Timely, consistent, transparent assessment of market access evidence: implementing tools based on the HTA Core Model® in a pharmaceutical company.

OBJECTIVES: Evidence requirements and assessment methods access differ between health technology assessment (HTA) agencies. The HTA Core Model® provides a standardized approach to HTA, targeting evidence sharing and collaboration between participating HTA bodies. It is fit for purpose from an industry perspective and was used by pharmaceutical company Roche to develop a framework for internal assessment of evidence required for market access and coverage/reimbursement ("access evidence"). METHODS: Tools were developed to systematically scope, assess, plan, and summarize access evidence generation. The tools were based mainly on the first four HTA Core Model® domains and rolled-out in selected development teams in 2017. Five months after full implementation, the impact of tools was assessed in an internal survey. RESULTS: Systematic access evidence generation started with the Access Evidence Questionnaire, to scope evidence requirements and identify evidence gaps. Findings were summarized in the Access Evidence Metric, which assessed the alignment of available/planned evidence against HTA bodies' requirements and developed scope mitigation strategies. The Access Evidence Plan was then used to plan and document (additional) evidence generation. Once generated, evidence was summarized in the Access Evidence Dossier. A survey of twenty-seven Roche employees involved in evidence generation showed that the tools made discussions around access strategies and evidence more efficient and transparent. CONCLUSIONS: The HTA Core Model® provided a useful framework around which to optimize internal evidence generation and assessment. The benefits of using a standardized HTA approach in industry mirror those expected from implementing the HTA Core Model® in HTA agencies.

Seven lipoprotein lipase gene polymorphisms, lipid fractions, and coronary disease: a HuGE association review and meta-analysis.

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism and a major candidate gene for coronary heart disease (CHD). The authors assessed associations between 7 LPL polymorphisms and lipid fractions and CHD risk in population-based cohort, case-control, and cross-sectional studies published by January 2007. Meta-analyses of 22,734 CHD cases and 50,177 controls in 89 association studies focused on the relations of the T-93G (rs1800590), D9N (rs1801177), G188E, N291S (rs268), PvuII (rs285), HindIII (rs320), and S447X (rs328) polymorphisms to high density lipoprotein cholesterol, triglycerides, myocardial infarction, or coronary stenosis. Carriers of 9N or 291S had modestly adverse lipid profiles. Carriers of the less common allele of HindIII or of 447X had modestly advantageous profiles. The combined odds ratio for CHD among carriers was 1.33 (95% confidence interval (CI): 1.14, 1.56) for 9N, 1.07 (95% CI: 0.96, 1.20) for 291S, 0.89 (95% CI: 0.81, 0.98) for the less common HindIII allele, and 0.84 (95% CI: 0.75, 0.94) for 447X. For T-93G (odds ratio (OR) = 1.22, 95% CI: 0.98, 1.52) and PvuII (OR = 0.96, 95% CI: 0.89, 1.04), there were null associations with lipid levels or CHD risk; information on G188E was limited (OR = 2.80, 95% CI: 0.88, 8.87). The study of LPL genotypes confirms the existence of close interrelations between high density lipoprotein cholesterol and triglyceride pathways. The influence of these genotypes on CHD risk warrants further investigation.

Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography.

BACKGROUND: Assessing quality and susceptibility to bias is essential when interpreting primary research and conducting systematic reviews and meta-analyses. Tools for assessing quality in clinical trials are well-described but much less attention has been given to similar tools for observational epidemiological studies. METHODS: Tools were identified from a search of three electronic databases, bibliographies and an Internet search using Google. Two reviewers extracted data using a pre-piloted extraction form and strict inclusion criteria. Tool content was evaluated for domains potentially related to bias and was informed by the STROBE guidelines for reporting observational epidemiological studies. RESULTS: A total of 86 tools were reviewed, comprising 41 simple checklists, 12 checklists with additional summary judgements and 33 scales. The number of items ranged from 3 to 36 (mean 13.7). One-third of tools were designed for single use in a specific review and one-third for critical appraisal. Half of the tools provided development details, although most were proposed for future use in other contexts. Most tools included items for selection methods (92%), measurement of study variables (86%), design-specific sources of bias (86%), control of confounding (78%) and use of statistics (78%); only 4% addressed conflict of interest. The distribution and weighting of domains across tools was variable and inconsistent. CONCLUSION: A number of useful assessment tools have been identified by this report. Tools should be rigorously developed, evidence-based, valid, reliable and easy to use. There is a need to agree on critical elements for assessing susceptibility to bias in observational epidemiology and to develop appropriate evaluation tools.

Comparative benefit of malaria chemoprophylaxis modelled in United Kingdom travellers.

BACKGROUND: Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. METHODS: The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. RESULTS: The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases--model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the 'background' reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the 'background' rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C ± P 170, Mq 146, Dx 114, AP 103. CONCLUSIONS: The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP.

Sources of European drug consumption data at a country level.

OBJECTIVES: This study aimed at outlining the characteristics of nationwide administrative databases monitoring drug consumption in Europe. METHODS: Internet and bibliographic databases (April 2010) were searched and experts in drug utilization (DU) research interviewed to find nationwide administrative medicines consumption databases in Europe, with data for the out- and inpatient healthcare sector. A questionnaire was developed to gather additional information. We collected data providers, websites, accessibility, data sources, healthcare settings, population coverage, medicines-related data, patient and prescriber data, periods covered, and linkage to other databases. RESULTS: Thirty-one administrative nationwide medicine consumption databases in 25 countries were identified. Questionnaires were responded for 20 databases. Eleven provided wholesalers' sales data, 11 on reimbursed, 5 on prescribed, and 4 on dispensing medicines. Fifteen databases provided inpatient drug consumption data, mainly wholesalers' sales. CONCLUSIONS: Nationwide administrative databases are of value to all stakeholders involved in the conduct and interpretation of post-marketing safety studies, and in the conduct of DU research. The endorsement of the anatomical therapeutic chemical/defined daily dose methodology by these databases contributes to data harmonization. However, there is still a lack of information on inpatient medicines consumption at a patient-level.

Malaria chemoprophylaxis regimens: a descriptive drug utilization study.

BACKGROUND: Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. METHODS: We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. RESULTS: Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%-13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%-0.1% among other antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%-15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%-1.4% among users of other antimalarials). CONCLUSIONS: The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women.

Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy.

BACKGROUND: Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non-B HIV-1 subtypes (A, C, D and the circulating recombinant form, CRF02-AG) in an ethnically diverse population of HIV-1-infected patients in south London. METHODS: A random sample of 861 HIV-1-infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi-level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. RESULTS: Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02-AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02-AG. However, a statistically significant four-fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01) CONCLUSIONS: This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D.

Evidence for onward transmission of HIV-1 non-B subtype strains in the United Kingdom.

An increasing proportion of new HIV diagnoses in the United Kingdom and other European countries are attributable to non-B subtype infections, mainly among black Africans with infections heterosexually acquired in sub-Saharan Africa. We examined whether there was evidence for onward transmission of non-B subtypes within an ethnically diverse HIV-1-infected cohort in South London. Three hundred eighty-four HIV-1-infected patients attending Kings College Hospital were subtyped using an in-house enzyme-linked immunoassay and env sequencing. Epidemiologic data were obtained from medical chart review and the patients' physician and were used to establish the most likely source and country of infection. Overall, 344 patients (154 black African, 148 white UK-born, and 42 black Caribbean) had an identifiable subtype. The prevalence of non-B subtypes among the black African, white, and black Caribbean patients was 96.8%, 14.2%, and 31%, respectively. Most non-B subtype infections were identified in black Africans (149 of 183 cases) and were mainly acquired in sub-Saharan Africa, but 22.9% (42 of 183 cases) of all non-B infections were probably acquired in the United Kingdom. Among the 21 white UK-born patients infected with a non-B subtype, 15 probably acquired the infection in the United Kingdom and only 6 of these patients reported a source sexual partner from an HIV endemic area. All 13 black Caribbean patients with a non-B infection most likely acquired their infection in the United Kingdom, most of whom (8 of 13 patients) were probably infected by a partner from an HIV endemic area. Potential acquisition of HIV infection in the United Kingdom was lowest among black African patients with a non-B infection, and most of these infections were probably acquired from a partner originating from an HIV endemic area. This study provides the first evidence for onward transmission of non-B subtypes in the United Kingdom, particularly among the black Caribbean population.

Surveillance of HIV-1 subtypes among heterosexuals in England and Wales, 1997-2000.

The molecular diversity and demographic characteristics among 976 anti-HIV-1-positive heterosexuals attending 15 sexually transmitted infection (STI) clinics participating in an unlinked anonymous HIV prevalence serosurvey in England and Wales during 1997-2000 were investigated. Subtypes were assigned by heteroduplex mobility assay or sequencing of the p17/p24 region of gag and the V3/V4 region of env and by sequencing of the protease gene. Overall, there was no significant change in the subtype distribution, with subtype C accounting for the majority (32%) of subtyped infections. Subtypes B (29%), A (12%), circulating recombinant forms (CRFs, 9%), unique recombinant forms (URFs, 8%), and subtypes D-H (8%) were also detected. Thirty-nine percent of infections in men were with subtype B, whereas subtype C was most common (38%) in women. Logistic regression analyses showed the relative risk (RR) of infection with a non-B subtype, compared with subtype B, to be greater in African-born individuals (RR = 28.9, P < 0.01), among newly diagnosed infections (RR = 3.4, P < 0.01), and in women (RR = 2.4, P < 0.01). These findings indicate a high level of genetic diversity among HIV-infected heterosexual STI clinic attendees in England and Wales. Recently, subtype C has become most prevalent, particularly in younger age groups, suggesting recent acquisition of this viral strain. The high proportion of non-B, CRF, and URF infections among UK-born individuals is consistent with mixing between migrants and UK-born individuals in England and Wales. As migration patterns change, continued monitoring of HIV genetic diversity will aid understanding of transmission patterns.