ASH Clinical News ACN_4.1_FULL_ISSUE_DIGITAL | Page 8

Pharmaceutical sponsors need to take more responsibility for their own studies .

Accept the legitimacy of our facilities , equipment , and test results .

14 ASH Clinical News December 2017

December 2017 Editor ’ s Corner

Editor ’ s Corner

I

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 .

Solving the Contract Research Agonization Problem

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 .

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 .

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

Contract research organizations ( CROs ), which are used by much of the pharmaceutical industry to outsource research regulatory requirements , should be the epitome of high-quality data collection and trial standardization , but they have developed a checkered reputation among clinical trial investigators .

In the December 2017 issue , ASH Clinical News Editor-in-Chief Mikkael A . Sekeres , MD , MS , and

CALQUENCE ® ( acalabrutinib ) capsules , for oral use Initial U . S . Approval : 2017

Brief Summary of Prescribing Information . For complete prescribing information consult official package insert .

INDICATIONS AND USAGE CALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma ( MCL ) who have received at least one prior therapy .

This indication is approved under accelerated approval based on overall response rate [ see Clinical Studies ( 14 ) in the full Prescribing Information ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials .

DOSAGE AND ADMINISTRATION

Recommended Dosage The recommended dose of CALQUENCE is 100 mg taken orally approximately every twelve hours until disease progression or unacceptable toxicity .

Advise patients to swallow capsule whole with water . Advise patients not to open , break or chew the capsules . CALQUENCE may be taken with or without food . If a dose of CALQUENCE is missed by more than 3 hours , it should be skipped and the next dose should be taken at its regularly scheduled time . Extra capsules of CALQUENCE should not be taken to make up for a missed dose .

Dose Modifications

Adverse Reactions Recommended dose modifications of CALQUENCE for Grade 3 or greater adverse reactions are provided in Table 1 .

Table 1 : Recommended Dose Modifications for Adverse Reactions

Event

Grade 3 or greater non-hematologic toxicities ,

Grade 3 thrombocytopenia with bleeding ,

Grade 4 thrombocytopenia or

Grade 4 neutropenia lasting longer than 7 days

Adverse Reaction Occurrence

First and Second

Third

Dose Modification ( Starting dose = 100 mg twice daily )

Interrupt CALQUENCE . Once toxicity has resolved to Grade 1 or baseline level , CALQUENCE therapy may be resumed at 100 mg twice daily .

Interrupt CALQUENCE . Once toxicity has resolved to Grade 1 or baseline level , CALQUENCE therapy may be resumed at 100 mg daily .

Fourth Discontinue CALQUENCE .

Concomitant Use with Gastric Acid Reducing Agents Proton Pump Inhibitors : Avoid concomitant use [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

H2-Receptor Antagonists : Take CALQUENCE 2 hours before taking a H2-receptor antagonist [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

Antacids : Separate dosing by at least 2 hours [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

CONTRAINDICATIONS None .

WARNINGS AND PRECAUTIONS

Hemorrhage Serious hemorrhagic events , including fatal events , have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy . Grade 3 or higher bleeding events , including gastrointestinal , intracranial , and epistaxis have been reported in 2 % of patients . Overall , bleeding events including bruising and petechiae of any grade occurred in approximately 50 % of patients with hematological malignancies .

The mechanism for the bleeding events is not well understood . CALQUENCE may further increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding . Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding .

Infection Serious infections ( bacterial , viral or fungal ), including fatal events and opportunistic infections have occurred in the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy . Consider prophylaxis in patients who are at increased risk for opportunistic infections . the members of the Editorial Board ( with insight from research nurses , coordinators , and colleagues ) offered several solutions to “ the CRO problem .”

Readers from around the world ( including members of the CRO enterprise ) wrote to share their frustrations with CROs and offer their own solutions . Here , one reader from an international CRO shares his experiences . Read more at ashclinicalnews . org / letters-to-the-editor .

Grade 3 or higher infections occurred in 18 % of these patients . The most frequently reported Grade 3 or 4 infection was pneumonia . Infections due to hepatitis B virus ( HBV ) reactivation and progressive multifocal leukoencephalopathy ( PML ) have occurred . Monitor patients for signs and symptoms of infection and treat as medically appropriate .

Cytopenias In the combined safety database of 612 patients with hematologic malignancies , patients treated with CALQUENCE monotherapy experienced Grade 3 or 4 cytopenias , including neutropenia ( 23 %), anemia ( 11 %) and thrombocytopenia ( 8 %) based on laboratory measurements . In the CALQUENCE clinical Trial LY-004 , patients ’ complete blood counts were assessed monthly during treatment .

Second Primary Malignancies Second primary malignancies , including non-skin carcinomas , have occurred in 11 % of patients with hematologic malignancies treated with CALQUENCE monotherapy in the combined safety database of 612 patients . The most frequent second primary malignancy was skin cancer , reported in 7 % of patients . Advise protection from sun exposure .

Atrial Fibrillation and Flutter In the combined safety database of 612 patients with hematologic malignancies treated with CALQUENCE monotherapy , atrial fibrillation and atrial flutter of any grade occurred in 3 % of patients , and Grade 3 in 1 % of patients . Monitor for atrial fibrillation and atrial flutter and manage as appropriate .

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling :

• Hemorrhage [ see Warnings and Precautions ( 5.1 ) in the full Prescribing Information ]

• Infection [ see Warnings and Precautions ( 5.2 ) in the full Prescribing Information ]

• Cytopenias [ see Warnings and Precautions ( 5.3 ) in the full Prescribing Information ]

• Second Primary Malignancies [ see Warnings and Precautions ( 5.4 ) in the full Prescribing Information ]

• Atrial Fibrillation and Flutter [ see Warnings and Precautions ( 5.5 ) in the full Prescribing Information ]

Clinical Trials Experience As clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .

The safety data described in this section reflect exposure to CALQUENCE ( 100 mg twice daily ) in 124 patients with previously treated MCL in Trial LY-004 [ see Clinical Studies ( 14 ) in the full Prescribing Information ]. The median duration of treatment with CALQUENCE was 16.6 ( range 0.1 to 26.6 ) months . A total of 91 ( 73.4 %) patients were treated with CALQUENCE for ≥ 6 months and 74 ( 59.7 %) patients were treated for ≥ 1 year .

The most common adverse reactions ( ≥ 20 %) of any grade were anemia , thrombocytopenia , headache , neutropenia , diarrhea , fatigue , myalgia , and bruising . Grade 1 severity for the non-hematologic , most common events were as follows : headache ( 25 %), diarrhea ( 16 %), fatigue ( 20 %), myalgia ( 15 %), and bruising ( 19 %). The most common Grade ≥ 3 non-hematological adverse reaction ( reported in at least 2 % of patients ) was diarrhea .

Dose reductions or discontinuation due to any adverse reaction were reported in 1.6 % and 6.5 % of patients , respectively .

Tables 2 and 3 present the frequency category of adverse reactions observed in patients with MCL treated with CALQUENCE .

Table 2 : Non-Hematologic Adverse Reactions * in ≥ 5 % ( All Grades ) of Patients with MCL in Trial LY-004

Body System Adverse Reactions

CALQUENCE 100 mg twice daily N = 124

All Grades (%) Grade ≥ 3 (%)