Some types of studies require unblinded personnel at the site and a matching unblinded monitoring and study management team. This presentation provides a little background on blinding and then reviews best practices for unblinding.

1. Unblinded Monitoring Programs:
Design and Education
SoCRA NW NC – 14 March 2013
SoCRA 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
1

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.
2

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]
3

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blind” outdated?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]
4

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”
5

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]
6

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]
7

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]
8

9. Who is really unblinded?
• At the Site
May be a pharmacist, nurse
or physician.
Administrative staff
Anyone with access to the
EMR.
9

10. Who is really unblinded?
• At the Sponsor/CRO
 Investigational Product (IP)
supply and IP quality monitoring
 Randomization
 Unblinded monitors and
unblinded clinical team leads
 Administrative staff
 Statistician
10

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.
11

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”)
12

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
13

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.
14

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]
15

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.
16

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
17

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.
18

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.
19

20. Step One: Request to Pharmacist
Original at SC, Fax/Carbon at Pharmacy
Fax Received: 10 January 2009, 1:00 PM
Visit One Treatment Request Form Visit One Treatment Request Form
Subject: 123/ABC Subject: 123/ABC
Weight: 25 kg Weight: 25 kg
Treatment Date: 15 January 2009 Treatment Date: 15 January 2009
Time (Please record expected time of Time (Please record expected time of
treatment, not appointment time.): 2:00 treatment, not appointment time.): 2:00
PM PM
Requestor: Jane Doe, 10 January 2009 Requestor: Jane Doe, 10 January 2009
Pharmacist Confirmation: Pharmacist Confirmation:
20

21. Step Two: Confirmation from Pharmacy
Fax/Carbon at SC, Original at Pharmacy
Fax Received: 11 January 2009, 2:00 PM Fax Received: 10 January 2009, 1:00 PM
Visit One Treatment Request Form Visit One Treatment Request Form
Subject: 123/ABC Subject: 123/ABC
Weight: 25 kg Weight: 25 kg
Treatment Date: 15 January 2009 Treatment Date: 15 January 2009
Time (Please record expected time of Time (Please record expected time of
treatment, not appointment time.): 2:00 treatment, not appointment time.): 2:00
PM PM
Requestor: Jane Doe, 10 January 2009 Requestor: Jane Doe, 10 January 2009
Pharmacist Confirmation: Maggie Smith, 11 Pharmacist Confirmation: Maggie Smith, 11
January 2009 January 2009
21

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!
22

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
23

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.
24

25. Principle Responsibilities of IP Prep at the Site
• Prepare the product to manufacturing
specifications.
• Complete appropriate documentation.
• Maintain the blind.
25

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.
26

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.
27

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.
28

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.
29

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.
30

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.
31

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.”
32

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
33

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.”
34

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.
35

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.
36

37. Questions
37

38. Notes
1. 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).
38

39. Notes
8. 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.
39

40. Notes
15.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
40

41. Notes
23. 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
41