You are on page 1of 10
SANOFI PASTEUR 39 Responses to Question dated 22December 2015 Reference submission: Sanofi Pasteur Dengue Vaccine Initial Marketing Autorisation Application Applicant Sanofi Pasteur Product Nae CYD Dengue Vaccine Submission Country __| The Philippines ThinkingPinoy ‘Canfidential/Proprietary Information RA_1159090 Page Vat Ut Sanofi Pasteur Respanses to Questions 323~ CYD Dengue Vaccine Table of Contents Routine Pharmacovigilance Practices ----usenernnnne 3 eee Enhanced PV Monit . Post-Authorization Safety Studies (PASS) .... 5 Post-Authotization Eilectiveness Studies (PALS) Clinical studies PV Plan for Specific Safety Concerns. ‘Comelusion aa nee 1eA_ 1159090 ‘ConfidentiaProprictary Page? of I Responses £8 Questions Sane: Paste Question 1 Sanofi Pasteur is required to provide & specific Pharmacovigilance Plan for Philippines. Response: id in endemic areas), no important with respect to cfaisned popalation (from 9 through 45 years ol reified inks Rave becn established for CYD dengue Qaeeine. Four important identified risks se been eseblished for CYD dengue vaccine: allergic anaphylactic reaction. visoerotropism and saurotropism, increasé in severity of dengue discase from the start of vaccination and waning, protection against dengue disease over Hime, To address these risks and to ensure appropriate post-markgeting surveillance in the Philippines aco the waceine is on market, Pharmacavigilance Plan deployed in Philippines will consist of passive (or routine) oo rcillance (described below in the sections Routine pharmacovigilance practices and Enhanced PV monitoring) an active surveillance (described below in the sections Post-Authorization Safety Studies (PASS), eet Authorization Effectiveness Studies (PATS) and clinical studies). Routine Pharmacovigilance Practices nce attivities are conducted al level by the Loeal Pharmacovigilance by Global Pharmacovigitance Department at Contact designated in Sanofi The Pharmacovi Global level and Loes Pasteur Philippines affiliate. Global Pharmacovigilance Department (C asteur products’ benefit-risk balance throu The mission of the PV) is to: Contribute to the evaluation of Sanof ighout their life-cycle (pre and post marketing) lated to Safety Signal detection/maai nent Planning, agement and Risk Meant «Lead activities plicable regulatory requirements ¢ with Company standards and Pt © Ensure _complianes worldwide, including Philippiaes Colle fry data The pharmacovigilaace practices of data from various worldwide sourees; including Spontaneous reporting, but alsa inelude scientific Tuerature (sereening of Philippines’s Hterature se aone by Philippincs's affiliate in ordes to detect say TCRs (Individaal Case Safety Report} or calety signal related to the vaccine), product complaints database amd manufacturing Srvcctigatign, solicited [CSRs ftom interventional and hron-interventional studies, Flealth Authorities. media. datahase {he GPV of Sanofi Posteur consist ofthe capture of safety Philippines. The main souree of reporting isthe ‘Central safety! — GoniSienTatropstesryInlereaton Page 3etl ThinkingPinoy Sanofi Pasteur [Responses tn Questions 324 —CYD Dengue Vaccine, [All adverse ovent reports received fiom Philippines and worldwide will be entered into a single Validated Global Pharmacovigilance System database. All cases are processed by trained and qualified personnel per standard operating procedures (SOPs) to ensure necessary quality standards throughout the cycle which includes case documentation, data collection, follow-up, validation, evaluation, reporting, and archiving, Expedited Reporting AIL ICSRs received worldwide (including Philippines) will be medically assessed and those requiced for submission in Philippines, will be submitted to FDA- PRSDD- PV unit, This will be done in clase collaboration between GPW and Philippines’s affiliatc. According to current regulations, all serious cases (related and not related) will be reported to the FDA on an expedited basis (within 15 calendar days) and non-serious euses (elated and not related) on @ quarterly basis. Signal detection management Safety signal detection and management is one of the major activities of GPV. It is the set of activities performed to determine whether, based on an cxamination of ICSRs, agersyated data from active surveillance systems or studies, literature information or other data sources, a new risk associated with an active substance or a medicinal product has been identified or whether known risks have changed (Turopean Medicines Agency Good Pharmacovigilance Practices Module 1X). The signal management process includes all steps from initial signal detection through their validation, assessment and confirmation up to recommending action, as well as the tracking of the steps taken and of any recommendations made. ‘Once the dengue vaccine is on market, the periodie Safety Evaluation Team (SET) aetivitics will start at Global level, with a systematic review of safety data to assess the benefit risk ratio of the product and detsetion of signal and. potential safety issues. In case of identification of safety ‘Signal, it will underge all above-mentioned steps of signal management process with involvement ‘of all needed intemal safely committees. If the signal is confirmed as safety risk or safety issue, appropriate risk minimization sctivities will have to be put in place for risk mitigation/minimization; these activities may consist of but are not limited to change of authorized product labelling and prompt communication to the Health Authorities. Periodic reporting Periodic Benefit Risk Evaluaiion Reports (PBRERs) with 1 6-month periodicity will be issued during the first two years af post-markeling experience. The PBRERs will provide a cumulative overview af adverse events received from worldwide sources during the reporting period. The PBRERs will bs prepared by GPV and provided to Philippines’s affiliate for submission to FDA- PRSDD- PV unit. 1090 ContidentialiProprietary age d of UL ThinkingPinoy ete Sauofi Pasteur Responses to Quest 325 CYD Dengue Vaccine enhanced PV Mot In addition to routine PV activities, enhanced PV surveillance in the post-markoting setlings is, planned by Sanofi Pasteur to strengthen the AE reporting systems in the countries where CYD vaccine will be licensed using the following methods: © To solicit reporting of AES To provide cducational training on the vaccine safety profile and phasuace vigilance activities, The following Lapics axe proposed for inclusion in these training materials: ‘+ Pharmacovigilance awareness (¢.g. basies in pharmacovigilance, Adverse Event Following Immunization (AFD) definition, APPT surveillance (reporting, signal investigation and. causality assessment) + Dengue virus, dengue epidemiology, dengue disease + Dengue vaevine safety profile and important potential risks, risk-benefit assessment = Dengue vaccine use (labeling information). + To [oster an cnvironment of exchaiges of AE information between Nutional Regulatory Authorities, Ministsivs of Heath, WHO and Sanofi Pasteur The plans for enkiunced PY surveillance will be further discussed with Health Authorities and relevant non-governmental organizations during technical meetings. They will be adapled amd customized accordingly. Post-Authorization Safety Studies (PASS) ‘Safety of the vaccine will also be evaluated through specific safely studies. Two PASS (DNGI5. and DNG16) will be conducted, both of them with sites in the Philippines, as dctailed below. For the DNGI6 study (pregnancy registry) however, the possibility to have sites in the Philippines needs to be confirmed during feasibility assessinieats, and will depend on national recomendations and targeted age groups. In addition to these two studies, there is an ongoing safety study((DNG IT} to determine background incidence rates of canditions that ean mimic visccrotropisin and neurotropism. This study 1s conducied in Malaysia, Mexico and Brazil. ~ ee ES DNGS/eohor event monitoring study DNGIS will be a mulkienational observational prospective cohort event monitoring (CEM) study using standardized data collection instruments to obtain information on selected AESIs among subjects Vaccinated with the CYD dengue vaccine as per routine practice, over a period of § years afler the first vaccine dose. The study will be conducted in countries where the dengue vaccine will first be introduced, in Latin America (Brazil, Mexico) and Southeast Asia (Philippines, Malaysia) and ii is planned to recruit 30,000 subjects across these four countrics. The total duration of surveillance of each subject is expected to be 5 years after the first vaccine dose. RA_is090 Confidentiaiopriet Page Set! Tinformatir ThinkingPinoy Responses to Questions Sanofi Pasteur 323 -€V Dengue Vaceine In the Philippines. itis anticipated that 2,500 subjects wall be recruited using a convenient sample of sites, in different regions and settings xo that these subjects should be broadly representative of the population in whom the vaccine is being used, according to vaccination introduetion strategy. “The primary objective of DNGIS is to evaluate the safety profile of CYD dengue vaccine when used in real-world immunization settings, In addition, an exploratory objective is to describe, by country, the population vaccinated with CYD dengue vaccine in real-world immunization seltings, according to age, gender, number of doses recived and interval between doses, comorbidities including immunosuppression, co-vaceination, history of recent vaccination, history of dengue, and off-label usc (ex. use in pregnancy of lactation, use in younger children « 9 years of age). Ench vaceine recipient will be followed for a total of S years after they receive the first dose of the vaceine, to cnable compleic and long-icrin monitoring of vaccine safety. This CEM study includes two components “Short-term safety surveillance with a follow-up at 1.5, 3 and 4.5 months after each CYD dengue vaccine dase to collect specific data on the frequency and timing of potential adverse ‘events following vaccination (u total of 9 contacts if the subject receives 3 doses. s, fora maximum of -Long-tcrm safety surveillance with 2 follow-up regularly, every 3 month five years after the first dose, in order to identify any SAFs that vaccinated subjects may have experienced, including dengue disease. Jn order to- assess the association between the dengue vaccine and the occurrence of selected AES ‘for which a risk window can be defined after vaccination, 2 selC-controlled case series analysis sill be conducted using daia collected after each dose. A risk-window period will be determined specifically [or each AT based on literature findings, and the remainder of this short-tesm follow- up perind will be considered to be the control period. Ths crude incidence rate tor each AE during, the risk-window period and the contrel peried will be caleulated. Incidence rate ratios (IRRs) with 495% confidence intervals will be determined in order to quantify the strength of the association hretween the dengue vaeeine and the risk of selected APs. In addition, during the study, salty monitoring will be performed to detect any safety signals on ongoing basis. ‘During the total study petiod (ic. for about 5 years of follow-up for each subject), u nested case contral study will he initiated 13 cases or more of serious or severe dengue disease are identified. The aim of the nested case control is to identify risk factors for serious or severe dengue among the vaceinces. In the nested cass-conlrol study, all individuals will have been expased to the vaccine. During the CEM study, a periodic safety monitoring will be performned to detect any salety signals and iTany will be timely shared with Health Authorities esq Salen Propet avormation Pave af tt ThinkingPinoy Sanofi Pasteur Responses to Questions 323—CYD Dengue Vaccine It is planned to bogin this study after the vaccine is launched in the Philippines, in the private sector. The study plans to cover both private and publi¢ sectors, depending on the intraduction stacey This study is currently in the feasibility planning phase, and five sites have been identified and visited, in different regions, It is anticipated that following feasibility assessments, ethical and coniractual processes, the study would start afler the introduction of vaceination in 2016. DNGlélpregnancy registry stray This will be a voluntary, multinational, prospective, observational study regarding exposure to CYD dengue vaccine during pregnancy and matemal, fetal, and infant outcomes (up t@ 6 months of age). The sudy will be conducted in countries where the dengue vaccine will first be Sntroduced, including Latin America (Brazil, Mexico) and Southeast Asia (Philippines, Malaysia. ‘A concurrent comparison group of unvaccinated pregnant women fram the same source populations will also be assembled. It is planned to recruit S00 pregnant women inadvertently exposed to the CYD vaceine and 1000 unexposed pregnant women (ratio 1:2), matehed on calendar month, country, recruitment site, maternal age, trimester of pregnancy. Depending on “vaccine implementation sinaleyies of these four countries, the target sample size and number af sted countries involved in the study may be adapted. In any case, it is planned that the pregnancy registry study should run only for a maximum of five years, from the date when the fest pationt is recruited to the conclusion of the last infant follow-up ~ in other words, the study vill stop afler five years, irrespective of whether or not the target sample size has been reached, or carlier if the target sample size is reached earlier. Exposed and unexposed pregnant women will be recruited in a sample of antenatal clinics located in areas where vaccine uptake is relatively high in women or adolescents who arc old enough ts be pregnant — thus the location of study sites should be driven by vaccination campaigns in each study country. In addition, women enrolled in DNGIS who were vaccinated within 30 days of last menstrual period (LMP) will be followed and assessed in a similar way as in the pregnancy registry, a5 far as possible. Structural and functional congenital anomalies ideutified in the perinatal period through 6 months of life will be collected and classified, and developmental status in infants will also be recorded. In addition, exposure Lo CYD dengue vaccine during lactation will be evaluated both in DNGIS and DNGI6 stuclies, in a consistent way as far ay possible. In case national recommendations and feasibility assessments allow the Philippines tw take part t0 the DNGI6 study, this registry will collect data on inadvertent vaccine usc in pregnancy in the Philippines and will be conducted concurrent with the cohort event monitoring with follow-up of women and infants as described in the pregnancy registry protocol. Plans for this activily will end on the implementation stratezy in cach of the faur countries involved (including the public sector), and should be discussed with experts RA_1159000 ‘Confidential Proprietary Page af 1 inkingPinoy Sanofi Pasteur Responses to Questions 383— CYD Dengue Vaccine (PAES). Four PAES will be conducted in Asia and Latin America to evaluate the impact of ‘vaccination, including one in the Philippines (CY 269). ‘These studies willl assess the vaccine effectiveness in community level, as well as redaeing Frequency of hospitalization and severe forms of dengue discasc. In addition, while not specitically designed to adress safety, these studies will provide a platform ta identify a potential incrcasc in discasc severity and a potential Wasting of protection over Lime. The Philippines will be included in Sanofi Pasteur’s long-term effectiveness monitoring. This will measure the impacts of vaccination on hospitalized dengue using a case-based approach. As such, this study design will also feature important safety end-points, enabling detection of incrcased hospitalized dengue in vaccine recipients, odds of dengue hospitalization based on compliance, and odds of dengue hospitalization based on duration since vaccination (poteat The calchment population is estimated to be 140,000 individuals targeted for vaeci preparatory phase of this sludy is de to hegin in Philippines in Ql 2016. Clinica! studies Other studies included in the RMP will alse contribute to fusther develop the safety database of the vaccine. These studies aref will he conducted under GCP where all AEFI will be recorded and documented. They will provide information on long-term safety, use in specific population. co- administration of CYD, and need for booster, Ea ns9090 ‘Canfidentia Proprietary Information Page 8 af 11 ThinkingPinoy Sunol Pasteur Responses to Questions 323—CYD Dengue Vaccine 2 eee C¥DI4 and CYDIS amendments t0 long-term follow-up Protocol amendments in CYDI4 and CYD15 will be implemented to caplure the full range of dengue discase in the study population prospectively (i.e, return te aetive detection of all symptomatic dengue eases). Stengilening the surveillance system afer the first year of the Hospital Phase will ensure that all cases of denguc disease are detected rapidiy and that participants have access to appropriate treatment; moreover, it will enable evaluation of lang team ctticacy! safety profile of the CYB dengue vaccine. The subjects will Be followed for 5 years after the third injeetion. ‘The Philippines is one of the $ countries int Asia where CYD14 is conducted with more than 3000 subjects included. Co-administeation Given the age range of the claimed population in the indication fram 9 years and above, Sanofi Pasicur will assess co-administration of CYD dengue vaccine with Tuman papillomavirus ‘vaccines, namely Cervarix® and Gardasil, as well as with adolescent booster against Tdap, both immunizations being the most frequently recommended in the countries where the CYD dengue vaccine is intended to be first registered, i.c. the Philippines, Mexico, Brazil and Malaysia. Three Phase IIb, randomized, opsn-lbel co-administration trials are planed to start in 2016. The study that will be conducted in the Philippines, will evuluate co-miminisimation of CYD dengue vaccine with Adacell® in population from 9 to 45 years of age. Booster studios (C¥D63 und C¥D6S) In addition, a need for booster will be evaluated in fallow-up studies from Phase I studies (CYD63 and CYD64), they will be conducted in Singapore, Colombia, Honduras, Mexica, Puerio Rico and Brazil. cYDs This Phase II immunogenicity and safery study include [IV adult subjcets with stable clinical cond planned ( be conducted in Brazil. It will mn-under antiretroviral therapy. PY Plan for Spee ifety Concerns ss of PV plan as per important risks, with respect to claimed population (from 9 mportaat identified risks have been established for Looking at acth through 45 years old in endemic arcas}, CYD dengue vaccine. Important potential risks are: allergic/anaphylactic reaction, viscerowopism and ncurotropism, increase in severity of dengue disease from the start of vaccination and waning protection against ma iss080 GontienttaPropriceary Information Page 9 oF ThinkingPinoy Sano Pasteur mp -cvn De dengue discasc over cal be implemented suc Vaccine he tuble below summrari7 ime. 7 pilippines 1 specifically inthe Pk pet esponset ta Qucsifom } cx these activities and highlights actions nat | the dengue vaccine RMP “pale 1: RMP: Overall Susmmary For Important Potential Risks ieee ae | aN POTENTIALS ram eae Ta & inweascin Wang } ee Tein ween “inmac | sateen | ee | Zener | | ace | ee Fae eae terete | sient mene x x « re Soy Sarees? Tang ees Monitor anal ase ate = ae ne oa wo osm x x CXDLIT 15 wih evens eae | Co andthe Pi! | | prominent ae —-- | eer ace CHG and DAH “ini tpn orton sae go le Z a a nets nhs 0h Te poe ieee a re TCvDS 3, CDT, CDOS | | crates es | x x Cr een pratt 1#800) is inort Event Monitoring __——_+— Sp | assent eit the «s | # Ra Parnes \ DAGI = Background inciden tee ae =| ela “Tho detailed action plan to adress these Gmmportant potential risks and further detailed in the RMP: Vigcqrebopism © RGure fragx Sh ‘Conclusion is a welltbalanced mix between active and passive safety ‘usc. Lt will further inform oa In conclusion, ao errllance tkng into account countty sf [EF and vaccine safety peofite and cfTectiveness of the ¥ 200 Overall for the global RMP, with the com ued Tl elimeal studies (CYDI4 and CD'S), 19088 ‘ham 60,000 Jong-term monitoring in phase —~ Conta Sajal Praprletary tatormation Page 10 of I ThinkingPinoy

You might also like