Review of industrially recognized polymers and manufacturing processes for amorphous solid dispersion based formulations.

Evolving therapeutic landscape through combinatorial chemistry and high throughput screening have resulted in an increased number of poorly soluble drugs. Drug delivery strategies quickly adapted to convert these drugs into successful therapies. Amorphous solid dispersion (ASD) technology is widely employed as a drug delivery strategy by pharmaceutical industries to overcome the challenges associated with these poorly soluble drugs. The development of ASD formulation requires an understanding of polymers and manufacturing techniques. A review of US FDA-approved ASD-based products revealed that only a limited number of polymers and manufacturing technologies are employed by pharmaceutical industries. This review provides a comprehensive guide for the selection and overview of polymers and manufacturing technologies adopted by pharmaceutical industries for ASD formulation. The various employed polymers with their underlying mechanisms for solution-state and solid-state stability are discussed. ASD manufacturing techniques, primarily implemented by pharmaceutical industries for commercialization, are presented in Quality by Design (QbD) format. An overview of novel excipients and progress in manufacturing technologies are also discussed. This review provides insights to the researchers on the industrially accepted polymers and manufacturing technology for ASD formulation that has translated these challenging drugs into successful therapies.

Confounding factors in exposure-response analyses and mitigation strategies for monoclonal antibodies in oncology.

Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on 3 different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (i) Cox-proportional hazards modelling and case-matching; (ii) tumour growth inhibition-overall survival modelling; and (iii) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programmes. Therefore, the strengths and weaknesses of the other 2 approaches are considered, and the favourable utility of tumour growth inhibition-overall survival modelling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials and proposes that development programmes be designed to study more dose levels in earlier trials.

Computational analysis of kinase inhibitor selectivity using structural knowledge.

Motivation: Kinases play a significant role in diverse disease signaling pathways and understanding kinase inhibitor selectivity, the tendency of drugs to bind to off-targets, remains a top priority for kinase inhibitor design and clinical safety assessment. Traditional approaches for kinase selectivity analysis using biochemical activity and binding assays are useful but can be costly and are often limited by the kinases that are available. On the other hand, current computational kinase selectivity prediction methods are computational intensive and can rarely achieve sufficient accuracy for large-scale kinome wide inhibitor selectivity profiling. Results: Here, we present a KinomeFEATURE database for kinase binding site similarity search by comparing protein microenvironments characterized using diverse physiochemical descriptors. Initial selectivity prediction of 15 known kinase inhibitors achieved an >90% accuracy and demonstrated improved performance in comparison to commonly used kinase inhibitor selectivity prediction methods. Additional kinase ATP binding site similarity assessment (120 binding sites) identified 55 kinases with significant promiscuity and revealed unexpected inhibitor cross-activities between PKR and FGFR2 kinases. Kinome-wide selectivity profiling of 11 kinase drug candidates predicted novel as well as experimentally validated off-targets and suggested structural mechanisms of kinase cross-activities. Our study demonstrated potential utilities of our approach for large-scale kinase inhibitor selectivity profiling that could contribute to kinase drug development and safety assessment. Availability and implementation: The KinomeFEATURE database and the associated scripts for performing kinase pocket similarity search can be downloaded from the Stanford SimTK website (https://simtk.org/projects/kdb). Supplementary information: Supplementary data are available at Bioinformatics online.

A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries.

Background: The long-term effectiveness of the quadrivalent human papillomavirus (qHPV) vaccine was assessed by monitoring the combined incidence of cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ (AIS), and cervical cancer related to HPV16 or HPV18. Methods: Women from Nordic countries of Denmark, Iceland, Norway, and Sweden who received a 3-dose regimen of the qHPV vaccine in the beginning of FUTURE II (Females United to Unilaterally Reduce Endo/Ectocervical Disease; V501-015, base study NCT00092534) are followed through different national registries. Effectiveness analyses were conducted approximately 2 years following completion of the base study and occur approximately every 2 years thereafter for 10 years (ie, 14 years from day 1 of the base study). Vaccine effectiveness against HPV16/18-related CIN2 or worse (CIN2+) was estimated by comparing the observed incidence with the expected incidence of CIN2+ in an unvaccinated cohort using historical registry data. Results: In the per-protocol population (2084 women) analysis of effectiveness after the first 12 years, there were no breakthrough cases of HPV16/18 CIN2+ after 9437 person- years of follow-up. Statistical power was sufficient to conclude that qHPV vaccine effectiveness remains above 90% for at least 10 years. The number of person-years during the follow-up interval of 10-12 years is continuing to accrue and shows a trend toward continuing effectiveness of the vaccine during that period. Conclusion: The qHPV vaccine shows continued protection in women through at least 10 years, with a trend for continued protection through 12 years of follow-up. Clinical Trials Registration: NCT00092534. Study Identification: V501-015.

Secondary sclerosing cholangitis in localized hepatobiliary tuberculosis simulating cholangiocarcinoma: a rare case report.

BACKGROUND: Hepatobiliary tuberculosis includes miliary, tuberculous hepatitis or localized forms. The localised form is extremely uncommon and can mimic malignancy. Still rarer is its presentation as sclerosing cholangitis. CASE PRESENTATION: A 50 year male presented with acute onset jaundice, significant weight loss and elevated liver enzymes with clinico-radiological suspicion of cholangiocarcinoma. A left hepatectomy was done and dilated bile ducts filled with caseous necrotic material were seen intra-operatively. Histopathology suggested localized hepatobiliary tuberculosis with features of secondary sclerosing cholangitis. CONCLUSION: Localised hepatobiliary tuberculosis can cause diagnostic difficulties and its possibility should be considered especially in endemic areas.

Melt-in-Mouth Multi-particulate System for the Treatment of ADHD: A Convenient Platform for Pediatric Use.

Generally, pellets obtained from extrusion/spheronization, containing microcrystalline cellulose (MCC), do not disintegrate. An attempt has been made to develop melt-in-mouth pellets of taste-masked atomoxetine hydrochloride, using extrusion-spheronization, for pediatric patients. Melt-in-mouth pellets were prepared using extrusion-spheronization method and optimized using 3(3) FFD. MCC (X1, %), mannitol (X2, %) and Indion 414: Pharmaburst 500 ratio (X3, ratio) were the factors (independent variables) studied, whereas responses studied (dependent variables) were friability (Y1, %), yield (Y2, %) shape (Y3, roundness) in vitro disintegration time (Y4, seconds). The optimized formulation obtained from FFD was characterized for friability, shape and morphology, in vitro disintegration time, porosity, moisture uptake, in vitro release study and in vivo taste and disintegration time in healthy human volunteers. Randomized, two-treatment, two-sequence, two-period, single dose, crossover sensory evaluation study of taste-masked melt-in-mouth pellet was carried out in 10 healthy human subjects. A statistically significant polynomial mathematical relationship was generated between the factors and responses to obtain an optimized formulation. The optimized formulation was characterized (in vitro and in vivo) and exhibited a rapid drug release in vitro attributed to fast disintegration of pellets and high solubility of drug in 0.1 N HCl and buffer (pH 6.8). In vivo, 40% of volunteers ranked taste-masked optimized formulation as slightly bitter while 60% ranked it as no taste. The optimized pellets were conveniently administered in volunteers and exhibited rapid in-vivo disintegration in the oral cavity. Melt-in-mouth pellets can be a used as a platform technology for administering drugs to paediatric patients accurately and conveniently resulting in patient compliance.

Fulminant amoebic colitis: a clinicopathological study of 30 cases.

AIMS: To review the clinical and pathological factors associated with fulminant amoebic colitis (FAC) requiring colonic resection and its outcome. METHODS: We retrospectively identified adult patients admitted to our centre between June 2007 and December 2011 with FAC who underwent colonic resection and were diagnosed with amoebic colitis based on the presence of trophozoites on histological examination. The clinical details were extracted from the medical notes and correlated with the pathological findings. RESULTS: Thirty patients (18 men and 12 women) met the inclusion criteria. Their mean age was 50.1 years (range 21-89). The most frequent symptoms were abdominal pain, vomiting and fever. More than half the patients (16/30) had underlying conditions associated with immunosuppression including diabetes mellitus and tuberculosis. Pathological investigation of colonic resections showed predominantly right-sided involvement with geographic colonic ulcers covered with a creamy-white pseudomembrane, perforations, gangrenous changes, amoeboma and lesions mimicking inflammatory bowel disease. All showed basophilic dirty necrosis with abundant nuclear debris and amoebic trophozoites on histological examination. 21/30 patients (70%) had involvement beyond the caecum. 17/30 patients (57%) died. Those with involvement beyond the caecum were more likely to die (15/21, 71.4%) than those with less extensive disease. CONCLUSIONS: FAC presents as acute abdomen and can mimic appendicitis, ischaemic bowel disease, tuberculosis and malignancy. Comorbidities causing immunosuppression frequently associated. Mortality remains high despite surgery, so FAC should be suspected in every case of acute abdomen with colonic perforation if associated with typical gross and microscopic findings and a history of stay in an endemic area.

Isolation of genes conferring salt tolerance from Piriformospora indica by random overexpression in Escherichia coli.

Piriformospora indica, a root endophytic fungus identified in the Indian Thar desert, colonizes the roots of plants and provides resistance towards biotic stress as well as tolerance to abiotic stress in the plants. Despite its positive impact on the host, little is known about the P. indica genes that are involved in salt stress tolerance. Therefore this study was conducted to identify and isolate high salinity-tolerance genes from P. indica. Thirty-six salinity-tolerance genes were obtained by functional screening, based on random over expression of a P. indica cDNA library in Escherichia coli grown on medium supplemented with 0.6 M NaCl. The salinity tolerance conferred by these 36 genes in bacteria was further confirmed by using another strain of E. coli (DH5α) transformants. However when the expression of these 36 genes was analysed in P. indica using quantitative RT-PCR, we found only six genes were up-regulated by salt stress. These six genes are involved in different cellular processes, such as metabolism, energy and biosynthetic processes, DNA repair, regulation of protein turnover, transport and salt stress tolerance. This work presents the basis for further molecular analyses of the mechanisms of salt tolerance in P. indica and for the use of this endophyte to confer salt tolerance to plants.

Leukemoid reaction, a rare manifestation of autoimmune hemolytic anemia in a case of small duct primary sclerosing cholangitis.

A 48 year old lady presented with jaundice and exertional breathlesness. Her laboratory reports showed anaemia, reticulocytosis, leucocytosis, elevated Lactate Dehydrogenase (LDH), alkaline phosphatase levels, hyperbillirubinemia and positive direct Coomb's test. After ruling out all the other causes of autoimmunity and hemolytic anemia, she was diagnosed as leukemoid reaction due to autoimmune hemolytic anemia with primary sclerosing cholangitis. Patient showed immediate improvement after corticosteroids.

The convergence of pharmacometrics and quantitative systems pharmacology in pharmaceutical research and development.

Quantitative systems pharmacology (QSP) models are an important facet of pharmaceutical and clinical research as they combine mechanistic models of physiology in health and disease with pharmacokinetics/pharmacodynamics to predict systems-level effects. The quantitative clinical pharmacology toolbox has traditionally included both mechanistic modeling and population approaches, collectively called pharmacometrics, but the current landscape requires the optimization and use of multiple models together. Here, we explore several case studies in drug development that exemplify three approaches for using QSP and pharmacometrics models together - parallel synchronization, cross-informative use, and sequential integration. While these approaches are increasingly applied in drug development, achieving a true convergence of QSP and pharmacometrics that fully exploits their synergy will require new tools and methods that enable greater technical integration, in addition to nurturing scientists with diverse modeling expertise that enable cross-discipline strategy. Extensions of existing methods used in each approach as well as additional resources including machine learning models, data-at-scale, end-to-end computation platforms, and real-time analytics will enable this convergence.

Anti-neuropilin-1 (MNRP1685A): unexpected pharmacokinetic differences across species, from preclinical models to humans.

PURPOSE: To compare the pharmacokinetics (PK) of MNRP1685A, a human monoclonal antibody (mAb) against neuropilin-1 (NRP1), in mice, rats, monkeys, and cancer patients from a Phase I study to model with parallel linear and nonlinear clearances. METHODS: Binding characteristics of MNRP1685A in different species were evaluated using surface plasmon resonance technology. PK profiles of MNRP1685A after single and/or multiple doses in different species were analyzed using population analysis. PK parameters were compared across species. RESULTS: MNRP1685A binds to NRP1 in all four species tested. Consistent with the wide expression of NRP1, MNRP1685A demonstrated pronounced non-linear PK over a wide dose range. PK profiles are best described by a two-compartment model with parallel linear and nonlinear clearances. Model-derived PK parameters suggest similar in-vivo target expression levels and binding affinity to target across all species tested. However, compared to typical human/humanized mAbs, non-specific clearance of MNRP1685A was faster in mice, rats, and humans (60.3, 19.4, and 8.5 ml/day/kg), but not in monkeys (3.22 ml/day/kg). CONCLUSIONS: Monkey PK properly predicted the target-mediated clearance of MNRP1685A but underestimated its non-specific clearance in humans. This unique PK property warrants further investigation of underlying mechanisms.

Population pharmacokinetic and pharmacodynamic modeling of MNRP1685A in cynomolgus monkeys using two-target quasi-steady-state (QSS) model.

MNRP1685A (anti-NRP1) is a fully human IgG1 monoclonal antibody against neuropilin-1 (NRP1), a protein necessary for blood vessel maturation. MNRP1685A binds to free membrane-bound NRP1 (mNRP1) and circulating NRP1 (cNRP1). Total cNRP1 increased in a dose-dependent manner following anti-NRP1 administration in mice, rats, and monkeys. The purpose of this study is to develop a mechanism-based model to simultaneously describe the kinetics of both unbound drug (MNRP1685A) and total cNRP1 in cynomolgus monkeys. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- or multiple-dose administrations were well described by the two-target quasi-steady-state (QSS) model. The estimated nonspecific clearance was 3.26 mL/day/kg and central compartment volume was 38.2 mL/kg. The maximum elimination rate for mNRP1-mediated disposition was 98.8 nM/day. The synthesis rate (3.8 nM/day), degradation rate constant (1.53 day(-1)), and complex elimination rate constant (0.260 day(-1)) for cNRP1 were also derived from the model. QSS constants were 6.94 nM for mNRP1 and 2.8 nM for cNRP1. The results suggest that cNRP1 has minimal effect on MNRP1685A PK while mNRP1 plays a major role in the target-mediated drug disposition. This finding is favorable as the desired pharmacological target is mNRP1, rather than cNRP1. The two-target QSS model provides mechanistic understanding of the nonlinear PK of MNRP1685A. Based on the model prediction, the free drug concentrations to maintain free mNRP1 and cNRP1 below 10% of baseline level are 10 and 20 µg/mL, respectively. This serves as a target concentration for clinical dose selection, assuming cynomolgus monkeys are predictive for humans.

Evaluation of atezolizumab immunogenicity: Clinical pharmacology (part 1).

Baseline patient characteristics and prognostic factors are important considerations in oncology when evaluating the impact of immunogenicity on pharmacokinetics (PK) and efficacy. Here, we assessed the impact of anti-drug antibodies (ADA) on the PK of the immune checkpoint inhibitor atezolizumab (an anti-PD-L1 monoclonal antibody). We evaluated data from ≈ 4500 patients from 12 clinical trials across different tumor types, treatment settings, and dosing regimens. In our dataset, ~ 30% of patients (range, 13-54%) developed treatment-emergent ADA, and in vitro neutralizing antibodies (NAb) were seen in ~ 50% of ADA-positive (+) patients. Pooled time course data showed a trend toward lower atezolizumab exposure in ADA+ patients, which was more pronounced in ADA+/NAb+ patients. However, the atezolizumab concentration distributions overlapped, and drug concentrations exceeded 6 µg/ml, the target concentration required for receptor saturation, in greater than 95% of patients. Patients had sufficient exposure regardless of ADA status. The dose selected to allow for dosing over effects from ADA resulted in a flat exposure-response relationship. Analysis of study results by ADA titer showed that exposure and overall survival were not affected in a clinically meaningful way. High tumor burden, low albumin, and high CRP at baseline showed the greatest association with ADA development but not with subsequent NAb development. These imbalanced factors at baseline can confound analysis of ADA impact. ADA increases atezolizumab clearance minimally (9%), and its impact on exposure based on the totality of the clinical pharmacology assessment does not appear to be clinically meaningful.

Effectiveness, immunogenicity, and safety of the quadrivalent HPV vaccine in women and men aged 27-45 years.

Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27-45 years versus women and men aged 16-26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27-45 years. Efficacy of qHPV vaccine in men aged 27-45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27-45 years versus 16-26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27-45 years of age, and vaccine efficacy was inferred in men 27-45 years of age based on the serological results.

N-Heteroaryl glycinamides and glycinamines as potent NPY5 antagonists.

Subtype specific ligands are needed to evaluate the therapeutic potential of modulating the brain's neuropeptide Y system. The benzothiazepine glycinamide 1a was identified as an NPY5 antagonist lead. While having acceptable solubility, the compound was found to suffer from high clearance and poor exposure. Optimization efforts are described targeting improvements in potency, microsomal stability, and PK properties. The low microsomal stability and poor PK properties were addressed through the optimization of the sulfonyl urea and replacement of the benzothiazepinone with other N-heteroaryl glycinamides. For example, the analogous benzoxazine glycinamide 2e has improvements in both affinity (human Y5 K(i) 4 nM vs 1a 27 nM) and microsomal stability (human CL(int) 2.5 L/min vs 1a 35L/min). However the brain penetration (B/P 43/430 nM at 10 mg/kg PO) remained an unresolved issue. Further optimization by decreasing the hydrogen bond donating properties and PSA provided potent and brain penetrant NPY5 antagonists such as 5f (human Y5 K(i) 9 nM, B/P 520/840 nM 10 mg/kg PO).

Risk factors for Barrett's esophagus in Indian patients with gastroesophageal reflux disease.

BACKGROUND AND AIMS: Barrett's esophagus (BE) is reported to be infrequent in Asians, with no data from India regarding its prevalence and risk factors. We investigated the frequency and risk factors of columnar mucosa with or without specialized intestinal metaplasia (SIM) in Indian patients with gastroesophageal reflux disease (GERD). METHODS: A total of 278 GERD patients over 2 years underwent gastroscopy and completed a questionnaire for possible BE risk factors. Patients with columnar mucosa on endoscopy underwent four-quadrant biopsy; BE was histologically defined as columnar mucosa with or without SIM. Patients without columnar mucosa at endoscopy were considered as controls and compared to patients with BE and those with SIM. RESULTS: Forty-six patients with GERD had columnar mucosa on histology (16.54%); 25 (8.99%) of these had SIM. The risk factors for BE were the presence of hiatus hernia (odds ratio [OR]: 3.14; 95% confidence interval [CI]: 1.2-8.17) and a history of eructation (OR: 2.28; CI: 1.11-4.66). The risk factors for SIM were age ≥ 45 years (OR: 2.63; CI: 1.03-6.71), hiatus hernia (OR: 3.95; CI: 1.24-12.56), and a history of eructation (OR: 3.41; CI: 1.19-9.78). Sex, severity of symptoms, dietary factors, tobacco or alcohol use, and body mass index were not associated with BE. The median circumferential segment length was 2 (1-10) cm, and the maximal length was 3 (2-11) cm in both groups. CONCLUSION: BE is not an uncommon finding among Indian GERD patients. Age ≥ 45 years, history of eructation, and the presence of hiatus hernia are associated with SIM.

Pea lectin receptor-like kinase promotes high salinity stress tolerance in bacteria and expresses in response to stress in planta.

The plant lectin receptor-like kinases (LecRLKs) are involved in various signaling pathways but their role in salinity stress tolerance has not heretofore been well described. Salinity stress negatively affects plant growth/productivity and threatens food security worldwide. Based on functional gene-mining assay, we have isolated 34 salinity tolerant genes out of one million Escherichia coli (SOLR) transformants containing pea cDNAs grown in 0.8 M NaCl. Sequence analysis of one of these revealed homology to LecRLK, which possesses N-myristilation and N-glycosylation sites thus corroborating the protein to be a glycoconjugate. The homology based computational modeling of the kinase domain suggested high degree of conservation with the protein already known to be stress responsive in plants. The NaCl tolerance provided by PsLecRLK to the above bacteria was further confirmed in E. coli (DH5alpha). In planta studies showed that the expression of PsLecRLK cDNA was significantly upregulated in response to NaCl as compared to K(+) and Li(+) ions, suggesting the Na(+) ion specific response. Transcript of the PsLecRLK gene accumulates mainly in roots and shoots. The purified 47 kDa recombinant PsLecRLK-KD (kinase domain) protein has been shown to phosphorylate general substrates like MBP and casein. This study not only suggests the conservation of the cellular response to high salinity stress across prokaryotes and plant kingdom but also provides impetus to develop novel concepts for better understanding of mechanism of stress tolerance in bacteria and plants. It also opens up new avenues for studying practical aspects of plant salinity tolerance for enhanced agricultural productivity.

Effect of cosurfactant addition on phase behavior and microstructure of a water dilutable microemulsion.

This study reports a detailed characterization of a nonionic microemulsion (µE) composed of n-butylacetate/α-tocopheryl polyethylene glycol succinate (TPGS)/alcohol/water. Two approaches of expanding the monophasic area were explored; (i) addition of Pluronic® 123 (P123) in aqueous phase, and (ii) use of short chain alcohol (CnHn+1OH; n = 2-4) as cosurfactant. Pseudo-ternary phase diagrams were constructed using water titration method. Characterizations were performed using dynamic light scattering (DLS), differential scanning calorimetry (DSC), small angle neutron scattering (SANS) and electron microscopic techniques. DSC and SANS results showed gradual structural transformation from water-in-oil to oil-in-water system. The optimized formulation (oil/Smix/water - 19/40/41) showed average hydrodynamic diameter of 22 nm, consistent with electron microscopic observations. Ethanol (EtOH), with its high fluidity and smaller headgroup area, offered maximum expansion in the phase boundary. Surfactant unimers, derived from EtOH-driven de-micellization, reinforced the interface and solubilized the incoming oil molecules. Oil incorporation was accompanied with improved loading of carbamazepine, a hydrophobic drug. Except marginal swelling, no significant microstructural changes were noticed during water dilution (≈90%) and salt addition (0.9% NaCl) in the optimized µE formulation. A linear increase in oil incorporation was noticed upon adding propylene glycol as a cosolvent.

Use of real-world data for HPV vaccine trial follow-up in the Nordic region.

Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501-015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14 years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.