Daniel A. Moros

De Minimis Risk: A Proposal for a New Category of Research Risk

De Minimis Risk: A Proposal for a New Category of Research Risk Rosamond Rhodes a , Jody Azzouni b , Stefan Bernard Baumrin c , Keith Benkov a , Martin J. Blaser d , Barbara Brenner a , Joseph W. Dauben c , William J. Earle c , Lily Frank c , Nada Gligorov a , Joseph Goldfarb a , Kurt Hirschhorn a , Rochelle Hirschhorn d , Ian Holzman a , Debbie Indyk a , Ethylin Wang Jabs a , Douglas P. Lackey c , Daniel A. Moros a , Sean Philpott e , Matthew E. Rhodes f , Lynne D. Richardson a , Henry S. Sacks a , Abraham Schwab g , Rhoda Sperling a , Brett Trusko a & Arnulf Zweig h a Mount Sinai School of Medicine b Tufts University c The Graduate Center, CUNY d New York University Medical School, CUNY e Union Graduate College f Pennsylvania State University g Indiana University, Purdue h University of Oregon (Emeritus)

Criteria to Assess In Vivo Performance and Bioequivalence of Generic Controlled-Release Formulations of Carbamazepine

Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled‐release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time‐concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical, and Capical, (the arithmetic mean of the POT times and concentrations within 25% of Cmax respectively). Additional parameters for multiple‐dose studies include the percentage fluctuation and the flatness of the steady state‐concentration curve.

Treatment of essential tremor with the barbiturate T2000 (1,3-dimethoxymethyl-5,5-diphenyl-barbituric acid).

The effect of the barbiturate T2000 (1,3‐dimethoxymethyl‐5,5‐diphenyl‐barbituric acid; DMMDPB) on essential tremor, given in twice daily doses of 400 and 300 mg, was assessed in two brief, randomized, placebo‐controlled, parallel‐group, double‐blinded, single‐center trials in 12 and 22 patients, respectively. These trials represent the first clinical use of T2000 for a specific indication. The primary endpoint was the change in the mean scores of the treated and control groups based on the Fahn‐Tolosa‐Marin tremor scale. In the first study of 12 patients treated with 400 mg or placebo twice daily for 14 days, the mean change from baseline at day 14 was 19.3 (P < 0.0001) in the treated group and 9.0 (P = 0.0121) in the control group. Using a two‐factor mixed ANOVA model to evaluate within group and between group changes, the effect of T2000 was significantly different from that of the placebo group (P = 0.03). In the second study of 22 patients treated with 300 mg of T2000 or placebo twice daily for 20 days, statistically significant changes were seen in treated patients compared to baseline, but the ANOVA model did not demonstrate a significant treatment effect of T2000 compared to placebo. When the treated groups from each study are compared, the 800‐mg daily group is significantly different from the 600‐mg daily group (P = 0.02). Some treated patients in each study, but no placebo patients, experienced marked improvement. These results support further evaluation of T2000 in the treatment of essential tremor.

Who Needs Individual Bioequivalence Studies for Narrow Therapeutic Index Drugs? A Case for Warfarin

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of “switching,” an individual bioequivalence study involving a replicate‐design study and three “switchings” in healthy subjects was undertaken using the U.S.‐brand warfarin sodium tablet and a generic product. A randomized, single‐center, open‐label, single‐dose, four‐way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Lius method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject‐by‐formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

A multiple‐dose safety and bioequivalence study of a narrow therapeutic index drug: A case for carbamazepine

Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single‐dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single‐dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple‐dose study was conducted that more closely reflected therapeutic use.

The Electronic Medical Record and the Loss of Narrative

The use of the electronic medical record (EMR) facilitates many aspects of patient care as well as clinical and outcomes research. However, our thought processes are directed differently when collecting data to be entered into a structured database compared with when collecting data to construct a narrative of the patient and his or her complaints. While recognizing that the EMR will improve overall patient care, it is worthwhile examining aspects of patient-doctor interaction that may be sacrificed.

Putting Universal Healthcare on the Religious Agenda

In modern industrial society the issue of access to healthcare is inseparable from the question of whether there is a right to healthcare and whether government has the correlative duty to assure a minimum level of care to all citizens. While discussion in terms of rights and duties tends to direct our attention to broader, more theoretical ethical issues, discussion in terms of ‘access’ invites consideration of more practical concerns. The news media rarely report in terms of whether a citizens right to healthcare has been abridged or disregarded, but rather offers tales of people being denied access. Advocacy groups for specific illnesses do not necessarily argue for universal health insurance, but rather press that certain conditions, such as renal failure requiring dialysis, receive unlimited insurance coverage and that people with the condition be given automatic access to care.