A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan: An evaluation of regulatory decision-making.

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management.

Case Report: Primary Spinal Lymphoma.

This is the report on the case of a 74 year old male patient who was admitted to hospital emergency because of a distended bladder, which was detected on an MRI. This MRI was performed because of an acute paralysis of the patient's left leg. After various examinations we could conclude that the patient's neurological symptoms were not due to metastases of a solid tumour as we expected, but to a primary spinal diffuse B-cell lymphoma. The central nervous system, and especially the spinal cord, are an extremely rare location for primary B-Cell lymphoma.

Disruption of autophagy by the histone deacetylase inhibitor MGCD0103 and its therapeutic implication in B-cell chronic lymphocytic leukemia.

Evading apoptosis is a hallmark of B-cell chronic lymphocytic leukemia (CLL) cells and an obstacle to current chemotherapeutic approaches. Inhibiting histone deacetylase (HDAC) has emerged as a promising strategy to induce cell death in malignant cells. We have previously reported that the HDAC inhibitor MGCD0103 induces CLL cell death by activating the intrinsic pathway of apoptosis. Here, we show that MGCD0103 decreases the autophagic flux in primary CLL cells. Activation of the PI3K/AKT/mTOR pathway, together with the activation of caspases, and to a minor extent CAPN1, resulting in cleavage of autophagy components, were involved in MGCD0103-mediated inhibition of autophagy. In addition, MGCD0103 directly modulated the expression of critical autophagy genes at the transcriptional level that may contribute to autophagy impairment. Besides, we demonstrate that autophagy is a pro-survival mechanism in CLL whose disruption potentiates cell death induced by anticancer molecules including HDAC and cyclin-dependent kinase inhibitors. In particular, our data highlight the therapeutic potential of MGCD0103 as not only an inducer of apoptosis but also an autophagy suppressor in both combination regimens with molecules like flavopiridol, known to induce protective autophagy in CLL cells, or as an alternative to circumvent undesired immunomodulatory effects seen in the clinic with conventional autophagy inhibitors.

Persistency with medical treatment for glaucoma and ocular hypertension in the United Kingdom: 1994-2005.

PURPOSE: To examine trends and demographic factors affecting persistence with ocular hypotensive therapy, from a period before prostaglandins were available to when they were the most common therapy. METHODS: Computerised patient records from 94 general practices across the United Kingdom, identified 5670 registered patients newly prescribed an ocular hypotensive drug (1993-2005). Persistence was defined as continuing therapy without a 90-day gap in prescription for (i) any ocular hypotensive and (ii) initial monotherapy. Time to failure with the treatment was compared using proportional hazard analyses, adjusted for age, gender, practice, year of initial treatment, and a sociodemographic indicator. Study findings were set in the context of a review of the literature. RESULTS: Percentage persistent at 1-year rose after 1997 when prostaglandins were introduced; from 61% in 1994-1996 to 70% in 2002-2004. Persistence with any treatment did not differ between those initiated on beta-blockers compared to prostaglandins (1.05, 95% CI 0.93-1.17). However, 20% of subjects initiated on beta-blockers received a prostaglandin by 1 year. Conversely, 8% of those initiated on prostaglandins received a beta-blocker. When failure with initial therapy was considered, beta-blockers appeared worse (1.35, 95% CI 1.21-1.50); this was consistent with findings from six studies in the review (1.40, 95% CI 1.34-1.46). Neither gender nor social factors were associated with persistence, but younger subjects (35-64 years) were significantly more likely to fail as were those over 85 years. CONCLUSIONS: Introduction of prostaglandins may explain an improvement in persistence over a decade. However, whether the higher cost of initiating patients on prostaglandins is justified remains questionable unless clinically indicated.

A patient with Hodgkin's lymphoma, antiphospholipid syndrome and severe mitral insufficiency.

The association between Hodgkin's lymphoma, antiphospholipid syndrome and severe mitral insufficiency is a very rare event. We report on a 25-year-old female patient suffering from Hodgkin's lymphoma and presenting with thromboembolic events and severe mitral insufficiency. The possible link between these symptoms being antiphospholipid antibodies, is discussed briefly.

The epidemiology of medical treatment for glaucoma and ocular hypertension in the United Kingdom: 1994 to 2003.

AIMS: To study trends in the prevalence of being treated for glaucoma and ocular hypertension from 1994 to 2003, and to examine factors determining treatment in 2002. METHODS: Computerised data (the DIN-LINK database) from 131 general practices across the United Kingdom, in which half a million patients aged 40 years or more were registered annually, were used. On average 10 000 patients were treated for glaucoma and ocular hypertension annually. RESULTS: Prevalence of being treated for glaucoma and ocular hypertension increased from 1.7% in 1994 to 2.3% in 2003. Those aged 85 years or more were 13 times (95% CI 12.2 to 13.8) more likely to be treated than those aged 40-64 years. Men were more likely to be treated than women (OR 1.24, 95% CI 1.19 to 1.28). Subjects "hard pressed" were less likely to be treated than "wealthy achievers" (OR 0.92, 95% CI 0.86 to 0.99). While use of topical beta blocker only medications has declined since 1995, use of topical prostaglandins and combination therapies has increased. In 2003, use of prostaglandins overtook beta blocker only medications. CONCLUSION: Prevalence of being treated for glaucoma has increased over time, and rises with age. Differences in treatment by sex and social status could be explained by use of or access to health care or by underlying prevalence of disease. Trends in treated glaucoma emphasise the shift from use of topical beta blockers to newer therapies.

A comparison of the recording of 30 common childhood conditions in the Doctor's Independent Network and General Practice Research Databases.

In this article we compare the recording of 30 common childhood conditions in two general practice databases of anonymised computerised medical records based on fundamentally different systems--the Doctor's Independent Network (DIN) database (Torex system) and the General Practice Research Database (GPRD) (In Practice Systems). Analysing the records of all children born 1990-1993 and followed for 5 years we found comparable results for most conditions, but differences between the hierarchical structures of the diagnostic coding systems (Read in DIN, OXMIS in GPRD) led to some differences between the databases. Practice variation was marked, but comparable between databases. Variation was greatest in conditions that are poorly defined clinically.