1

PubH 7420Clinical Trials

Instructor: Jim Neaton612-626-9040jim@ccbr.umn.edu2221 University Ave SE, Room 200

Text: Fundamentals of Clinical TrialsFriedman, Furberg, and DeMets

Evaluation: Homework: 3 exercises (15%)Group debates (5%)Protocol project (20%)Mid Term (30%)Final (30%)

Web Site: http://www.biostat.umn.edu/~ph7420

2

Books on Reserve

• Pocock: Clinical Trials. A Practical Approach.

• Meinert: Clinical Trials. Design, Conduct and and Analysis

Reading Room – 4th floor Mayo

3

TAs for PubH 7420

ChiHyun Lee – leex5865@umn.edu

Donald Musgrove – musgr007@umn.edu

Debashree Ray – rayxx267@umn.edu

4

Group Work: Protocol and Debate Topics

• Eight multidisciplinary groups, 7-8 members.

• Four protocol topics, 2 groups assigned to each.

• Eight debate topics; 2 groups will debate (each group twice)– 20 minute debate, 10 minutes per group (max of 7

slides per group)– Each side of the debate should be presented by 1

person. Pro side goes first. All group members are expected to participate (see calendar for schedule).

5

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.

6

Outline of Protocol

1. Background and rationale for study

2. Study design Objectives (primary, secondary, subgroup hypotheses)

Primary and secondary endpoints (efficacy and safety)

Inclusion and exclusion criteria

Treatments

Sample size

3. Data collection plan and follow-up schedule

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

7

Advice for Groups

• Elect a chairperson and rapporteur.

• Divide up the work among all group members.

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

• Plan to meet 6-7 times during the semester.

• Plan to have 1 member present the debate slides and 3 members present the protocol.

8

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 plannedconcurrentcomparisongroup

Yes

Did Investigator Assign Exposures?Yes

Randomised controlled

trial

Non-randomised controlled

trial

Yes No

No

Experimental study

Random allocation?

Observational study

Comparison group?

Analyticalstudy

No

Descriptivestudy

Direction?

Cohortstudy

Case-controlstudy

Cross-sectional

study

Exposure Outcome

Exposure andoutcome at

the same timeExposure Outcome

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

10

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.

11

Oxford Center for Evidence-Based Medicine Levels of Evidence+

Grade of Recommendation

Level of Evidence Type of Study

A 1a Systematic review (SR) (with homogeneity) of RCTs

1b Individual RCT with narrow confidence interval

1c All or none studies++

B 2a SR (with homogeneity) of cohort studies

2b Individual cohort study

2c Outcomes research, ecological studies

3a SR of case control studies

3b Individual case control study

C 4 Case/series case report, poor quality cohort or case-control studies

D 5 Expert opinion, or based on physiology, bench research, or “first principles”

+ www.cebm.net/index.aspx?o=1025++ e.g., all died before treatment became available and now some survive

12

Rating Schemes for Clinical Guidelines

• Quality of Evidence– I: One or more trials with clinical outcomes– II: One or more well-designed, non-randomized

trials or cohort studies with clinical outcomes– III: Expert opinion

• Strength of Recommendation+

– A: Strong– B: Moderate– C: Optional

+ from DHHS guidelines for the treatment of HIV http://www.aidsinfo.nih.gov/Guidelines

13

Rating Schemes Are Used in Guidelines for the Prevention and Treatment of Disease

• Guideline panels regularly, systematically develop statements to assist practitioners and to avoid inappropriate heath care variation

• Guidelines are used to develop performance measures and benchmarks for quality of care

14

A Review of American College of Cardiology/American Heart Association

(ACC/AHA) Guidelines

• 16 guidelines with an increasing number of recommendations over time

• 314/2711 were Level A (median = 11%)

• 1246/2711 were Level C or D (median = 48%)

A = multiple randomized trials or meta-analysis

C = case studies, standard of care or expert opinion

Tricoci P et. al. JAMA 2009; 301: 831-841

15

Recent Reports of Interest

• Updated guidelines for management of high blood pressure– JNC 8: JAMA, published online December 18,

2013 with 2 editorials– ASH: J Clin Hyper, published online December

17, 2014.– JNC 8 Minority View, published online January

14, 2014 in Ann Intern Med • Review of WHO expert guidelines

– “WHO recommendations are often strong based on low confidence in effect estimates”.

16

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

17

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)

18

Case Histories (or Case Report)

1. Most ancient and widely used method of clinical investigation

2. Most useful for disease with a specific etiologic agent

3. Standard for comparison is usually implicit

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

http://www.nejm.org/browse?category=clinicalcases

19

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

Weaknesses• 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

20

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.

21

22

Case DefinitionEligibility Criteria:1. Biopsy proven Kaposi sarcoma (KS) or2. Biopsy, histology, or culture proven infection moderately

predictive of cellular immune deficiencya. Protozoal and helminthic (parasitic worms) infections, e.g., Pneumocystis carinii pneumonia (now Pneumocystis jiroveci and recognized to be a fungal disease)b. Fungal infections, e.g., esophageal candidiasisc. Bacterial infections, e.g., atypical mycobacterial diseased. Viral infections, e.g., cytomegalovirus disease

Exclusion Criteria:1. Previous immunosuppressive therapy2. Illness associated with immunosuppression3. Persons with KS over 60 years of age4. Persons under 10 years of age

23

Surveillance

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

24

Results

• 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

25

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

26

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)

27

Case Series Helped Define Prospective Cohort Studies 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.

28

Example: 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.

29

“New Laetrile Study Leaves Cancer Institute in the Pits”

Science, October 1978

Yes

Did Investigator Assign Exposures?Yes

Randomised controlled

trial

Non-randomised controlled

trial

Yes No

No

Experimental study

Random allocation?

Observational study

Comparison group?

Analyticalstudy

No

Descriptivestudy

Direction?

Cohortstudy

Case-controlstudy

Cross-sectional

study

Exposure Outcome

Exposure andoutcome at

the same time

Exposure Outcome

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

31

Eligibility Criteria

1. Histologically proven cancer2. No surgery, radiation or chemotherapy in past

month3. Good general condition (able to eat and get

about alone)4. No known cure5. Measurable tumors

Treatment: Naturally derived laetrile

– 21-day intravenous schedule followed by oral dose

– High doses of vitamins– Restricted diet

32

Response Variables (Endpoints):

• Tumor size–Regression–Stable–Progression

• Weight

• Performance status

• Side effects

• Mortality

33

Results

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

34

Conclusion

“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.”

35

Important Features of This Study

• 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

36

Laetrile Study: What is the Comparison Group?

Laetrile

PartialResponse

NoResponse

1 174 175*

* One patient was ineligible and

3 could not be evaluated

37

Remarks by Commentators:

“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.”

38

Uncontrolled Trial of ART Interruption

Skiest DJ et al. JID 2007; 195:1426-1436.

Purpose: To determine safety of ART interruption.

39

Eligibility Criteria

1. CD4+ > 350 cells/mm3 before 1st ART and currently2. HIV RNA <55,000 copies/mL3. Combination ART for at least 6 months4. No prior AIDS events

Treatment: ART interruption (TI) with strong recommendation to resume when CD4+ declined to < 250 cells.

40

Outcomes:

• Symptomatic HIV, AIDS, death or CD4+ <250

• Changes in CD4+ and HIV RNA

• Signs, symptoms and laboratory abnormalities

41

Results

167 patients entered; 144 completed 96 weeks of follow-up

– 5 deaths

– 2 patients with AIDS events

– 2 with symptomatic (Category B) events

– 54 patients with death, AIDS, Cat B, or CD4+ <250

– 26 grade ¾ symptoms or lab abnormalities

42

Conclusion

“In summary, …TI was not associated with rapid disease progression. TI in selected patients could avoid drug toxicity…but this possibility must be weighed against concerns about infrequent adverse events.”

43

TI Study

TI

AIDS or DeathNo

AIDS or Death

7 160 167

44

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.

45

Planned Observational Studies

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.

Yes

Did Investigator Assign Exposures?Yes

Randomised controlled

trial

Non-randomised controlled

trial

Yes No

No

Experimental study

Random allocation?

Observational study

Comparison group?

Analyticalstudy

No

Descriptivestudy

Direction?

Cohortstudy

Case-controlstudy

Cross-sectional

study

Exposure Outcome

Exposure andoutcome at

the same time

Exposure Outcome

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

47

Cross-Sectional Study

• 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

http://www.cdc.gov/nchs/nhanes.htm

48

Cross-Sectional StudyMRFIT: Association of left ventricular hypertrophy (LVH)

by ECG and hypertensive status at baseline of trial

Hypertensive

LVH No LVH

231 7,781 8,012

Prevalence of LVH among hypertensives =

231 / 8,012 = 2.9%

Prevalence of LVH among normotensives =

43 / 4,854 = 0.9%

Normotensive 43 4,811 4,854

274 12,592 12,866

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

49

Cross-Sectional StudyAssociation of PCP and gender

at baseline in trials and cohort studies carried out by the Community Programs for Clinical Research on AIDS (CPCRA)

Men

PCP No PCP

371 1,189 2,260

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

Women 58 493 551

429 2,382 2,811

50

CD4+ Percent Distribution for Men and Women

CD4+ Total< 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

Men Women

51

Interrelationship Between Gender, CD4+ Count, and PCP

Gender(risk factor)

PCP(diseaseendpoint)

CD4+(confounder)

52

Percent of Patients with History of PCP According to CD4+ Count

CD4+ (cells/mm3) TotalPercent with

PCP< 50 561 43.3

50 - 99 272 27.6

100 - 149 226 15.5

150 - 199 212 8.5

≥ 200 1,541 3.8

53

Confounding

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

54

Modified Question

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?

55

Percent of Patients with Historyof PCP by CD4+ Count and Gender

< 50 43.9 39.450 - 99 28.9 18.2100 - 149 16.1 12.5150 - 199 10.7 0.0≥ 2003.3 5.2

Total 16.4 10.5

CD4+ Men WomenPercent with PCP

56

Unadjusted and CD4+ Adjusted Percent with History of PCP by Gender

Unadjusted16.4 10.5 0.001

CD4+ adjusted 15.6 13.5 0.22(direct method)

P-valueMen Women

57

Common Problems with Inferences from Cross-Sectional Surveys

• 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

58

Incidence and Prevalence

Incidence

Recovery/Death

Prevalence