Data privacy protection in scientific publications: process implementation at a pharmaceutical company.

BACKGROUND: Sharing anonymized/de-identified clinical trial data and publishing research outcomes in scientific journals, or presenting them at conferences, is key to data-driven scientific exchange. However, when data from scientific publications are linked to other publicly available personal information, the risk of reidentification of trial participants increases, raising privacy concerns. Therefore, we defined a set of criteria allowing us to determine and minimize the risk of data reidentification. We also implemented a review process at Takeda for clinical publications prior to submission for publication in journals or presentation at medical conferences. METHODS: Abstracts, manuscripts, posters, and oral presentations containing study participant information were reviewed and the potential impact on study participant privacy was assessed. Our focus was on direct (participant ID, initials) and indirect identifiers, such as sex, age or geographical indicators in rare disease studies or studies with small sample size treatment groups. Risk minimization was sought using a generalized presentation of identifier-relevant information and decision-making on data sharing for further research. Additional risk identification was performed based on study participant/personnel parameters present in materials destined for the public domain. The potential for participant/personnel identification was then calculated to facilitate presentation of meaningful but de-identified information. RESULTS: The potential for reidentification was calculated using a risk ratio of the exposed versus available individuals, with a value above the threshold of 0.09 deemed an unacceptable level of reidentification risk. We found that in 13% of Takeda clinical trial publications reviewed, either individuals could potentially be reidentified (despite the use of anonymized data sets) or inappropriate data sharing plans could pose a data privacy risk to study participants. In 1/110 abstracts, 58/275 manuscripts, 5/87 posters and 3/58 presentations, changes were necessary due to data privacy concerns/rules. Despite the implementation of risk-minimization measures prior to release, direct and indirect identifiers were found in 11% and 34% of the analysed documents, respectively. CONCLUSIONS: Risk minimization using de-identification of clinical trial data presented in scientific publications and controlled data sharing conditions improved privacy protection for study participants. Our results also suggest that additional safeguards should be implemented to ensure that higher data privacy standards are met.

Pre-vaccination immunity and immune responses to a cell culture-derived whole-virus H1N1 vaccine are similar to a seasonal influenza vaccine.

BACKGROUND: Immune responses to novel pandemic influenza vaccines may be influenced by previous exposure to antigenically similar seasonal strains. METHODS: An open-label, randomized, phase I/II study was conducted to assess the immunogenicity and safety of a non-adjuvanted, inactivated whole-virus H1N1 A/California/07/2009 vaccine. 408 subjects were stratified by age (18-59 and >60 years) and randomized 1:1 to receive two vaccinations with either 3.75 or 7.5 µg hemagglutinin antigen 21 days apart. Safety, immunogenicity and the influence of seasonal influenza vaccination and antibody cross-reactivity with a seasonal H1N1 strain was assessed. RESULTS: A single vaccination with either dose induced substantial increases in H1N1 A/California/07/2009 hemagglutination inhibition (HI) and neutralizing (MN) antibody titers in both adult and elderly subjects. A single 7.5 µg dose induced seroprotection rates of 86.9% in adults and 75.2% in elderly subjects. Two 7.5 µg vaccinations induced seroprotection rates in adult and elderly subjects of 90.9% and 89.1%, respectively. The robust immune response to vaccination was confirmed by analyses of neutralizing antibody titers. Both HI and MN antibodies persisted for ≥ 6 months post-vaccination. Between 34% and 49% of subjects had seroprotective levels of H1N1 A/California/07/2009 antibodies at baseline. Higher baseline HI titers were associated with receipt of the 2008-09 or 2009-10 seasonal influenza vaccine. High baseline A/California/07/2009 neutralizing antibody titers were also associated with high baseline titers against A/New Caledonia/20/99, a seasonal H1N1 strain which circulated and was included in the seasonal vaccine from 2000-01 to 2006-07. Pre-adsorption with A/H1N1/New Caledonia/20/99 antigen reduced A/H1N1/California/07/2009 baseline titers in 55% of tested sera. The vaccine was well tolerated with low rates of fever. CONCLUSIONS: A whole-virus H1N1 A/California/07/2009 vaccine was safe and well tolerated and a single dose induced substantial immune responses similar to seasonal influenza vaccines, probably due to immunological priming by previous seasonal influenza vaccines or infections.

Safety and immunogenicity of two different doses of a Vero cell-derived, whole virus clade 2 H5N1 (A/Indonesia/05/2005) influenza vaccine.

A successful vaccine development strategy for areas with clustered H5N1 events requires conduct of vaccine trials in potentially non-naïve subjects and evaluation of post-vaccination responsiveness. An open-label, randomized, phase I/II study therefore assessed the immunogenicity and safety of two different dose levels of an inactivated, non-adjuvanted, whole virus clade 2.1 (A/Indonesia/05/2005) H5N1 Vero cell-derived influenza vaccine in healthy adults (21-45 years) from a region where the virus has been circulating (Hong Kong) as well as Singapore. Subjects (N=110) were randomized 1:1 to receive two vaccinations with either 3.75 µg or 7.5 µg H5N1 haemagglutinin antigen 21 days apart. Safety, immunogenicity (microneutralization [MN] and single radial haemolysis [SRH] at baseline and post-vaccination) and cross-reactivity against a heterologous clade 1 strain (A/Vietnam/1203/2004) of the vaccine were assessed. Pre-existing immunity to the vaccine strain was 14% which is higher than previously reported for these regions. Two vaccinations with either vaccine formulation induced high seroprotection rates (MN titre ≥ 1:20) against the vaccine strain A/Indonesia/05/2005: 82.7% and 86.5% in the 3.75 µg and 7.5 µg dose groups. Seroconversion rates and fold increase exceeded the CPMP criterion of >40% and >2.5 for MN and SRH in both dose groups after the second vaccination, while the seroprotection rate in the 7.5 µg dose group determined by SRH was only marginally lower (69.2%) than the CPMP criterion of >70%. Thus, 11 of 12 CHMP criteria were fulfilled. A cross-reactive antibody response against the heterologous A/Vietnam/1203/2004 strain was demonstrated after the second vaccination (>21% by MN and ≥ 25% by SRH). Persistence of antibodies against the vaccine strain was also demonstrated 6 months after the first vaccination, indicating that a booster vaccination would be effective in those who have received two priming doses. No serious adverse events were reported. The H5N1 influenza vaccine against clade 2.1 strain A/Indonesia/05/2005 was well tolerated and immunogenic after two vaccinations, and induced a cross-neutralizing antibody response, with no dose effect.

Clinical evaluation to determine the appropriate paediatric formulation of a tick-borne encephalitis vaccine.

Two dose-finding studies and one open label safety study with a paediatric FSME-IMMUN formulation were conducted in children and adolescents aged 1-15 years (N=3697). The 1.2 microg antigen dose was identified as the optimal dose, inducing high seroconversion rates following the primary vaccination series. Adolescents (aged 12-15 years) vaccinated with the optimal paediatric dose (1.2 microg) attained similarly high seroprotective rates to adults (aged 16-35 years) vaccinated with the 2.4 microg formulation of FSME-IMMUN. We concluded that the FSME-IMMUN paediatric vaccine formulation is safe and highly immunogenic, not only for children <12 years, but also for adolescents <16 years.

Comparison of immunogenicity and safety between two paediatric TBE vaccines.

TBE vaccination strategies capable of inducing strong paediatric immunogenicity and acceptable reactogenicity are still under evaluation. This single-blind, multi-center, randomized, controlled, phase III clinical study compared the immunogenicity and safety of the two paediatric TBE vaccines available in Europe (FSME-IMMUN Junior and Encepur Children) following administration of two doses of either vaccine in 303 children aged 1-11 years. Regardless of immunological test or viral antigen used, immunological responses were consistently higher in children vaccinated with FSME-IMMUN Junior than those vaccinated with Encepur Children. FSME-IMMUN Junior is also non-inferior to Encepur Children, with respect to NT seropositivity rates (p<0.0001). Systemic reaction rates were low and similar between the vaccines. However, among children aged 7-11 years, local reactions were significantly higher after the first (p<0.01) and second (p<0.001) vaccination with Encepur Children than with FSME-IMMUN Junior, affecting half the children in the former group: 22.4% and 10.2% with FSME-IMMUN Junior vs. 49.0% and 51.0% for Encepur Children.

A cell culture (Vero)-derived H5N1 whole-virus vaccine induces cross-reactive memory responses.

Novel strategies are required to provide rapid vaccine coverage in the event of an influenza pandemic. A phase I/II dose finding/formulation study was performed with a whole-virus H5N1 clade 1 A/Vietnam vaccine (2-dose priming regimen) to evaluate safety and immunogenicity. Seventy-seven of 141 subjects in this study received a booster (12-17 months after priming) with a 7.5-microg dose of a clade 2.1 A/Indonesia vaccine. The prime-boost regimen resulted in antibody responses against clade 1, 2.1, 2.2, and 2.3 viruses that were significantly higher than those after the priming regimen. These findings demonstrate that a prime-boost regimen may alleviate vaccine supply constraints in a pandemic.

Randomized, phase II dose-finding studies of a modified tick-borne encephalitis vaccine: evaluation of safety and immunogenicity.

Two clinical studies were conducted to identify the optimal dose of a modified tick-borne encephalitis (TBE) vaccine (FSME-IMMUN "new") in adults. A prospective, randomised, phase II, double-blind dose-finding study with the FSME-IMMUN "new" vaccine was performed in volunteers aged 16-65 years (n=405) to evaluate the immunogenicity and safety of two vaccinations with three vaccine doses (0.6, 1.2 and 2.4microg antigen). The safety and immunogenicity of the third vaccination were investigated in a follow-up study on the same study population. Antibody response to vaccination was assessed by enzyme-linked immunosorbent assay (ELISA) and, after the third vaccination, by neutralisation test (NT). Seroconversion rates (ELISA) in the different dose groups (0.6, 1.2 and 2.4 microg) were 85.1, 96.2 and 97.0%, respectively, after the second vaccination, which 73% of the volunteers received only 21 days after the first vaccination. Seroconversion rates after the third vaccination were 96, 99.2 and 100% (ELISA) as well as 77, 93 and 96.6% (NT) with the 0.6, 1.2 and 2.4 microg doses, respectively. No unexpected AEs or vaccine-related serious adverse events (SAE) were observed during either study. Local and systemic reactions were mainly mild and not dose-dependent, with an overall fever rate of <1% after the first vaccination. The 2.4 microg dose is the optimal dose for the FSME-IMMUN "new" preparation in adults, as it was found to: (1) be non-inferior to the 1.2 microg dose with respect to fever rate after the first vaccination; (2) induce the highest seroconversion rate; and (3) be well-tolerated with respect to local and systemic reactions. The results of both studies demonstrate that the FSME-IMMUN "new" vaccine is safe and highly immunogenic in adults.