Adaptive licensing: taking the next step in the evolution of drug approval.

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

Detection of 13q abnormalities in multiple myeloma using immunomagnetically selected plasma cells.

Accurate prognostic evaluation of patients with multiple myeloma (MM) is required for their stratification for more adequate therapy. Chromosomal G-banding and interphase fluorescence in situ hybridization (FISH) on cell-nonspecific samples and on myeloma cells selected by magnetic-activated cell separation (MACS) were used to study 13 samples from 12 multiple myeloma (MM) patients. Bone marrow (BM) samples were analysed using three approaches. Standard mitotic samples were prepared and analysed after G-banding. Interphase FISH was performed to detect the 13q14 deletion in unselected BM cells. In parallel, myeloma cells were selected from the BM using the CD138-specific antibody. The high-purity myeloma cell suspension was then analysed by interphase FISH for the 13q14 deletion. Magnetic separation yielded enriched myeloma cell suspensions with the mean viability of 98.0% (range: 97.0%-99.0%), and the purity of 97.6% (range: 87.2%-99.2%) as detected morphologically, and 85.2% (range: 44.8%-98.4%) as detected by immunophenotyping for CD138+ cells. Interphase FISH revealed the 13q14.3 deletion in 5 of 13 (38.5%) of cell-nonspecific samples and in 9 of 13 (69.2%) of enriched myeloma cell suspensions. In conclusion, interphase FISH on immunomagnetically selected MM cells increases the detection of the 13q14 deletion in BM samples from the patients with MM.

Location of the BCR/ABL fusion genes on both chromosomes 9q34 in Ph negative chronic myeloid leukemia.

We present two patients with Ph-negative chronic myeloid leukemia (CML) and fusion signal BCR/ABL on both chromosomes 9, located in region 9q34. The first case was a 27 years old man with CML. Molecular studies (RT-PCR) revealed the rearrangement in the major-BCR region and expression of chimeric BCR/ABL mRNA of b3a2 configuration. By classical cytogenetic studies (G-banding) karyotype 46,XY was found in short-term cultivated bone marrow cells and phytohemagglutinin (PHA) stimulated peripheral lymphocytes. FISH studies revealed the BCR/ABL fusion signals on both chromosomes 9 and green BCR signals on both chromosomes 22 in all mitoses studied. Detection of the alleles of ABL1 intragenic STR locus by fluorescence PCR followed by fragmentation analysis in the patient and his parents provided no information about transmission of the ABL gene. Quantitative assessment of BCR/ABL transcript level by RT-PCR showed 60 and 70% BCR/ABL positivity in two peripheral blood samples at 6,5 and 10,5 months after diagnosis, respectively, which does not correspond to the expression from two identical BCR/ABL hybrid genes. Therefore, the possible mechanism of the origin of two BCR/ABL fusion signals present on both chromosomes 9 could not be resolved and remains speculative. The second case was a 53 years old male with diagnosis of chronic phase of CML, with first sign of acceleration one month after diagnosis and death because of sepsis in blastic phase within four months. The cytogenetic findings were identical to those in case No. 1., i.e. karyotype 46, XY by G-banding, two BCR/ABL fusion signals on both chromosomes 9 and RT-PCR molecular studies proved b3a2 breakpoints. It is generally accepted that prognosis of the patients with fused BCR/ABL gene located on chromosome 9 is poor. The presence of two fused genes could be anticipated as two Ph chromosomes in accelerated and blastic phases of the disease. However, in our study, quantitative findings of BCR/ABL transcripts did not corresponded to the expression of two BCR/ABL genes originating from duplication. If this assumption is correct then the expression of both fused genes BCR/ABL was in case No. 1 equally suppressed and total expression reached about the level of one BCR/ABL gene.

Neurobehavioral dysfunctions associated with dietary iron overload.

Excessive dietary Fe is known to be toxic, but the extent of neurobiological involvement is not clear. In the present study male weanling rats were fed diets containing Fe at 35 (control), 350, 3500, or 20000 ppm for 12 wk. An Fe-deficient group (4 ppm) was included for comparison. Rats were tested for behavioral and body weight changes at various times after initiation of diets, and liver and brain nonheme Fe were measured at term. Excess dietary Fe, primarily at 20000 ppm, significantly decreased activity, habituation, reflex startle, and conditioned avoidance response performance, and enhanced prepulse modulation of startle. Body weights were also markedly decreased. Fe-deficient animals showed similar behavioral effects but more moderate body weight changes. Liver nonheme Fe varied directly with dietary levels. Whole-brain nonheme Fe was significantly reduced in Fe-deficient animals but increased only at the 20000-ppm level. Homeostatic mechanisms appear to regulate whole-brain Fe more effectively under conditions of dietary Fe overload than under conditions of Fe deficiency. The behavioral changes associated with dietary Fe overload may represent secondary consequences of systemic toxicity.

Teratogenesis induced by short- and long-term exposure of Xenopus laevis progeny to lead.

Short-term (96-h) tests on Xenopus laevis embryos are advocated for rapid screening of teratogens, as an alternative to the use of mammals. The objective of the present investigation was to determine whether extending the short-term tests beyond 96 h would detect the teratogenicity of chemicals that would otherwise be missed by the short-term tests. Lead teratogenicity was examined in Xenopus, using lead concentrations of 0.02, 0.05, 0.1, 0.5, 1.0, and 3.0 mg/L, which bracket the U.S. Environmental Protection Agency (EPA) maximum allowable concentration of 0.05 mg/L in water. Short-term exposure times were 72 or 96 h, starting on d 1, 2, or 3 postfertilization, while long-term exposure covered d 1 through metamorphosis. Short-term exposure resulted in neural tube defects (when exposure included d 1 and/or d 2) and tail curvatures, but only at the higher lead concentrations (1 and 3 mg/L). Lower lead concentrations produced no malformations upon short-term exposure, and this corresponded with the absence of tissue lead uptake. On the other hand, long-term exposure to lead (> 3 wk) resulted in the delayed appearance of lordoscoliosis at low lead concentrations (0.02-0.1 mg/L). The delayed appearance of lordoscoliosis corresponded roughly with the attainment of stable lead tissue levels, and this malformation persisted after metamorphosis. Thus, short-term observation tests alone may fail to detect the teratogenicity of low concentrations of environmental chemicals, and may result in the setting of inappropriately liberal exposure standards.

Use of generic screening criteria for clinical interventions that link prescribing to credentialing.

Current JCAHO standards require hospitals to link the use of drugs to prescriber credentialling. The pharmacy service at the Veterans Affairs Medical Center, Iowa City, Iowa, has developed a prescriber-specific program that documents clinical interventions and links that information to physician credentialling through the Pharmacist Intervention Report and associated quality assurance (QA) program. A severity index level was also developed to rate the significance of the interventions. The Pharmacist Intervention Report is used by all medical departments in their respective QA programs.

A retrospective study of compliance with recommended hematologic monitoring of carbamazepine.

Early case reports of fatal hematologic effects associated with carbamazepine (CBZ) resulted in manufacturer recommendations for extensive laboratory monitoring. Several alternative monitoring protocols have been published, indicating disagreement with those recommendations. The manufacturer has removed specific monitoring guidelines allowing physicians to monitor CBZ during treatment based on their clinical judgment. This study was designed to determine the frequency of CBZ hematologic monitoring in one academic setting. Data on complete blood counts (CBCs) were retrospectively obtained and were compared with 1975-88 Physicians' Desk Reference recommendations for weekly CBCs during the first three months of treatment. Eighty-three patients were identified: 32 psychiatry, 37 neurology, and 14 from other clinics. Only one patient met guidelines for monitoring during the entire first three months of treatment. Comparisons between clinics demonstrated no statistically significant differences in monitoring rates. Prospective studies in academic and private practice settings are needed to provide more information on actual monitoring practices. Due to the removal of specific manufacturer recommendations, a standard approach is needed to establish consistent and adequate monitoring and to provide legal support to prescribers.

A review of carbamazepine's hematologic reactions and monitoring recommendations.

Early case reports of fatal hematologic effects attributed to carbamazepine (CBZ) resulted in extensive monitoring recommendations by the manufacturer. The rarity of blood dyscrasias led many authors to question the manufacturer's guidelines. Thus the manufacturer removed specific monitoring guidelines, allowing physicians to monitor CBZ using their clinical judgment. This article reviews case reports and studies of CBZ's hematologic effects. Due to their rapid onset, daily laboratory checks would be necessary to monitor for aplastic anemia, agranulocytosis, and thrombocytopenia. These adverse effects are best monitored by informing patients and physicians to carefully watch for signs and symptoms. Leukopenia develops more slowly, occurring in approximately 12 percent of children and 7 percent of adults. Its onset is typically within the first three months of treatment, with patients at risk having a low or low-normal pretreatment white blood cell (WBC) count. Leukopenia often reverses, even if CBZ is continued. Based upon our review of the literature, we recommend monitoring of those high-risk patients during the first three months of treatment with the frequency being determined by results of each laboratory value. WBC counts less than 3000/mm3 or neutrophil counts below 1000/mm3 warrant a decrease in dose with frequent monitoring or CBZ discontinuation, if necessary.

Anxiety and the menstrual cycle in panic disorder.

Nineteen females with panic disorder were studied using daily prospective home diary ratings of various general health related items, a short anxiety self-rating scale, a survey of late luteal phase dysphoric symptoms, as well as a record of the number and severity of panic attacks. The subjects collected information for 60 consecutive days, and information regarding 30 menstrual cycles was available for analysis. Overall, subjects retrospectively reported increases in their anxiety symptoms during premenstrual days, but this was not demonstrated consistently on daily prospective ratings.

[Pregnancy and serum lipids--possible relations to cholelithiasis]. / Schwangerschaft und Serumlipide--Mögliche Beziehungen zur Cholelithiasis.

The authors follow up the connection between raised lipid levels in serum during pregnancy and the occurrence of gall-stones in the woman's family respectively later cholecystectomia.

Protective effect of rabbit immune serum administered orally to rats infected by a human pathogenic strain of E. coli.

1-week-old rats were inoculated orally with a strain of E. coli (serotype 078) isolated from the blood of a newborn baby who had died of septicemia. During the 3 weeks following inoculation, approximately 50% of the animals died of septicemia and 60% of the surviving rats had pathogenic bacteria in their rectum. Some of the surviving rats were severely impaired in their development. Autopsy showed evidence of active intestinal infection localized mainly in the ileum and cecum. A rabbit anti-E. coli (strain 23) serum (agglutinating titer: 1/2,500) afforded 100% protection when as little as 0.03 mg of serum protein per gram of rat body weight was orally administered in a single dose. The immune serum had an effect both on the mortality rate and on the growth of the rats. However, it never affected the survival of pathogenic bacteria in the rectum, even when administered at a daily dose of 1.5 mg of serum protein per gram of rat body weight on 4 consecutive days. The immune rabbit serum had only a weak bactericidal effect in vitro. The hemagglutination test showed the presence in the immune serum of antibodies against the fimbriae of the pathogenic E. coli strain (titer: 1/1,000). The role of antibody in inhibiting the adherence of bacteria to epithelial cells and/or their progression across the mucous layer are discussed as possible immune mechanisms in the intestinal lumen.