Randomized Controlled Trials 随机临床试验 Xu Xiong, MD, DrPH School of Public Health and Tropical Medicine Tulane University

Why Do RCTs? Compare new drugs, treatment, medical and health care technology against the current clinical standard Evaluate the effectiveness of prevention Assess the usefulness of programs for screening and early detection of disease Evaluate the impact of new policies in health care and health care financing Make a causal inference

RCTs: Basic Study Design

RCTs The major distinctions between cohort studies and RCTs: Intervention (exposure) Randomization Group assignment is unknown to researcher and subject whenever possible - “blinding”

Identifying Study Participants Representative of the reference population. Population versus hospital-based. Depending on the nature of intervention, e.g., Vitamin E/C for preventing pre-eclampsia Preventing congenital syphilis in Africa Lecture 6

Old/Current Treatment The treatment, drug, existing behavior, health care system, or even a placebo that we use as a reference against the “new treatment”. For both ethical and practical reasons the old treatment should be the best currently available treatment.

Placebo Specifically - an inert substance that looks, tastes and smells like the agent being tested. Any alternate drug, treatment, behavior change that closely replicates the treatment of interest, so that the participants are unable to determine what treatment they are receiving (i.e. used to blind/mask participants). Placebo effect – any effect attributable to the expectation that the regimen (treatment) will have an effect (Last JM)

Randomization Assignment of an individual or group to a treatment arm/study group by a means of chance. Normally by use of a random number table, computer generated random number pattern or other random generator (coin, dice, etc.).

Primary Goal of Randomization Remove all subjective biases which may be introduced by investigators and participants Investigators can’t choose their favorite patients. Participants can’t choose the treatment they receive. Any differences in characteristics of the study groups at baseline should be purely due to chance, and chance alone.

Randomization does not always work Study Population 2000 1000 men, 1000 women Randomization 1000 1000 550 men, 450 women 450 men, 550 women Treatment Arm 1 Treatment Arm 2

Stratification Stratify the population by certain variables to help improve comparability of study arms/groups. Will guarantee comparability for the stratified variables within the study arms/groups

Stratification

Masking - Definition Last JM – “Procedures intended to keep participants in a study from knowing some facts or observations that might bias or influence their actions regarding the study”

Masking (Blinding) Three levels of masking Participants Allocaters/ Data collectors Investigators/Analysts Basic intention is to remove conscious or sub-conscious bias (prior opinion) on the part of participants or investigators.

Masking (Blinding) Participant Masking: Achieved through proper randomization and use of placebos. Investigator Blinding If both participant and investigator are masked, then the study is termed: “Double Blinded” Lecture 6

Phases of Clinical Trials - FDA Phase 1: Small studies to assess human safety Phase 2: Efficacy and safety Phase 3: Randomized controlled trials Phase 4: Post-marketing surveillance Phases Main article: Phases of clinical research Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population. Phase 1: Screening for safety Phase 2: Establishing the testing protocol Phase 3: Final testing Phase 4: Postapproval studies Clinical trials are conducted in phases. The trials at each phase have different purposes and help scientists answer different questions: In Phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In Phase 2 trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. In Phase 3 trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. In Phase 4 trials, postmarketing studies delineate additional information, including the drug's risks, benefits, and optimal use. Before pharmaceutical companies start clinical trials on a drug, they conduct extensive preclinical studies. Lecture 6

Generalizability The ultimate goal of any Randomized Controlled Trial is to generalize the results of a trial to the general/reference population. Must consider Internal Validity and External Validity

Problems and Issues relating to RCTs Ethics Non-participation Non-compliance Crossover Loss to follow-up Sample size Multicentered Collaborative Trials

Ethics in RCTs Is randomization ethical? Can truly “informed” consent be obtained? Under what circumstances can a trial be stopped prior to the original plan? (DSMB: Data and Safety Monitoring Board) Laws and regulations (HIPAA, …) Lecture 6

Non-Participation Selection of a study population may be limited/difficult. Try as hard as possible to get a population representative of reference population but also voluntary. Non-participation may limit the ability to even conduct a study. People who come in (or are willing) to participate in clinical trials are different from those who refuse. Lecture 6

Refusal to Participate

Non-Compliance After randomization, participants may overtly or covertly not take the assigned treatment. They “do not comply” with their allocation. Lecture 6

Non-Compliance The net effect of non-compliance on a controlled trial is a reduction in the differences seen between study groups. Compliance monitoring May be done by keeping track of treatments taken Biological testing for treatment evidence

Loss to Follow-up Complete loss of contact, either through personal movement or death, that results in a participant not being able to be fully followed or treated. Must be assessed to ensure generalizability High loss to follow-up may indicate a poor study

What do you do with the non-compliers, etc.?

Sample Size Estimates

Example: Sample Size Calculation for RCTs Lecture 6

Single Institution vs. Multiple Site Collaborative Controlled Trials Multi-center trials can be beneficial when: Generalization is important Limited number of patients are available from a single clinic We wish to bring together expertise However, multi-center trials add a significant amount of overhead to a study.

Registration of Clinical Trials http://www.clinicaltrials.gov/ http://www.who.int/ictrp/en/ https://www.clinicaltrialsregister.eu/index.html Lecture 6

Data Collection in RCTs Prognostic profile at entry Treatment Outcome Criteria for outcome, data management, and acquisition must explicit and written out.

Data Collection – Treatment Data Assigned: The treatment arm/group that the subject was allocated to (placebo or active). Treatment A, Treatment B, or Treatment C Received: The actual treatment that the participant received. During the study, the investigators must assess compliance to the treatment Interview/ specimen collection

Outcome Data Look for “improvement”, i.e. the desired effect Also must record any and all “side effects” Beneficial Harmful SAEs (severe adverse events)

Intention To Treat (ITT) What do you do with the non-compliers, etc.? Intention to Treat analysis (ITT) – “All patients allocated to each arm of treatment regimen are analyzed together “as intended” upon randomization, whether or not they actually received or completed the prescribed regimen. Failure to follow this step defeats the main purpose and advantage of random allocation and can cause serious bias.” –A Dictionary of Epidemiology, 5th Edition Lecture 6

Intention to Treat The validity of a randomized controlled trial depends greatly on the process of randomization. Randomization insures that both measurable and immeasurable factors will balance out on average. If a factor other than the treatment itself could possibly influence an outcome measure in your study, then randomization provides the best possible insurance that patients with this factor are equally likely to receive either one treatment or the other. This prevents many types of bias that can occur in a non-randomized trial. Lecture 6

Results of RCTs Risk of incident event/death Relative Risk (the same as cohort studies) Efficacy Number of patients who need to be treated (NNT) Survival curves/Cumulative incidence Lecture 6

Results of RCTs Efficacy = Relative risk reduction A measure of the reduction in risk attributable to the treatment of interest. = % e.g., if RR = 0.7? Lecture 14

Question about efficacy In RCTs, we only study factors that may be beneficial (not harmful) Therefore, in calculating efficacy, we will be talking about a risk reduction (i.e., RR<1) If it turns out the incidence is higher in the treatment group then we stop the study and the efficacy is considered 0.

Results of RCTs Number of patients who need to be treated (NNT) to prevent one event Assesses the impact on medical practice of the investigated treatment.

Results of RCTs The incidence in the non-treatment group is 10 % The incidence in the treatment group is 7 % 1 1 NNT = = = 33.3 Cost-effectiveness analysis: cost, side effects, etc. 0.10 – 0.07 0.03 In order to prevent one event, we need to treat 33 patients. Lecture 6

Survival Curves Apply to the RCTs with long-term follow-up (loss to follow-up). Lecture 6

Estrogen/Progestin and Heart Disease Nurses Health Study: a prospective cohort study N=59,337; follow-up period: up to 16 years Grodstein et al. NEJM 1996

Age-Standardized Baseline Characteristics of Participants in the Nurses’ Health Study in 1990 AGE-STANDARDIZED DISTRIBUTION OF CHARACTERISTICS OF WOMEN PARTICIPATING IN THE NURSES’ HEALTH STUDY IN 1990, ACCORDING TO THE USE OR NONUSE OF POSTMENOPAUSAL HORMONES . Grodstein et al. NEJM 1996 Lecture 6

Why Women’s Health Initiative (a RCT)? Observational evidence Hard evidence lacking Political reasons Lecture 6

Flow Chart of Women’s Health Initiative WHI. JAMA 2002

Baseline Characteristics Grodstein et al. NEJM 1996

Estrogen plus Progestin and CHD and Stroke WHI. JAMA 2002

Estrogen plus Progestin and Colorectal Cancer and Hip Fracture WHI. JAMA 2002

RCT – GOLD STANDARD The randomized controlled trial is an experiment. Provides the strongest evidence for inferring causality compared to observational studies. Must be wary of poorly conducted studies.

Summary Study designs Uses Randomization Blinding ITT NNT