mopv & bopv: licensing, clinical trials, and strategies · panacea mopv1 india nigeria,...
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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
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