A call to incorporate systems theory and human factors into the existing investigation of harm in clinical research involving healthcare products.

This is a joint statement from individual pharmacology and pharmaceutical professionals acting in their own capacity, including members of the Alliance for Clinical Research Excellence and Safety (ACRES) and the International Society of Pharmacovigilance (ISoP). By building on the extensive pharmacological and regulatory investigations that already take place, we are calling for a fuller and more robust systems-based approach to the independent investigation of clinical research when serious incidents of harm occur, starting with first-in-human clinical trials. To complement existing activities and regulations, we propose an additional approach blending evidence derived from both pharmacological and organizational science, which addresses human factors and transparency, to enhance organizational learning and continuous improvement.

An experimental investigation of masking in the US FDA adverse event reporting system database.

Background: A phenomenon of 'masking' or 'cloaking' in pharmacovigilance data mining has been described, which can potentially cause signals of disproportionate reporting (SDRs) to be missed, particularly in pharmaceutical company databases. Masking has been predicted theoretically, observed anecdotally or studied to a limited extent in both pharmaceutical company and health authority databases, but no previous publication systematically assesses its occurrence in a large health authority database.

Objective: To explore the nature, extent and possible consequences of masking in the US FDA Adverse Event Reporting System (AERS) database by applying various experimental unmasking protocols to a set of drugs and events representing realistic pharmacovigilance analysis conditions.

An evaluation of three signal-detection algorithms using a highly inclusive reference event database.

Background: Pharmacovigilance data-mining algorithms (DMAs) are known to generate significant numbers of false-positive signals of disproportionate reporting (SDRs), using various standards to define the terms 'true positive' and 'false positive'.

Objective: To construct a highly inclusive reference event database of reported adverse events for a limited set of drugs, and to utilize that database to evaluate three DMAs for their overall yield of scientifically supported adverse drug effects, with an emphasis on ascertaining false-positive rates as defined by matching to the database, and to assess the overlap among SDRs detected by various DMAs.

Methods: A sample of 35 drugs approved by the US FDA between 2000 and 2004 was selected, including three drugs added to cover therapeutic categories not included in the original sample.

Systematic investigation of time windows for adverse event data mining for recently approved drugs.

The optimum timing of drug safety data mining for a new drug is uncertain. The objective of this study was to compare cumulative data mining versus mining with sliding time windows. Adverse Event Reporting System data (2001-2005) were studied for 27 drugs.

Drug-versus-drug adverse event rate comparisons: a pilot study based on data from the US FDA Adverse Event Reporting System.

Background: A number of published studies compare adverse event rates for drugs on the basis of reports in the US FDA Adverse Event Reporting System (AERS). While the AERS data have the advantage of timely availability and a large capture population, the database is subject to many significant biases, and lacks complete patient information that would allow for correction of those biases. The accuracy of comparative AERS-based data mining has been questioned, but has not been systematically studied.

Influence of the MedDRA hierarchy on pharmacovigilance data mining results.

Purpose: To compare the results of drug safety data mining with three different algorithms, when adverse events are identified using MedDRA Preferred Terms (PT) vs. High Level Terms (HLT) vs. Standardised MedDRA Queries (SMQ).

Predicting response of vitreous hemorrhage after intravitreous injection of highly purified ovine hyaluronidase (Vitrase) in patients with diabetes.

Purpose: To develop a predictive model for patients with diabetes who are most likely to have vitreous hemorrhage clearing by 3 months after a single, intravitreous injection of highly purified, preservative-free, ovine hyaluronidase (Vitrase; ISTA Pharmaceuticals, Inc., Irvine, CA).

Methods: Post hoc data analysis was performed on two randomized, double-masked, placebo-controlled, phase 3 clinical trials of a single intravitreous injection of Vitrase for severe vitreous hemorrhage.

Insulin-like growth factor type-I receptor internalization and recycling mediate the sustained phosphorylation of Akt.

Previously we demonstrated that insulin-like growth factor-I mediates the sustained phosphorylation of Akt, which is essential for long term survival and protection of glial progenitors from glutamate toxicity. These prosurvival effects correlated with prolonged activation and stability of the insulin-like growth factor type-I receptor. In the present study, we investigated the mechanisms whereby insulin-like growth factor-I signaling, through the insulin-like growth factor type-I receptor, mediates the sustained phosphorylation of Akt.

Intensive lifestyle modification: impact on cardiovascular disease risk factors in subjects with and without clinical cardiovascular disease.

Intensive lifestyle modification programs are intended to stabilize or promote regression of coronary artery disease; however, clinical response is often nonuniform, complicating appropriate utilization of resources and prediction of outcome. This study assessed physiological and psychological benefits to 72 persons participating in a prospective, nonrandomized, four-component lifestyle change program and compared response between patients with clinical cardiovascular disease (CVD) and patients with elevated risk factors for CVD but without clinical manifestations of disease. Subjects entering the program due to elevated risk factor levels alone demonstrated equal or greater benefit, in terms of improvement in primary CVD risk factors and reduction in measures of coronary disease risk developed in the Framingham Heart Study, than those with clinical CVD.

Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration.

Background: To evaluate the association of long-term continuous mycophenolate mofetil (MMF) versus azathioprine (AZA) therapy and renal allograft function, as measured by the slope of reciprocal creatinine, we analyzed 49,666 primary renal allograft recipients reported to the United States Renal Data System between October 31, 1988 and June 30, 1998.

Methods: The primary study endpoint was defined as a greater than 20% decrease below a 6-month baseline of 1/serum creatinine (SCr) (slope of reciprocal creatinine) at or beyond 1 year after transplantation. A secondary endpoint was defined as reaching an SCr value greater than 1.

Long-term use of mycophenolate mofetil is associated with a reduction in the incidence and risk of late rejection.

To evaluate the association of long-term continuous (minimum 1 year) mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of late acute rejection, we analyzed 47 693 primary renal allograft recipients reported to the United States Renal Data System between 1988 and 1998. The primary study endpoint was acute rejection beyond 1 year after transplantation.