Clinical Trials and Drug Approval

Clinical Trial Phases

• Progress to the next phase of a clinical trial depends on positive results from the previous phase and meeting the trial's endpoint.

Drug Approval Process

• Health Canada and the FDA approve drugs for their intended use in the intended patient population, primarily relying on Phase 3 clinical trial data.
• Risk decisions involve determining what level of safety is adequate for a population or an individual.
• The preclinical testing stage takes approximately 6.5 years and involves laboratory and animal studies to assess safety and biological activity, with about 5,000 compounds evaluated.
• Phase I trials take around 1.5 years, involving 20-100 healthy volunteers to determine safety and dosage, after filing an Investigational New Drug (IND) application with the FDA.
• Phase II trials last about 2 years, with 100-500 patient volunteers, evaluating effectiveness and looking for side effects, based on about 5 trials.
• Phase III trials take 3.5 years, involving 1,000-5,000 patient volunteers to confirm effectiveness and monitor adverse reactions from long-term use.
• FDA review and approval takes 1.5 years after filing a New Drug Application (NDA); resulting in approximately 1 approved drug.
• Health Canada evaluates the safety, efficacy, and quality of data, and assesses the potential benefits and risks of the drug.
• If approved, a drug is issued a Notice of Compliance and a Drug Identification Number (DIN), officially approving it for use in Canada.
• If denied, the sponsor can supply additional information, re-submit with more data, or appeal the decision.

Activism and Drug Approval

• Public pressure affects the drug development process.
• The HIV epidemic in the 1980s led to patient frustration that fueled activism concerning slow research and treatment.
• The FDA, according to a 1988 presidential report, was not adequately meeting the needs of people with AIDS.
• ACT UP (AIDS Coalition To Unleash Power) closed down the FDA outside of Washington, D.C., resulting in approximately 180 arrests.
• AIDS activists demanded a shortened drug approval process and immediate free access to drugs proven safe after Phase 1 trials.
• Activists wanted an end to double-blind placebo trials for life-threatening illnesses.
• Activists also wanted clinical trials to include all affected populations (women, people of color, children, poor people, IV drug users, hemophiliacs, and gay men).
• Eight days after the ACT-UP demonstration, the FDA announced new regulations to accelerate drug approval for AIDS treatment.
• Community groups became involved in research, and hurdles to clinical testing were eased.
• February 1989: The FDA approved a drug for AIDS-related pneumonia.
• August 1989: AZT clinical results demonstrated the slowing of AIDS progression in HIV-positive individuals.
• October 1989: A second drug was made available even though clinical trials were not complete.
• April 1993: 15 pharmaceutical organizations formed a coalition to speed the development of HIV antiviral drugs.
• The FDA and Health Canada have fast-track drug approval pathways as a result of activist actions.
• Toronto activists created AIDS Action Now! and conducted "Die-ins" at major Toronto intersections.
• Emergency Drug Access program for access to drugs not yet approved in Canada and Trillium Drug Program for drug access to low-income individuals resulted from activism.
• Canada has a Priority Review Process for faster review of drugs for life-threatening or severe conditions, especially if there are few effective drugs on the market.

Phase IV and Drug Recalls

• Phase IV clinical trials are conducted after drug approval, related to the approved indication, and may involve thousands of people.
• They provide post-market evaluation in a "real-world" setting and identify less common side effects.
• These studies look at safety over time, quality of life, and cost-effectiveness.
• Pre-market studies involve thousands of patients to demonstrate efficacy and provide risk-benefit information.
• Populations evaluated in premarket trials are restricted (e.g., excluding young/old, mild/severe conditions, co-morbidities, pregnant/lactating women, and diverse ethnicities).
• FDA can recall drugs because of manufacturing issues/purity concerns, mild side effects, and major side effects.
• A drug can be recalled even after being on the market for many years.

Emergency Use Authorization (EUA)

• During an emergency, an EUA increases the accessibility of an unapproved medication or vaccine, or of an approved medication for unapproved uses.
• An EUA is not the same as full FDA approval.
• Manufacturers with EUAs continue their clinical trials.

Off-Label Use of Medications

• Prescribing a drug inconsistently with the approved label (e.g., for a different condition, population, dosage, frequency, duration, or route).
• This differs from experimental use as part of a trial.
• Common in oncology, pediatrics, and with the elderly.
• Approximately 40%-60% of prescriptions in the U.S. are for off-label use.

Approved Drug

• On January 30, 2025, the FDA approved suzetrigine as a new, first-in-class, non-opioid pain drug for acute pain after minor surgery.
• Suzetrigine acts on the nerves, not the brain, targeting channel proteins. Clinical trials involving ~900 people showed side effects of itching, rash, and kidney and muscle spasms.
• FDA designations for suzetrigine included Fast Track, Breakthrough Therapy, and Priority Review.