Dr Jane Cook discusses balancing pre-market requirements with post-market monitoring of new drugs. International trends show increased demand for early access to promising new therapies and different regulatory approaches between Europe and the US. This includes adaptive licensing in Europe and breakthrough therapy designation in the US. Ensuring benefits are realized requires effective post-market monitoring as initial trials may overstate benefits or overlook safety issues. Opportunities exist to learn from other regulators and focus on the drug lifecycle to confirm benefits, inform patients of limitations, and withdraw products if risks outweigh benefits.

1. Balancing post-market monitoring with pre-market
requirements
Dr Jane Cook
Branch Head
Post-market Surveillance Branch
Monitoring and Compliance Division, TGA
ARCS Scientific Congress 2015
6 May 2015

2. Outline
• International trends
• Challenges
• Opportunities
Balancing post-market monitoring with pre-
market requirements
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3. International trends
• Ensuring promising therapies are available
as soon as possible
• Patient and clinician demand
• Different approaches by the European
Medicines Agency (EMA) and the Food
and Drug Administration (FDA) but some
commonalities
2Balancing post-market monitoring with pre-
market requirements

4. Europe
• EMA - adaptive licensing
• Intended to allow early access to medicines for
treating unmet needs
• Innovative medicines available before they have
been given final regulatory approval
• Approval followed by further evidence gathering
• Ability to adapt the approval to expand to access
to broader patient groups
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5. United States
• Range of pathways
• Breakthrough therapy designation
– intended alone or in combination with one or more
other drugs to treat a serious or life threatening
disease or condition and;
– preliminary clinical evidence indicates that the drug
may demonstrate substantial improvement over
existing therapies on one or more clinically
significant endpoints, such as substantial treatment
effects observed early in clinical development.
• Sponsors work closely with the FDA - shorten or
combine traditional phases of drug development
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6. Why this trend?
• Patient demand
– people with life-threatening illnesses, where there are no satisfactory treatments available, want
access to new therapies
– are willing to trade off greater certainty about a drugs efficacy for speed of access
– belief that clinical development is sometimes prolonged beyond what is necessary
• Rise of molecularly targeted therapies (often with companion diagnostics) for treatment of cancer,
genetic disease and other serious conditions
• Targeting of sub-groups within broader populations can result in larger treatment effects than
currently available therapies
• When evidence of a benefit in these subgroups is evident early on in trials, it seems excessive to
require that a prolonged clinical program is conducted
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7. Issues
• Need to accept that not all products designated as breakthrough will have the anticipated benefits
as subsequent trials may show a smaller treatment effect or unacceptable adverse events
• How is this best communicated to clinicians and patients?
• Example - in the US this is communicated through the following statement in the ‘Indications and
Usage’ section of the Prescribing Information of the medicine
– Accelerated approval was granted for this indication based on overall response rate. Continued
approval for this indication may be contingent upon verification of clinical benefit in confirmatory
trials.
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8. What do patients understand as clinical benefits?
• Is there agreement between patients, doctors and sponsors about what benefit is?
• Many different terms used to describe response
• Range from:
– progression free survival and disease free survival
– improved quality of life
– increased survival but no increase in cure rate
– complete response or partial response
– cure
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9. Challenges
• The need to respond to this international trend
• Consideration of whether the current processes for approval and monitoring are ‘fit for purpose’ in this
environment
• How to manage earlier approval in an environment where there is potentially less known safety and efficacy
information
• Use of surrogate end points, such as:
– an investigation (laboratory or radiographic measurement) which are thought to predict clinical benefit but
are not a measure of clinical benefit, or
– the use of intermediate clinical endpoints that measure a therapeutic effect that is likely to predict the
clinical benefit of a drug
• Importance of the Risk Management Plan in including these risks - identifying appropriate monitoring
(Pharmacovigilance) and risk minimisation activities such as the Product Information and additional risk
minimisation, such as education
• What happens when further trials do not confirm the expected clinical benefit or do not confirm sufficient
clinical benefit to mitigate the risks associated with the drug
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10. Opportunities
• Learning from other regulators' experiences
• Developing ways that allow earlier access to breakthrough therapies that also ensure patients and
clinicians are informed of the limitations of the evidence
• Developing effective monitoring activities that ensure breakthrough therapies deliver the expected
benefits
• Incorporating mechanisms that can remove products that do not deliver the anticipated benefits or
if further evidence has altered the risk-benefit profile of the product in a negative way
• Focusing on the life cycle of the product rather than a point in time
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11. Possible ways to manage uncertainty
• Public communication about the uncertainty associated with safety and efficacy, such as:
– ensuring informed patient consent
– acknowledging differences in risk tolerance between different population groups and where
adverse events are experienced
• Ensuring greater adherence to use in treatment-eligible populations and consideration of
compliance with treatment protocols
• Utilisation of risk minimisation activities to reduce occurrence of any known adverse events able to
be mitigated with robust evaluation of their effectiveness
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12. Possible ways to manage uncertainty 2
• More efficient monitoring:
– recognising the limitations of relying only on spontaneous adverse reporting
– increased cooperation between the regulator and the reimbursement agencies to require and facilitate
safety and efficacy data collection
– utilisation of available databases such as the PBS, MBS and hospital discharge data
– development of registries
• Effective post-market controls:
– clear expectation that ongoing registration and /or funding dependent on timely data collection and
provision, including evidence of efficacy and safety
– sponsor requirement to provide updates about information provided to, and considerations of, other
regulatory and reimbursement agencies
– need to ensure that surrogate or intermediate endpoints have translated into true clinical benefit – when
and how?
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13. Final thoughts
• Medicines considered to be ‘breakthrough therapies’ (to date) have been for the treatment of conditions
where there are few or no other effective treatment options
• The conditions treated are serious, life-threatening and (with or without treatment) usually result in death
• Breakthrough therapies demonstrate their ability to extend life expectancy, either through early clinical trials
(phase I or II) or the use of surrogate/intermediate clinical benefits
• How do we make sure these potential benefits translate to clinical benefit?
• How do we make sure both clinicians and patients make informed decisions about the use of these
treatments and can accurately assess the risks and benefits of these therapies?
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14. Questions?
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