Good Publication Practice (GPP) Guidelines for Company-Sponsored Biomedical Research: 2022 Update.

These updated Good Publication Practice (GPP) guidelines include recommendations for publishing company-sponsored biomedical research. The GPP guidelines apply to peer-reviewed or peer-oriented biomedical publications, such as manuscripts, meeting presentations, posters, and abstracts, as well as enhanced content, such as plain-language summaries. The current GPP guidelines incorporate guidance on ethics and transparency as well as the planning, development, review, and approval of biomedical publications and policies and procedures that describe these practices. Supplemental materials lay out processes for steering committees, publication plans, publication working groups, determining authorship, and documentation. Information about new topics, such as alliances and working with patients, has been included where appropriate within these supplemental materials. Incorporating the principles and best practices presented in these GPP guidelines will result in increased transparency and a firm ethical footing. This guidance is also intended to enable the compliant incorporation of new and emerging publication tools for the ethical publication of company-sponsored research.

Ghostwriting in biomedicine: a review of the published literature.

Introduction: The systematic review of biomedical ghostwriting has proven challenging due to problems in consistency and in study design. Moreover, authorship guidelines established by the International Committee of Medical Journal Editors (ICMJE) may have inadvertently created opportunities to potentiate ghostwriting. Given continued interest in ghostwriting by the International Society of Medical Publication Professionals (ISMPP) and other organizations, we undertook an analysis of ghostwriting in the biomedical literature.Methods: We searched PubMed (search terms: ghost writ*, ghostwrit*, ghost writer, ghostwriter, ghostwriting and ghost writing). Results, including abstracts, were reviewed for relevance (relationship to ghostwriting in biomedical journals) to aid in removal of inapplicable work and duplicate publications. After review, we consolidated expert opinions for publication professionals.Results: Overlap was poor across search terms; of 181 unique papers identified, most (112/181) were opinion pieces. An increasing number of papers are using the term "ghostwriting" to describe genetics as well as diverse phenomena of misattributed authorship, including "ghost authorship". Eight primary studies and 1 systematic review of ghostwriting incidence were identified, reporting prevalence ranging from <1% to 91%, in varied settings using differing methods and definitions of ghostwriting. Suggestions for avoiding ghostwriting include early consensus building and better definitions of authorship among manuscript teams.Discussion: The prevalence and definition of ghostwriting remain unclear. Increased transparency and auditable authorship practices that align with specific guidelines may aid in the avoidance of ghostwriting. In addition, MeSH or clearer indexing terms may be helpful to separate usages of ghostwriting in scientific settings (e.g. genetic research) versus biomedical publishing.

Substantial contribution and accountability: best authorship practices for medical writers in biomedical publications.

OBJECTIVE: To provide clarity on the professional medical writer as author or contributor by examining what "a substantial contribution" and "accountability" mean with respect to authorship in a biomedical publication. These terms relate to criteria 1 and 4 of the International Committee of Medical Journal Editors (ICMJE) authorship guidelines. METHODS: We reviewed the ICMJE and Good Publication Practice authorship guidelines, which recommend that individuals not meeting all four authorship criteria should be acknowledged as contributors. We also surveyed and assessed selected journals for published guidance on authorship versus contributorship. RESULTS: We found that journals often vary in their authorship guidelines for medical writers. Notwithstanding, and to assist in determining the contribution made by the medical writer, we have expanded on current guidelines to develop recommendations for important intellectual contribution to the design of the work (developing the protocol, choosing endpoints) or the interpretation of data for the work (developing the discussion, interpreting new statistical output), which should result in inclusion of the medical writer as an author, as well as when accountability is relevant. If the medical writer does not qualify as an author, then their inclusion in the acknowledgements section is appropriate. CONCLUSIONS: Authors and contributors have a responsibility to create a publication that is accurate and true to the study results, but only authors must provide a substantial contribution and are accountable for that contribution. Contributions made by authors and non-author contributors should be fully described in the publication, to enable the reader to assess credit and responsibility.

Publication ethics from the ground up.

It is relatively easy to begin policy documents with a general assertion that ethics will be followed. Less obvious is how to ensure that day-to-day activities are consonant with ethical standards. We suggest that using day-to-day publication activities as the driver for building policies and procedures can promote ethical practices from the ground up. Although basic principles of ethical publication practice may seem straightforward to some, for others this information may require explanation, interpretation and context. Effective policy development includes big-picture items as well as more day-to-day tactical responsibilities such as those discussed below. Research questions, disciplinary practices, applications and team structures may vary. Thus, no single publication plan or policy solution is right for all teams. It is up to team members to review guidelines for best practices and find the optimal implementation for their situations. Experts in publication management, planning and writing can help large teams manage publication activities. These experts have an obligation to maintain and enhance their skills continually. A strong acumen in publication best practices will allow these publication professionals to better address any possible ethical dilemmas in the future.

Factors impacting time to acceptance and publication for peer-reviewed publications.

OBJECTIVE: Timely publication of data is important for the medical community and provides a valuable contribution to data disclosure. The objective of this study was to identify and evaluate times to acceptance and publication for peer-reviewed manuscripts, reviews, and letters to the editor. RESEARCH DESIGN AND METHODS: Key publication metrics for published manuscripts, reviews, and letters to the editor were identified by eight Amgen publications professionals. Data for publications submitted between 1 January 2013 and 1 November 2015 were extracted from a proprietary internal publication-tracking database. Variables included department initiating the study, publication type, number of submissions per publication, and the total number of weeks from first submission to acceptance, online publication, and final publication. RESULTS: A total of 337 publications were identified, of which 300 (89%) were manuscripts. Time from submission to acceptance and publication was generally similar between clinical and real-world evidence (e.g. observational and health economics studies) publications. Median (range) time from first submission to acceptance was 23.4 (0.2-226.2) weeks. Median (range) time from first submission to online (early-release) publication was 29.7 (2.4-162.6) weeks. Median (range) time from first submission to final (print) publication was 36.2 (2.8-230.8) weeks. Time from first submission to acceptance, online publication, and final publication increased accordingly with number of submissions required for acceptance, with similar times noted between each subsequent submission. CONCLUSIONS: Analysis of a single-company publication database showed that the median time for manuscripts to be fully published after initial submission was 36.2 weeks, and time to publication increased accordingly with the number of submissions. Causes for multiple submissions and time from clinical trial completion to first submission were not assessed; these were limitations of the study. Nonetheless, publication planners should consider these results when evaluating timelines and identifying potential journals early in the publication planning process.

Two years into the Sunshine Act: synopsis of opportunities, challenges, learnings, and potential implications.

Responsible transparency helps to promote integrity between industry and researchers and has the potential to increase public trust. As part of its inevitable evolution, the Open Payments database is likely to have opportunities to increase and improve the context around the data that it reports, thus leading to a decrease in the currently encountered confusion and misinterpretation of the data. A major challenge faced by the Centers for Medicare and Medicaid Services is to make the data more informative and educational, to allow the Sunshine Act to meet its transparency goals while improving healthcare innovation.

Systematic review of reports describing potential impact of the Sunshine Act on peer-reviewed medical publications.

OBJECTIVE: The Physician Payments Sunshine Act, enacted in 2010, is intended to increase the transparency of relationships between US physicians and teaching hospitals and manufacturers of drugs, biologics, and medical devices. We examined current opinion regarding the impact of the Sunshine Act on peer-reviewed medical publications. RESEARCH DESIGN AND METHODS: We searched indexed databases (NLM/PubMed, EMBASE, and Scopus) and nonindexed sources (lay and medical press, medical websites, congress abstracts) for articles published between January 2010 and June 2015 that contained terms indicative of content related to the Sunshine Act (e.g., 'Sunshine Act', 'open payment program'). Nine publication professionals then systematically reviewed identified articles for publications-related content. MAIN OUTCOME MEASURES: Quantification and characterization of publications that focused on the Sunshine Act and its implications for medical publishing. RESULTS: Among 1200 indexed publications, 113 had content on the Sunshine Act. Thirty-one discussed its implications for publications; nine distinguished between financial and nonfinancial transfers of value. Of the 117 nonindexed publications with content on the Sunshine Act, 16 discussed implications for publications, and seven distinguished between financial and nonfinancial transfers of value. Reporting of such transfers of value was viewed as a potential barrier to participation in publications with industry support. CONCLUSIONS: There is limited literature on the impact of the Sunshine Act on peer-reviewed publications and limited physician awareness that publication support may be reported as a transfer of value.

The sunshine act and medical publications: Guidance from professional medical associations.

OBJECTIVE: To review guidance from professional medical associations to physicians on the Sunshine Act, with a focus on industry support for medical publications. METHODS: Using 'Sunshine Act' as a search term, we searched PubMed (dates February 2013 to November 2014) and the 'grey literature' using Google and Google Scholar. Online information was extracted from websites of pre-identified professional medical associations. RESULTS: Some professional medical associations have published peer-reviewed recommendations, position statements or general advice on their websites and in journals around the Sunshine Act. Associations also provided broad online educational resources for physicians. There was universal agreement between peer-reviewed publications, including guidelines, for the need for full transparency and disclosure of industry support. Surveys by some professional associations showed variance in opinion on the forecasted impact of the Sunshine Act on physician-industry relationships. There was scarce information specifically related to reporting requirements for industry-supported medical publications. CONCLUSIONS: There is a shortage of information for physicians from professional associations regarding the Sunshine Act and support for medical publications. Due to the lack of clear guidance regarding support for publications, there are presently varying interpretations of the Sunshine Act. The literature debates the potential impact of the Sunshine Act and expresses some concerns that physician-enabled innovation in drug development may be hindered.

Age-related decrease in expression of mitochondrial DNA encoded subunits of cytochrome c oxidase in Drosophila melanogaster.

A key feature of the aging process is that the mitochondrial respiratory capacity declines and, the production of reactive oxygen species increases in the later part of life span. In previous studies, cytochrome c oxidase (CcO), the terminal component of the mitochondrial electron transport chain, was found to be the only oxidoreductase exhibiting an age-related decrease in activity in Drosophila melanogaster. The present study tested the hypothesis that decreases in the abundance of catalytic subunits of CcO, encoded in mitochondrial DNA, could underlie the age-associated loss of enzyme activity. Protein amounts of subunits I, II and III, which form the catalytic core of CcO, were determined by immunoblot analysis in 15-, 25-, 35-, 47- and 60-day-old flies. Subunits II and III decreased with age by up to 43% and 75%, respectively, whereas the decrease in subunit I was only 15%. The results pinpoint specific changes in a component of the mitochondrial electron transport chain, which could underlie the age-related decrease in mitochondrial respiratory activity and an increase in oxidant production. Apparently, the stoichiometry of CcO holoprotein is dynamically altered during the aging process in D. melanogaster.

Carbonylation of mitochondrial proteins in Drosophila melanogaster during aging.

Age-related changes in carbonylation of mitochondrial proteins were determined in mitochondria from the flight muscles of Drosophila melanogaster. Reactivity with antibodies against (i) adducts of dinitrophenyl hydrazone (DNP), commonly assumed to react broadly with derivatized carbonyl groups, (ii) malondialdehyde (MDA), or (iii) hydroxynonenal (HNE), was compared at five different ages of flies. MDA and HNE are carbonyl-containing products of lipid peroxidation, which can form covalent adducts with proteins. Specific objectives were to address the following inter-related issues: (1) what are the sources of adducts involved in protein carbonylation in mitochondria during aging; (2) is carbonylation by different adducts detectable solely by the DNP antibodies, as assumed widely; (3) can the adducts formed by lipid peroxidation products in vivo, be used as markers for monitoring age-associated changes in oxidative damage to proteins. The total amounts of immunoreactive proteins, detected by all three antibodies, were found to increase with age; however, the immunodensity of individual reactive bands and the magnitude of the increases were variable, and unrelated to the relative abundance of a protein. While some protein bands were strongly immunopositive for all three antibodies, others were quite selective. The amounts of high molecular weight cross-linked proteins (>200kDa) increased with age. In general, the anti-HNE antibody reacted with more protein bands compared to the anti-MDA or -DNP antibody. The results suggest that sources of the carbonyl-containing protein adducts vary and no single antibody reacts with all of them. Overall, the results indicate that HNE shows robust age-associated increases in adductation with mitochondrial proteins, and is a good marker for monitoring protein oxidative damage during aging.

Age-associated perturbations in glutathione synthesis in mouse liver.

The nature of the mechanisms underlying the age-related decline in glutathione (GSH) synthetic capacity is at present unclear. Steady-state kinetic parameters of mouse liver GCL (glutamate-cysteine ligase), the rate-limiting enzyme in GSH synthesis, and levels of hepatic GSH synthesis precursors from the trans-sulfuration pathway, such as homocysteine, cystathionine and cysteine, were compared between young and old C57BL/6 mice (6- and 24-month-old respectively). There were no agerelated differences in GCL V(max), but the apparent K(m) for its substrates, cysteine and glutamate, was higher in the old mice compared with the young mice (approximately 800 compared with approximately 300 microM, and approximately 710 compared with 450 microM, P<0.05 for cysteine and glutamate in young and old mice respectively). Amounts of cysteine, cystathionine and Cys-Gly increased with age by 91, 24 and 28% respectively. Glutathione (GSH) levels remained unchanged with age, whereas GSSG content showed an 84% increase, suggesting a significant pro-oxidizing shift in the 2GSH/GSSG ratio. The amount of the toxic trans-sulfuration/glutathione biosynthetic pathway intermediate, homocysteine, was 154% higher (P<0.005) in the liver of old mice compared with young mice. The conversion of homocysteine into cystathionine, a rate-limiting step in trans-sulfuration catalysed by cystathionine beta-synthase, was comparatively less efficient in the old mice, as indicated by cystathionine/homocysteine ratios. Incubation of tissue homogenates with physiological concentrations of homocysteine caused an up to 4.4-fold increase in the apparent K(m) of GCL for its glutamate substrate, but had no effect on V(max). The results suggest that perturbation of the catalytic efficiency of GCL and accumulation of homocysteine from the trans-sulfuration pathway may adversely affect de novo GSH synthesis during aging.

Mechanisms of gamma-glutamylcysteine ligase regulation.

The principal objective of this study was to investigate the mechanisms regulating the activity of gamma-glutamylcysteine ligase (GCL; EC 6.3.2.2), the rate limiting enzyme in glutathione biosynthesis. Two phylogenetically divergent species, mouse and the fruitfly, Drosophila melanogaster were used to test the hypothesis that reversible protein phosphorylation and pyridine dinucleotide phosphate dependent allostery regulate GCL activity. GCL was almost completely inhibited under phosphorylating conditions, involving preincubations with MgATP and endogenous protein kinases. Maximal GCL inhibitions of 94%, 77%, 85%, 87%, 83%, 95% and 89% occurred, respectively, in mouse cerebellum, hippocampus, brainstem, striatum, cortex and heart, and Drosophila. These changes in GCL activity were detected using saturating levels of substrates, suggesting that V(max) was dramatically affected, whereas K(m) values showed no differences. In vitro activation of GCL, presumably due to dephosphorylation, was blocked by inhibitors of protein phosphatases, suggesting that GCL exists in vivo as a mixture of phosphorylated and dephosphorylated forms. The reversibility of the dephosphorylation-dependent activation was indicated by the time-dependent inactivation of the in vitro activated Drosophila GCL, by preincubation with MgATP. NADPH increased maximal GCL activity by up to 93%, whereas several other nucleotide analogues did not, thereby demonstrating specificity. Kinetic analysis using Hanes-Woolf replots of initial velocity data suggested that the NADPH-dependent stimulation of GCL activity is brought about by a change in the maximal activity, V(max), rather than changes in substrate affinity. Results of this study suggest that mechanisms of modulation of eukaryotic GCL enzymes may include specific binding of ligands such as pyridine dinucleotide phosphates and reversible protein phosphorylation.

Aconitase is the main functional target of aging in the citric acid cycle of kidney mitochondria from mice.

The activities of the citric acid cycle enzymes were determined in mitochondria isolated from kidneys of relatively young, middle age, and old mice. Aconitase exhibited the most significant decrease in activity with age. The activity of alpha-ketoglutarate dehydrogenase exhibited a modest decrease in activity, while NADP(+)-isocitrate dehydrogenase (NADP(+)-ICD) activity increased moderately with age. Activities of citrate synthase, NAD(+)-isocitrate dehydrogenase (NAD(+)-ICD), succinyl-CoA synthetase (SCS), succinate dehydrogenase (SD), fumarase (FUM), and malate dehydrogenase (MD) were not affected. The molar ratio of the intra-mitochondrial redox indicator, NADPH:NADP(+), was higher in young compared to old animals, while the NADH:NAD(+) molar ratio remained unchanged. It is suggested that an age-related decrease in aconitase activity along with relatively subtle alterations in activities of some other citric acid cycle enzymes are likely to contribute to a decline in the overall efficiency of mitochondrial bioenergetics. The biological consequences of such alterations include age-related fluctuations in the citric acid cycle intermediates, which are precursors of protein synthesis, activators of fatty acid synthesis, and can also act as ligands for orphan G-protein coupled receptors.

Overexpression of glutamate-cysteine ligase extends life span in Drosophila melanogaster.

The hypothesis that overexpression of glutamate-cysteine ligase (GCL), which catalyzes the rate-limiting reaction in de novo glutathione biosynthesis, could extend life span was tested in the fruit fly, Drosophila melanogaster. The GAL4-UAS binary transgenic system was used to generate flies overexpressing either the catalytic (GCLc) or modulatory (GCLm) subunit of this enzyme, in a global or neuronally targeted pattern. The GCL protein content of the central nervous system was elevated dramatically in the presence of either global or neuronal drivers. GCL activity was increased in the whole body or in heads, respectively, of GCLc transgenic flies containing global or neuronal drivers. The glutathione content of fly homogenates was increased by overexpression of GCLc or GCLm, particularly in flies overexpressing either subunit globally, or in the heads of GCLc flies possessing neuronal drivers. Neuronal overexpression of GCLc in a long-lived background extended mean and maximum life spans up to 50%, without affecting the rate of oxygen consumption by the flies. In contrast, global overexpression of GCLm extended the mean life span only up to 24%. These results demonstrate that enhancement of the glutathione biosynthetic capability, particularly in neuronal tissues, can extend the life span of flies, and thus support the oxidative stress hypothesis of aging.

Kinetic characteristics of native gamma-glutamylcysteine ligase in the aging housefly, Musca domestica L.

The catalytic activity of gamma-glutamylcysteine ligase (gamma-GCL; EC 6.3.2.2) was compared between relatively young (4-day-old) and old (19-day-old) houseflies (Musca domestica) in order to understand the mechanism of putative deterioration of glutathione homeostasis during the aging process. Hanes-Woolf analyses ([S]/v vs [S]) indicated that gamma-GCL had significantly higher affinities for its substrates in the young than in the old flies. The K(m) values in the young and old flies were, respectively, for glutamate 0.6 and 5.5 mM; for cysteine 0.3 and 4.6 mM; and for ATP 1.2 and 2.9 mM. Furthermore, young but not old flies exhibited substrate-dependent inhibition of gamma-GCL activity at >5 mM cysteine indicating a loss of metabolic regulation during aging. The age-associated differences in the affinity of native gamma-GCL towards its substrates suggest that de novo synthesis of glutathione would be relatively less efficient in the old houseflies.