This document summarizes a presentation on whether adaptive approaches to drug approval provide a viable commercial strategy now and in the future. It discusses how adaptive licensing may increase the expected net present value of drugs and get more patients access to treatments more quickly. However, it also notes that adaptive pathways require coordination between regulators, health technology assessors, and insurers to be successful. The document also examines scenarios for the future of clinical evidence generation and real-world data use in the EU and US and implications for adaptive pathways.

1. Is There a Viable Commercial Strategy for the Use of Adaptive Approaches, Now and in the Future?
Adrian Towse
Workshop on MedicinesAdaptive Pathways: A Practical Strategy to Improve Patient Access to Medicines?
Centre for Innovation in Regulatory Science
London• 1-2 October 2014

2. CIRS Workshop on Medicines Adaptive Pathways • 1-2 October 2014 2
•
A viable commercial strategy that meets HTA requirements?
•
Can adaptive licensing increase expected net present value (eNPV)?
•
Baird et al. (2013)
•
Industry perceptions of current EMA pathways
•
Escher Report (Boon et al., 2014)
•
Role of managed entry agreements?
•
Handling uncertainty
•
Future scenarios for the EU and the US for RE/CER
•
Conclusions
Agenda

3. CIRS Workshop on Medicines Adaptive Pathways • 1-2 October 2014 3
A viable commercial strategy that meets HTA requirements?
•
eNPVdepends on revenues, costs, success rates, discount rates (and therefore timing of revenues and costs)
•
Do adaptive pathways improve eNPV?
•
Depends on prices, volumes, costs, timing, success rates
•
What is the counter factual / comparator?
•
We seem to be on a path to making the economics of drug development unsustainable

4. CIRS Workshop on Medicines Adaptive Pathways • 1-2 October 2014 4
Baird et al. (2013) Comparison of stakeholder metrics
Drug
Scenario
eNPVUS$
Adaptive- ness
Score
Change in Patient Access years
Inappro- priatelytreated patients
Comments
Zelboraf
1:Traditional
$23m
NA
NA
-
(skin cancer)
2: Actual
$34m
5
9100
-
3:Adaptive
$30m
10
9100
-
As per fast track butwith continuous planned data collection
Gilenya
1: Actual
$127M
NA
NA
-
(relapsing MS)
2: Staged
$169M
12
41,000
-
Smaller quickertrials for narrower authorisation. Later expansion of label
Acomplia
(anti- obesity)
1:Actual
($73M)
NA
NA
0.9M
Withdrawn in EU after 2 years, never approved in the US
3: Post MarketSurveillance
($43)
13
11.5M
1.7M
Controlledfor off label, adherence, maintained over life cycle
5:Staged
($16M)
16
10.1M
None
Smaller quicker trials for narrower authorisation. Later expansion of label. Controlledfor off label, adherence, maintained over life cycle

5. CIRS Workshop on Medicines Adaptive Pathways • 1-2 October 2014 5
Boon et al. 2014 Escher Report*
•
CMA is granted on the base of less comprehensive data, but assessment timelines were longer. CMA is perceived as a ‘rescue option’ by regulators and companies, rather than as a prospectively planned pathway to provide early access.
•
Of the cohort of 47 NASs approved in 2007, at least one PASS was requested at market entry for 22. Yet PASSs are not the main source of new safety information listed in the SmPC, but the costs of conducting these studies appear substantial.
•
‘Adaptive licensing has been discussed for a long time with very little action . . . new regulatory pathways will only be useful if they are considered in a holistic approach including health technology assessment (HTA) and payers’. Furthermore, the importance of ‘understanding the business needs for new pathways’ is stressed.
*Improving the EU system for the marketing authorisation of medicines. Learning from regulatory practice. Escher Foundation

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The story so far. . .
•
Modelling suggests adaptive licensing can improve eNPV, increase overall numbers of patients treated, but also do the opposite
•
The CMA does not seem to be working in the way intended
•
Some PASS schemes may not be a good use of resources.
•
Industry interest in adaptive pathways but concern about lack of HTA / payer ‘buy in’
•
Need a coordinated EMA HTA/payer approach

7. CIRS Workshop on Medicines Adaptive Pathways • 1-2 October 2014 7
•
MEAs are used to give access to new technologies where traditional reimbursement is deemed inappropriate
•
Three different forms of MEAs have been identified:
•
Management of uncertainty relating to clinical and/or cost- effectiveness
•
Management of utilization to optimize performance
•
Management of budget impact.
•
The rationale for using these approaches and their advantages and disadvantages differs
•
All forms of MEA should take the form of a formal written agreement among stakeholders, clearly identifying the rationale for the agreement, aspects to be assessed, methods of data collection and review, and the criteria for ending the agreement.
Managed Entry Agreements*
*Klemp, Frønsdaland Faceyon behalf of the HTAiPolicy Forum (2011) IJTAHC 27: 77-83

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Categorising Payer Options
Payer options:
Payers adopts: no new evidence required (YES)
Payer refuses to adopt. (NO)
Payer adopts with additional evidence (CED) (YES BUT)
CED with renegotiation. No pre-specifiedagreement
CED linked to performance agreement
Reapply with a price cut
Manufacturer has the option to reapply with more evidence

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ISPOR Performance-Based Risk-Sharing Task Force
Performance-Based Risk-Sharing Arrangements—
Good Practices for
Design, Implementation, and Evaluation
Garrison, L.P., Towse, A., Briggs, A., de Pouvourville, G., Grueger, J., Mohr, P.E., Severens, J.L., Siviero, P. and Sleeper, M. (2013 Report of the ISPOR Good Practices for Performance-based Risk-sharing Task Force. Value in Health. 16(5), 703-719.

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Performance based risk sharing arrangements (PBRSA)
To manage utilization in the real world
To provide evidence regarding decision uncertainty
-Outcomes guarantees
-Money back guarantees
-Conditional treatment continuation
Cost sharing arrangement
-Budget capping
-Utilization capping
-Discounts
-Price/volume
MEA: Payer- producer/provider
arrangement
Coverage with evidence development
Performance linked reimbursement
Intermediate endpoint
Clinical endpoint
-Only with research
-Only in research
-Process of care
Pre-specified agreement
No pre-specified agreement

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MEAs / PBRSAs: lessons and challenges
•
Study design has to address the uncertainty
•
Observational, PCTs, RCTs, use other jurisdictions
•
Transaction costs are key barrier:
•
Mostly evidence collection
•
Pre-agreement covering adjustment and exit
•
Challenge of Price flexibility?
•
Price per unit of health gain, not per pill
•
Withdrawal of (or increase in) discounts rather than change in list price
•
Differential pricing by indication
•
Retrospective price adjustment / rebate/ premium

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Addressing uncertainty
•
Uncertainty only matters if decision makers can do something about it
•
Concentrate on the expected value
•
PBRSAs offer a route to address uncertainty with additional evidence collection
•
Discount if data collection possible, but no willingness to undertake it
•
Incentives matter –it is a ‘repeat game’

14. MOVEMENT TOWARD HARMONIZATION IN EUROPE
Post-authorisation efficacy studies (PAES) implemented
Greater HTA and EMA coordination pre-launch
Disease registries in some countries , and progress in EHRs
Coordination across HTA bodies in demand for P-L studies, often linked to CED, P4P schemes
Collaborations across large registries
Full use of EHRs
Good progress in methods
Public-private partnerships
have a major role
AL applied to a variety of drugs
Joint HTA and EMA coordinationfor pre-and post-launch
Most Likely Scenario
Most Conducive
To RE Scenario
Anticipating the future for CER and RE in the pharmaceutical industry. Research conducted by CMTP and OHE, sponsored by Amgen, GSK, Lilly, Novartis, Sanofi. Publications in progress.

15. MOVEMENT TOWARD INTEGRATION OF HEALTH SYSTEM IN THE US
ACA and private payers driving investment in ACOs
Increasing data systems ability to produce quality measures
Federal investments to
improve research infrastructure/methods/processes
Risk-based payments move towards capitation
Increasing willingness and ability to invest in EHRs and desire to reduce system costs
Changing locus of
decision-making
providing opportunities
for new partnerships
Most Conducive
To CER Scenario
Most Likely Scenario
Anticipating the future for CER and RE in the pharmaceutical industry. Research conducted by CMTP and OHE, sponsored by Amgen, GSK, Lilly, Novartis, Sanofi. Publications in progress.

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Implications of the scenarios
•
Key drivers for Europe are:
•
HTA coordination
•
Regulatory innovation (PAES, adaptive licensing)
•
Regulatory / HTA interaction
•
Data availability / methods evolution
•
In the US:
•
No regulatory reform / interaction with payers
•
Data generation and integration are key drivers
•
Early US access requires an EU response:
•
Adaptive pathways offer such a response
•
Use US post-launch evidence in EU and vice versa?

17. CIRS Workshop on Medicines Adaptive Pathways • 1-2 October 2014 17
•
The commercial model for an adaptive pathway requires:
•
Coverage with evidence development (MEAs/PBRSAs)
•
Pricing/use flexibility
•
Adaptive pathways require a transformation in evidence collection costs through EHRs, disease registries, and methods evolution
•
Regulatory/HTA body/company interaction post-launchis going to be key
•
Use of the PAES must be linked to MEA/PBRSA requirements
•
The alternatives to using adaptive pathways are not easy options, either.
Conclusions

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