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PubH 7- 420 Clinical Trials. Instructor: Jim Neaton 612-626-9040 2221 University Ave SE, Room 200 Text: Fundamentals of Clinical Trials Friedman, Furberg , and DeMets Evaluation: Homework: 3 exercises (15%) Group discussion topics (5%) Protocol project (30%)

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Pubh 7 420 clinical trials
PubH 7- 420Clinical Trials

Instructor: Jim Neaton 612-626-9040 2221 University Ave SE, Room 200

Text: Fundamentals of Clinical Trials Friedman, Furberg, and DeMets

Evaluation: Homework: 3 exercises (15%) Group discussion topics (5%)

Protocol project (30%)

Mid Term (20%) Final (30%)

Web Site:

Tas for pubh 7420
TAs for PubH 7420

YunBai –

Kristin Cunanan –

Debashree Ray –

Group work protocol and discussion topic groups
Group Work: Protocol and Discussion Topic Groups

  • Six groups, 10-11 multidisciplinary members.

  • Three protocol topics, 2 groups assigned to each protocol topic.

  • Twelve discussion topics, 2 per group:

    • 15 minute presentation on topic (max of 7 slides)

    • Each topic should be presented by 2 people; each person should only present one topic. All group members are expected to participate (see calendar for schedule).

Protocol project
Protocol Project

  • Protocol

    • 10 -12 pages.

    • On the last page of the protocol indicate the members of the team and the sections they contributed to.

    • Turn in by the last day of class.

  • Presentation

    • 20 minutes during the last 2 weeks of class, followed by questions and discussion.

Outline of protocol
Outline of Protocol

  • Background and rationale for study

  • Study design

    • Objectives (primary, secondary, subgroup hypotheses)

    • Primary and secondary endpoints (efficacy and safety)

    • Inclusion and exclusion criteria

    • Treatments

    • Sample size

  • Data collection plan and follow-up schedule

  • Data analysis plan, including plan for interim monitoring and guidelines for early termination

Advice for groups
Advice for Groups

  • Elect a chairperson and rapporteur

  • Divide up the work among all group members

  • Give each member a list of names and email addresses in group

  • Plan to meet 6-7 times during the semester

  • Plan to have 2 members present the discussion topic and 3 members present the protocol

General methods of investigation
General Methods of Investigation

1. Chance observations

2. Case histories

  • individual cases

  • case series

    3. Uncontrolled trials of an intervention

    4. Cross-sectional (naturalistic) studies

    5. Case-control studies

    6. Prospective follow-up studies

    7. Randomized clinical trial

No planned




Did investigator assign exposures
Did Investigator Assign Exposures?



Observational study

Experimental study

Random allocation?

Comparison group?







Non-randomised controlledtrial

Randomised controlledtrial


Exposure and outcome atthe same time

Exposure Outcome

Exposure Outcome




Grimes and Schulz, Lancet, 359:57-61, 2002.

Hierarchy of evidence
Hierarchy of Evidence

Coherence of evidence from multiple sources

Systematic review of well-designed, large randomized trials

Strong evidence from one large randomized trial

Systematic review of small trials (e.g., surrogate outcome studies)

Systematic review of from well-designed cohort studies

Strong evidence from one cohort study

Unsystematic observations (expert opinions)

Adapted from Devereaux PJ et al, Evidence-Based Cardiology, 2nd Edition, BMJ Books, 2003.

Rating schemes for clinical guidelines
Rating Schemes for Clinical Guidelines

  • Quality of Evidence (as per previous slide)

  • Strength of Recommendation+

    • A: Strong

    • B: Moderate

    • C: Optional

+ from DHHS guidelines for the treatment of HIV

Types of clinical research in journals and press
Types of Clinical Research in Journals and Press

  • Fletcher and Fletcher (N Engl J Med 1979)

    • Review of articles published from 1946-1976

    • In 1976, 44% cross-sectional, 34% cohort studies, 5% randomized trials

    • “Predominant designs in 1976 were less accurate ways of conducting clinical research”.

  • Lai and Lane (PLoS One 2009)

    • Of 734 front-page stories 43% were presentations/abstracts

    • Of the journal articles reported, 3% were overviews of trials and 21% were randomized trials, 42% cohort studies and 31% expert opinions

Chance observations examples
Chance ObservationsExamples

  • Bleeding among children chewing gum containing aspirin to relieve the pain from tonsillectomies

    (Dr. Lawrence Craven) (see Dalen J, Arch Int Med 1991; 151:1066-1069)

  • Discovery of penicillin (Fleming) and digitalis (purple foxglove) (Withering)

Case histories or case report
Case Histories (or Case Report)

  • Most ancient and widely used method of clinical investigation

  • Most useful for disease with a specific etiologic agent

  • Standard for comparison is usually implicit

    The New England Journal of Medicine usually has a case described in each issue

Case series
Case Series

  • Def. – aggregation of individual cases in one report; the series may include all persons with an outcome or all persons with an exposure and outcome, e.g., an epidemic or spontaneously reported adverse events


  • No concurrent control

  • Usually inadequate information about persons not developing the disease

  • Cases may not be representative; persons with disease are survivors of unknown population

Example case series
Example: Case Series

Jaffe et al. Acquired immune deficiency syndrome in the United States: The first 1,000 cases. J Inf Dis 148:339-45, 1983.

Purpose: To describe characteristics of the cases.

Case definition
Case Definition

Eligibility Criteria:

1. Biopsy proven Kaposi sarcoma (KS) or

2. Biopsy, histology, or culture proven infection moderately predictive of cellular immune deficiency

a. Protozoal and helminthic infections, e.g., Pneumocystis carinii pneumonia (now Pneumocystis jiroveci and recognized to be a fungal disease)

b. Fungal infections, e.g., esophageal candidiasis

c. Bacterial infections, e.g., atypical mycobacterial disease

d. Viral infections, e.g., cytomegalovirus disease

Exclusion Criteria:

1. Previous immunosuppressive therapy

2. Illness associated with immunosuppression

3. Persons with KS over 60 years of age

4. Persons under 10 years of age


1. Review of selected cancer tumor registries

2. Contact with selected physicians in 18 communities

3. Review of request for pentamidine isethionate by CDC Parasitic Diseases Drug Service

4. Reports from individual physicians and state health departments


  • 727 cases were homosexual or bisexual males; of remaining cases 155 were IV drug users

  • 75% of homosexual men were from New York or California

  • 48% of cases were 30 - 39 years of age

  • There was an excess of KS among homosexual / bisexual men

  • Distribution of cases by risk group changed over time

Case series summary
Case Series Summary

  • A descriptive study, i.e., not designed to address a specific hypothesis or estimate absolute risk of an outcome.

  • Key feature: Clear, reproducible case definition with a focus on person, place and time

  • Addresses 5 “W” questions: who, what, why, when, and where

  • Often the 1st approach taken and the results are used to generate specific hypotheses

Other examples of case series pandemic influenza a h1n1v
Other Examples of Case Series: Pandemic Influenza A (H1N1v)

  • Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico (N Engl J Med 2009;361:680-689)

  • Critically ill patients with 2009 influenza A(H1N1) in Mexico (JAMA 2009; 302:1880-1887)

  • Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009 (N Engl J Med 2009;361:1935-1944)

  • Emergence of a novel swine-origin influenza A (H1N1) virus in China (N Engl J Med 2009;360:2605-2615)

Case series helped define cohort studies as below with specific hypotheses
Case Series Helped Define Cohort Studies as Below with Specific Hypotheses

  • INSIGHT H1N1v Outpatient Study

    • Characterize patients with influenza-like illness, influenza A and H1N1v

    • Identify risk factors for hospitalization within 14 days of diagnosis

  • INSIGHT H1N1v Hospitalization Study

    • Characterize patients hospitalized with influenza A and H1N1v

    • Identify risk factors for death within 60 days of admission

  • For both studies:

    • Molecularly characterize the virus

    • Establish a repository of serum to study biomarkers.

Dwyer D et al. Vaccine 2011;295:B56-B62.

Example uncontrolled trial of an intervention
Example: Specific Hypotheses Uncontrolled Trial of an Intervention

Moertel et al. A clinical trial of amygdalin (laetrile) in the treatment of human cancer. NEJM 306:201-6, 1982.

Purpose: To determine if laetrile was an effective and safe treatment for cancer.

Study preceded by retrospective analysis of laetrile users (estimated 70,000 people, 93 cases submitted, 67 with medical records, 6 “responders”). NEJM 299:549-552, 1978.

New laetrile study leaves cancer institute in the pits

“New Laetrile Study Leaves Cancer Institute in the Pits” Specific Hypotheses

Science, October 1978

Did investigator assign exposures1
Did Investigator Assign Exposures? Specific Hypotheses



Observational study

Experimental study

Random allocation?

Comparison group?







Non-randomised controlledtrial

Randomised controlledtrial


Exposure and outcome at the same time

Exposure Outcome

Exposure Outcome




Grimes and Schulz, Lancet, 359:57-61, 2002.

Pubh 7 420 clinical trials

Eligibility Criteria Specific Hypotheses

1. Histologically proven cancer

2. No surgery, radiation or chemotherapy in past month

3. Good general condition (able to eat and get about alone)

4. No known cure

5. Measurable tumors

Treatment: Naturally derived laetrile

  • 21-day intravenous schedule followed by oral dose

  • High doses of vitamins

  • Restricted diet

Pubh 7 420 clinical trials

Response Variables (Endpoints) Specific Hypotheses :

  • Tumor size

    • Regression

    • Stable

    • Progression

  • Weight

  • Performance status

  • Side effects

  • Mortality

Results Specific Hypotheses

179 patients entered; 178 followed

  • 1 partial responder

  • 54% with progression at end of IV schedule

  • All had progression after 7 months

  • Median survival: 4.8 months

Conclusion Specific Hypotheses

“It must be concluded that amygdalin (Laetrile) in combination with high doses of vitamins, pancreatic enzymes, and a diet of the type employed by ‘metabolic therapists’ is of no substantive value in the treatment of cancer. Further investigation of clinical use of such therapy is not justified.”

Important features of this study
Important Features of This Study Specific Hypotheses

  • Well-defined cases and treatment

  • Protocol for patient evaluation and analysis

  • Objective endpoints

  • Complete data with nearly all patients meeting evaluability criteria; and

  • The study was described in sufficient detail so that it could be replicated

Questions Specific Hypotheses :

1. What is the comparison group?

2. Are the inferences to all cancer patients justified since the study was restricted to “uncurable” cases?

3. Is it ethical to conduct a randomized controlled clinical trial of laetrile?

  • Then?

  • Now?

    4. Are uncontrolled studies reasonable alternatives to randomized clinical trials when the endpoint is objective?

Laetrile study
Laetrile Study Specific Hypotheses









* One patient was ineligible and

3 could not be evaluated

Remarks by commentators
Remarks by Commentators: Specific Hypotheses

“From a public health standpoint, it was unethical to conduct a clinical study that would supposedly test orthodox versus unorthodox treatments to resolve the laetrile controversy, but could not do so scientifically.”

“These conclusions are not justified … there was no control group with which the group of treated patients could be compared.”

Pubh 7 420 clinical trials

Special Situations When Uncontrolled Study May Be Appropriate

  • No other treatment to use as control

  • Untreated patients have very poor prognosis

  • Treatment not expected to have serious side effects

  • Potential benefit to patients large and unambiguous

  • Result of study likely to be widely accepted

  • Byar D, et al. NEJM, Vol 323, 1990.

Pubh 7 420 clinical trials

In the author’s response, they cited data from historical controls

  • Historical controls (def.) – a group of patients used for comparison that were diagnosed and treated for the disease of interest in the past.

  • Varying amounts of rigor are employed to define historical controls.

Disadvantages of historical controls
Disadvantages of Historical Controls controls

  • Comparability of controls and those given new treatment cannot be ensured.

  • May not be possible to reproduce inclusion/exclusion criteria or data when treatment follow-up begins (“time zero”).

  • Efficacy and safety outcomes may not be defined identically.

  • Concomitant treatments may vary (hopefully better now).

  • Outcomes may improve over time due to greater clinical experience.

  • Numbers of historical controls available may be small resulting in imprecise outcome rates.

Planned observational studies
Planned Observational Studies controls

1. Cross-Sectional – data collected at a single point in time (risk factors and disease endpoints measured simultaneously).

2. Case-Control - controls (non-cases) sampled from base population.

3. Prospective Follow-up (cohort) - controls (non-cases) not sampled; risk factor measurements made before endpoints occur.

Did investigator assign exposures2
Did Investigator Assign Exposures? controls



Observational study

Experimental study

Random allocation?

Comparison group?







Non-randomised controlledtrial

Randomised controlledtrial


Exposure and outcome at the same time

Exposure Outcome

Exposure Outcome




Grimes and Schulz, Lancet, 359:57-61, 2002.

Cross sectional study
Cross-Sectional Study controls

  • National Health and Nutrition Examination Survey (NHANES) – ongoing national survey conducted by the National Center for Health Statistics

    In 2007-2008 almost 17% of children and adolescents aged 2-19 years were obese

Pubh 7 420 clinical trials
Cross-Sectional Study controlsMRFIT: Association of left ventricular hypertrophy (LVH) by ECG and hypertensive status at baseline of trial














Prevalence of LVH among hypertensives =

231 / 8,012 = 2.9%

Prevalence of LVH among normotensives =

43 / 4,854 = 0.9%

Cross-sectional study + follow-up = cohort study.

Pubh 7 420 clinical trials

Cross-Sectional Study controlsAssociation of PCP and genderat baseline in trials and cohort studies carried out by the Community Programs for Clinical Research on AIDS (CPCRA)














History of PCP among men = 371 / 2,260 = 16.4%

History of PCP among women = 58 / 551 = 10.5%

P-value = 0.001 for difference

Cd4 percent distribution for men and women
CD4+ Percent Distribution for Men and Women controls





< 50 22 13 20

50 - 99 11 6 10

100 - 149 8 7 8

150 - 199 7 8 8

≥ 200 52 66 54

Total 100 100 100

Median 213 328 232

Interrelationship between gender cd4 count and pcp

Gender controls

(risk factor)






Interrelationship Between Gender, CD4+ Count, and PCP

Percent of patients with history of pcp according to cd4 count
Percent of Patients with History of PCP According to CD4+ Count

CD4+ (cells/mm3)

Percent with



< 50 561 43.3

50 - 99 272 27.6

100 - 149 226 15.5

150 - 199 212 8.5

≥ 200 1,541 3.8

Confounding Count

Confounder (def.)

  • A variable whose effect is entangled with the effect of other variables under study

  • A factor related to the disease endpoint being studied and to the risk factor being investigated

Modified question
Modified Question Count

To what extent do differences in the CD4+ distribution between men and women explain the difference (or lack of difference) in the prevalence of PCP between men and women?

Percent of patients with history of pcp by cd4 count and gender
Percent of Patients with History Countof PCP by CD4+ Count and Gender

Percent with PCP

< 50 43.9 39.4

50 - 99 28.9 18.2

100 - 149 16.1 12.5

150 - 199 10.7 0.0

≥ 200 3.3 5.2

Total 16.4 10.5




Unadjusted and cd4 adjusted percent with history of pcp by gender
Unadjusted and CD4+ Adjusted Percent with History of PCP by Gender

Unadjusted 16.4 10.5 0.001

CD4+ adjusted 15.6 13.5 0.22

(direct method)




Common problems with inferences from cross sectional surveys
Common Problems with Inferences from Cross-Sectional Surveys Gender

  • Chicken/egg dilemma (except for genetic factors)

  • By definition must consider prevalent cases rather than incident cases, thus data reflect determinants of death/recovery as well as etiology (Neyman bias or incidence-prevalence bias).

    Primary Utility: descriptive; hypothesis generation

Incidence and prevalence
Incidence and Prevalence Gender