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 Requirements Scientists 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 Requirements Authors 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) c with independent comparisons where c is the number of performed comparisons and SIGN the significance level (usually 0.05). c = 1 => OSIGN = 0.05 c = 2 => OSIGN = 0.10 c = 5 => OSIGN = 0.23 c = 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 the most clinically relevant evidence directly related to the primary objective of the trial Secondary Either measurements supporting the primary 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)
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-set FAS + 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 same conclusions, 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 be preserved 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 CONSORT Academic 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 Archives of Ophthalmology Archives of Otolaryngology Archives of Pathology and Laboratory Medicine Archives of Pediatrics & Adolescent Medicine Archives of Surgery Armenian Medical Review Journal Arthritis Research & Therapy Atencion Primaria Australia and New Zealand Health Policy Australian and New Zealand Journal of Surgery Bandolier Behavioral and Brain Functions BioMagnetic Research and Technology BioMed Central Biomedical Digital Libraries Biomedical Engineering Online BioPsychoSocial Medicine BMC Anesthesiology BMC Blood Disorders BMC Cardiovascular Disorders BMC Clinical Pathology BMC Clinical Pharmacology BMC Complementary and Alternative Medicine BMC Dermatology BMC Ear, Nose and Throat Disorders BMC Emergency Medicine BMC Endocrine Disorders BMC Family Practice BMC Gastroenterology BMC Geriatrics BMC Health Services Research BMC Infectious Diseases BMC International Health and Human Rights BMC Medical Education BMC Medical Ethics BMC Medical Genetics BMC Medical Imaging BMC Medical Informatics and Decision Making BMC Medical Research Methodology BMC Medicine BMC Musculoskeletal Disorders BMC Nephrology BMC Neurology BMC Nuclear Medicine BMC Nursing BMC Ophthalmology BMC Oral Health BMC Palliative Care BMC Pediatrics BMC Pregnancy and Childbirth BMC Psychiatry BMC Public Health BMC Pulmonary Medicine BMC Surgery BMC Urology BMJ Brazilian Journal of Cardiovascular Surgery Breast Cancer Research British Dental Journal British Journal of Dermatology British Journal of Obstetrics & Gynaecology British Journal of Ophthalmology British Journal of Surgery Canadian Journal of Anesthesia Canadian Journal of Emergency Medicine Canadian Journal of Infectious Diseases & Medical Microbiology Canadian Journal of Neurological Sciences Canadian Journal of Occupational Therapy Canadian Journal of Respiratory Therapy Canadian Medical Association Journal Cancer Cardiovascular Diabetology Cardiovascular Ultrasound Cell Division Cerebrospinal Fluid Research Chest Child and Adolescent Psychiatry and Mental Health Chinese Journal of Evidence-based Medicine Chinese Medical Journal Chinese Medicine Chiropractic & Osteopathy Circulation Climacteric Clinical and Molecular Allergy Clinical Cancer Research Clinical Chemistry Clinical Journal of the American Society of Nephrology Clinical Nutrition Clinical Oral Investigations Clinical Practice and Epidemiology Comparative Hepatology Conflict and Health Cost Effectiveness and Resource Allocation Cough Critical Care Croatian Medical Journal CytoJournal Diabetes Care Diagnostic Pathology Diseases of the Colon & Rectum Dynamic Medicine East African Medical Journal eHealth International Equine Veterinary Journal European Journal of Anaesthesiology European Journal of Cancer European Journal of Oral Sciences European Journal of Vascular and Endovascular Surgery Environmental Health Eye Foot (The) Gastroenterology Gujarat Medical Journal Genetic Vaccines and Therapy Globalization and Health Gut Harm Reduction Journal Health Psychology Head & Face Medicine Health and Quality of Life Outcomes Health Research Policy and Systems Heart Hepatobiliary & Pancreatic Diseases International Huisarts & Wetenschap Human Resources for Health Human Reproduction Immunome Research Implementation Science Indian Journal of Cancer Indian Journal of Critical Care Medicine Indian Journal of Dermatology Indian Journal of Dermatology, Venereology, and Leprology Indian Journal of Human Genetics Indian Journal of Medical Microbiology Indian Journal of Medical Sciences Indian Journal of Occupational and Environmental Medicine Indian Journal of Ophthalmology Indian Journal of Otolaryngology and Head and Neck Surgery Indian Journal of Palliative Care Indian Journal of Pharmacology Indian Pediatrics Indian Journal of Plastic Surgery Indian Journal of Surgery Infectious Agents and Cancer Intensive Care Medicine International Breastfeeding Journal International Endondontic Journal International Journal for Equity in Health International Journal of Clinical Oncology International Journal of Behavioral Nutrition and Physical Activity International Journal of Health Geographics International Journal of Mental Health Systems International Journal of Nursing Studies International Journal of Surgery International Seminars in Surgical Oncology International Urogynecology Journal and Pelvic Floor Dysfunction Japanese Journal of Clinical Oncology Journal of Advanced Nursing Journal of Alternative & Complementary Medicine Journal of Antimicrobial Chemotherapy Journal of Autoimmune Diseases Journal of Bone & Joint Surgery Journal of Cancer Research and Therapeutics Journal of Carcinogenesis Journal of Cardiothoracic Surgery Journal of Chinese Integrative Medicine Journal of Clinical Pathology Journal of Consulting and Clinical Psychology Journal of Endodontics Journal of Ethnobiology and Ethnomedicine Journal of Experimental & Clinical Assisted Reproduction Journal of Experimental & Clinical Cancer Research Journal of Family Planning & Reproductive Health Care Journal of General Internal Medicine Journal of Geriatric Care Journal of Hand Surgery (European Volume) Journal of Health Services Research and Policy Journal of Hepatology Journal of Immune Based Therapies and Vaccines Journal of Indian Association of Pediatric Surgeons Journal of Indian Society of Pedodontics and Preventive Dentistry Journal of Indian Prosthodontist Society Journal of Manipulative & Physiological Therapeutics Journal of Medical Internet Research Journal of Minimal Access Surgery Journal of Molecular Signaling Journal of Neurological Science (Turkey) Journal of NeuroEngineering and Rehabilitation Journal of Neuroinflammation Journal of Neurology, Neurosurgery & Psychiatry Journal of Nuclear Medicine Journal of Nutrition Journal of Occupational Medicine and Toxicology Journal of Orthodontics Journal of Orthopaedic Surgery and Research Journal of Pediatric Orthopaedics Journal of Pediatric Psychology Journal of Pediatric Surgery Journal of Pediatrics Journal of Postgraduate Medicine Journal of Speech, Language and Hearing Research Journal of the American Academy of Child & Adolescent Psychiatry Journal of the American College of Surgeons Journal of the American Geriatrics Society Journal of the American Medical Association Journal of the American Podiatric Medical Association Journal of the American Society of Nephrology Journal of the Canadian Chiropractic Association Journal of the Canadian Dental Association Journal of the International Society of Sports Nutrition Journal of the National Cancer Institute Journal of the Society of Laparoendoscopic Surgeons Journal of Thoracic and Cardiovascular Surgery Journal of Translational Medicine Journal of Traumatic Stress Kinetoplastid Biology and Disease Kuwait Medical Journal Lancet (The) Lancet Oncology (The) Language, Speech, and Hearing Services in Schools Lipids in Health and Disease Malawi Medical Journal Mayo Clinic Proceedings Medical Acupuncture Medical Immunology Medical Journal of Australia MIdentistry Molecular Pathology Movement Disorders National Medical Journal of India Nederlands Tijdschrift voor Geneeskunde Neurology Neurology and Urodynamics Neurology India Neuropsychology New England Journal of Medicine New Zealand Journal of Medical Laboratory Science Nordic Journal of Music Therapy Nursing Research Nutrition & Metabolism Nutrition Journal Obstetrics and Gynecology Oncologist (The) Onkologie Ophthalmic and Physilogical Optics Ophthalmology Osteopathic Medicine and Primary Care Orphanet Journal of Rare Diseases Pain Palliative Medicine Particle and Fibre Toxicology Pediatric Pulmonology Pediatric Rheumatology Pediatrics Physical Therapy Physical Therapy Reviews Phytomedicine PLoS Medicine PLoS Neglected Tropical Diseases PLoS ONE Population Health Metrics Psychopharmacology Bulletin Psychosomatic Medicine Radiation Oncology Radiotherapy & Oncology Rehabilitation Psychology Reproductive Biology and Endocrinology Reproductive Health Research in Nursing and Health Respiratory Research Resuscitation Revista Brasileira de Cirurgia Cardiovascular Revista Espanola de Allergol Immunol Clinica Revista Espanola de Salud Publica Revista Sanidad Militar de Mexico Rheumatology Rinsho Hyoka (Clinical Evaluation) Rural and Remote Health Journal Saline Systems São Paulo Medical Journal Scandinavian Journal of Gastroenterology Scoliosis Der Schmerz Sexually Transmitted Infections Spine Substance Abuse Treatment, Prevention, and Policy Theoretical Biology and Medical Modelling Thrombosis Journal Transfusion Trials Ugeskrift for Laeger Veterinary Journal (The) Virology Journal World Journal of Emergency Surgery World Journal of Surgical Oncology Zeitschrift für ärztliche Fortbildung und Qualitätssicherung