Postmarketing surveillance of pandemic H1N1 vaccines

Transcription

1 Postmarketing surveillance of pandemic H1N1 vaccines Dr Dina Pfeifer and Dr Claudia Alfonso Department of Immunization, Vaccines and Biologicals Quality, Safety and Standards

2 Scene To date major public health interventions using similarly formulated vaccines (polio, measles, small pox, yellow fever ) H1N1 - large number of products with quite distinct formulations whole virion split subunit vaccines egg cell based live inactivated adjuvanted non adjuvanted preserved unpreserved

3 Scene Inherent characteristics of priority or risk groups (population as a whole, pregnant women, individuals with underlying conditions) Background morbidity and mortality data Stratified! Seasonal patterns!

4 Scene Public acceptance of the intervention (recent scares, risk-benefit perception may not want may not need the vaccine) Impact for the immunization programmes in general (mistrust) Safety concerns expressed outside of scientific context and by media are repeatedly raised Vigorous anti-vaccine campaigns are occurring in several parts of the world

5 Safety SEASONAL influenza vaccines Relatively few adverse events are reported after TIV and LAIV in children and adult population when compared with AEFI reporting rate for other vaccines. Reactogenicity profile differs by type of vaccine and age of vaccine recipient (local reactions "very common", systemic reaction common) Observed reactions are mostly mild and self-limited WHO Position paper GACVS reviews (neurological side effects, safety in pregnancy, review of Bells palsy and ORS signal and review of clusters of events)

6 Safety of pandemic H1N1 vaccines in clinical trials Most of the evidence generated on phase 2 trials with H1N1 vaccines, and by reference to H5N1 pandemic vaccines Profile most reactions mild in nature, of short duration, fewer reaction with second dose (inactivated vaccines=blue, LAIV=orange) Very common Common Uncommon Administration site conditions (induration, swelling, pain, redness), fever, chills, fatigue, headache, arthralgia, myalgia Rhinorrhoea, nasal congestion, irritability, malaise Sweating Lymphadenopathy, dizziness, influenza like illness, cough, rhinorrhoea, nasal congestion, malaise Cough, lethargy, headache, sore throat, myalgia Fever, chills, abdominal pain Pruritus, rash, urticaria, diarrhoea, vomiting, abdominal pain, nausea, insomnia, paraesthesia

7 Safety ph1n1 vaccines Expect similar safety profile as with seasonal TIVs, however. Priming not boosting Adjuvants Aluminium salts, MF-59, AS03, (AF04) May lead to increased reactogenicity Focus on autoimmune diseases Antigen properties Limited safety information for certain subpopulations Limited or no information on use of different vaccines for 1 st and 2 nd dose, or on concurrent use of novel H1N1 vaccine with seasonal influenza vaccine Preservative / oil-in-water adjuvant interactions Programmatic errors associated with vaccine delivery

8 Current status App. 25 ph1n1 vaccines licensed Over 100 million doses distributed Varying uptake >>> from shortages to hesitation No new safety signals identified to date High media coverage

9 Safety - general comments Frequency of AEFI reports depends on the monitoring system rough estimate AEFI reports/ doses distributed serious AEFI reports/ doses distributed due to strengthened monitoring systems and better public recognition, rate of reporting may be expected to be higher than for seasonal influenza vaccines Rates of AEFI denominator issues data on doses administered are unconfirmed, capture delayed, or else authorities report crude data and distribution figures

10 Safety - general comments Designation of vaccine Reports failing to distinguish seasonal and ph1n1 vaccine, or no indication of vaccine in countries using more than one product Investigation Quick validation and follow-up of severe cases essential Use of standardized case definitions (e.g. Brighton Collaboration) for case validation essential.

11 Update example (Google translation of Norwegian site) aspx

12 Update example (Google translation of Norwegian site) aspx

13 Update example (Google translation of Norwegian site) aspx

14 Safety general comments Comparisons of safety profile between vaccine types limited data at this stage, as most countries use one type only, or predominantly one type) (e.g. China, Australia, Japan inactivated nonadjuvanted Switzerland, Norway, Italy inactivated adjuvanted) Reports by SOC (system organ class) noticeable difference by reporting countries varies with time from the point of vaccine introduction reflects background characteristics of risk groups receiving the vaccine

15 Safety ph1n1 vaccines Local and systemic reactions are common pain and swelling at injection site, fever, chills, malaise, fatigue, headache, muscle pain Variety of allergic reactions hives, rash, angioedema, anaphylaxis rate of anaphylaxis within expected range, note use of standardized case definitions for case review is essential Deaths in temporal association with immunization majority >65yr, so far follow-ups indicate unrelated causes 1x death due to delayed treatment of anaphylaxis 1x death due to programmatic error

16 Safety ph1n1 vaccines Guillain Barré syndrome currently estimated rate = 0.3/ doses of vaccine distributed many of reported cases don't meet case definitions, or have records of other concurrent infections Gastrointestinal symptomatolgy diarrhoea, vomiting, nausea somewhat higher than expected rate mild and self limited, in meantime rate of reporting declining in several countries Neurological symptoms lip tingling, fainting, dizziness potential for misclassification as anaphylaxis

17 Safety events Programmatic errors Netherlands - cluster of 11 elderly who received insulin instead of ph1n1 vaccine, one person died High frequency of anaphylaxis with one lot (A80CA007A) in Canada doses, 80% administered 3.5 cases of anaphlylaxis/ doses (overall rate 0.32/ doses in Canada) lot is currently on hold for the use (no recall) tests conducted to date and other results of investigation found no explanation for the observation, review is ongoing

18 Postmarketing surveillance influenza vaccines Vaccine utilization monitoring Adequate for EPI vaccines, but limited for influenza vaccines Certain modes of vaccine delivery require auxiliary systems to capture the data Vaccine safety monitoring Reporting mainly through ADR systems (industrialized counties) Missing specific information (e.g. lot number, dose of vaccine) Problems with monitoring programmatic errors through ADR systems Causality assessment process

19 Postmarketing surveillance influenza vaccines Effectiveness monitoring Complex methodological issues Disease burden monitoring Outcome measures Case definitions Background rates of conditions likely to be associated as an AEFI Signal evaluation Setting up special studies

20 Postmarketing surveillance types of surveillance Passive surveillance are national systems capable of monitoring vaccine-associated events in all age groups, at distant points of time, and by all health care providers Self reporting by health care workers immunized against ph1n1 Surveillance for programmatic errors Active surveillance for GBS acute flaccid paralysis surveillance modified to capture cases in all age groups using common case definition or neurologist network reporting all GBS cases Active surveillance of other selected serious events Phase IV studies in selected locations Disease surveillance and assessment of vaccine effectiveness MULTITUDE OF DESIGNS, VARIETY OF LIMITATIONS, TIMELINESS

21 Postmarketing surveillance methodologies Minimal data set for AEFI reporting Source of data (health care databases, AEFI reports) Linkage of vaccine administration and AEFI report data (correct identification of specific product/lot for each dose) Signal generation Analysis Further steps additional studies STRONG LEADERSHIP, NEW COLLABORATIVE STRUCTURES, RAPID DECISION MAKING,FUNDING

22 Essential requirements Measuring exposure to the vaccine Vaccine delivery mechanism? Measuring outcome Large scale screening for unexpected events Focused assessments for a-priori events e.g. GBS Most of today's national surveillance systems inadequate for rapid vaccine safety assessments

23 PMS - Influenza vaccines PSUR INDUSTRIALISED COUNTRIES Long experience with influenza vaccine safety surveillance ADR system through out health system Capacity to rule out coincidental and confirm vaccine reactions at higher level of certainty Ability to monitor outcomes in subpopulations Background data generated more easily Little to no experience with safety monitoring of influenza vaccines Irregular reviews, signals often limited to clusters of events EPI centred AEFI surveillance Limited or no diagnostic capacity i.e. presumptive outcomes Not available DEVELOPING COUNTRIES

24 Regulatory preparedness Licensing requirements in countries differ Regulatory pathways affect vaccine approval Varying capacity for clinical trial authorization, monitoring and review of safety profile of candidate vaccine Post marketing surveillance systems in place are not uniform and in many countries are very weak Necessity to understand conditions and limitations under which the data were generated and analyzed

25 Postmarketing surveillance international collaboration Signal generation National programmes WHO International Drug Monitoring Programme (consider delays and limitations for vaccine reports) Multicentre active surveillance for GBS Information sharing Bilateral regulatory agreements WHO regulatory networks (weekly safety teleconference) Publicly disclosed information Interaction with manufacturers Rapid alert systems Regulatory and public health authority interactions Pharmacovigilance networks (at present limited) International Health Regulation Surveillance tools Study protocols Guidelines for recognizing and reporting of AEFI

26 Conclusion LIMITED INFORMATION TIME CRUNCH UNCERTAINTIES Timely collection and assessment of safety and immunogenicity data MODIFICATIONS WHEN WARRANTED RAPID INFORMATION SHARING

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