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

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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.