Needle-Free Devices Latest Developments - WHO

1 Needle-Free Devices Latest Developments 11th WHO/UNICEF Consultation with OPV/IPV Manufacturers and National Regulatory Authorities WHO Geneva, Switzerland October 25, 2012 Darin Zehrung, MBA Senior Technical Officer Portfolio Leader, Delivery Technologies Vaccine Technologies Group PATH/Amynah Janmohamed Presentation Outline FDA Disposable Syringe Jet Injector (DSJI) Update FDA Communication on Jet Injectors Requirements for Jet Injectors and Vaccine Labeling PharmaJet (Stratis) Influenza Vaccine Study WHO DSJI Prequalification Update Device Developer Updates Bioject (ID Pen Injector, Zetajet) PharmaJet (Tropis) Planned Intradermal DSJI Research 1/14/2013 Page 2 FDA DSJI Update Slide 3 FDA Communication Jet Injectors Requirement for relabeling for jet injection - influenza vaccines and other medications / vaccines.

2 FDA / DSJI Manufacturers Meeting held January 2012. Studies now being pursued to include jet injection in labeling. 1/14/2013 Page 4 FDA Process Jet Injectors and Vaccine Labeling The FDA Center for Biologics Evaluation and Research (CBER) now requires non-inferiority-based clinical studies to relabel vaccines for DSJI delivery. The vaccine manufacturer must submit a Biologics License Application (BLA) amendment to the FDA in order to change the label. DSJI Devices will continue to be cleared by the Center for Devices and Radiological Health (CDRH) through the 510(k) process. The vaccine label may indicate delivery by jet injection as a class of Devices , enabling any 510(k)-cleared DSJI to be used, or can identify a specific jet injector.

3 Page 5 PharmaJet Stratis Influenza Vaccine Study A Phase 4 randomized controlled clinical trial assessing the immunologic response to an FDA-approved influenza vaccine delivered using an FDA-cleared jet injection vaccine delivery device versus a needle and syringe. The study is currently ongoing in Colorado, USA. A total of 1,400 patients will be enrolled. Vaccine: AFLURIA Slide 6 +influenza&rank=2 WHO DSJI Prequalification Update Slide 7 WHO DSJI Prequalification Prequalification requirements based upon ISO standard for jet injectors (ISO+). Requires device clearance through global recognized NRA.

4 PharmaJet Stratis technology first DSJI to complete process. Page 8 Device Developer Updates Slide 9 Bioject Slide 10 Injection placement & dispersion Slide 11 12 Bioject Robust Design Paradigm The Bioject design paradigm is to use robust materials in all critical areas of the device. The housings of these Devices are of metal alloy construction. The disposables are Polycarbonate, a plastic capable of withstanding high injection pressures. Slide 12 Biojector 2000 - Gas Powered Device Bioject ZetaJet - Spring Power Gas-powered FDA cleared for ID, SC and IM Used in many human studies in all age groups for ID over last 10 years Spring-powered FDA cleared for SC and IM Currently being used in several human clinical studies for ID application Slide 13 The Future for ID Injections The New ID PEN It is a re-usable Needle-Free ID PEN !

5 !!! Investigational use only Slide 14 Bioject Zetajet Device Data Three treatment, single blind, Phase I study comparing ID ( ml), SC ( ml) and IM ( ml) saline injections using the Zetajet in 60 adults. ID injections formed wheals 100% of the time. A drop of visible moisture without flow was seen at 23% of the ID injection sites. 47% felt no pain when given the ID injection, compared with 34% with the SC and 22% with the IM injection. Slide 15 Bioject ID Pen Device Data ml and ml saline injections given intradermally in opposite deltoids of 30 adults. Wetness and wheal size measured quantitatively.

6 Average wetness: ml: ml ml: ml Average wheal diameter: ml: mm ml: mm Slide 16 PharmaJet Slide 17 Click to edit Master title style Optimizing delivery to the skin: The development of Tropis , a Needle-Free intradermal delivery solution Mantoux ( needle and syringe) PharmaJet Slide 18 Confidential Stage of Device development FDA 510k filing Preclinical Testing Adult Evaluations (USA) Pediatric Optimization (India) Clinical Trials Commercial Transition 2012 2013 Tropis - Stage of Device development Slide 19 Confidential Pediatric Optimization Study, Pune India Design: Age de-escalation 6 age-grouped cohorts 30/cohort Age range 2-36 months 2 injections normal saline/child in R/L deltoid (D), or if 1 y-o, R thigh (T), L deltoid Goal.

7 To assess injection quality, as indicated by: 1)Bleb diameter 2)Residual surface moisture 2-3 year-old subjects D/D 18-24 month-old subjects D/D 12-17 month old subjects D/D 6-11 month old subjects D/T 4-5 month-old subjects D/T 2-3 month-old subjects D/T Slide 20 Confidential Bleb sizes by cohort (age), 60 injections/cohort ISO standard for expelled volume accuracy (volume ejected from syringe) of doses 100 l is +/- 10%. In this study, Tropis achieved DELIVERED volume accuracy of >90%, 95% of the time. Published data on Mantoux success rates are 75-85%. >40%20% - 39%10% - - Percent % Moisture Category Residual Moisture Data 90% of vaccine delivered to patient when data falls to the right of the dotted line Slide 21 Confidential Tropis demonstrated large improvement in pediatric injection performance when compared to device 0246810121425-3618-2412-176-114-52-3 Bleb Diameter (mm) Cohort (months of age) Comparative device performance across cohorts Means (95% CI for means)

8 Tropis 25 children/cohort x 2 injections/child = 50 injections/cohort and a device total of 300 injections 30 children/cohort x 2 injections/child = 60 injections/cohort and a device total of 360 injections Device performance objective: to create ID blebs 5 mm Slide 22 Confidential Step 4: Inject Step 2: Charge Step 3: Load - ID Workflow Step 1. Fill Slide 23 Confidential Very Efficient Vaccine Usage: Tropis has a retained dead space volume of 3 l, a reduction of 28x over a conventional 3cc syringe and needle . BD's Low Waste Space white paper # 0554 Slide 24 Confidential Creating Pre-filled Capacity Slide 25 Confidential Planned Clinical Trials - Tropis Rab ies Domestic: US, ID Rabies Completes rabies efficacy data for PJ technology International: 1) Leiden University, Netherlands Commercial use in travel clinic 2) IIL/PATH Hyderabad On Label?

9 Polio Cuba, WHO, Q4 2012 To support use within global polio eradication program. China, BMGF, Kunming (KIMB) Q2 2013 Sabin ID IPV, first in preclinical models, followed by clinical trial(s). BCG EU-member country, Q4 2012 1,000 infant safety study. Slide 26 Planned Intradermal DSJI Research Slide 27 Overview of planned intradermal DSJI studies Vaccine Location When Partners Device(s) Rabies India 2013 PATH, IPM, IIL ID adapter, PharmaJet Tropis BCG South Africa Q4 2012 PATH, SATVI, University of Cape Town, GPEI Bioject ID Pen IPV Cuba Q1 2013 GPEI PharmaJet Tropis, Bioject ID Pen, Bioject B2000 sIPV China 2013 Kunming, BMGF TBD Slide 28 IPV Cuba Study 5 arm comparison study of immune response of full and fractional dose of inactivated poliovirus vaccine (IPV)

10 Administered intramuscularly and intradermally using different techniques. IM needle and syringe ( ) ID needle and syringe ( ) Device A: Bioject B2000 (ID, ) Device B: Bioject ID Pen Injector (ID, ) Device C: PharmaJet Tropis (ID, ) Purpose: To demonstrate the non-inferiority of a fractional dose of IPV administered intradermally with needle free Devices compared with full doses of IPV. The data generated by this clinical trial are intended to facilitate the regulatory approval for use of fractional doses of IPV. Device A Device B Device C Slide 29 Darin Zehrung, MBA Portfolio Leader, Vaccine Delivery Technologies PATH Vaccine Technologies Group Thank you!