Clinical Trials

Who conducted the first controlled clinical trial and what was it for?

Dr. James Lind in 1747; he tested 6 treatments for scurvy on 12 patients aboard HMS Salisbury and found oranges and lemons to be most effective

What was the significance of Ambroise Paré's 1537 experiment?

It was the first clinical trial of a novel therapy; he compared boiling oil vs. a mixture of egg yolks, rose oil, and turpentine for treating battle wounds

Who introduced the placebo in drug trials and when?

US physician Austin Flint in 1863; he used a dummy placebo remedy to treat 13 rheumatism patients and compared results to known active treatments

What was the first properly randomized double-blind placebo-controlled trial?

The 1948 Streptomycin trial for pulmonary tuberculosis

What disaster led to the Federal Food, Drug and Cosmetic Act of 1938?

The Sulfanilamide Disaster of 1937, where over 100 people died after the drug was dissolved in diethylene glycol (a toxic solvent)

What is the Nuremberg Code and what triggered it?

A set of 10 ethical principles for human experimentation, enacted in 1947 following the revelation of Nazi war crimes and inhumane medical experiments during WWII

Name two key principles highlighted by the Nuremberg Code

Voluntary consent and the right to stop participation

What drug caused over 10,000 birth defects including phocomelia and when was it withdrawn?

Thalidomide; withdrawn from the European market in 1961

What three regulatory outcomes followed the Thalidomide tragedy?

Committee on Safety of Drugs (1963), Medicines Act (1968), and Declaration of Helsinki

What was the Tuskegee Syphilis Experiment?

A 1932–1972 study where Black American men with syphilis were observed without treatment or informed consent, even after penicillin became available

What are the 3 core principles of the Belmont Report?

Respect for persons, Beneficence, and Justice

What are the 3 primary applications of the Belmont Report principles?

Informed consent, assessment of risks and benefits, and selection of subjects

Define a clinical trial

A prospective study comparing the effects and value of intervention(s) against a control in human beings

What is an Investigational Medicinal Product (IMP)?

Any drug or micronutrient examined in a clinical trial with the specific purpose of treating, preventing, or diagnosing disease

What is the ideal form of a clinical trial?

Randomized and double-blind

What are the 7 goals of clinical trials?

Treatment, prevention, screening/early detection, diagnosis, prognosis, genetics, and quality of life/supportive care

What is Phase 0 / Microdosing?

First-in-human studies using sub-pharmacological doses (less than 1/100 of active dose, max 100 micrograms) to obtain early pharmacokinetic data

What is the central concept behind microdosing?

"The best model for man is man" — human data is obtained directly rather than extrapolated from animals

How many subjects participate in a Phase 0 study?

10–15 subjects

What is the primary objective of Phase 0 studies?

To obtain preliminary pharmacokinetic data without therapeutic intent

What type of subjects are used in Phase I trials?

15–30 healthy volunteers; patients are used for cytotoxic/anticancer drugs

What is the duration of a Phase I trial?

6–12 months

What does Phase I assess?

Safety, tolerability, pharmacokinetics (primary); pharmacodynamics (secondary)

Define Maximum Tolerated Dose (MTD)

The highest dose of a drug that can be administered before unacceptable toxicity (dose-limiting toxicity) is experienced

How is MTD determined in Phase I?

Dose escalation starting from a low dose; typically 3 patients per dose level; escalation stops when unacceptable toxicity occurs in patients

What is dose-limiting toxicity (DLT)?

The level of toxicity that is unacceptable and determines the upper limit of dosing in Phase I trials

What is Phase II and who participates?

Therapeutic exploratory trial; 50–300 patients who have the disease; tests efficacy and safety

What is the primary objective of Phase II?

To assess drug efficacy in patients; secondary objective is safety

What is the therapeutic window?

The range of drug concentrations that produce a therapeutic response without significant adverse effects

What are Phase III trials?

Large-scale, multicenter, randomized controlled trials (hundreds to 3,000+ patients) to confirm efficacy and safety over up to 5 years

What is Phase IV?

Post-marketing surveillance (PMS) conducted after drug approval to monitor long-term safety and detect rare adverse effects

Give an example of a drug withdrawn after Phase IV findings

Rofecoxib (Vioxx) was withdrawn by Merck on September 30, 2004 due to increased risk of heart attack and stroke with long-term use

What is a parallel design?

A trial design where patients are randomly assigned to one treatment group only and groups run simultaneously

What is a crossover design?

A design where each patient receives both treatments in sequence (AB or BA), with each patient serving as their own control

What is the washout period in a crossover design?

A gap between treatments to eliminate carryover effects from the first treatment before starting the second

Name two diseases suited for crossover design

Asthma and hypertension (chronic, stable conditions with short-term treatment effects)

What is group allocation/cluster randomization?

A design where whole groups (villages, clinics, schools) are randomized instead of individuals

What is a factorial design?

A design that tests two interventions simultaneously; assumes treatments do not interact and have independent modes of action

Give an example of a factorial design trial

ISIS-3 (International Study of Infarct Survival–3): tested 3 fibrinolytics vs. 2 antithrombotic regimens in 41,299 patients

What is a large simple design?

A trial with very large patient numbers, broad eligibility criteria, and minimal data collection to detect modest treatment benefits

What is an equivalence design?

A trial designed to show that a new treatment is equally effective as the existing standard treatment

What is a non-inferiority design?

A trial designed to show that a new treatment is not worse than an established treatment by more than a defined margin

What is a superiority trial?

A trial designed to show that a new intervention is better than the control/existing treatment

What is an adaptive design?

A trial design that allows pre-specified modifications (e.g., sample size, dose, population) based on interim data collected during the study

What must be true for adaptations in adaptive trial designs?

All adaptations must be pre-specified in the protocol before the trial begins; IRB approval must include the adaptation plan

Name two advantages of adaptive designs

Greater flexibility and potentially shorter duration/fewer patients needed

Name two limitations of adaptive designs

Difficult to explain/interpret results and may be hard to implement due to need for quick data access

What is the IND Application?

Investigational New Drug Application submitted to the FDA or EMA requesting approval to begin testing a drug in humans after preclinical studies

What are the phases of clinical trials in order and their focus?

Phase 0: target hitting/PK; Phase I: dose/safety; Phase II: efficacy and safety; Phase III: clinical outcome; Phase IV: long-term post-marketing outcome