Clinical Research: How to Avoid Magical Thinking

Reese H. Clark, MD

Director of Clinical Research, Pediatrix

And

Consulting Associate Professor

Duke University

Objectives

• Define the different levels of evidence use to change clinical care

• Review how failure to do good clinical research is associated with bad outcomes

• To discuss different study designs, their strengths and weaknesses.

• To provide guidance on how to perform good clinical studies that improve neonatal care

What Changes Care?

• Evidence– Publications– Meta-analysis– Consensus opinion

• Personal opinion (in my experience)

• Institutional history (the way we do it)

• Personal history (the last case I had)

Experience is the abilityto make make the same mistake

repeatedly with increasing confidence

The goal of research is to The goal of research is to

discover, learn, understand and discover, learn, understand and

teach principles that improve teach principles that improve

the quality of lifethe quality of life

Levels of Evidence

• Level 1 – Results from randomized control trials with meaningful outcome measure

• Level 2 – Case Control type of studies with treated and untreated patients and minimal evidence of selection biases

• Level 3 – The patient acts as his or her own control or Case control with some selection bias i.e., historical controls

• Level 4 – Case series• Level 5 – Expert opinion based on experience

Pediatrics 2004;114(3):874

Problem

• “The best available evidence, however, is not always sound or valid evidence. Sometimes, when faced with a collection of reports that do not constitute good evidence, attempts to choose the best evidence become pointless; in this case, a statement of no good evidence is preferable.”

• Ambalavanan N et al. Clin Perinatol 2003; 30:305-31

Definition of Researchhttp://www.nsf.gov/bfa/dias/policy/docs/45cfr690.pdf

• Research means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.

• Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes.

• For example, some demonstration and service programs may include research activities.

What is Research?http://www.hhs.gov/ohrp/humansubjects/guidance/decisioncharts.htm#c2

• Human Subject Regulations Decision Charts• The Office for Human Research Protections (OHRP)

provides the following graphic aids as a guide for institutional review boards (IRBs), investigators, and others who decide if an activity is research involving human subjects that must be reviewed by an IRB under the requirements of the U.S. Department of Health and Human Services (HHS) regulations at 45 CFR part 46. OHRP welcomes comment on these decision charts. The charts address decisions on the following:– whether an activity is research that must be reviewed by an IRB – whether the review may be performed by expedited procedures,

and – whether informed consent or its documentation may be waived.

Most Important Research Issue

Protect the people who are volunteering to participate in a clinical research study.

Drug Misadventures

The Willowbrook StudyVulnerable Population Rules

• The site where a highly controversial medical study was conducted there between 1963 and 1966 by medical researcher Saul Krugman,

• Healthy children were intentionally inoculated, orally and by injection, with the virus that causes the disease, then monitored to gauge the effects of gamma globulin in combating it. A public outcry forced the study to be discontinued.

• Researchers defended the deliberate injection of these children by pointing out that the vast majority of them would acquire the infection anyway.

Iatrogenesis:Iatrogenesis: “Brought forth by a healer"“Brought forth by a healer"

Since Hippocrates's Since Hippocrates's time, the potential time, the potential damaging effect damaging effect

of a healer's actions of a healer's actions has been recognized:has been recognized:

First do no harmFirst do no harm

““primum non nocere”primum non nocere”

BloodlettingBloodletting

480 BC

The road to hell is paved with The road to hell is paved with good intentions……good intentions……-St. Bernard of Clairvaux ~1150 AD-St. Bernard of Clairvaux ~1150 AD

Iatrogenesis in NeonatologyIatrogenesis in Neonatology• Lowered thermal

environment increased increased mortalitymortality 1900–1964

• Supplemental oxygen RLF RLF (ROP)(ROP) 1941–1954

• Initial thirsting and starving neurological neurological deficitsdeficits 1945–1970

• Synthetic vitamin K kernicteruskernicterus 1945–1961

• Sulfisoxazole kernicteruskernicterus 1953–1956

• Chloramphenicol ‘‘gray ‘‘gray baby’’ syndromebaby’’ syndrome 1956–1960

• Novobiocin jaundicejaundice 1957–1962

• Hexachlorophene brain brain lesionslesions 1952–1971

• Epsom salts enemas magnesium intoxicationmagnesium intoxication 1964–1965

• Feeding gastrostomy increased mortalityincreased mortality 1963–1969

• Benzyl alcohol ‘‘gasping’’ ‘‘gasping’’ syndromesyndrome –1982

From: Robertson AF, Reflections on Errors in Neonatology (Part I,II,III) J Perinatology 2003

With the best intent we can do great harm.

• Eferol -- Increases NEC, liver injury and death

• Verapamil -- Causes profound bradycardia

• Post-natal steroids -- May increase brain injury

• Overventilation -- Increases the risk of PVL

Martone WJ et al. Illness with fatalities in premature infants: association with an intravenous vitamin E preparation, E-Ferol. Pediatrics. 1986;78:591-600.

• A role for vitamin E in the prevention of retrolental fibroplasia was first reported in 1949.

• A number of clinical studies between 1978 and 1983 suggested that vitamin E supplementation (to normal or supranormal serum levels) might prevent or ameliorate the course of retrolental fibroplasia and other complications of prematurity, especially following oxygen exposure.

• Vitamin E’s therapeutic or preventive role had not yet been clarified before it was used.

MMWRApril 13, 1984 / 33(14);198-9

http://www.cdc.gov/mmwr/preview/mmwrhtml/00000319.htm

• CDC has received reports from two hospitals of clusters of an unusual illness occurring among low-birth weight (less than 1,500 grams), premature infants in neonatal intensive-care units.

• Thirteen affected infants developed clinically significant ascites, in addition to some or all of the following abnormalities: hepatomegaly, splenomegaly, cholestatic jaundice, azotemia, and thrombocytopenia.

• All affected infants had received parenteral nutrition therapy, in addition to other supportive measures.

• An intravenous vitamin E preparation, containing 25 mg/ml vitamin E, 9% polysorbate 80 and 1% polysorbate 20 in 2-ml vials (E-Ferol Aqueous SolutionR, distributed by O'Neal, Jones & Feldman, St. Louis, Missouri), was introduced in each hospital for addition to parenteral nutrition solutions approximately 1 month before the onset of illness in the first infant in both clusters.

• All affected infants received E-Ferol; some affected infants received up to 1 ml or more daily. Both outbreaks ceased shortly after use of E-Ferol was discontinued.

Do You Remember E-Ferol? The Penalty for Selling Untested Drugs in Neonatology

Jerold F. Lucey Pediatrics 1992;89;159;

• In 1984, E-Ferol killed at least 38 newborns.• Iatrogenic disasters are often caused primarily by well-

intentioned physicians using logical therapies which turned out to have unexpected, lethal side effects.

• A poorly managed, avaricious company, O’Neil, Jones and Feldman, Inc. decided to get the jump on the market and sell an untested preparation of intravenous vitamin E.

• Physicians assumed E-Ferol had been tested and approved for use by the FDA. It hadn’t been tested.

• An astute clinician spotted the problem.• On January 19, 1989, three defendants pleaded guilty and

were sentenced to fines of $130 000 each and 6-month jail sentences. These penalties were for conspiracy, mail fraud, and Cosmetic Act Felony.

Problems

• Clinical practice is dynamic

• Study design and execution can take years

• Muticenter studies require coordination which can further delay the process

• Publication delay is terrible

• Evidence-based practice requires continuous reevaluation of practice

Change in Event Rate With TimeTerm Neonates With Meconium Aspiration Syndrome

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Surfactant Vasopressors iNO ECMO

Study Types

Study Designs

• Case Series– Retrospective– Prospective

• Case-Control

• Randomized Control Trial– Crossover design– No Crossover

Case Series -- Reporting Our Experiences

• Evaluates the occurrence of an outcome and the factors associated with that outcome

• Examples– The effect of iNO on oxygenation

– What factors are associated with, not that cause, IVH?

• Advantage: Easy to do. Easy to get consent.• Disadvantage: No concurrent controls• Never proves efficacy or safety

Ways to Strengthen a Case Series

• Define study plan, outcomes measures, and statistical methods prospectively

• Avoid hunting for an effect

• Be careful to evaluate the study sample for selection bias (e.g., ECMO centers admit other institutions treatment failures)

• Do not over-interpret the results

Case-Control Trials

• Similar to case series except the cases are compared to a defined group of controls

• Type of controls:– Historical

– Same period, different location

– Matched for factors that influence the outcome

• Gives a better sense of efficacy but selection bias and confounding variables remain a problem

Randomized Controlled Trials

• Patients are randomly assigned to one of several defined groups. The management of each group is strictly defined.

• Crossover design allows patients to “crossover” into other treatment groups. While easier to get consent for, the results are difficult to interpret.

Outcomes = Study Endpoint = What is really important?

• Physiology -- Heart rate, blood pressure, PaO2

• Health consequence -- Survival, chronic lung

disease, seizures, stroke, learning disability

• Quality of life -- Joyful participation in life

• Health economics -- Did we produce the same

outcome more efficiently?

““Not everything that can be Not everything that can be counted counts,counted counts,

and not everything that and not everything that counts can be counted.”counts can be counted.”

Albert Einstein

Outcomes

Outcomes

• Primary -- The outcome we are most interested in studying. Sample size is determined by estimating the number of patients needed to evaluate this endpoint. Every aspect of study design is directed at getting a clean measure of this outcome.

• Secondary -- All other measures of outcome.

Characteristics of a Good Study Endpoint or Outcome Measure

• Easy to measure and to define– Survival is easy to define but hard to study

– Chronic lung disease is easy to study but hard to define

• Valuable– Healthy survival

– Not a transient rise in PaO2

• Occurs at a frequency that is feasible to study• Outcome change must be attributable to the

intervention studied

Surrogate Outcome Measures

• Definition -- A measure that predicts or is closely associated with another measure of outcome

• Example -- Grade 3-4 IVH is often used as a surrogate measure (or proxy) of neurological outcome. If we decrease the rate of severe IVH, we predict that we will improve neurological outcome.

Failure of Surrogate Markers

• Ment LR et al. Pediatrics 1994;93:543-550– Low-dose prophylactic indomethacin decreased IVH

from 18 to 12% in neonates 0.6-1.25 kg

– Also reduced the rate of grade 3-4 IVH from 5 to 1.4%

– Survival was not significantly different but was better (92 vs. 87%) in the treated group

• Ment LR et al. Pediatrics 1996;98:714-718– Follow-up showed no difference in IQ or the

occurrence of cerebral palsy

Prophylactic IndomethacinMent et al. Pediatrics 1996;98:714-718

0%

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10%

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Mortality All IVH IVH 3-4 CP

Indomethacin Control

Postnatal Steroids

• Meta-analysis shows that steroids reduce the risk of CLD in premature neonates (Bhuta et al. Arch Dis Child 1998;79:F26)

• CLD is associated with poor neurodevelopmental outcome.

• It might be expected that steroids might improve neurodevelopmental outcome

• Instead early steroids increase neurodevelopmental problems (Yeh et al. Pediatrics 1998;101)

Meta-analysis

• Summarize the results of different research studies of related problems

• Systematic approach to the identification and abstracting the critical information held in each study

• Present a comprehensive best estimate meant to summarize what is known about the clinical problem

Meta-analysisLeLorier et al. NEJM 1997;337:536

Positive Negative

Positive 13 6 19

Negative 7 14 21

Total 20 20 40

Evaluation of Meta-analysis

Sensitivity 65%

Specificity 70%

Positive Predictive Value 68%

Negative Predictive Value 67%

Kappa value 0.35 (0.06-.64)

Definitions

• Relative Risk -- The probability (risk) of being treated with ECMO if you get iNO compared to if you did not get iNO (%ECMO use in iNO treated/ %ECMO in control not treated with iNO)

• Odds Ratios -- The rate that ECMO patients are treated with iNO compared to patients who do not get ECMO. (%iNO exposure in ECMO patients) / (%iNO use in non ECMO patients). Better applied to morbidity factors like ICH, or CLD

Definitions

• Confidence intervals -- How certain are you that the observation falls within your measured result. Usually the number is 95% CI

• Standard Deviation -- a measure of average variance from the mean (Square root of {Sum(individual values - mean value)2/number of measurements}

• Standard Error of the Mean -- STD/Square root of the sample size.

Effect but noEffect but noConfidenceConfidence

Relative Risk of OutcomeRelative Risk of Outcome

.2.2 .25.25 .5.5 11 22 33 44 55.33.33

No effectNo effect

Relative Risk of Outcome

Decreased deathDecreased deathGood confidenceGood confidence

Increased deathIncreased deathGood confidenceGood confidence

Efficacy or Equivalency or Non-inferiority?

• Efficacy trials are directed at proving that one therapy is better than another with 95% confidence

• Equivalence implies that the two therapies produce the same outcome– If one therapy reduces health care cost, then we may only want to

show that the two approaches produce similar outcomes

• Non-inferiority are done to show that patients treated with X do no worse than those treated with Y. Like efficacy but only one tail-test are used. Required sample size is smaller.

Effect but noEffect but noconfidenceconfidence

Relative Risk of OutcomeRelative Risk of Outcome

.2.2 .25.25 .5.5 11 22 33 44 55.33.33

Equivalent but noEquivalent but no confidenceconfidence

Relative Risk of Outcome

The new therapy isThe new therapy isbetter and no riskerbetter and no risker

EquivalentEquivalentGood confidenceGood confidence

Relative Risk of Death and/or ECMO(% Death or ECMO iNO/ % in Control)

0.000.00 0.500.50 1.001.00 1.501.50

Relative Risk of Death/ECMO Relative Risk of Death/ECMO iNO/ControliNO/Control

INOSG (n = 58)INOSG (n = 58)

Boston (n = 90)Boston (n = 90)

Ohmeda (n = 155)Ohmeda (n = 155)

Total (n = 538)Total (n = 538)

NINOS (n = 235)NINOS (n = 235)

INOSG (n = 58)INOSG (n = 58)

Boston (n = 90)Boston (n = 90)

Ohmeda (n = 155)Ohmeda (n = 155)

Total (n = 538)Total (n = 538)

NINOS (n = 235)NINOS (n = 235)

Relative Risk of DeathRelative Risk of Death

00 11 33 44 55 66 77 8822

Relative Risk of Death

Rate of ECMO or DeathNINOS trial, NEJM 1996

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iNO Control

Problems With the General Application of Any Model

• Standardized Rate -- Observed outcome rate divided

by the predicted rate

• Inadequate sample size

• Selection biases

• Neonatal care changes and the model must be

recalibrated

• May be slow in identifying poor performers if we

have to wait for adequate sample size

Sample Size Calculations

• Dependent on:

– The absolute event rate in the population being studied

– The absolute difference between the two groups

– How certain you want to be in the measured difference

Effect of Sample Size On Confidence Interval and Probability that the Proportions are Different

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Grp 2 (n=10)

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Grp 2 (n=100)

Grp 1 (n=1000)

Grp 2 (n=1000)

Sample Size

Ou

tco

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p=0.6 p=0.16 p<0.001

Site Variation

Center Differences & Outcomesof Extremely Low Birth Weight Infants

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Vohr B et al. Pediatrics April 2004, pp 781

Across Site Variability

• Most sites randomize within center• Each site is a mini-trial• Differences in care are variable within sites and

may effect the efficacy of the drug being studied within that site– steroids

– nosocomial sepsis

– nutrition

– saturation targets

Site Variability in Proportion of Neonates Alive & Off OxygenTreatment Study (“All Treated”)

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Difference between Group 1 and Group2Alive and off oxygen PMA36 for Treatment Study

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Surfactant 2 better

Testing a Test

Test DiseasePresent

DiseaseAbsent

Positive A B PPVA/(A+B)

Negative C D NPVD/(C+D)

SensitivityA/(A+C)

SpecificityD/(B+D)

Solutions

• Create a network of centers with a common goal to answer important questions

• Define answerable questions

• Limit data collection to confounding variables

• Define strict time lines and review progress on a quarterly basis

• Present findings at national meetings

• Interpret results carefully

“For I was assailed by so many doubts and errors that the only profit I appeared to have drawn from trying to become educated,

was progressively to have discovered my ignorance.”

Descartes, Discourse on Method, 1637.