Coverage with evidence

Grard de Pourvouville
ESSEC Business School
Co-speakers from ISPOR Task Force on
PBRSAs
Co-Chairs: Lou Garrison (UW, Seattle) and Adrian Towse (OHE,
UK)

Task Force Members:
Ron Akehurst, BSc (Econ) (London), Hon MFPHM, University of
Sheffield, Sheffield, UK
Andrew Briggs, MSc, DPhil, University of Glasgow, Glasgow,
Scotland
Jens Grueger, Ph.D., Pfizer Inc., New York, New York, USA
Penny Mohr, M.A., Center for Medical Technology Policy,
Baltimore, Maryland
Hans Severens, Ph.D, Erasmus, Rotterdam, Netherlands
Paolo Siviero, AIFA, Rome, Italy
Miguel Sleeper, Glaxo SmithKline, Inc. Guildford, UK

ISPOR Support: Elizabeth Molsen.

A change of paradigm?
Access to reimbursement used to be based on the
following principles
Companies invest in the drug market because of its financial
attractiveness, related to the development of large-scale
insurance, but also because licensing grants them a temporary
monopoly that protects their markets and profits during a fixed
period.
To gain access to the market companies must demonstrate a
favourable benefit-risk ratio, using a highly standardized
process of development with a central role given to randomized
control trials.
Once on the market, it is agreed (and subject to regulations)
that potential adverse events should be monitored. This
uncertainty regarding the clinical risks associated with a drug is
accepted at the time of distribution.

What changes?
Funding constraints have incited public
authorities/payers to question other residual
uncertainties after market launch;

Concern is either for cost-effectiveness, for cost-control,
for targeting patients, and increasing political
responsibility as healthcare costs continue to rise;

Payers focus more on effectiveness, i.e. observed
benefits in real practice;

Thus, effectiveness is questioned beyond the initial
evidence provided by regulatory clinical trials.


The context of biologics
This aversion to uncertainty has been exacerbated by
new innovative biologics:
High prices and cost-effectiveness ratio substantially higher
than accepted thresholds;
In some cases, uncertainty on long term safety because of
tinkering with the immune system;
In other cases, risk of severe adverse events to balance with
benefits;
Because of mechanisms of action, potential multiple indications;
Growing complexity of combination therapies;
Because of high costs, need to identify high responders.

What type of uncertainties?
Quoting task force:
Uncertainty in Internal validity (efficacy; surrogate markers;
small sample size; inappropriate comparators);
Uncertainty in external validity (real-world performance; link
from surrogate to long-term outcomes);
Heterogeneity - differential response/benefits among patients;
Diffusion uncertainty (beyond initial indication) changing or
appropriate population subgroups and usage over time?

What responses to manage uncertainty?
More and more, companies are required to provide with
additional evidence to reduce uncertainty.

Coverage is accepted conditionally to the provision of
this evidence



COVERAGE WITH EVIDENCE DEVELOPMENT (CED)

CED is global! (from Sean Sullivan)
A wide variety of CED agreements
The agreements that are signed may take a wide variety
of forms, and include/not include specific financial
provisions

When they do include such provision, they are often
called Risk Sharing Agreements, or Performance
Based Risk Sharing Agreements

A general definition
de Pouvourville G, EJ HE, 2006
The risk for whom?
The payer takes the risk of covering the treatment at a
given cost, although not sure of real treatment
benefits: risk of overspending, but also risk of having to
pay more if results are positive

The company takes the risk of a financial penalty if
targets are not met, and has to pay for the ED

The ISPOR Task Force Taxonomy
Three ideal types
No cure, no pay
NICE Velcade agreement
AIFA payback schemes
Patient based performance: disguised price discounts?
Evidence?
See and pay
NICE MS agreement on interferons and glatiramer
Australia Bosenten scheme for PAHT
Population based performance

See and talk
French post-launch studies
Population based agreements

Are risk sharing
agreements desirable?
Payers perspective
Why?
A PBRSA allows access:
Response to patient need
A PBRSA allows controlled access:
Generation of data to reduce uncertainty;
Control of budget impact.

What alternative?
Refuse coverage, with the risk of facing political pressure
But allows to free resources for other less uncertain innovations


Companys perspective
When?
The development program was good enough for registration,
but payers resistance is anticipated:
Surrogate endpoints versus morbidity-mortality;
Incompleteness of comparative data;
Trial duration;
High expected budget impact:
High prices;
Large target population.

Companys perspective
Why?
PBRSAs may be a way to overcome payers aversion for risk:
Goodwill;
Limit public health risk;
Limit financial risk by accepting to share the burden.
Expected revenues over life cycle, including risk of loss, is
higher than expected revenues with additional clinical
development costs.

Companys perspective
What alternatives?
The alternative is extending the clinical development
Extra cost or sometimes major difficulties (recruitment)
Risk of not getting positive results
Shorter time before LOP
Risk of facing competition

Limitations
In the case of an agreement with a pre-specified target:
Payers may fear opportunistic pricing of companies, adjusting
their price level to anticipated risk of failure:
Ask for a lower price upfront and agree to readjust after
conclusion of the agreement;

Opportunistic behaviour is probable if agreement is
proactive/reactive;

For companies, higher uncertainty on revenues during
the test-period.

Are risk sharing
agreements feasible?
Key issues
Protocol design and choice of methodology
Quality of monitoring and data management capacities
Independence of monitoring
Completeness of contract
Legal value of contract
Timing
Publicity of results
Publicity of financial clauses
Funding
Externalities

Perspective
It is predictable that CED will be one of the alternative
ways to organize access to innovative treatments in the
future, when there are perceived uncertainties on major
outcome parameters
They do not need to be specifically linked to financial ex
ante defined clauses
If they are, they can be either patient based (no cure
no pay) or population based
The second category can be assimilated to the
extension of the clinical trial development plan, but
designed for the payers needs as opposed to
registration

Perspective (Followed)
Are no cure no pay agreements CED based, or
disguised price discounts?
Population based agreements are more complex to
implement and evaluate, and raise timing issues.
Therefore, predictable that they will be reserved to very
specific cases where companies meet specific
difficulties to demonstrate outcomes in clinical trials.
Could the need for CED we minimized with better
pre-registration discussions between payers,
registration authorities and companies?