Disease pathogenesis, treatment effectiveness, and co-morbid burden among adult patients with primary immune thrombocytopenia (ITP)

Background Primary immune thrombocytopenia (ITP) is an autoimmune disease involving autoantibody-mediated platelet destruction, suboptimal platelet production, and T-cell-mediated platelet lysis. These processes cause a decreased peripheral blood platelet count (< 150 x 109/L), resulting in an increased susceptibility to bleeding events. While the course of primary ITP is often acute (< 6 months) among children, it is generally chronic in adults. Despite a marked increase in epidemiological research over the past decade, unresolved questions remain with regard to disease pathogenesis, treatment effectiveness, and co-morbid burden among adults with primary ITP. Objectives 1. To launch a registry for adults with primary ITP in the United Kingdom (UK) 2. To evaluate associations of candidate single nucleotide polymorphisms (SNPs) with primary ITP 3. To assess the effectiveness of 111In-labelled platelet studies in predicting outcomes from splenectomy 4. To document health-related lifestyle concerns among patients 5. To gauge the effectiveness of Helicobacter pylori (H. pylori) eradication in elevating platelet counts 6. To characterise associations of primary ITP with both arterial and venous thromboembolic events (TEs) Data sources 1. The UK Adult ITP Registry (17 centres, 327 patients) 2. The UK Adult ITP Registry-affiliated, 111In-Labelled Platelet Study Database (117 centres, 256 patients) 3. The Wellcome Trust Case-Control Consortium (WTCCC) 1958 British Birth Cohort (3,000 individuals) 4. The General Practice Research Database (GPRD) (500+ centres, 4 million+ patients) 5. The UK ITP Support Association Health-Related Lifestyle Survey (790 patients) 6. Systematic reviews of published epidemiological studies Methods and Results SNP Study Caucasian patients from the UK Adult ITP Registry were gender-matched (1:3) with healthy controls from the WTCCC 1958 British Birth Cohort. Six functional candidate SNPs in cytokine or cytokine receptor genes were measured in cases and retrieved for controls from the European Genome-phenome Archive. Associations were evaluated using logistic regression models. A statistically significant per allele odds ratio (OR) of 1.34 (95% confidence interval [CI], 1.03- 1.75) was observed for TNFA -308 g>a, implicating increased disease susceptibility among carriers of the rare allele. 111In Study The effectiveness of autologous 111In-labelled platelet sequestration studies in predicting short (1-3 months), medium (6-12 months), and long-term (last follow-up) complete response (CR; count < 100 x 109/L) to splenectomy in patients with primary ITP was evaluated using multivariable logistic regression models. Significant adjusted (gender, age at splenectomy, and mean platelet lifespan) ORs were uncovered for short (7.47 [95% CI, 1.89-29.43], medium (4.85 [95% CI, 1.04-22.54]) and long-term (5.39 [95% CI, 1.34-21.65]) CR in patients with purely or predominantly splenic versus mixed or hepatic splenic platelet sequestration, highlighting the utility of platelet sequestration studies as an adjunct predictive tool prior to splenectomy. H. pylori Eradication Study A systematic literature review was conducted of studies evaluating the effects of H. pylori eradication on platelet count in patients with primary ITP. Twenty-five studies were identified, encompassing 696 evaluable patients. The weighted mean complete response (count > 100 x 109/L) and overall response (platelet count > 30 x 109/L) were 42.7% (95% CI, 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. Observed responses were higher in countries with a higher prevalence of H. pylori infection and in patients with milder thrombocytopenia. These findings support the benefits of H. pylori detection and eradication in patients with primary ITP. Health-Related Lifestyle Study A 43-question, closed-field questionnaire was used to identify health-related lifestyle concerns among patient members of the UK Adult ITP Support Association. Completed surveys were returned by 790 (44.7%) members, with nearly one-third of adults reporting having an elective surgery delayed due to a low platelet count and experiencing difficulty in obtaining travel insurance. Notably, 12.5% of all patients reported “always” or “often” missing work or school due to fatigue. These results highlight several promising avenues for future health-related quality of life (HRQoL) research. Thromboembolic Event Studies Using the GPRD, 1,070 adults with primary ITP were matched (1:4) with 4,280 ITP-free controls by age, gender, practice, and observation time. Comparative risks of TEs were assessed using Cox proportional hazards models. Over a median time of 47.6 months (range: 3.0-192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01-2.48) and 1.37 (95% CI, 0.94-2.00) were found for venous and arterial TEs, respectively. A similar investigation was conducted comparing age and sex-stratified incidence rates of TEs among patients in the UK Adult ITP Registry with population-based estimates for the general adult population, yielding significant standardised rate ratios of 2.43 (95% CI, 1.01-5.83) and 2.45 (95% CI, 1.48-4.06) for venous and arterial TEs, respectively. These results collectively highlight an increased risk of venous and arterial TEs in adults with primary ITP. Conclusions Primary ITP is a pro-inflammatory (i.e., TH-1-mediated), pro-thrombotic disease in adults. Available evidence supports testing for and eradication of H. pylori infection in patients with primary ITP and the utility of autologous 111Inlabelled platelet sequestration studies in identifying patients likely to respond to splenectomy. The development of a prospective, international registry will help assemble the sample sizes needed for promising further research, namely genome-wide disease association studies and investigations into the effects of the eradication of strain-specific H. pylori infection on platelet count, the precise relative risk of non-response to splenectomy in patients with mixed or hepatic platelet sequestration, and the associations of TEs with primary ITP in antiphospholipid antibody-negative

Transformative Models to Promote Prescription Drug Innovation and Access: A Landscape Analysis

The patent-based pharmaceutical innovation system in the US does not incentivize the development of drugs with the greatest impact on patient or public health. It has also led to drug prices that patients and health care systems cannot afford. Three alternate approaches to promoting pharmaceutical innovation have been proposed to address these shortcomings. Delinkage models involve payments for drug innovation based on public health value rather than on a per-use basis. Public manufacturing models call upon governments and nonprofit organizations to lead drug discovery, development, and production. Public-private partnership models entail publicly-funded organizations working closely with for-profit partners on drug development and price-setting. Each model exhibits promise in promoting prescription drug innovation and access. This paper reviews these transformative models in detail, examining their key characteristics, advantages, and limitations

Battling Over Patents: The Impact of Oil States on the Generic Drug Industry

In the 2018 case of Oil States Energy Services v. Greene’s Energy Group, the U.S. Supreme Court upheld the constitutionality of inter partes review, a non-judicial proceeding for challenging patents that was created by Congress as part of the 2011 Leahy-Smith America Invents Act. By establishing inter partes review, Congress hoped to rebalance patent policy to make it faster and less costly to invalidate erroneously granted patents in all fields of technology. In the pharmaceutical industry, generic drug companies have embraced inter partes review, filing hundreds of challenges in the first five years after its creation, with moderate success. Biologics, which make up a growing class of pharmaceutical products, are sometimes covered by dozens or scores of patents. As more of these complex therapeutics are developed and approved, inter partes review is expected to play an increasingly important role

Regulatory Solutions to the Problem of High Generic Drug Costs

Recent reports have highlighted dramatic price increases for several older generic drugs, including a number of essential products used to treat deadly infectious diseases. Although most of these medicines have been widely available at reasonable prices for decades, some manufacturers have seized on unique features of the pharmaceutical marketplace to seek substantial profits. In this Perspective, we examine limitations in current price regulation among public and private payors and consider several reforms that could address the problem of expensive generic drugs through improved competition

Use of Artificial Intelligence in Drug Development

Considerable focus has been placed on the health care applications of artificial intelligence (AI). Already, machine learning, a subset of AI that involves “the use of data and algorithms to imitate the way that humans learn” has been used to predict diseases, while AI-powered smartphone apps have been developed to promote mental health and weight loss. Owing in part to such successes, the market for AI in health care has been forecasted to increase more than 1000% between 2022 and 2029, from $13.8 billion to$164.1 billion. One area of substantial promise is drug development, which is poised to benefit from advances in the use of AI to predict protein folding, molecular interactions, and cellular disease processes. Successful application of AI to drug development, however, faces several obstacles, including poor model performance caused by nondiverse training data and shortcut learning. Additionally, the often opaque ways that AI systems reach their predictions conflict with regulatory approval frameworks that require a rationale for decision-making. Given these obstacles, we sought to identify the scope and breadth of AI use in drug development

Crowdsourcing Public Health Experiments: A Response to Jonathan Darrow\u27s Crowdsourcing Clinical Trials

We are pleased to have this opportunity to respond to Jonathan Darrow\u27s article, Crowdsourcing Clinical Trials (CCT).\u27 We seek to highlight its important contributions and to commence debate over some of its arguments. In particular, we qualify the ethical arguments that characterize early clinical use of drugs as if they were research, and suggest instead that, in either domain, the ethical (and legal) analysis should remain focused on whether all material information is provided so patients may make informed decisions. We also highlight the limits of what can be gleaned from the observational data collection efforts envisioned by CCT. Ultimately, we exploit the core insights of CCT to expand the potential use of crowdsourcing from observational studies to truly randomized interventional trials. Randomized experiments allow causal inference because they assign subjects to a treatment and control group, and collect data from each. Furthermore, we draw attention to the fact that much of public health is driven not by pharmaceuticals, but by lifestyle factors. We suggest that CCT\u27s envisioned platform for crowdsourcing also has great potential to engage the public in producing new and trustworthy knowledge in the domains of diet, exercise, nutritional supplements, and integrative medicine, which are primary drivers of health outcomes and spending

COVID-19 vaccine boosters for all adults: An optimal U.s. approach?

By 20 October 2021, the U.S. Food and Drug Administration (FDA) had amended its Emergency Use Authorizations for immunocompetent adults who previously received the Pfizer-BioNTech, Moderna, or Johnson & Johnson COVID-19 vaccines. For the 2-dose Pfizer-BioNTech and Moderna vaccines, the FDA permitted a single booster dose for adults aged 65 years or older and adults aged 18 to 64 years at high-risk for severe COVID-19 or at high risk for occupational or institutional COVID-19 exposure. For the single-dose Johnson & Johnson vaccine, the FDA permitted a single booster dose for all adults aged 18 or older. These eligibility schemes were endorsed by the Centers for Disease Control and Prevention shortly after FDA approval

Influence of drug safety advisories on drug utilisation: an international interrupted time series and meta-analysis

OBJECTIVE: To evaluate the association between regulatory drug safety advisories and changes in drug utilisation. DESIGN: We conducted controlled, interrupted times series analyses with administrative prescription claims data to estimate changes in drug utilisation following advisories. We used random-effects meta-analysis with inverse-variance weighting to estimate the average postadvisory change in drug utilisation across advisories. STUDY POPULATION: We included advisories issued in Canada, Denmark, the UK and the USA during 2009-2015, mainly concerning drugs in common use in primary care. We excluded advisories related to over-the-counter drugs, drug-drug interactions, vaccines, drugs used primarily in hospital and advisories with co-interventions within ±6 months. MAIN OUTCOME MEASURES: Change in drug utilisation, defined as actual versus predicted percentage change in the number of prescriptions (for advisories without dose-related advice), or in the number of defined daily doses (for dose-related advisories), per 100 000 population. RESULTS: Among advisories without dose-related advice (n=20), the average change in drug utilisation was -5.83% (95% CI -10.93 to -0.73; p=0.03). Advisories with dose-related advice (n=4) were not associated with a statistically significant change in drug utilisation (-1.93%; 95% CI -17.10 to 13.23; p=0.80). In a post hoc subgroup analysis of advisories without dose-related advice, we observed no statistically significant difference between the change in drug utilisation following advisories with explicit prescribing advice, such as a recommendation to consider the risk of a drug when prescribing, and the change in drug utilisation following advisories without such advice. CONCLUSIONS: Among safety advisories issued on a wide range of drugs during 2009-2015 in 4 countries (Canada, Denmark, the UK and the USA), the association of advisories with changes in drug utilisation was variable, and the average association was modest