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 guidelinesICH Topic E9 - Statistical Principles for Clinical TrialsEMEA Points to consider: baseline covariates - missing data - multiplicity issues - etc.and similar documents from the FDAThese guidelines can all be found on the internet.
Uniform Requirements“When reporting experiments on human subjects,authors should indicate whether the proceduresfollowed were in accordance with the ethical standardsof the responsible committee on humanexperimentation (institutional and national) and with theHelsinki Declaration of 1975, as revised in 2000 (5).”
Uniform Requirements“The ICMJE member journals will require, as acondition of consideration for publication in theirjournals, registration in a public trials registry.”“The ICMJE recommends that journals publish thetrial registration number at the end of the Abstract.”
Uniform RequirementsScientists have an ethical obligation to submitcreditable research results for publication. Moreover,as the persons directly responsible for their work,researchers should not enter into agreements thatinterfere with their access to the data and their ability toanalyze them independently, and to prepare andpublish manuscripts.
Uniform RequirementsAuthors should identify individuals who providewriting or other assistance and disclose the fundingsource for this assistance.Editors should ask corresponding authors to declarewhether they had assistance with study design, datacollection, data analysis, or manuscript preparation.If such assistance was available, the authors shoulddisclose the identity of the individuals who providedthis assistance and the entity that supported it in thepublished article.
Uniform Requirements“As you may know, US Public Law 110-85, Title VIII,mandates the submission of “basic results” data forcertain clinical trials of drugs, biologics, and devices,effective September 27, 2008. The law applies to trialsthat are not Phase 1 or small device feasibility studies,and that have at least one site in the US, regardless ofwho sponsors, finances, or conducts the trial. Certainother trials may also be covered by the law. In general,these summary results data must be submitted within 12months of the completion of data collection for the primaryoutcome measure.”
How to deal with multiplicity1. Avoid multiplicity adjustments is possible2. 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.
EndpointsPrimary The variable capable of providing the most clinically relevant evidence directly related to the primary objective of the trialSecondary Either measurements supporting the primary endpoint or effects related to secondary objectives
Internal vs. external validityInternal validity - no confounding bias - no selection bias - no misclassification bias (at least no differential)External validity - representative (inclusion/exclusion criteria)
Study populationsIntention-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- written prior to randomization- specifies primary endpoint in detail- describes how bias will be avoided and how the type-1 error rate will be preservedSAP (Statistical Analysis Plan)- written prior to code breaking- detailed description of statistical analyses
Primary endpointVery often vague or inexplicit like: - “quality of life” or - “hand strength”Should be“quality of life as measured by SF-36 PCS at 6weeks of follow up”, or“strength in the dominant hand measured usingone reading of the Smedley hand dynamometerat two weeks of follow up”.
With manuscripts reporting trialsInclude 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 inHealth and Medicine American Journal of Audiology American Journal of Kidney Diseases American Journal of Occupational Therapy American Journal of Speech Language Pathology Amyotrophic LateralSclerosis and Other Motor Neuron Disorders Anesthesiology Annals of Behavioral Medicine Annals of Clinical Microbiology and Antimicrobials Annals of Emergency Medicine Annals of Family MedicineAnnals 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 SurgeryArchives 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 ofNeurology 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