Blinding: History and Current Issues

Clinical Trial Blinding:
History and Analysis
of an
Imperfect Research Method,
with new
21st Century Challenges
SoCRA RTP, 01 June 2015
Mary K.D. D’Rozario
MSCR, MBA, CCRP, RAC, CCRA
President, CRP Social Media by Clinical Research Performance, Inc.
mary.drozario@crplink.com
www.crplink.com
@marydrozario
marydrozario
marykddrozario

Blinding: Do we know it when we see it?
Results:
“Physician respondents identified 10, 17 and 15
unique interpretations of single, double, and triple
blinding, respectively, and textbooks provided 5, 9
and 7 different definitions of each.”
PJ Devereaux, BJ Manns, WA Ghali et al. Physician interpretations and textbook definitions of blinding terminology in randomized
controlled trials. Journal of the American Medical Association. 2001;285(15):2000-2003

Blinding: Do we know it when we see it?
• Some suggest “masking” rather than blinding. [1]
• Some suggest blinding be specifically explained
in the study report. [1]
KF Schulz, I Chalmers, DG Altman. The landscape and lexicon of blinding in randomized trials. Annals of Internal Medicine.
2002;136:254-9

Blinding: Why do we do it?
• scientific legitimacy
• persuasion
• competition for resources
• flight to quality
• subject retention
TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History
of Medicine. 1998;72.3:389-433

Blinding: How well are we doing?
• Of 200 randomly chosen studies from 2001, 19%
stated they were “double blind” but had not
blinded either patients, health care providers, or
data collectors. [1]
M Haahr, A Hróbjartsson. Who is blinded in randomized clinical trials? A study of 200 trials and a survey of authors. Clin Trials.
2006;3:360-5

Blinding: How well are we doing?
Literature Review 1 (2004) 2 (2000) 3 (2004)
Type of study
evaluated:
Placebo-controlled Antidepressant Nicotine Replacement
Therapy
Number of studies: 97 91 73
Number of studies
that evaluated the
blind:
7 8 17
Number which noted
the blind
compromised:
5 4 12
1. “Turning a blind eye: the success of blinding reported in a random sample of randomized, placebo controlled
trials,” British Journal of Medicine, doi:10.1135/bmj.37952.631667.EE published 2004
2. “Critical approach to antidepressant trials: Blindness protection is necessary, feasible and measurable,” The
British Journal of Psychiatry, 2000:177:47:51
3. “The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials,”
Addictive Behavior, 2004:29:673-684

History of Blinding: How we got here.
• Blinding Discovered and Re-discovered at several
times and places.
• Contributing issues include:
 competing concepts of scientific truth and medical
treatment
 social barriers between different groups of
scientists and physicians
 language barriers
of Medicine. 1998;72.3:389-433
Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins
University Press. 1997
Hacking I. Telepathy: Originals of Randomization in Experimental Design. Isis. Sept 1988, A Special Issue on Artifact and
Experiment (79);3:427-51

Galen: Canon of Medicine
–Galen (129 – c. 200)
–Canon compiled by Ibn
Sīnā (Avicenna) in Arabic,
completed 1025
–Considered authoritative
on some subjects into the
early 20th century

James Lind’s Treatise of the Scurvy, 1753
• Detailed study of the
available literature.
• Detailed study of actual
patients.
• Empirical study of
treatments.

Mesmerism
• 1784
• Commission appointed by
King Louis XVI
• Headed by Benjamin Franklin
of Medicine. 1998;72.3:389-433

Nuremberg Salt Test
• 1835
• Test of
homeopathy
Stolberg M. Inventing the randomized double-blind trial: the Nuremberg salt test of 1835. J R Soc Med. 2006;99:642-643

Test of “Smallest Discernible Difference in
Sensation”
• 1884
• Charles Sanders Peirce
(founder of the philosophy
known as American
pragmatism)
• student Joseph Jastrow
of Medicine. 1998;72.3:389-433

Subcutaneous Injection of Animal Testicles
• 1889, announced to
the Société de
Biologie, Paris, by
Charles E. Brown-
Séquard
• Tested by M.G. Variot
at the Hôtel Dieu
• Controlled for
“suggestion”
of Medicine. 1998;72.3:389-433

Diphtheria Trial (randomized, not blinded)
• 1897
• Designed by Johannes
Fibiger, age 28 (Dutch)
• Systematic randomization
to either standard
treatment or standard
treatment plus serum

Anglo-American Tests of Psychotropics
• 1910 through 1920
• W.H.R. Rivers at
Cambridge
• H.L. Hollingsworth at
Columbia University
• Torald Sollmann at the
AMA Council of
Pharm. and Chem.
• David Macht at Johns
Hopkins University
• Control for “interest
and excitement”
of Medicine. 1998;72.3:389-433
Cambridge University. © Andrew Dunn, 2004, Creative Commons
Licensing

Blinded Test of Diphtheria Serum
• 1914
• Adolf Bingel
• First major blinded trial of
a pharmaceutical product
• 937 randomized subjects
• Double-blind
• Control for “suggestion”
of Medicine. 1998;72.3:389-433
Braunschweig, Germany, circa 1900. Library of Congress.

1920’s English Speaking
• Michigan Tuberculosis Trial (1926-1931) [1]
 Single blind
 Control for instability of disease state
• Cardiac Department of London Hospital Angina Study,
1930 [1]
 Control for variations of symptoms
• Claude Bernard’s paper “An Introduction to the Study of
Experimental Medicine” translated and published in New
York, 1927 [2]
 Used the term “comparative method” and described blinding
1. TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the
History of Medicine. 1998;72.3:389-433
2. Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins

Paul Martini, Methodenlehre der
therapeutischen Untersuchung
• 1932
• “exclude suggestive or
other irrelevant factors in
the unwissentliche
Versuchsanordnung”
• Literally, “unwitting test” or
“test without knowing”
of Medicine. 1998;72.3:389-433
Stoll S, Raspe H. Paul Martini and the development of clinical epidemiology in Germany. The Paul Martini Foundation. [poster]

R.A. Fischer, The Design of Experiments
• 1935
• Botanist
• Inventor of the field of
experimental design
 Made experiment “scientific”
• Considered randomization
important
• Blinding less important and
easy to do

Harry Gold: The Invention of “Pharmacology” and
the Gold Standard of Blinding for Research
• 1937, conducted first blinded study
• No previous exposure to blinding
methods
• Got the word “blinding” from a cigarette
advertisement
• First person assigned a professorial
position in “pharmacology,” at Cornell
University
of Medicine. 1998;72.3:389-433
Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins
Gold H. Clinical pharmacology: historical note. Journal of Clinical Pharmacology and Journal of New Drugs. 1967(7):309-11

Streptomycin Clinical Trial
• 1948
• Austin Bradford Hill
• “deliberately left out the words
‘randomization’ and ‘random
sampling numbers’ at the time
because… I might have scared
them [collaborating physicians]
off.”
of Medicine. 1998;72.3:389-433

Acceptance of Randomized Controlled Clinical
Trials Grows
• 1976, JAMA Special Article: Randomized Clinical
Trials: Perspectives on Some Recent Issues
 “Ethical considerations suggest that randomized
trials are more suitable than uncontrolled
experimentation in protecting the interests of
patients. Randomized clinical trials remain the
most reliable method for evaluating the efficacy of
therapies.”

ICH Definition (ICH launched 1990)
“Blinding is an important means of reducing or minimizing the risk of
biased study outcomes. A trial where the treatment assignment is not
known by the study participant because of the use of placebo or other
methods of masking the intervention, is referred to as a single blind
study. When the investigator and sponsor staff who are involved in the
treatment or clinical evaluation of the subjects and analysis of data are
also unaware of the treatment assignments, the study is double blind.”

Declaration of Helsinki, October 2013
Amendment, Section 33: Use of Placebo
The benefits, risks, burdens and effectiveness of a new intervention must
be tested against those of the best proven intervention(s), except in the
following circumstances:
Where no proven intervention exists, the use of placebo, or no
intervention, is acceptable; or
Where for compelling and scientifically sound methodological
reasons the use of any intervention less effective than the best proven
one, the use of placebo, or no intervention is necessary to determine the
efficacy or safety of an intervention
and the patients who receive any intervention less effective than
the best proven one, placebo, or no intervention will not be subject to
additional risks of serious or irreversible harm as a result of not receiving
the best proven intervention.
Extreme care must be taken to avoid abuse of this option.

Some other thinking on blinding:
• Kolahi J. Abrishami M. Multiple-blind: Towards a new blinding protocol for
future generations of clinical trials. Med Hypotheses. 73(2009):843-5
 Suggest expanding blinding, including requiring blinded creation of dual study reports and
blinding evaluation of study reports. (Some of these techniques were implemented by
Gold, but did not catch on for general use. [1])
• Bang H et al. Assessment of blinding in clinical trials. Controlled Clinical
Trials 2004;(25):143-56
 Provides a method for arriving at a blinding index.
• JR Rees, TJ Wade, DA Levy, JM Colford Jr., JF Hilton. Changes in beliefs
identify unblinding in randomized controlled trials: a method to meet
CONSORT guidelines. Contemporary Clinical Trials. 2005;26:25-37
 Suggest adding patient preference arms to studies.
• -D’Rozario MKD, Unblinded monitoring programs: design and education.
SoCRA Source. February 2011: 70-75
 Discusses the need for unblinded monitoring and how to implement an unblinded
monitoring program.
1. Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician.
Baltimore: The Johns Hopkins University Press. 1997

HIV Activism • 1984
 FDA credited (some were unofficial “look
the other way”) with first allowing
compassionate use.
• 1987
 AIDS Quilt first displayed on the National
Mall
 Drugs typically took 10 years to be
approved.
 AZT was the first fast-track (law itself not
established until 1997) drug, approved in
25 months.
 Lengthened life by about a year.
 First Study:
• 12 centers. All with different standard-of-
care protocols.
• Had been designed as a 6 month blinded
study.
• Mean participation of 120 days when study
was unblinded.
• Claims that they study was never blinded
because of obvious adverse events, product
testing by subjects, product pooling, etc.
*Highlighted information from a variety of
sources, not necessarily covered in this
book.

HIV Activism
• 1989: Compound Q
 Open-label patient-led study of an
herbal product.
 Closed after patient deaths.
 Made famous in the movie Dallas
Buyers Club.
*Highlighted information from a variety of
sources, not necessarily covered in this
book.

Ebola
• 11 AUG 2014: Advisory Panel meets, creates
publication “Ethical considerations for use of
unregistered interventions for Ebola virus
disease”
 Determine that it is ethical to offer unproven therapies
• Consent required
 Therapies should be distributed fairly
 Communities should be involved in distribution
decisions
 Moral requirement to collect data from such
interventions

Ebola
• 20-21 OCT 2014: WHO Ethics Working Group
meets, creates publication “Ethical issues related
to study design for trials on therapeutics for Ebola
virus disease
 “monitored emergency use of unregistered and
experimental interventions (MEURI)” instead of
“compassionate use”
 Trials should not take away from the care received by
other patients
 Real time data collection and sharing
 Provides a worksheet to compare a randomized
controlled trial against other options.

Right to Try
• Current Law in 19 states
 Arizona Arkansas Colorado Indiana Louisiana
Maine Michigan Minnessota Mississipi Missouri
Montana Nevada North Dakota Oklahoma
South Dakota Tennessee Utah Virginia
Wyoming
 Link to all current and draft legislation:
http://www.raps.org/regulatory-
focus/news/right-to-try

Right to Try Example: Arkansas
 Terminally ill
 No current treatment
 No clinical trial within 100 miles of home
 Manufacturer can charge for the product
• Insurance may, but not required, to pay
for product
• Insurance must pay for all other
treatment
• Debt related to product cannot be
collected from family

Right to Try Example: DRAFT North Carolina
 Terminally ill
 No current treatment
 Detailed informed consent requirements
 Manufacturer protected from liability
 Prescribing doctor protected from sanctions
 Manufacturer can charge for the product
• Insurance may, but not required, to pay
for product
• Insurance must pay for all other treatment
• Debt related to product cannot be
collected from family

Blinding: History and Current Issues

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