Effects of the COVID-19 Pandemic on Pharmacovigilance Strategy, Systems, and Processes of Large, Medium, and Small Companies: An Industry Survey.

PURPOSE: The COVID-19 pandemic poses an unprecedented threat to global business relationships and dynamics. The pharmacovigilance function of pharmaceutical companies is particularly susceptible to changing external pressures because of its highly structured compliance activities. We conducted an industry-wide survey to provide insights on how the pharmacovigilance function responded to the challenges posed by the pandemic. We compared smaller companies and larger companies regarding impact on portfolios and operational activity metrics. METHODS: We conducted a survey through the Navitas Life Science annual benchmark of pvnetTM, a network of large enterprise (LE) companies, and pvconnectTM, a network of small and medium enterprise (SME) companies, using an online surveying tool during the first quarter of 2021. We collected information on pharmacovigilance activities, including quantitative measures of workload, costs, and key performance indicators, and qualitative data on the effects of the pandemic on product portfolios and operations. FINDINGS: Survey questions were posed to LE (pvnet) network members (n = 12) and SME (pvconnect) network members (n = 18) for the period from January 1 through December 31, 2020. The date of data collection was March 26, 2021. Descriptive median values of parameter metrics included the following: revenue ($28.4 billion for LE companies and $1.6 billion for SME companies), number of products (127 for LE companies and 19 for SME companies), and volume of individual case safety reports (391,000 for LE companies and 13,000 for SME companies). SME companies reported a greater impact on 2 survey categories, remote working and employee well-being, than did LE companies. However, LE companies reported a greater impact than did SME companies on all other survey categories: effect on strategic priorities, shift in product focus, workload changes, changes in sourcing model, effect on case reporting compliance, effect on business continuity, changes in pharmacovigilance technology strategy, impact of interactions with health authorities, effect on resource capacity, and impact on recruitment. IMPLICATIONS: Four major themes emerge from this survey: (1) shift to remote working, (2) recognition of the impact on employee well-being, (3) shift in strategic priorities, and (4) newly recognized aspects of risk mitigation. The COVID-19 pandemic has had a marked effect on every aspect of pharmaceutical companies' pharmacovigilance functions, although the effects appear to be different for LE companies than for SME companies.

Stable isotope labeling method for the investigation of protein haptenation by electrophilic skin sensitizers.

The risk of contact sensitization is a major consideration in the development of new formulations for personal care products. However, developing a mechanistic approach for non-animal risk assessment requires further understanding of haptenation of skin proteins by sensitizing chemicals, which is the molecular initiating event causative of skin sensitization. The non-stoichiometric nature of protein haptenation results in relatively low levels of modification, often of low abundant proteins, presenting a major challenge for their assignment in complex biological matrices such as skin. Instrumental advances over the last few years have led to a considerable increase in sensitivity of mass spectrometry (MS) techniques. We have combined these advancements with a novel dual-labeling/LC-MS(E) approach to provide an in-depth direct comparison of human serum albumin (HSA), 2,4-dinitro-1-chlorobenzene (DNCB), 5-chloro-2-methyl-4-isothiazolin-3-one (MCI), trans-cinnamaldehyde, and 6-methyl coumarin. These data have revealed novel insights into the differences in protein haptenation between sensitizers with different reaction mechanisms and sensitizing potency; the extreme sensitizers DNCB and MCI were shown to modify a greater number of nucleophilic sites than the moderate sensitizer cinnamaldehyde; and the weak/non-sensitizer 6-methyl coumarin was restricted to only a single nucleophilic residue within HSA. The evaluation of this dual labeling/LC-MS(E) approach using HSA as a model protein has also demonstrated that this strategy could be applied to studying global haptenation in complex mixtures of skin-related proteins by different chemicals.

Effectiveness of computational methods in haplotype prediction.

Haplotype analysis has been used for narrowing down the location of disease-susceptibility genes and for investigating many population processes. Computational algorithms have been developed to estimate haplotype frequencies and to predict haplotype phases from genotype data for unrelated individuals. However, the accuracy of such computational methods needs to be evaluated before their applications can be advocated. We have experimentally determined the haplotypes at two loci, the N-acetyltransferase 2 gene ( NAT2, 850 bp, n=81) and a 140-kb region on chromosome X ( n=77), each consisting of five single nucleotide polymorphisms (SNPs). We empirically evaluated and compared the accuracy of the subtraction method, the expectation-maximization (EM) method, and the PHASE method in haplotype frequency estimation and in haplotype phase prediction. Where there was near complete linkage disequilibrium (LD) between SNPs (the NAT2 gene), all three methods provided effective and accurate estimates for haplotype frequencies and individual haplotype phases. For a genomic region in which marked LD was not maintained (the chromosome X locus), the computational methods were adequate in estimating overall haplotype frequencies. However, none of the methods was accurate in predicting individual haplotype phases. The EM and the PHASE methods provided better estimates for overall haplotype frequencies than the subtraction method for both genomic regions.