Balancing post-market monitoring with pre-market requirements Dr - PowerPoint PPT Presentation

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

Outline • International trends • Challenges • Opportunities Balancing post-market monitoring with pre- 1 market requirements

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 Balancing post-market monitoring with pre- 2 market requirements

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 Balancing post-market monitoring with pre- 3 market requirements

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 Balancing post-market monitoring with pre- 4 market requirements

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 Balancing post-market monitoring with pre- 5 market requirements

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. Balancing post-market monitoring with pre- 6 market requirements

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 Balancing post-market monitoring with pre- 7 market requirements

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 Balancing post-market monitoring with pre- 8 market requirements

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 Balancing post-market monitoring with pre- 9 market requirements

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 Balancing post-market monitoring with pre- 10 market requirements

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? Balancing post-market monitoring with pre- 11 market requirements

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? Balancing post-market monitoring with pre- 12 market requirements

Questions? Balancing post-market monitoring with pre- 13 market requirements