Clinical Trial Blinding:History and Analysis

of anImperfect Research Method,

with new21st Century Challenges

SoCRA RTP, 01 June 2015Mary 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, 2000:177:47:513. “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

TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins University Press. 1997Hacking 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

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

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

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

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”

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

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”

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

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”

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

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 University Press. 1997

Paul Martini, Methodenlehre der therapeutischen Untersuchung

• 1932• “exclude suggestive or

other irrelevant factors in the unwissentliche Versuchsanordnung”

• Literally, “unwitting test” or “test without knowing”

TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433Stoll 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

TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins University Press. 1997Gold 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.”

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

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