Randomised Clinical Trials

Randomised trials are special

- Ethics (HD)- Statistics (special methodology)- Scientific evidence (basis for highest level of evidence)- Authorities (required for marketing of drugs & devices)- Reporting (CONSORT)- Publishing (public registration and other requirements)- Performance (guidelines & requirements)- Expensive- Professional

International regulatory guidelines

ICH Topic E9 - Statistical Principles for Clinical Trials

EMEA Points to consider: baseline covariates- missing data- multiplicity issues- etc.

and similar documents from the FDA

These guidelines can all be found on the internet.

Uniform Requirements

“When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).”

Uniform Requirements

“The ICMJE member journals will require, as a condition of consideration for publication in their journals, registration in a public trials registry.”

“The ICMJE recommends that journals publish the trial registration number at the end of the Abstract.”

Uniform RequirementsScientists have an ethical obligation to submit creditable research results for publication. Moreover, as the persons directly responsible for their work, researchers should not enter into agreements that interfere with their access to the data and their ability to analyze them independently, and to prepare and publish manuscripts.

Uniform RequirementsAuthors should identify individuals who provide writing or other assistance and disclose the funding source for this assistance.

Editors should ask corresponding authors to declare whether they had assistance with study design, data collection, data analysis, or manuscript preparation. If such assistance was available, the authors should disclose the identity of the individuals who provided this assistance and the entity that supported it in the published article.

Uniform Requirements

“As you may know, US Public Law 110-85, Title VIII, mandates the submission of “basic results” data for certain clinical trials of drugs, biologics, and devices, effective September 27, 2008. The law applies to trials that are not Phase 1 or small device feasibility studies, and that have at least one site in the US, regardless of who sponsors, finances, or conducts the trial. Certain other trials may also be covered by the law. In general, these summary results data must be submitted within 12 months of the completion of data collection for the primary outcome measure.”

Let's now focus on methodological aspects

1 Precison

2 Validity

Induction Deduction(observational studies) (Randomized trials)

1. Data 1. Hypothesis

2. Pattern 2. Data

3. Statistical test 3. Statistical test

4. Hypothesis 4. Confirmation

Induction Deduction(observational studies) (Randomized trials)

1. Data 1. Hypothesis

2. Pattern 2. Data

3. Statistical test 3. Statistical test

4. Hypothesis 4. Confirmation

Multiplicity issues

Uncertainty of sampling

Assume that the cumulative 10-year revision rate of the Oxford knee prosthesis is 8%

Patients with knee prostheses

Not revised

Revised

375 randomly ordered patients of which 30 (8%) are revised within 10 years

6% revised

12% revised

Sampling uncertainty

6% revised

12% revised

Sampling uncertainty is evaluated using probability theory with a specified type-1 error rate (each comparison has 5% error chance).

Multiplicity

The overall significance level (OSIGN) or chance of at least one false positive finding

OSIGN = 1 - (1 – SIGN)cwith independent comparisons

where c is the number of performed comparisons and SIGN the significance level (usually 0.05).

c = 1 => OSIGN = 0.05c = 2 => OSIGN = 0.10c = 5 => OSIGN = 0.23c = 10 => OSIGN = 0.40

Example 1. OSIGN = 0.10

Example 2. OSIGN = 0.23

Example 3. OSIGN = 0.40

Example 4. OSIGN = 0.999

How to deal with multiplicity

1. Avoid multiplicity adjustments is possible

2. Use “intelligent design “

“Intelligent design”

1. Distinguish between confirmatory and exploratory analyses.

2. Distinguish between primary and secondary endpoints.

3. Define the primary endpoint in such a way that it consists of only one confirmatory analysis.

Endpoints

Primary The variable capable of providing themost clinically relevant evidencedirectly related to the primary objectiveof the trial

Secondary Either measurements supporting theprimary endpoint or effects related to

secondary objectives

1 Precison

2 Validity

Internal vs. external validity

Internal validity

- no confounding bias- no selection bias- no misclassification bias (at least no differential)

External validity

- representative (inclusion/exclusion criteria)

Internal vs. external validity

Internally valid

- efficacy

Externally valid

- effectiveness

Study populations

Intention-to-treat Analyse all randomised subjects(ITT) principle according to planned treatment

regimen.

Full analysis set The set of subjects that is as close(FAS) as possible to the ideal implied by

the ITT-principle.

Per protocol The set of subjects who complied(PP) set with the protocol sufficiently to ensure

that they are likely to exhibit the effects of treatment according to the

underlying scientific model.

FAS vs. PP-setFAS + no selection bias

- misclassification problem (effect dilution)

PP-set + no contamination problem- possible selection bias (confounding)

When the FAS and PP-set lead to essentially the sameconclusions, confidence in the trial is supported.

Study protocol and SAP

Study protocol

- written prior to randomization- specifies primary endpoint in detail- describes how bias will be avoided

and how the type-1 error rate will bepreserved

SAP (Statistical Analysis Plan)

- written prior to code breaking- detailed description of statistical analyses

Primary endpoint

Very often vague or inexplicit like: - “quality of life” or- “hand strength”

Should be

“quality of life as measured by SF-36 PCS at 6 weeks of follow up”, or

“strength in the dominant hand measured using one reading of the Smedley hand dynamometer at two weeks of follow up”.

With manuscripts reporting trials

Include study protocol and statistical analysis plan

- Check endpoint(s)

- Sample size

- Analysis techniques

Journals endorsing CONSORTAcademic Emergency Medicine Acta Neurologica Scandinavia Advances in Neonatal Care African Journal of Medicine AIDS AIDS Research and Therapy Alcohol and Alcoholism Alternative Therapies in Health and Medicine American Journal of Audiology American Journal of Kidney Diseases American Journal of Occupational Therapy American Journal of Speech Language Pathology Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders Anesthesiology Annals of Behavioral Medicine Annals of Clinical Microbiology and Antimicrobials Annals of Emergency Medicine Annals of Family Medicine Annals of General Psychiatry Annals of Internal Medicine Annals of Neurology Annals of Oncology Annals of Rheumatic Diseases Annals of Surgical Innovation and Research Annals of Thoracic Surgery Archives of Dermatology Archives of Disease in Childhood Archives of Facial Plastic Surgery Archives of Family Medicine Archives of General Psychiatry Archives of Internal Medicine Archives of Neurology 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