1

Unblinded Monitoring Programs:Design and Education

SoCRA NW NC – 14 March 2013SoCRA Mid NC – 20 March 2013

Mary K.D. D’Rozario

MSCR, CCRP, RAC, CCRA

President / Clinical Research Consultant

Clinical Research Performance, Inc.

mary.drozario@crplink.com

www.crplink.com

@marydrozario

marydrozario

marykddrozario

2

Abstract

Expanded research in biologics and other novel therapies has increased the need for unblinded monitoring programs.  This presentation will focus on the management and monitoring of clinical studies which require unblinded site staff and site monitoring.  Study design will be discussed with a consideration toward site staffing structures.  Appropriate documentation of unblinded staffing delegation, source document requirements, and monitoring considerations will be discussed.  Management of unblinded monitoring at the sponsor and CRO will also be reviewed.

3

Double-blind studies: Main currents of thought.

• Double-blind studies have been viewed as critical to the scientific validity of clinical trials. “Reading over the last two decades of

Cephalalgia and Headache it is amazing how many treatment options were effective in open trials and failed in a spectacular way in clinical trials.” [1]

• This is not a cut-and-dry issue. NHS funded monograph. [2]

4

History and future of blinding.

• Benjamin Franklin commissioned by King Louis XVI to investigate mesmerism in 1784 [3]

• Improved retention [4]• Are the terms “double-blind” and “single-

blind” outdated? Do we know what they mean? [5, 6]

• What about the use of triple-blind studies? [6]

5

Why not just go to a single blind? [7]

• Ethical concerns Lower scientific validity Feels wrong when explained to subjects

• Placebo arms may improve subject retention

• The “Gold Standard”

6

When is unblinded monitoring needed?

• Device insertion and sham surgeries. “A Controlled Trial of Arthroscopic Surgery for

Osteoarthritis of the Knee,” [8]

• Behavioral studies. Sham relaxation techniques for headache

relief. Patients instructed to engage in “mental control” and “body awareness” but told not to relax because “relaxation would interfere with proper meditation.”[9]

• High Mortality Studies. [10]

7

When is unblinded monitoring used?• Undisguisable differences in study agent

appearance or preparation . Biologics & Chemotherapies

• Undisguisable differences in study agent effect upon the subject. Antidepressants- experienced patients and

evaluators can identify treatment effects and side effects [11]

• Differences in use of the study agent and care of the subject. For antiepileptic drugs, an unblinded physician

may need to evaluate and adjust dosing [12]

8

Who is unblinded?

• “The general rule in a double-blind trial is that as few persons as possible should be unblinded to treatment. These people should be identified and their relationship to other portions of the study should be minimal, if any, and predefined. Obviously, the patients, the treating physicians, and other medical personnel responsible for patient care and evaluation must be blinded throughout the study.” [13]

9

Who is really unblinded?

• At the SiteMay be a pharmacist, nurse or physician.

Administrative staffAnyone with access to the EMR.

10

Who is really unblinded?

• At the Sponsor/CRO Investigational Product (IP)

supply and IP quality monitoringRandomizationUnblinded monitors and

unblinded clinical team leadsAdministrative staffStatistician

11

Who is really unblinded?

• External Independent Statistician [14]Data Safety Monitoring

Committee [14] IRB

•Unblinded responsible person may need to make direct reports to the IRB.

12

Who is really unblinded?

• THE SUBJECT! “Old fashioned” unblinding methods:

• Guessing [15]• Rumors of IP tested at independent

laboratories.• Subjects on antidepressant studies with prior

antidepressant experience are known to have opened and tasted their IP capsules in order to determine dosing arm. [16]

• Treatment effects and adverse events (ongoing literature dispute whether this is “unblinding”)

13

Who is really unblinded?

• THE SUBJECT! Increased network effect increases the likelihood of

unblinding.• Your subjects are online talking about your

study.• Should we be talking to subjects about their role

in maintaining the blind? Wording of the informed consent may influence the

subjects’ expectation of being unblinded. [16, 17]• Placebo = “sugar pill”• Explanations of side-effects expected only by

certain IP• Randomization percentages

14

Are we doing enough to assess the blind?

• General Medical trials [18]: 7 in 97 assessed the blind, 5 of the 7 reported blinding

issues

• Psychiatric trials [19]: 8 in 91 assessed the blind, 4 of the 8 reported blinding

issues

• Nicotine trials [20]: 17 of 73 assessed the blind, 12 of the 17 reported the

subjects accurately judged their treatment arm.

15

Resolving problems with blinding:Acknowledging the issue

“…researchers should be aware of the scope that exists for foiling a sophisticated piece of equipment. In the final analysis, it leads to a degradation of data that have been obtained at great const in terms of time and effort. “If the display panel were to be masked and sealed, for example, it might well prevent fraud. However, it should be borne in mind that fraud is not committed by machines, but by the human beings operating them. The underlying assumption is that everybody works honestly. That notwithstanding, things should not be made too easy for those wishing to cheat the system.” [21]

16

Resolving problems with blinding.

• Evaluate blinding issues during study set-up. [22, 23] Example: community-acquired pneumonia Example: antibiotic study

• Test the blind as part of the study. [24, 25] Currently rare; possibly becoming more

common. Usually finds a blinding issue, only sometimes

statistically significant.

17

Unblinded study management: the step-child

• The need for unblinded monitoring is often discovered late in study development or even after study kick-off

• Unblinded clinical leads and staff have the same responsibilities as blinded clinical leads and staff but may have reduced budget and influence

• Unblinded monitoring is usually on a schedule that is different from the main study trajectory

18

Study Set-Up• As little difference in appearance and processing of study

arms as possible.• Treatment schedule: Is this when unblinded personnel are

available? More people involved means more limitations on the

schedule.• Data collection method. Are there unblinded CRFs?• Protection of the blind.

Separate call-in numbers for blinded and unblinded meetings for study management, DSMBs, statisticians, etc.

Secured storage for unblinded documents. Secured electronic systems.

19

Treatment Communication

• Clear documentation processes for the hand-off of site records between the blinded and unblinded side, such that both the blinded and unblinded monitors can adequately review cross over information. Document scheduling communication. Share drug compliance and dosing information. Information about patient scheduling based on supply

levels and drug prep. Blinded communication of drug issues.

• Three methods for storing the documentation: Carbon copy forms. Shared communication storage binder. *Originals of outgoing communication and faxes of

incoming communication.

20

Step One: Request to PharmacistOriginal at SC, Fax/Carbon at Pharmacy

Visit One Treatment Request Form

Subject: 123/ABCWeight: 25 kgTreatment Date: 15 January 2009Time (Please record expected time of treatment, not appointment time.): 2:00 PMRequestor: Jane Doe, 10 January 2009Pharmacist Confirmation:

Fax Received: 10 January 2009, 1:00 PM

Visit One Treatment Request Form

Subject: 123/ABCWeight: 25 kgTreatment Date: 15 January 2009Time (Please record expected time of treatment, not appointment time.): 2:00 PMRequestor: Jane Doe, 10 January 2009Pharmacist Confirmation:

21

Step Two: Confirmation from PharmacyFax/Carbon at SC, Original at Pharmacy

Fax Received: 10 January 2009, 1:00 PM

Visit One Treatment Request Form

Subject: 123/ABCWeight: 25 kgTreatment Date: 15 January 2009Time (Please record expected time of treatment, not appointment time.): 2:00 PMRequestor: Jane Doe, 10 January 2009Pharmacist Confirmation: Maggie Smith, 11 January 2009

Fax Received: 11 January 2009, 2:00 PM

Visit One Treatment Request Form

Subject: 123/ABCWeight: 25 kgTreatment Date: 15 January 2009Time (Please record expected time of treatment, not appointment time.): 2:00 PMRequestor: Jane Doe, 10 January 2009Pharmacist Confirmation: Maggie Smith, 11 January 2009

22

Site Startup

• Unblinded staff may be a hospital or medical center “back office.”

Did the unblinded office/staff have access and feedback into the budget?

Do they understand the study? Are adequate communication procedures

in place?

• Sponsor/CRO must insert themselves into this relationship!

23

Regulatory Documentation at the Site

• Delegation of the primary unblinded responsible party by the Principal Investigator

• Statement of responsibilities of the primary unblinded responsible party Responsibilities form. Process manual.

• Delegation of additional staff• Training documents

24

Study Documentation at the Site

• Create tools for maintaining the blind. Templates Door tags Fax machine reminders

• Review processes carefully for potental unblinding! Product shipments. Supply shipments. Testing sample shipments.

25

Principle Responsibilities of IP Prep at the Site

• Prepare the product to manufacturing specifications.

• Complete appropriate documentation.

• Maintain the blind.

26

Prepare the IP to manufacturing specifications.

• The site personnel responsible for IP preparation are likely more expert in their processes than the monitor is.

• The site personnel may have processing standards which deviate from the study standard. These are often points of professionalism

and pride. Review the expected deviations and explain

whether or not they are permitted on the study.

27

Complete appropriate documentation.

• Study personnel may have little to no clinical study experience.

• As a “back office” of the medical center or hospital, they may be understaffed and overwhelmed.

This is especially true of biologic therapies which are in a period of rapid expansion.

28

Maintain the blind.

• Explain the FDA review of the study and approval of blinding procedures. Blinding procedures may be different from standard product ID requirements.

• Provide site personnel with support in maintaining the blind. Peer support: At least two unblinded personnel

at every site. Monitor support: Explanation of the importance

of the blind and rational for the study. Provide outlet for discussion of individual cases and continue to support the rational for the study.

29

Maintain the blind.

• Sites that maintain the blind can be identified by: An attitude of ownership for the blind. Signs and binder notes that support

maintaining the blind.

• Any discussion of unblinded information should start with the question, “Are you unblinded on this protocol?”

• Create an unblinding procedure that removes responsibility from unblinded site personnel and places it on central Sponsor/CRO personnel.

30

Maintain the blind.

• Ensure that blinded and unblinded personnel are not the same person.

• Ensure that unblinded personnel understand which information has the potential to be unblinding. Drug shipment and use. Supply shipment and use. Use of template study documents. Preparation or procedure time. Testing sample shipment.

31

Monitoring

• Visits may be very short and infrequent.

• Remote monitoring.

• Review for signs of additional unauthorized labeling of the IP or unnecessary references to unblinding information.

32

FDA Audit of CSL Influenza Vaccine- with or without thimerosal [26]

Three sites inspected. Failure to ensure that an investigation is conducted according to the

investigational plan.• Storage temperature and adequate records.

– Edwards. “The sponsor’s monitor noted this problem and the sponsor subsequently added an additional 101 subjects at this site.”

– Decker. “In a note to file at Dr. Dekker’s site the pharmacy indicated that the temperature in the cooler where the vaccines were stored stayed between 2°C and 6°C degrees. However, no temperatures were recorded for the storage of the vaccines at the clinic.”

• Test Article Accountability Records– Edwards. “A note to file completed by the unblinded vaccine administrator at Dr. Edwards

site said the site did not maintain such accountability records until pointed out by the monitor…”

• Notable Issue– Walter. “At least four subjects… were family members of the study personnel including two

subjects that were family members of each of the unblinded study personnel. Further, in one of the instances, the vaccine was administered by the unblinded vaccine administrator to her own family member.”

• Sponsor Issue– Dekker. “…the nine blinded and five unblinded monitoring visits… failed to identify that the

site did not document the vaccine storage temperature prior to administration. Our inspection revealed that the pharmacy records indicated the date and not the time the vaccines were dispensed to the clinic.”

33

Case Study Six [27]

• A Single-Centre Double-Blind Study of the Pharmacokinetics and Tolerability of Single and Multiple Doses of Drug X in Approximately 30 Healthy Male Volunteers (UK) Full text of findings available on Google Books

34

Monitoring• Avoid unnecessary references to the unblinding in your unblinded

follow-up letter to the unblinded responsible person. Bad example: “On page 5 of the IP testing record for subject 123/ABC

(placebo), the testing start and stop time do no reconcile with the expected testing duration.”

• Clearly identify unblinded follow-up letters and documents on the outside of the envelope.

• Provide the investigator enough information for oversight in the blinded follow-up letter. Good example: “A blinded protocol violation occurred in the preparation of

IP for subject 123/ABC on 12 January 2009, performed by Mr. Smith. This issue was reported to the IRB on 14 January 2009. Mr. Jones, unblinded responsible person, re-trained Mr. Smith regarding IP preparation and a training log was completed.”

35

Monitoring

• Avoid unblinded paper. Unblinded secure electronic systems are best.

• Do not copy blinded personnel and unblinded personnel on the same email. Use separate emails.

• Use the question, “Are you unblinded on this Protocol?” in internal sponsor and/or CRO conversations and with your sites.

• Even more than usual, take care with conversations and computer use in public areas, especially when traveling to/from major medical centers.

36

Conclusion

With new biologics and novel therapies, increased evidence-based review of old surgeries, and improved understanding of the limits of blinding, more variations of blinded and unblinded personnel can be expected in the future. Unblinded personnel hold a special trust regarding the “gold standard” integrity of medical research and need to ensure the proper processes are used to be equal to that trust.

37

Questions

38

Notes1. Rains, J.C. & enzein, D.B. (2005). Behavioral Research and the Double-Blind

Placebo-Controlled Methadology: Challenges in Applying the Biomedical Standard to Behavioral Headache Research. Headache. 45:479-486. Quoting Diener (2003). Cephalagia. 23:485-486

2. McLehose, R.R. et al. (2000). A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies. Health Technology Assessment 34(4) [monograph]

3. Kaptchuk, T.J. (1998). Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine. Johns Hopkins University Press.

4. Heckerling, P.S. (2005). The Ethics of Single Blind Trials. IRB: Ethics & Human Research. 27(4):12-16

5. Devereux, P.J., Bhandari, M., Montori, V.M., Manns, B.J., Ghali, W.A. & Guyatt, G.H. (2002). Double blind, you are the weakest link – goodbye!, Evidence Based Medicine. 37(6): 557-558

6. Even, C., Siobud-Dorocant, E. & Dardennes, R.M. (2000).

7. Heckerling, P.S. (2005).

39

Notes8. Moseley, J.B. et al. (2002, July 11). A controlled trial of arthroscopic surgery for

osteoarthritis of the knee. The New England Journal of Medicine, 347(2):81-88

9. Rains, J.C. & Penzian, D.B. (2005). Behavioral Research and the Double-Blind Placebo-Controlled Methodology: Challenges in Applying the Biomedical Standard to Behavioral Headache Research. Headache. 45:479-486

10.Freeman, B.D., Danner, R.L., Banks, S.M. & Natanson, C. (2001). Safeguarding Patients in Clinical Trials with High Mortality Rates. Journal of Respiratory Critical Care Medicine .164:190-192

11.Even, C., Siobud-Dorocant, E. & Dardennes, R.M. (2000). Critical approach to antidepressant trials: Blindness protection is necessary, feasible and measurable,” The British Journal of Psychiatry .177: 47-51

12. Willmore, L.J., Shu, V. & Wallin, B. (1996). Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. Willmore et al., Neurology. 46:49-53

13.Matoren, G.M. (ed). (1984.)The Clinical Research Process in the Pharmaceutical Industry, Informa Health Care. 157

14.Statistics in Medicine 2004:23 contains several articles discussing the independence of the unblinded statician and the Data Safety Monitoring Committee.

40

Notes15.Schnoll, R.A. et al. (2008, March). Can The Blind See? Participant Guess about

Treatment Arm Assignments may Influence Outcome in a Clinical Trial of Bupropion for Smoking Cessation. Journal of Substance Abuse Treatment. 34(2): 234-241

16. Even, C., Siobud-Dorocant, E. & Dardennes, R.M. (2000).

17.Rains, J.C. & Penzien, D.B. (2005). Behavioral Research and the Double-Blind Placebo-Controlled Methadology: Challenges in Applying the Biomedical Standard to Behavioral Headache Research. Headache. 45:479-486

18.Boutron, I., Estellat, C. & Ravaud, P. (2005). A review of blinding in randomized controlled trials found results inconsistent and questionable. Journal of Clinical Epidemiology. 58:1220-1226

19.Devereaux et al, 2002.

20.Mooney, M., White, T. & Hatsukami, D. (2004). The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials. Addictive Behaviors. 29:673-684

21.Wolf, C. (2008). Security Consideration in Blinded Exposure Experiments Using Electromagnetic Waves. Bioelectromagnetics. 29:658-659

22. Walter, S.D., Awasthi, S. & Jeyaseelan. (2005). Pre-trial evaluation of the potential for unblinding in drug trials: A prototype example. Walter et al., Contemporary Clinical Trials. 26:459-468

41

Notes23. Boucher, H.W. (2008). Is It Possible to Blind a Trial for Community-Acquired

Pneumonia? Clinical Infectious Diseases. 47(Suppl 3):210-215

24. Fergusson, D., Glass, K.C. Waring, D. & Shapiro, S. (2004, January 22). Turning a blind eye: the success of blinding reported in a random sample of randomised, placebo controlled trials. British Journal of Medicine. doi:10.1136/bmj.37952.631667.EE

25. Hrobjartsson, A., Fofang, E., Haahr, M.T., Als-Nielsen, B & Brorson, S. (2007). Blinded trials taken to the test: an analysis of randomized clinical trails that report tests for the success of blinding. International Journal of Epidemiology. 36:654-663

26. Kannan, B. (2007, September 05). [Meorandum]. Bhanu Kannan, Bioresearch Monitoring Branch, Division of Inspections and Surveillance.

27. Bohaychuck, W. & Ball, G. (1999) Conducting GCP-compliant clinical research. John Wiley and Sons.184-188