pharmacovigilance and risk minimisation plans for ... · • gcp principles and approval process of...
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Pharmacovigilance and Risk Minimisation Plans for
Nanomedicines
Jan PetracekPartner, PharmInvent
1st International Workshop on NanomedicinesEuropean Medicines Agency
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“Nanomedicine has unbelievable transformational potential, but we must be as brave, persistent and smart as the biotechnology innovators were when that field was emerging 20 years ago.”
Ferrari, M, In: Gewin, V: Big opportunities in a small world, Nature, 460:540-1
3 September 2010 2Dr Jan Petracek, PharmInvent
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Anything that can go wrong,
will go wrong.
Murphy’s law
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In this talk• How to
– plan pharmacovigilance– plan risk minimisation
• for nanomedicines• in pre and post-authorisation
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PhV Timing in a med. product lifecycle
Authorisation
MarketSurveillance
Res. Devel. Testing
Observednew
effectsPost-authorisation lessons
WithdrawalVariations
Pre- PhV
Post - PhV
RMP
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Pre-clinical safety testing
Risk Management priorities:• Controlled and isolated facilities to prevent
human exposure as well as any leak of the tested nanomaterials to environment
• Does not need to be described in the EU-RMP as a risk minimisation (not related to administration to patients)
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Clinical Trials – Phase I
• For Phase I see the Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products
• High-risk products: “when there are concerns that serious adverse reactions in first-in-man clinical trials may occur” = almost always
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Clinical Trials• Development risk management plan is only a
recommendation so far• GCP principles and approval process of
individual trials usually suffice for good management of risks to both subjects and environment
• Development Safety Update Reports (ICH E2F) provide framework for summary of important risks that would create a basis for post-authorisation risk management
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Pre-submission planning
• Early consultation with the Agency about the draft risk management plan
• Scientific advice available for the overall EU-RMP structure, as well as for the studies to be included in the plan
• Well drafted EU-RMP will save time during the application evaluation
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General EU-RMP philosophy
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EU-RMP for ATMP - overview
3 September 2010 11Dr Jan Petracek, PharmInvent
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Pharmacovigilance Plan
• Designed to learn more about safety profile of a medicine in post-authorisation phase
• In addition to routine pharmacovigilance system, intensive monitoring schemes, observational trials as well as interventional trials and pre-clinical studies may be included in the pharmacovigilance plan
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Pharmacovigilance plan elements
Action plan for safety concerns:
•Safety concern•Objective of proposed actions(s) •Action(s) proposed•Rationale for proposed action(s)•Monitoring by the MAA/MAH for safety
concern and proposed actions•Milestones for evaluation and reporting
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Evidence gathering in pharmacovigilance plan of
“high risk products”
• Pragmatic trials• Randomised trials in individual patients• Adaptive design trials (while respecting the
regulatory requirements)• Long term non-interventional trials,
including patient registries
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Risk Minimisation Plan(1)
Drug Information Association
www.diahome.org 15
• Only needed if additional risk minimisation activities needed
• Should list safety concerns and discuss which risk minimisation activities needed for each concern
• Should include both routine and additional risk minimisation activities
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Action plan for safety concerns
• Safety concern• Objective and rationale of proposed
actions(s)
• Proposed actions
• Proposed review period
• Criteria to be used to verify the success of proposed risk reduction actions
Risk Minimisation Plan(2)
Drug Information Association
www.diahome.org 16
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Risk Minimisation Tools (examples)
1. Provision of information• Routine communication docs – labelling• Specific (additional) - Educational plans• Informed consents
2. Control of the use of medicine• Legal status of a medicine• Restricted access programs• Control of prescription size or validity
Drug Information Association
www.diahome.org 17
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Efficacy Follow-up System
• Both interventional and non-interventional designs
• May measure “real-life” specificity and sensitivity of mandated tests
• Typically may include studies of long-term effectiveness, as well as studies of risk minimisation effectiveness (e.g., how well the trained physicians are using the medicines).
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Measuring Effectiveness of Risk Minimisation Tools
• Conditio sine qua non• Adaptation of the activities based on the
measurements• Examples:
– Comparison of healthcare provider sites– Tests and questionnaires– Registries
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Ref: http://www.observatorynano.eu/project/filesystem/files/Executive%20summary%20April%202009.pdf
Possible categorisation of “nanomedicines products”
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An individual product needs an individual EU-RMP
• Varieties in the nanotechnology applications in medicinal products make it impossible to apply one approach for all
• However, current flexibility of the EU-RMP allows for accommodation of this variability
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Nanotechnology approach may be seen as a risk minimisation activity
• EU-RMP safety specification works with the toxicity of active substance, so a delivery system that enables toxicity reduction can be presented as a risk minimisation activity (e.g., for drugs like daunorubicin, doxorubicin, amphothericin B)
• Reduction of toxicity originally caused by solvents or other excipients (e.g. paclitaxel in Abraxane)
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New toxicity concerns of drug delivery systems
• The major toxicity usually discovered in pre-clinical studies and clinical trials prior to authorisation
• Examples – carbon nanotubes, nanohorns, nanodiamonds…
• Long term safety follow-up is likely to be required for these delivery systems
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Drug Delivery System Failure –New Type of Potential Risks
• For example with magnetoliposomes, micro-bubble based delivery systems, nanoshells…)
• Include potential of medical errors caused by physicians, or errors caused by a medical device failure (MR, ultrasound, other release control systems…)
• Training programs, rescue procedures, early warning systems and barriers to errors should be considered
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Shift from one-size-fits-all towards personalised medicines
• Are there models within personalised medicines paradigm that could be economically as appealing as the blockbuster approach?
• Nanotechnology enables both - better understanding of intracellular functions and its targeting by therapeutics –excellent possibilities for personalisation
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Risk Management framework could make the effective
personalisation of therapy possible while maintaining revenues of a blockbuster!
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EU-RMP mandated personalisation
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Conclusions 1
• The current EU-RMP framework is flexible enough to accommodate nanomedicines specific risks
• Higher use of efficacy follow-up systems, novel designs of trials included in the pharmacovigilance plan, and number of additional risk minimisation measures might be anticipated
• The application of nanotechnology itself may also work as a risk minimisation tool
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Conclusions 2
• Closer links with Environmental Risk Assessment might be needed, most likely in the form of common instructions and trainings for users of the medicinal products
• EU-RMP may facilitate personalisation of therapy while maintaining some attributes of blockbusters
• EU-RMP is the way to further improve benefit/risk balance of any high-risk medicine
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