RG Peterson MD, PhD, MPH
Faculty of Medicine
CADTH Symposium University of British Columbia
April 7, 2014 Executive Director
Hilton Lac-Leamy, PQ Drug Safety and Effectiveness Network
Canadian Institutes of Health Research
Chair, Canadian Drug Expert Committee
Proof of Claim
vs. Proof of Value
Bridging the Gap
Regulatory Requirements Dominate Drug
Development
Evidence must support product’s labeled claim
An
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Who needs Evidence ?
• Manufacturers: Investment decisions
• Investigators: Each level of CT Phase
• Regulators: MA decisions -efficacy/safety/quality
• HTA: Recommendations on value
• Payers: Formulary listing decisions
• Prescribers: Benefit-to-Harm judgments
- Reducing population studies to single patient
• Patients: Greatest benefit, least harm - access and affordability
Limitations of Proof of Claim RCT’s
• Typically new drug vs. placebo – short duration
• Only a few questions can be addressed in a single RCT
• RCT’s powered for efficacy outcome have limited safety
data
– The drug is not “proven safe”, it is observed to be
without “substantial” harm
– RCTs powered for safety have a narrow safety focus
• Limited extrapolation to populations specifically excluded
from the clinical trial
- Patient Horizon rarely addressed
The Patient Horizon Decision Analysis
• By definition, patients “in the horizon” are the
multitude who are given the therapy after the
trial. These are the “real world” patients.
• The true utility of any trial is its generalizability to
the prediction of harms and benefits across the
patient horizon.
• “Risk” is a composite of the probability of an
event and the significance of the event. – It is a concept that must address not only harm, but also benefit,
i.e., the risk of not achieving a benefit.
European Medicines Agency
• Following Directive 2004/27/EC of the European Parliament and of
the Council and as described in EMEA/119319/04, “it is not
necessary for the benefit-risk profile of an experimental medicine to
be at least as favourable as the benefit-risk profile of any or all
established medicines in order to receive marketing authorisation.”
Therefore,
• “Where feasible, three-arm trials including experimental medicine,
placebo and active control represent a scientific gold-standard and
there are multiple reasons to support their use in drug development.”
– For example, where: “…treatment with a medicine of inferior
efficacy might conceivably lead to significant, long-term or
irreversible harm for the patient.” Reflection paper, Committee for Medicinal Products for Human Use, 2010
Regulatory Modernization
Within life-cycle authorities:
One strategy to close the evidence gap is to have regulators require
that RCTs have greater external validity.
“Substantive evidence of an effect…”
is not the same as evidence of
a substantive effect !
This will require more than just
post-market risk management plans
and must begin with new pre-market
expectations.
Evidence Challenges for HTA Can these be addressed in Unison with the Regulator?
• Information about the usefulness of a new drug in the general population:
– Efficacy in the RCT needs to be translated into RW
Effectiveness Can generalizability be a requirement?
– Where does the product fit with respect to other therapies, including non-pharmacologic therapies? Multi-arm RCTs?
– How to deal with sub-populations not studied in the RCTs?
– How to deal with the uncertainty in safety for a new drug compared to an established one? Risk management plans made public?
– How limited and appropriate will prescribing practices be? Can the initial product label be more conservative?
Devolution of Product Label
Early Phase Conceptualization
End of Phase 3
Approved Label
HTA “Optimized” Listing
(Evidence of Claim)
(Evidence of Value)
Thank You !
Disclaimer
The views expressed in this presentation are those of the presenter and do
not necessarily represent any organizations, past or present, with which the
presenter has been affiliated.
