PPHC 12: Drugs – How do drugs go from molecule to market? Flashcards
(32 cards)
What are the 4 hurdles of drug approval?
- quality – phase I-III trials
- safety – phase I-III trials
- efficacy – phase I-III trials
- value – phase IV trials
Regulatory Approval Process
How is value assessed?
phase IV trials
- effectiveness in real world, cost-effectiveness
- health technology assessment – consider: epidemiology (evidence-effectiveness), health economics (cost-effectiveness), other considerations
List the different parts of the regulatory approval process.
pre-market:
- drug discovery
- pre-clinical – find something new
- clinical trials – phase I (safety and dosage), phase II (efficacy and dosing), phase III (confirm efficacy and safety)
- approval – can it be sold in Canada
post-market:
- CDA submission – does it look good value in Canada (CDR/DEC review, HTA)
- provincial submission – should we provide it (HTA)
- formulary listing – can we get a better price (pCPA negotiation), can we avoid being exploited (PMPRB review)
- phase IV/post-market surveillance clinical trial – long-term safety monitoring
(outcome: patent expiry, generic/biosimilar entry)
Regulatory Approval Process – Pre-market
Drug Discovery
at this stage, want to protect these discoveries
- file patents (grants exclusivity)
Regulatory Approval Process – Pre-market
Clinical Trials
phase I-III
Regulatory Approval Process – Pre-market
What is the phase I clinical trial?
safety and dosage – is it safe
- first in human – ~20-100 volunteers who do not necessarily have the disease/condition
- open label, uncontrolled
- safety – potential risks, side effects, safe dosing range
- tolerability/dosing range – balancing intended effects with minimal side effects
- pharmacokinetics and pharmacodynamics – how drug is absorbed, distributed, metabolized, and excreted into the body, biological effects
Regulatory Approval Process – Pre-market
What is the phase II clinical trial?
efficacy and dosing – does it work
- very strict inclusion criteria for participants – ~30-300 patients who have the disease or condition
- further evidence on efficacy, optimal dosing and safety
- efficacy – does it work on important outcomes compared with placebo or another standard treatment
- dose optimization – balancing efficacy and tolerability (inform design on phase III trials)
- safety – looking for side effects in a larger group of people (identify rarer side effects)
- therapeutic exploratory – evidence of efficacy for a particular indication
Regulatory Approval Process – Pre-market
What is the phase III clinical trial?
confirm efficacy, safety – is it better than what we have
- larger number and diversity of participants – ~300+ patients, often in multiple sites/countries
- compare safety and efficacy against the current standard of treatment
- confirming efficacy – drug works in this population, statistically significant benefits
- comparative analysis – is it better than existing treatment or placebo
- likely to have randomization and blinding
- expensive and time-consuming – last step before applying to regulatory agencies (ie. Health Canada)
Regulatory Approval Process – Pre-market
Approval
Health Canada submission
- result is 1 drug with NOC
Regulatory Approval Process – Post-market
CDA Submission
CDR/CDEC review
Regulatory Approval Process – Post-market
Provincial Submission
Drug Benefit Council (DBC)
- review after evaluation by CDA/CADTH CDR – supported by the CDA reviews/recommendation
- possibly include individual components (ie. ethics, environment)
- recommendations (to the Leadership Council in the Provincial Ministry of Health): list, list but not at listed price, do not list
- consistency across hospitals – General Hospital Formulary
Regulatory Approval Process – Post-market
Formulary Listing
pCPA negotiation, PMPRB review
- list of prescription drugs covered by a health insurance plan
Regulatory Approval Process – Post-market
What is the phase IV / post-market surveillance clinical trial?
long-term safety monitoring – are there any unexpected safety effects in the real world
- primary goal is to assess the drug’s long-term safety and effectiveness in the general population
- long-term and rare/delayed safety signals – rare but serious adverse events, chronic toxicity
- effectiveness in real-world setting (vs. efficacy established in phase II): use in special groups (ie. children, pregnancy, elderly), potential uses in new indications
- open-label, non-randomized, no eligibility restrictions – not for all treatments
- may include thousands of people for long periods of time
Regulatory Approval Process – Post-market
Patent Expiry
Generic/Biosimilar Entry
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What is the order of the government/provincial bodies in the regulatory approval process?
- Health Canada
- Canada’s Drug Agency (CDA)
- pan-Canadian pharmaceutical alliance (pCPA)
- patented medicine prices review board (PMPRB)
What is the purpose of Health Canada?
notice of compliance (NOC)
- can the drug legally be sold in Canada (quality, safety, efficacy)
Health Canada
What is the goal of Health Canada in drug approval?
Notice of Compliance (NOC)
- confirmation a drug meets regulatory standards of safety, efficacy, and quality
- means that drugs can become commercially available (can legally be marketed and sold in Canada) for a specific indication (but opens up to off-label use)
- product is entered onto the Drug Product Database
Health Canada
What does the Therapeutics Products Directorate do?
- looks at evidence of pivotal trials (usually at least 4–5)
- need to be convinced that benefits outweigh risk
What is the purpose of Canada’s Drug Agency (CDA)?
common drug review (CDR)
- does the drug look good value for formularly listing by the provinces
Canada’s Drug Agency (CDA)
What does the CDA do?
assessment of (commercially available) drugs (procedures, devices):
- effectiveness
- value for money (reasonable cost) – clinical, economic, patient and clinician evidence
- equitable use
Canada’s Drug Agency (CDA)
What is the audience?
- federal/provincial/territorial drug plans
- provincial cancer agencies
- Canadian Blood Services
- hospital
- private payers
Who conducts a common drug review (CDR)?
Canada’s Drug Agency (CDA)
Canada’s Drug Agency (CDA)
What is the common drug review (CDR)?
purpose is to assess the effectiveness and cost-effectiveness of new drugs for public drug plans
- triggered by manufacturer
- pan-Canadian process for conducting objective, rigorous reviews of the clinical, cost-effectiveness, and patient evidence for drugs
- provides formulary listing recommendations to Canada’s publicly funded drug plans (except Quebec)
Canada’s Drug Agency (CDA)
What are the objectives of the common drug review (CDR)?
- reduce duplication of reviews by jurisdictions
- provide equal access to timely, evidence-based information and expert advice
- consolidate the submission filing process for pharmaceutical manufacturers
