THE  RANDOMIZED  TRIAL  –    65  IS  THE  NEW  40?    

(What’s  it  all  about,  David?)      

Stan  Shapiro  McGill  University  

SMBD  Jewish  General  Hospital      

The Second David Sackett Symposium

   Stan      Shapiro      has  no  poten-al  for  conflict  of  

interest  with  this  presenta-on    

Faculty/Presenter  Disclosure  

Ancestry and Age of the Controlled Trial a matter of some uncertainty – Some, such as Fred Mosteller, trace its lineage back to Daniel in the lion’s den (Science 1981) Although there are many intervening events along the way, http://www.jameslindlibrary.org/illustrating/articles/why-the-1948-mrc-trial-of-streptomycin-used-treatment-allocation Most consider Bradford Hill’s trial: Streptomycin treatment of pulmonary tuberculosis as marking the start of the RCT era (BMJ 1948)

( Although 65 years old retirement is certainly not mandated.)

An impressive array of accomplishments since it entered the work force: Salk Polio Vaccine trial (complex study of mixed heritage - both randomized and observational components - involving over one million school children and over 3000 communities) whose design, execution and dissemination took place in roughly three years. Project impACT , directed by Steve Goodman, provides research on the most important RCTS carried out since Bradford Hill’s seminal study

Society for Clinical Trials “Trial of the Year Award” winners for the past 3 years http://www.sctweb.org/public/about/toty.cfm A double blind RCT of intravenous versus intramuscular treatment for individuals in status epilepticus carried out using paramedics the emergency medical system and with a consent waiver A complex surgical trial of prenatal vs postnatal surgery for severe spina bifida (myelomeningocele) A cluster randomized trial of the impact of village women’s groups on neonatal mortality and maternal depression ;

However, the road has not always been smooth and we will revisit some historical challenges and their modern incarnations shortly Gehan and Freireich (NEJM 1974)

Hellman and Hellman (NEJM 1991)

Before that though let’s turn to a classic:

Seek to compare 2 therapeutic regimens 1.  Radiotherapy 2.  Radiotherapy preceded by a drug which

may enhance effect of radiotherapy , but has no effect by itself

Drug will be administered over a 30 day period.

(Schwartz & Lellouch JCD 1967)

Which of the following designs should we employ?

Design I Design II

Xray

30 days Xray Drug

Exp

Control

Drug Xray

Xray 30 Days

“We wish here to describe other ( than randomization) methods of entering patients and shall discuss here technics of selecting patients to achieve comparability. The primary assumptions that must be made in all studies involving the selection of patients are that the important patient characteristics related to prognosis are known, so that there is a firm basis for the selection of comparable groups, and that the differences existing between the groups selected . . . have little or no relation to the outcome of treatment.”

Seductive appeal of the argument is that if the past has established the performance of the standard treatment, than one can obtain essentially the same amount of information from a sample ¼ the size needed for a 2 arm trial that randomizes on a 1:1 basis. The paper created quite a stir initially in the oncology community. Meier (1975) allayed much of that concern by showing that when one accounts for the variation in the historical data there are very few circumstances which permit for claimed savings. Pocock(1976) put forward an intermediate approach which did not ignore the variability in historical data, but attempted to explicitly incorporate it.

The developments in causal inference in the past years have been an exciting addition to our methodologic armamentarium. However , a crucial point, is that the conclusions resulting from a causal model directed acyclic graph approach rest on the pivotal assumption of no unmeasured confounders.

Of Mice but not Men Problems of the Randomized Controlled Trial

(Hellman and Hellman NEJM 1991)

Hellman and Hellman argued that physicians’ roles as care-givers is inconsistent with their roles as investigators. They argued that practitioners are obligated to act in concert with their own opinions (even in the absence of supporting data).

If confirmed by rigorously designed longitudinal studies, the improved case-control technique could serve as a useful "screening" device to assess the efficacy of medical or surgical treatments that cannot be tested with randomized clinical trials. Minnesota Domestic Violence Experiment

“ . . . If an RCT were attempted, women agreeing to be randomly assigned to breast-feed or formula-feed their infant would be so few and so atypical that the results would have little meaning for mothers and infants in general.”

Promotion of Breastfeeding Intervention Trial (PROBIT): a randomized trial in the

Republic of Belarus JAMA 2001 Jan 24-31;285(4):413-20

BACKGROUND: Current evidence that breastfeeding is beneficial for infant and child health is based exclusively on observational studies. Potential sources of bias in such studies have led to doubts about the magnitude of these health benefits in industrialized countries

CONTEXT: Current evidence that breastfeeding is beneficial for infant and child health is based exclusively on observational studies. Potential sources of bias in such studies have led to doubts about the magnitude of these health benefits in industrialized countries. OBJECTIVE: To assess the effects of breastfeeding promotion on breastfeeding duration and exclusivity and gastrointestinal and respiratory infection and atopic eczema among infants. DESIGN: The Promotion of Breastfeeding Intervention Trial (PROBIT), a cluster-randomized trial conducted June 1996-December 1997 with a 1-year follow-up.

SETTING: Thirty-one maternity hospitals and polyclinics in Belarus. PARTICIPANTS: A total of 17 046 mother-infant pairs consisting of full-term singleton infants weighing at least 2500 g and their healthy mothers who intended to breastfeed. INTERVENTIONS: Sites were randomly assigned to receive an experimental intervention (n = 16) modeled on the Baby-Friendly Hospital Initiative of the World Health Organization and United Nations Children's Fund, which emphasizes health care worker assistance with initiating and maintaining breastfeeding and lactation and postnatal breastfeeding support, or a control intervention (n = 15) of continuing usual infant feeding practices and policies.

The Promotion of Breastfeeding Intervention Trial (PROBIT) is the largest cluster-randomised controlled trial ever conducted in the area of human lactation during infancy.

The intervention produced two randomised

cohorts with substantially different exposure to breastfeeding, providing a unique opportunity to test the affects of breastfeeding on various health outcomes.

Effects of prolonged and exclusive breastfeeding on child height, weight, adiposity, and blood pressure at age 6.5 y: evidence from a large randomized trial. Am J Clin Nutr. 2007 Dec;86(6):1717-21. PMID: 18065591

Promotion of Breastfeeding Intervention Trial (PROBIT) Study Group. Effects of prolonged and exclusive breastfeeding on child behavior and maternal adjustment: evidence from a large, randomized trial. Pediatrics. 2008 Mar;121(3):e435-40. PMID: 18310164

The effect of prolonged and exclusive breast-feeding on dental caries in early school-age children. New evidence from a large randomized trial. Caries Res. 2007;41(6):484-8. Epub 2007 Sep 18. PMID: 17878730 Promotion of Breastfeeding Intervention Trial (PROBIT) Study Group. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry. 2008 May;65(5):578-84  PMID: 18458209 . . . http://www.bris.ac.uk/social-community-medicine/projects/probit/publications

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An epidemic disease struck a small community and killed many people. The victims lapsed into a deathlike coma and it was hard to know when and, indeed, if they had succumbed. The townspeople worried about burying the “dead” too soon, and they were hard-pressed for a solution to the dilemma.

It was suggested that coffins be well stocked with food and an air vent provided just in case the victim happened to be alive. Although this was expensive, it certainly seemed worth the effort.

However, a second proposal was made that

was both inexpensive and quite efficient. A twelve-inch stake was to be mounted on the inside of the coffin lid exactly at the level of the heart. When the coffin was closed, all uncertainty would end.

It is of interest that the two solutions were generated by two different questions.

The first solution was an answer to the question, “How can we make sure that we do not kill people who are alive? “

The second was a response to the question, “How can we be sure that everyone we bury is dead?”

The point is that the only answers we get are

responses to questions. Although questions that refer to certain assumptions may not be evident, they design the form that our knowledge will take and, thus, determine the course of our actions. ( Silverman, Human Experimentation)