The Brazilian experience: the role of national regulatory agency in technology development, production, importation and in the approval of future products

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In s titu to d e Tec no lo g iaem Im uno b io ló g ic o s

The Brazilian experience: the role The Brazilian experience: the role of national regulatory agency in of national regulatory agency in

technology development, technology development, production, importation and in the production, importation and in the

approval of future productsapproval of future products

Dr. Akira HommaDiretor Bio-Manguinhos

Fundação Oswaldo Cruz

Ministério da Saúde

Brasília, DF, 4-5 Outubro 2006

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Fonte: Ministério da Saúde, SI-PNI.

%

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Vacinas Laboratórios Quant. TOTAL R$Quantidades Dispêndios

Impor. Nac. Impor. Nac.

BCG-IDFAP 16.500.000 8.738.400,00 - 8,4% - 1,5%

BUTANTAN 2.000.000 1.059.200,00 - 1,0% - 0,2%

Febre Amarela BIO-MANGUIN 10.000.000 8.383.000,00 - 5,1% - 1,5%

Poliomielite oral

BIO-MANGUIN 20.000.000 34.320.000,00 - 10,2% - 6,0%

GSK 27.000.000 8.127.000,00 13,7% 1,4%

Sanofi Pasteur 9.000.000 2.902.500,00 4,6% 0,5%

Chiron 9.000.000 2.709.000,00 4,6% 0,5%

DTP BUTANTAN 13.200.000 4.620.000,00 - 6,7% - 0,8%

Hepatite B

BUTANTAN 11.000.000 15.876.000,00 - 5,6% - 2,8%

LG 3.000.000 1.244.850,00 1,5% 0,2%

Herber Biotec 1.000.000 473.000,00 0,5% 0,1%

Tríplice Viral SCR BIO-MANGUIN 20.000.000 120.000.000,00 - 10,2% - 20,9%

Dupla Adulto dT BUTANTAN 15.000.000 4.536.000,00 - 7,6% - 0,8%

Tetra DTP+HibBIO-MANGUINBUTANTAN 12.000.000 109.784.400,00 - 6,1% - 19,1%

Influenza BUTANTAN 19.000.000 120.460.000,00 - 9,7% - 21,0%

Rotavírus oral GSK 8.670.000 130.483.500,00 4,4% 22,7%

Total 196.370.000 573.716.850,00 29,4% 70,6% 25,4% 74,6%

Fonte: MS / SVS

Domínio de todas tecnologias de produção de vacinas do calendário básico de imunização – exceto rotavirus

Vacinas do Calendário Básico e Campanhas - Aquisições do PNI - 2006Vacinas do Calendário Básico e Campanhas - Aquisições do PNI - 2006

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REGULATION OF VACCINES IN REGULATION OF VACCINES IN PRODUCTION & NEW VACCINES - HIV PRODUCTION & NEW VACCINES - HIV

IN PRODUCTION - BRAZILIAN REGULATION (RDC 210 & 315) & INTERNATIONAL: - PRODUCTION PROCEDURES;- RAW MATERIAL;- INTERMEDIATE PRODUCTS - PURITY; - FINAL PRODUCT; - EFFICACY & POTENCY; - CONSISTENCY OF PRODUCTION;- STABILITY, THERMAL-STABILITY; - PERSONNEL; - OPERATION VALIDATION;- PRODUCT VALIDATION;

- PRE-CLINICAL STUDIES; - CLINICAL TRIALS – PHASE 1, 2 AND 3;- POS-MARKETING

ANTI- HIV/aids vaccines – Prophylatic and Therapeutic - New and complex, requires new regulatory approach with early participation of regulatory authority

Facilities & Equipments

BIOSAFETY

ENVIRONMENT

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STEPS FOR VACCINE DEVELOPMENTSTEPS FOR VACCINE DEVELOPMENT

Characteristics: multiples steps; multiple specialized teams; each step, specific requirement; long period; not linear --- need strong coordination

Early participation of Regulatory Authority is essential !!!

> 10-20 years

Discovery- 1 -

Pre-Clinical- 3 -

Experimental Lots – clinical studies - GMP

- 4 -

Clinical StudiesPhase I

- 5 -

Phase II- 6 -

Fase III- 7 -

License- 8 -

Phase IV - 10 -

Proof of concept

- 2 - Producion

- 9 -

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The scientific strategic plan of the Enterprise identifies six key challenges to the development of an effective AIDS vaccine, and proposes the formation of consortia or centers to further accelerate vaccine research. Adapted with permission from a figure created by the Bill & Melinda Gates Foundation

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DIVERSITY OF TECHNOLOGICAL APPROACHDIVERSITY OF TECHNOLOGICAL APPROACH

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Potential advantages and disadvantages of major HIV vaccine design strategies.

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HIV poses a formidable challenge for vaccine developers: it mutates rapidly, attacks immune cells that might destroy it,

An effective vaccine will be two-pronged: generating antibodies, stimulate immune cells.

Gates Funding: 11 consortia selected.

five will seek ways of generating effective antibodies when the immune system is exposed to HIV. a consortium led by Robin Weiss of University College London, ($25.3-million), will screen antibodies from humans and animals that seem naturally active against HIV, and then work backwards to see which regions they target and design new vaccine candidates.

a consortium led by Leo Stamatatos at Seattle Biomedical Research Institute ($19.4-million ) will use computers to design molecules that might trigger antibodies against the virus.

six consortia will focus on stimulating a cellular response. Timothy Zamb of the International AIDS Vaccine Initiative ($23.7 million) to try to modify other viruses to act as vectors for the vaccine.

Giuseppe Pantaleo at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, ($15.3-million ) hopes to improve the ability of poxvirus, a known vaccine vector, to trigger a response to HIV.

Declan Butler - Nature 442, 610-611(10 August 2006)

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Lancet 2006; 368: 511–21

Mother-to-child transmission (MTCT) of HIV-1 is the major mode of paediatric infection. The rapidly increasing incidence of MTCT worldwide has resulted in an urgent need for preventive strategies. Antiretroviral regimens can prevent intrapartum HIV transmission; however, these regimens do not prevent HIV transmission through breastfeeding.

Furthermore, children who escape MTCT are again at risk of infection when they become sexually active as adolescents.

An infant vaccine regimen, begun at birth, would hence be a more attractive strategy and might also provide the basis for lifetime protection.

Unique features of MTCT and paediatric HIV disease could be helpful in understanding correlates of immune protection and could facilitate rapid assessment of vaccine e. cacy. Thus, there is compelling rationale to develop safe, e. ective HIV vaccines for use in infants and children.

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ANTI-HIV UNDER DEVELOPMENTANTI-HIV UNDER DEVELOPMENTJULY 2006JULY 2006

• CANARYPOX VECTOR -ALVAC vCP 1452 (Sanofi Pasteur)

• DNA PLASMIDIAL -Clade C Gag-Env plasmids (Chiron) -EP HIV-1090 (Epimmune) -pGA2/JS2 DNA (Emory) -VRC-HIVDNA-009 (NIH VRC) -WLV003 (Wyeth) -Gag and Env DNA/PLG microparticles (Chiron)

http://www.sanofipasteur.com/

http://www.sanofipasteur.com/

http://www.chiron.com/

http://www.epimmune.com/templates/epmn.cfm

http://www.emory.edu/WHSC/YERKES/VRC/

http://www.niaid.nih.gov/vrc/

http://www.wyeth.com/

http://www.chiron.com/

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• FOWLPOX VECTOR -TBC-F357;TBC-F349(Therion Biologics)

• LIPOPEPTIDE -LIPO-5 (Sanofi Pasteur/ ANRS)

• MAV (Ankara) -MVA pGA/JS2 (NIAID-LVD) -TBC-M358; TBC-M335 (Therion Biologics)

• ADENOVIRUS VECTOR NO REPLICABLE -MRKAd5 HIV-1 Gag (Merck) -VRC-HIVADV-010 (NIH VRC)

• PEPTIDE -Multi-epitope CTL peptide vaccine (Wyeth)


http://www.therionbio.com/

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• PROTEIN -AIDSVAX B/B (VaxGen) -Clade C Env subunit (Chiron) -gp120 MN (VaxGen) -AIDSVAX B/B (VaxGen) -gp140 SF-162 -- oligomeric, V2-deleted (Chiron) -gp120W61D (GlaxoSmithKline) -NefTat (GlaxoSmithKline)

• YEAST VECTOR -HIVAX-GS (GlobeImmune)


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CHALLENGES: ANVISA FACING CHALLENGES: ANVISA FACING NEWNEW VACCINES HIVVACCINES HIV

Variety of technologies used for anti HIV/aids vaccines

• The establishment of ANVISA is relatively new - gaining experience;

• BIOLOGICAL AND IMMUNOLOGICAL COMPLEXITY OF HIV/aids

• Each country has to establish their own regulations; • RELATIVE SMALL NUMBER OF RESERCHERS

INVOLVED IN HIV/aids

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CHALLENGES: ANVISA FACING CHALLENGES: ANVISA FACING NEWNEW HIV HIV VACCINESVACCINES

• For live attenuated virus vaccine there are general requirements established;

• For DNA vaccines there is FDA´s guidance; • For subunits and recombinant vaccines there are

requirements established;For viral and bacterial vector vaccines there is no

requirement established; Lack of information on technology aspects from

developer laboratories.

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SIX-SYSTEM INSPECTION MODELSIX-SYSTEM INSPECTION MODEL

FDA – Pharmaceutical CGMPs – Sept. 2006

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PROPOSAL FOR TECHNOLOGICAL PROPOSAL FOR TECHNOLOGICAL DEVELOPMENT STRENGTHENING DEVELOPMENT STRENGTHENING

POLICY, LEGAL, ETHICAL OPERATIONAL: Organization of Technical Advisory Committee

with participation of Anvisa, MoH, MC&T, MRE, MF, R&D institutions with following functions:

• Identification and selection of the most promising technological approach for development in Brazil;

• Identification of anchor institutions that must take part in R&D of anti-HIV/aids vaccines.

• Set out specific projects, with defined tasks and schedules, with participation of the correspondent authority, to follow, monitor, evaluate the steps up to production process.

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PROPOSAL FOR TECHNOLOGICAL PROPOSAL FOR TECHNOLOGICAL DEVELOPMENT STRENGHTHENINGDEVELOPMENT STRENGHTHENING

• Establishment of technical cooperation among countries and companies that work with HIV/aids vaccine development;

• Establish specific technical projects dealing with improvement of regulatory issues involved;

• Networking/consortium should be organized in order to address different aspects of development;

• Globalization must contribute to facilitate the R&D.

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PROPOSAL TO STRENGTHEN TECHNOLOGICAL PROPOSAL TO STRENGTHEN TECHNOLOGICAL DEVELOPMENTDEVELOPMENT

A strong coordination and project management procedures with definition of specific targets and timetable for each institution;

Strengthen the administrative (professional) management

Integration of related R&D activities – Research institution&technological development & regulatory authority + Ministry of Finance/Science &Technology/External Relations

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• THANK YOU FOR YOUR ATTENTION !!!

Documents

The Brazilian experience: the role of national regulatory agency in technology development, production, importation and in the approval of future products