . Email the editor at ACNeditor @ hematology . org .
Emmanuel C . Besa , MD Retired Professor of Medical Oncology
Kimmel Cancer Center Thomas Jefferson University
Philadelphia , PA
For the latest news in hematology , visit ASHClinicalNews . org !
In her case , a splenectomy might be a good option . You might consider a partial splenectomy if your surgeons can do it . In my experience , most patients with HbH disease run an Hb around 10 to 12 g / dL when not in crisis .
Carole Hurvitz , MD Cedars-Sinai Medical Center
Los Angeles , CA
Splenectomy in HbH disease usually does not improve the clinical status . I do not suggest splenectomy .
Maria Cappellini , MD University of Milan
Milan , Italy
See more reader responses at ashclinicalnews . org / you-make-the-call .
4 ASH Clinical News August 2018