Assessing Benefit and Risk across the Drug Life Cycle Flashcards
What is the Precautionary Principle?
To be sold in this country, a drug must be approved by Health Canada (HC).
- Regulatory processes focus on confirming drug efficacy, safety and quality prior to awarding market access
What are some concerns with the drug review process? (2)
- Generating evidence is an expensive and time-consuming process.
- What is considered sufficient evidence is based in part on the degree of uncertainty that is acceptable to the regulator. - Recently, HC has indicated a desire to balance the objectives of efficacy, safety, and quality with other, sometimes competing objectives:
- Reduce barriers to innovation; and
- Provide more timely patient access.
Why is sample size important when designing a clinical research study? (2)
- To detect a unintended drug effect (UDE) the number of subjects to be followed must be three times the estimated frequency of the event.
- The “rule of three.” - Phase III RCT are designed to identify common, dose-related UDE based on the pharmacology of the drug, and usually involve around three thousand participants.
- A typical RCT can detect a UDE if the occurrence is at least 1 in 1000.
What are some concerns with pre-market studies? (2)
- Rare UDE, such as allergic and idiosyncratic effects have little likelihood of being detected during the pre-marketing phase.
- For example, if an UDE only occurs in 1 in 10,000 users (rare occurrence), need to observe 30,000 users to show statistical significance. - Due to other aspects of RCT design, UDE can go undetected if there is a long induction period (delayed effects), or if the UDE is due to an interaction with another drug or some other characteristic of the user
What are the 5 Too’s (concerns of pre-market studies)
- Too few: Usually less than 3000 patients in a clinical trial prior to approval.
- Too simple: Patients with complicated conditions or concurrent therapy are usually excluded.
- Too median aged: Very young and very old rarely included.
- Too narrow: Indications much be clearly specified.
- Too brief: UDE occurring after many years cannot be captured.
The target for completing a standard review is 300 days; but metting that target has become increasingly difficulty. Why might that be?
In part, delays were the result of capacity constraints due to limited in-house expertise.
- As well, market withdrawals and post-NOC product relabeling have led to ever increasing demands for up-front data, and additional scrutiny.
- Re-enforces the precautionary principle
What are 2 alternative pathways to minimize delays for potentially impactful medicines?
- Priority reviews (180 days)
- NOC with Conditions (200 days)
What are priority reviews?
Priority Reviews may be granted to new drug submissions intended for serious, life-threatening and severely debilitating illnesses or conditions if:
- No product is currently marketed in Canada; or
- It represents a significant increase in efficacy and/or decrease in risk
What are NOCs with Conditions? (2)
- Notice of Compliance with Conditions (NOC/c) may be granted to expedite access to potentially life-saving drugs.
- Same criteria as priority review drugs - The manufacturer must also undertake additional studies to confirm clinical benefit and no additional safety concerns.
– Post-marketing studies
When do post-marketing studies begin? Why are they important?
Begin once a drug enters the general market (also known as Phase IV).
- PM studies are important because at the additional information they provide.
- At the time a drug is approved for marketing, a number of clinically and epidemiologically important questions are unknown.
Post-marketing studies can provide information on? (3)
- Uncommon side effects, as well as adverse events occurring over a longer period.
- Permits evaluation of delayed effects. - Efficacy that is only apparent after the drug has been marketed.
- Longer term benefits - Effectiveness in the real world
- Benefits and adverse effects based on actual patterns of prescribing and patient use.
- Also allows for the ethical observation of the effects of over-dosing.
What is a concern with NOC/c and PM studies?
- It is unclear whether PM studies required for NOC/c drugs are being conducted as required.
- No public disclosure until conditions are met, or a license is suspended
- Many NOC/c drugs continue with the designation for many years
What is adaptive licensing? (2)
- Regulation is not a binary process
- The ‘magic moment’ between non-approval and approval is replaced with progress management and the gradual reduction of uncertainty. - Patient access is incremental
- Uses both RCT and observational data to determine safety, efficacy and effectiveness based on use in the real world.
What did the EMA conclude about adaptive licensing when they did their trial?
EMA concluded that AL might be suitable when data collection is challenging (e.g. rare cancers); but overall, EMA appeared ambivalent about AL
What were the significant criticisms from stakeholders about adaptive licensing? (4)
- Actual need for AL
- Data quality
- Rising drug prices
- Pre-mature release with greater/unnecessary patient risk.
What is real-world evidence (RWE)/what is it used for? (2)
- RWE refers to evidence obtained from observational data obtained outside RCTs and during routine clinical practice.
- Data is collected from various sources such as patient registries, medical records, and hybrid, pragmatic, and late phase trials. - The use of RWE during the drug life-cycle gained momentum with the development of electronic medical databases and our increasing capacity to analyze large datasets.
HC initiates the RWE Project In 2018 to improve its ability to monitor dug safety and effectiveness across the drug life cycle. What are the expected outcomes of the project? (4)
- Increased use of RWE to enhance regulatory decision-making and risk communications across the drug life cycle.
- Increased clarity for stakeholders on where and how RWE can be used to support regulatory decision making
- Improved access to drugs by using new sources of evidence to support the approval of drug applications.
- Improved use and sharing of RWE with health care system partners.
How does Health Canada compare to the FDA and EMA in terms of using RWE in its regulatory decision-making for oncology drugs and drugs for rare diseases?
HC uses less than the FDA and EMA.
- Health Canada 24.1%, FDA 75.9% and EMA 56.0%
What is the Advanced Therapeutic Pathway (ATP)? (2)
- Amendments to the F&D Act in 2019 creates a new licensing framework (ATP).
- To address the competing goals of efficacy and safety vs. quicker market access.
- Reflected a life-cycle approach to regulation with a broader definition of clinical trials. - Plan for a slow roll-out with broad consultation around implementation…
- Covid-19, and the rush for effective vaccines, led to expedited approval of clinical trials and rolling drug reviews to speed up market access
What are some concerns about the Advanced Therapeutic Pathway (ATP)? (3)
- Consultations limited to a few key private sector stakeholders: biotech, medical tech; digital health firms, and financial services companies.
- Patient groups, health professions, and health policy researchers were largely excluded.
- Even Innovative Medicines Canada complained the process lacked meaningful consultation.
What is pharmacovigilance? (2)
- “(The) science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem”
- Activities that are increasingly integrated into drug safety surveillance systems throughout the drug life-cycle.
What is after market authorization? (2)
- For most drugs, once a company receives market authorization (NOC and DIN), the drug can be obtained throughout Canada with only a few, very clearly defined restrictions:
- i.e. Ordered by a licensed prescriber and dispensed by a licensed pharmacist. - Post-marketing studies, if they occur, are generally business decisions, rather than to monitor or establish effectiveness and safety per se.
In 2010 Health Canada did not have the authority to do what? (3 things focused on drug safety)
- Require drug companies to conduct post-market studies
- Make labelling changes in response to safety issues.
- Monitor drug company patient registries or impose penalties.
In 2014, Vanessa’s Law allowed Health Canada to do what? (4 things focused on drug safety)
- Initiate mandatory recalls
- compel manufacturers to provide more safety information
- Impose conditions on market authorizations, and
- Compel companies to revise labels on risk information
