PPHC 12: Drugs – How do drugs go from molecule to market? Flashcards
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
Canada’s Drug Agency (CDA)
What is the outcome of the CDA’s review?
- recommendations: reimburse, reimburse with conditions, do not reimburse
- note: recommendations are recommendations – they are non-binding
Does Canada affect drug prices around the world?
NO – Canada is a relatively small market (in the world) and has little power to influence on price
- within Canada, we effectively have 13 health systems diluting this further – inconsistency between provinces
What is the purpose of the pan-Canadian pharmaceutical alliance (pCPA)?
can interested provinces group together to negotiate a better price
pan-Canadian Pharmaceutical Alliance (pCPA)
What does the pCPA do?
allows provincial, territorial and federal governments to jointly negotiate for brand name and generic drugs in Canada
- better power combined negotiating power
pan-Canadian Pharmaceutical Alliance (pCPA)
What are pricing decisions based on?
pricing decisions are a precondition of having a medication covered on provincial drug formularies
- last stage before public plans decide whether or not to list
pan-Canadian Pharmaceutical Alliance (pCPA)
Process Diagram
see notes
What is the purpose of the patented medicine prices review board (PMPRB)?
have prices of approved drugs remained reasonable
Patented Medicine Prices Review Board (PMPRB)
What does the PMPRB do?
- monitors the prices charged by patentees for patented drugs on an ongoing basis – patentees file information about price and sales at introduction and every 6 months for all forms of the patented drug sold in Canada
- tries to ensure the prices of patented medicines in Canada are not excessive
- prices relative to prices in other markets – fines to compensate for the high prices
