When Context Is Hard to Come By: External Comparators and How to Use Them.

External comparators, also referred to as historical or synthetic controls, present transformational opportunities for broad context and insights alongside clinical research results. The recent confluence of access to quality real-world data (RWD), advanced epidemiologic methods, and legislative directives to regulators for expanded use of RWD is increasing interest in real-world external comparators, opening the door to achieve broader generalizability and learn more, faster. In this less standardized area of research, tailored scientific methodology must be applied for external comparators to accomplish clinical development objectives. Here, we describe methodological considerations for design and illustrate how RWD comparators have been used for regulatory and reimbursement decisions.

When Context Is Hard to Come By: External Comparators and How to Use Them.

External comparators, also referred to as historical or synthetic controls, present transformational opportunities for broad context and insights alongside clinical research results. The recent confluence of access to quality real-world data (RWD), advanced epidemiologic methods, and legislative directives to regulators for expanded use of RWD is increasing interest in real-world external comparators, opening the door to achieve broader generalizability and learn more, faster. In this less standardized area of research, tailored scientific methodology must be applied for external comparators to accomplish clinical development objectives. Here, we describe methodological considerations for design and illustrate how RWD comparators have been used for regulatory and reimbursement decisions.

Validating a Framework for Coding Patient-Reported Health Information to the Medical Dictionary for Regulatory Activities Terminology: An Evaluative Study.

BACKGROUND: The availability of and interest in patient-generated health data (PGHD) have grown steadily. Patients describe medical experiences differently compared with how clinicians or researchers would describe their observations of those same experiences. Patients may find nonserious, known adverse drug events (ADEs) to be an ongoing concern, which impacts the tolerability and adherence. Clinicians must be vigilant for medically serious, potentially fatal ADEs. Having both perspectives provides patients and clinicians with a complete picture of what to expect from drug therapies. Multiple initiatives seek to incorporate patients' perspectives into drug development, including PGHD exploration for pharmacovigilance. The Food and Drug Administration (FDA) Adverse Event Reporting System contains case reports of postmarketing ADEs. To facilitate the analysis of these case reports, case details are coded using the Medical Dictionary for Regulatory Activities (MedDRA). PatientsLikeMe is a Web-based network where patients report, track, share, and discuss their health information. PatientsLikeMe captures PGHD through free-text and structured data fields. PatientsLikeMe structured data are coded to multiple medical terminologies, including MedDRA. The standardization of PatientsLikeMe PGHD enables electronic accessibility and enhances patient engagement. OBJECTIVE: The aim of this study is to retrospectively review PGHD for symptoms and ADEs entered by patients on PatientsLikeMe and coded by PatientsLikeMe to MedDRA terminology for concordance with regulatory-focused coding practices. METHODS: An FDA MedDRA coding expert retrospectively reviewed a data file containing verbatim patient-reported symptoms and ADEs and PatientsLikeMe-assigned MedDRA terms to determine the medical accuracy and appropriateness of the selected MedDRA terms, applying the International Council for Harmonisation MedDRA Term Selection: Points to Consider (MTS:PTC) guides. RESULTS: The FDA MedDRA coding expert reviewed 3234 PatientsLikeMe-assigned MedDRA codes and patient-reported verbatim text. The FDA and PatientsLikeMe were concordant at 97.09% (3140/3234) of the PatientsLikeMe-assigned MedDRA codes. The 2.91% (94/3234) discordant subset was analyzed to identify reasons for differences. Coding differences were attributed to several reasons but mostly driven by PatientsLikeMe's approach of assigning a more general MedDRA term to enable patient-to-patient engagement, while the FDA assigned a more specific medically relevant term. CONCLUSIONS: PatientsLikeMe MedDRA coding of PGHD was generally comparable to how the FDA would code similar data, applying the MTS:PTC principles. Discordant coding resulted from several reasons but mostly reflected a difference in purpose. The MTS:PTC coding principles aim to capture the most specific reported information about an ADE, whereas PatientsLikeMe may code patient-reported symptoms and ADEs to more general MedDRA terms to support patient engagement among a larger group of patients. This study demonstrates that most verbatim reports of symptoms and ADEs collected by a PGHD source, such as the PatientsLikeMe platform, could be reliably coded to MedDRA terminology by applying the MTS:PTC guide. Regarding all secondary use of novel data, understanding coding and standardization principles applied to these data types are important.

Evaluation of FDA safety-related drug label changes in 2010.

PURPOSE: This study characterizes drug safety-related label changes by evidence source contribution, time from drug approval to label change, initiator (FDA or sponsor), and drug class. METHODS: A retrospective review of the FDA's internal files was used to obtain regulatory documentation on drugs undergoing a 2010 label change. Contribution of evidence sources were identified and label change initiator and drug class were determined for each drug. RESULTS: A total of 371 drugs were analyzed. Spontaneous reports contributed to 52% and 55% of label changes when analyzed by unique safety issue and drug, respectively. The median time from approval to 2010 safety-related label change was 11 years. The sponsor was more likely than the FDA to initiate a label change (58% and 42%). Label changes were most common among nervous system drugs (23%), antiinfectives for systemic use (17%), and cardiovascular system drugs (14%). CONCLUSIONS: Drug label changes involve contributions from multiple evidence sources. The findings from this comprehensive review are consistent with previous findings and demonstrate (i) the continued importance of the spontaneous reporting system and complementary evidence sources and (ii) safety-related label changes take place years after postmarket approval, emphasizing the importance of continued drug safety surveillance throughout a product's lifecycle.

Determinants of arsenic metabolism: blood arsenic metabolites, plasma folate, cobalamin, and homocysteine concentrations in maternal-newborn pairs.

BACKGROUND: In Bangladesh, tens of millions of people have been consuming waterborne arsenic for decades. The extent to which As is transported to the fetus during pregnancy has not been well characterized. OBJECTIVES: We therefore conducted a study of 101 pregnant women who gave birth in Matlab, Bangladesh. METHODS: Maternal and cord blood pairs were collected and concentrations of total As were analyzed for 101 pairs, and As metabolites for 30 pairs. Maternal urinary As metabolites and plasma folate, cobalamin, and homocysteine levels in maternal cord pairs were also measured. Household tube well-water As concentrations exceeded the World Health Organization guideline of 10 microg/L in 38% of the cases. RESULTS: We observed strong associations between maternal and cord blood concentrations of total As (r = 0.93, p < 0.0001). Maternal and cord blood arsenic metabolites (n = 30) were also strongly correlated: in dimethylarsinate (DMA) (r = 0.94, p < 0.0001), monomethylarsonate (r = 0.80, p < 0.0001), arsenite (As(+3)) (r = 0.80, p < 0.0001), and arsenate (As(+5)) (r = 0.89, p < 0.0001). Maternal homocysteine was a strong predictor of %DMA in maternal urine, maternal blood, and cord blood (beta = -6.2, p < 0.02; beta = -10.9, p < 0.04; and beta = -13.7, p < 0.04, respectively). Maternal folate was inversely associated with maternal blood As(5+) (beta = 0.56, p < 0.05), and maternal cobalamin was inversely associated with cord blood As(5+) (beta = -1.2, p < 0.01). CONCLUSIONS: We conclude that exposure to all metabolites of inorganic As occurs in the prenatal period.

A prospective study of blood selenium levels and the risk of arsenic-related premalignant skin lesions.

Arsenic exposure from drinking water is considered to be a risk factor for skin and internal cancers. Animal studies suggest a potential antagonism between arsenic and selenium in the body. We did a case-cohort analysis to prospectively evaluate the association between arsenic-related premalignant skin lesions and prediagnostic blood selenium levels in 303 cases of skin lesions newly diagnosed from November 2002 to April 2004 and 849 subcohort members randomly selected from the 8,092 participants in the Health Effects of Arsenic Longitudinal Study with available baseline blood and urine samples collected in 2000. Incidence rate ratios for skin lesions in increasing blood selenium quintiles were 1.00 (reference), 0.68 [95% confidence interval (95% CI), 0.39-1.18], 0.51 (95% CI, 0.29-0.87), 0.52 (95% CI, 0.30-0.91), and 0.53 (95% CI, 0.31-0.90). Effect estimates remained similar with adjustments for age, sex, body mass index, smoking status, excessive sunlight exposure (in men), well water arsenic concentration at baseline, and nutritional intakes of folate, iron, protein, vitamin E, and B vitamins. At any given arsenic exposure level, the risk of premalignant skin lesions was consistently greater among participants with blood selenium lower than the average level. The findings support the hypothesis that dietary selenium intake may reduce the incidence of arsenic-related premalignant skin lesions among populations exposed to arsenic exposure from drinking water.

Blood arsenic as a biomarker of arsenic exposure: results from a prospective study.

Exposure to arsenic (As)-contaminated drinking water affects millions of people worldwide. Arsenic exposure is associated with skin lesions, skin, lung, kidney and liver cancers, neurologic and cardiovascular effects. Past studies involving biomarkers of As exposure have typically examined urinary As (UAs) (adjusted for urinary creatinine), hair or toenail As, but not blood As (BAs) since blood concentrations are exceedingly low and are not detectable by conventional atomic absorption spectrophotometric techniques. In a case-cohort analysis of 303 newly diagnosed cases of skin lesions, and 849 subcohort members randomly selected from 8092 participants in the health effects of as longitudinal study (HEALS) in Araihazar, Bangladesh, we measured blood, urine and water As concentrations, and examined their associations with each other, and with the risk for skin lesions. BAs concentrations were highly correlated with creatinine-adjusted UAs concentrations (r=0.85) and with water As (WAs) (r=0.75). We observed consistent dose-response relationships between the risk of skin lesions and all the measures of As exposure. Rate ratios (RRs) for skin lesions by quintile of As exposure, adjusted for age and gender, revealed that the two highest quintiles were significantly related to an increased risk of skin lesions for each measure of exposure: BAs, UAs, WAs and a time-weighted water As variable. This prospective study confirms the increased risk of skin lesions in relation to As concentrations in blood, urine and water and also establishes that BAs is a useful biomarker of As exposure in this study population.

Selective uptake from LDL is stimulated by unsaturated fatty acids and modulated by cholesterol content in the plasma membrane: role of plasma membrane composition in regulating non-SR-BI-mediated selective lipid transfer.

We previously reported that unsaturated fatty acids stimulated low-density lipoprotein (LDL) particle uptake in J774 macrophages by increasing LDL receptor activity. Since free fatty acids (FFA) also change plasma membrane properties, a putative cholesteryl ester (CE) acceptor for selective uptake (SU), we questioned the ability of FFA to modulate SU from LDL. Using [(3)H]cholesteryl ether/(125)I-LDL to trace CE core and whole particle uptake, we found that oleic acid and eicosapentaenoic acid, but not saturated stearic acid, increased SU by 30% over control levels. An ACAT inhibitor, Dup128, abolished FFA effects on SU, indicating that increased SU by FFA was secondary to changes in cell-free cholesterol (FC). Consistent with these observations, ACAT inhibition increased cell FC and reduced LDL SU by half. The important role of plasma membrane composition was further demonstrated in that beta-cyclodextrin- (beta-CD-) mediated FC removal from the plasma membrane increased SU from LDL and was further stimulated by U18666A, a compound that inhibits FC transport between lysosomes and the plasma membrane. In contrast, cholesterol-saturated beta-CD markedly reduced LDL SU. In contrast to LDL SU, oleic acid, ACAT inhibition, U18666A, or beta-CD had no effects on HDL SU. Moreover, HDL SU was inhibited by antimouse SR-BI antibody by more than 50% but had little effect on LDL SU. In C57BL/6 mice fed a high fat diet, plasma FFA levels increased, and SU accounted for an almost 4-fold increased proportion of total cholesterol delivery to the arterial wall. Taken together, these data suggest that LDL SU is mediated by pathways independent of SR-BI and is influenced by plasma membrane FC content. Moreover, in conditions where elevated plasma FFA occur, SU from LDL can be an important mechanism for cholesterol delivery in vivo.

Long-chain polyunsaturated fatty acid accretion in brain.

Brain is highly enriched in long-chain polyunsaturated fatty acids (PUFAs), particularly arachidonic acid and docosahexaenoic acid, which play important roles in brain structural and biologic functions. Plasma transport, in the form of free fatty acids or esterified FAs in lysophosphatidylcholine and lipoproteins, and de-novo synthesis contribute to brain accretion of long-chain PUFAs. Transport of long-chain PUFAs from plasma may play important roles because of the limited ability of brain to synthesize long-chain PUFAs, in the face of high demand for them. Although several proteins involved in facilitated fatty acid transport (e.g. fatty acid transport protein, fatty acid binding protein and very-long-chain acyl-coenzyme A synthetase) have been found in brain, their roles in fatty acid accumulation in brain are poorly defined. The primary pathways that are involved in long-chain PUFA accumulation in brain may vary according to brain region and developmental stage.