mOPV & bOPV: Licensing, Clinical Trials, and Strategies

Manufacturer's Meeting, Geneva, 30 October 2008

Research and Product Development Team, Polio Eradication Initiative,WHO, Geneva

Focus of GPEI Research & Product Development

• To accelerate eradication.• To provide the scientific base,

and develop the necessary products, to make policy decisions and implement the post-eradication strategies.

Presentation Overview

• Background– WHO Commitment

• Development of mOPVs– Licensure– Clinical trials– Use

• Status of bivalent OPV development• Conclusions

Background mOPV1• In September 2004 Ad-hoc Advisory Committee

on Polio Eradication (ACPE) recommended development of mOPV1

• Initial development in France (sanofi pasteur & AFSAAPS) licensure in March 2005 (and India (Panacea Biotec Ltd licensure in December 2004)

• ACPE defined policy guidance for mOPV1 use• First uses in April 2005 in India and May 2005 in

Egypt• Followed by mOPV3 (and mOPV2) licensure

Policy Guidance for mOPVs Use

• mOPV1 only recommended for campaign use• mOPV1 not substitute for tOPV in routine

programs• With licensure of mOPV3, program had to make

sometimes difficult decisions which vaccine to use to optimize immunity

• More recently, use of short-interval rounds (~2 weeks) in difficult-to-access areas (Somalia & Afghanistan)

WHO Commitment for mOPV1

• Guarantee minimum purchase (50 million doses of mOPV1)

• Prepare of key documents (clinical historical data, and expert report)

• Conduct clinical trials for WHO-prequalification

• Assist with discussions with national regulatory agencies

mOPV Licensure

IndiamOPV1HaffkineNigeriaIndonesiamOPV1Bio FarmaPakistan, IndiaItalymOPV3Nigeria, Pakistan, India ItalymOPV1Novartis

PendingmOPV2Nigeria, Pakistan, IndiaBelgiummOPV3

Egypt, Nigeria, Pakistan, India, Indonesia+

BelgiummOPV1GSKIndiamOPV2

Nigeria, Pakistan*IndiamOPV3Nigeria, Pakistan*, Indonesia+IndiamOPV1PanaceaEgypt, PakistanFrancemOPV1Sanofi-Pasteur

Licensure elsewhereOriginal licensure

ProductProducer

*in process; +special access scheme

Clinical Trials of mOPVs• Evaluate standard potency (same as

in tOPV) for WHO-prequalification:– mOPV1&, mOPV2, mOPV3

• Optimize formulation of mOPV1:– Evaluate higher-potency (10^6.8 CCID50)

with regular-potency mOPV1 (10^6.15 CCID50) in India

• Evaluate bivalent (1&3) OPV:– Added to evaluation of mOPV2 and

mOPV3&N Engl J Med 2008;359:1655-65.

Overview of Clinical Trials

Equivalency of fractional dose

Almost completedFractional IPV GSK/ 2 arms 2,4,6 mos

Oman

NAPlannedFractional IPV / 2 arms at 4&8 mos

Cuba2

Inferiority of fractional dose

CompletedFractional IPV / 2 arms (SSI) 6,10,14 w

Cuba1

NAField work in progress

mOPV1 + 3 / 4arms (GSK)

South Africa

NAPlannedFractional IPV / mOP1 (4 arms)

India4

NAField work in progress

bOPV Panacea/ 5 arms (mOPV1, 2, + 3)

India3

Negative for birth dose /positive for 1-mos dose

Completedhigh-titer mOPV1 Panacea/ 4 arms

India2

Negative for birth doseCompletedmOPV1 Panacea / 3 arms

India1

Superiority of mOPV1CompletedmOPV1 sp / 2 armsEgypt

Main findingsStatusVaccine/armsCountry

mOPV1 vs tOPV Seroconversion After a Dose Given at Birth

<0.00132.1%55.4%Egypt&

NS

NS

P values

11.2%9.6-18.3%India 2

10.2%10.4-15.6%India 1

tOPVmOPV1

&N Engl J Med 2008;359:1655-65.

mOPV1 vs tOPV Seroconversion After a Dose Given at 1 Month of Age

NSND58.3%Egypt&

<0.001

NS

P values

57.9%86.6-88.6%India 2

NDNDIndia 1

tOPVmOPV1

&N Engl J Med 2008;359:1655-65.

Two-Dose Cumulative Seroconversion of mOPV1 vs tOPV At Birth & 1 Month

NAND81.4%Egypt&

<0.001

NA

P values

62.6%89.1-90.0%India 2

NDNDIndia 1

tOPVmOPV1

&N Engl J Med 2008;359:1655-65.

Global mOPVs Use, 2005-Present

368.0*1,216.8*2008

196.41,203.32007

7.5986.02006

8.4466.42005

mOPV3 (million)

mOPV1 (million)

Year

*2008 as of to date

Source: data in WHO/HQ as of 28 Oct 08

Countries using mOPV1NID (12 countries*)

* a mix of mOPV1 and mOPV3 used in Nepal

a mix of mOPV1, mOPV3 and tOPV used in Pakistan

a mix of mOPV1 and tOPV used in Afghanistan, Chad, India and Sudan

SNID (7 countries)

Countries using mOPV3NID (5 countries*)

* a mix of mOPV1 and mOPV3 used in Nepal

a mix of mOPV1 mOPV3 and tOPV used in Pakistan

SNID (2 countries**)

Countries using tOPVNID (16 countries*)

* a mix of mOPV1, mOPV3 and tOPV used in Pakistan

a mix of mOPV1 and tOPV used in Afghanistan, Chad, India and Sudan

SNID (11 countries)

** a mix of mOPV1 and mOPV3 used in India

Supplementary Immunization Activities, by Vaccine Type, Endemic Regions, 2008

Bivalent (1&3) OPV Development

• Background– All 4 polio-endemic countries have type 1 and

3 co-circulation– Making programmatic decisions on which

mOPVs to use sometimes difficult• Recommendation

– The ACPE recommended during November 2007 meeting that a bOPV arm be added to an already planned clinical trial in India

bOPV Trial Design• Objective:

– To determine whether bOPV may provide similar immunity gains as do mOPV1 and mOPV3 administered individually

• bOPV formulation:– Identical to tOPV (except no Sabin 2 strain)

• Design:– 5-arm study, bOPV, mOPV1, mOPV2, mOPV3 and

tOPV– Two doses administered at birth and 30 days, and

blood collected at birth (cord blood), 30 + 60 days• Timeline:

– Field work expected to be finished by end 2008; preliminary results expected at end of 1st quarter 09

Possible Trial Outcome I• Scenario 1

– bOPV performs satisfactorily& (no decreases in type 1 seroconversion)

• Seek licensure of bOPVin India

• Invite other WHO manufacturers to seek licensure in country of production and use

• Issue tender

• Scenario 2– bOPV performs

intermediately (small decreases in type 1 seroconversion)

• Decide to whether a formulation trial is needed to determine the optimal ratio & potency of type 1 and 3 Sabin strains

&Please note: bOPV should be as immunogenic as mOPV1 for type 1; andas immunogenic as tOPV for type 3.

Possible Trial Outcome II• Scenario 3

– bOPV performs unsatisfactorily& (large decreases in type 1 seroconversion)

• Abandon development efforts for bOPVvaccine

&Please note: bOPV >20% less immunogenic as mOPV1 for type 1;and as immunogenic as tOPV for type 3 or lower.

bOPV Final Thoughts

• Clinical trial results will guide next steps• Risk/benefit for bOPV has changed since

evaluation in 2000 (Parkman)• Risk of VDPV emergence following bOPV

use needs to be assessed– Reversion / recombination

• Risk management plan– Designated staff for post-marketing

surveillance

Conclusions• Unprecedented collaboration for

development & licensure of mOPV1, mOPV3, and more recently mOPV2 (manufacturers & regulatory agencies)

• Evaluated product refinement in mOPV1 (i.e., higher-potency mOPV1)

• Unprecedented use of mOPV1 and mOPV3 in campaigns for polio eradication

• Evaluation for possible innovationcontinue with clinical trial of bOPV to make best tools available to polio eradication