Drug Life Cycle Flashcards
What is the Precautionary Principle in relation to the drug approval process in Canada?
Regulatory processes focus on confirming drug efficacy, safety, and quality prior to awarding market access
Evidence presented by manufacturers provide portfolio of results from PK/PD studies, pre-clinical, and clinical trials
What are some concerns with the review process?
Generating evidence is expensive and time-consuming
Recently, Health Canada has indicated a desire to balance concerns about efficacy, safety, and quality with concerns about over-regulation (low innovation and delayed patient access)
What are some concerns with pre-market studies?
- Too study participants (under 3000)
- Too simple (patients with compilicated comorbidities or using concurrent therapy are excluded)
- Too median aged (very young and old are rarely included)
- Too narrow (Indications can be very precise)
- Too brief (UDE occurring after many years cannot be captured within scope of clinical trial)
What are some challenges with too few trial subjects during clinical trials?
- To detect unintended drug effects (UDEs), the number of subjects enrolled but be 3x the event rate (rule of three). Most clinical trials involve 3000 subjects, therefore events with occurence rates less than 1/1000 cannot be reliably detected
- The consequence is not being able to pick up very rare UDEs, such as allergic and idiosyncratic significance
What is the concern with timelines with Health Canada approval of drug safety, efficacy, and quality?
Approximately 2/3 exceeded 300 days with about five percent requiring more than 2 years
In part, these delays are due to limited in-house expertise
Reinforces precautionary principles
What are some ways by which drug approval by Health Canada can be expedited?
Priority reviews and NOC with conditions (used for potentially impactful drugs)
When are priority reviews or NOC with conditions by Health Canada performed?
Granted to new drug submissions intended for serious, life-threatening, and severely debilitating illnesses or conditions if no current product is available or shows significant increase in efficacy or decrease in risk
What are some characteristics of NOC with conditions applications?
Same criteria as priority review drugs
Granted before full risk assessment, but benefit and need is really high
All patients on drug with conditional NOC is enrolled in a study (increased monitoring for adverse events)
The manufacturer must engage in post-marketing
What are post-marketing studies and why are they done?
Begin once a drug enters the general market (Phase 4 trial)
Provide additional information (address the 5 concerns with clinical trials and pre-market studies, too few/simple/median/narrow/brief)
Also monitor effectiveness and ADRs in the real world (outside controlled environment)
What are some concerns with conditional NOC post-marketing studies?
No public disclosure until conditions are met
Many conditional NOC remain with designation for many years
What is adaptive licensing?
An alternative to the chronically delayed approval process we have now
A prospectively planned, flexible approach to regulation of drugs and biologics through iterative phases of evidence gathering to reduce uncertainties following regulatory evaluation and license adaption
How is adaptive licensing potentially a better method for the drug approval process in Canada?
Seeks to maximize positive impact of new drugs by balancing timely access for patients. There is continual submission of new evidence on benefits and harms being released by the manufacturer to the regulator
Regulation is not a binary process (gradual reduction of uncertainty) and patient access is incremental (RCT and observational data is used to determine safety, efficacy, and effectiveness based on real world use)
Review slide 21 for comparisons between the current licensing process vs. adaptive licensing process
What is the contextual differences in how adaptive licensing would be used for different drugs?
Drugs for serious conditions and few treatments would need less intial data (helps examine drugs that have potential benefits, but we don’t know enough about risks and have to study in larger population groups)
Increasing role of patient, practitioner, and other stakeholders to accept risk relative to potential benefits (less blind trust in approval, but also early/increased access to critical drug options)
What were some concerns about adaptive licensing following a pilot program in Europe?
Leading researchers, HTAs, health authorities, and advocacy groups were critical of adaptive licensing:
- Actual need for adaptive licensing
- Data quality
- Rising drug prices
- Pre-mature release with greater/unnecessary risk
The Europeans suggested adaptive licensing may be suitable for when data collection is challenging (ex. rare cancers)
Review slide 27 for the drug life-cycle concept
What is real-world evidence for the drug approval process?
Data is collected from various sources outside of RCTs and during routine clinical practice
Sources of evidence:
- Patient registries
- Medical records
- Hybrid, pragmatic, and late phase trials
Increasing ability to utilize real-world data via eMRs and ability to analyze big-data
What are the potential benefits of using real-world data to make drug approval decisions?
- Ability to monitor drug safety and effectiveness across the drug cycle
- Enhanced regulatory decision-making and risk communication
- Improve access to drugs due to new sources of evidence
- Improved use and sharing of real-world evidence with healthcare system partners
Compared to its US and European peers, does Canada use more real-world evidence to make drug approval decisions?
Not at all, Canada uses less real-world evidence
Health Canada (24%)
EMA (56%)
FDA (75%)
What is the advanced therapeutic pathway (ATP) in relation to the drug approval process in Canada?
Expanded the definition of an RCT and falls under a new licensing framework
Addresses competing goals of efficacy and safety vs. quicker market access
Reflects a life-cycle approach to regulation with a broader definition of clinical trials
ex. Covid vaccines (data is reviewed on a rolling basis to speed approval process)
What are some concerns with the Advanced Therapeutic Pathway in drug approvals?
- Consultations limited to key private sector stakeholders (biotech, medtech, digital health firms, and financial services)
- Patient groups, HCPs, and health policy researchers were largely excluded
- Seen as an attempt to expand the regulator’s mandate to encourge drug development and innovation (reduced adherence to precautionary principle, competing interest with patient safety)
What is pharmacovigilance?
The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem throughout the drug-life cycle
Review slide 38
Why do drug manufacturers engage in post-marketing studies?
Generally business decisions (new indications), rather than to monitor or establish effectiveness
What authorities does Health Canada have after the passing of Vanessa’s Law?
Allows Health Canada to:
- Initiate mandatory recalls
- Compel manufacturers to provide more safety information
- Impose conditions on market authorizations
- Compel manufacturers to revise labels on risk information
