Extent of Safety Database in Pediatric Drug Development: Types of Assessment, Analytical Precision, and Pathway for Extrapolation through On-Target Effects

Pediatric patients should have access to medicines that have been appropriately evaluated for safety and efficacy. Given this goal of revised labelling, the adequacy of the pediatric clinical development plan and resulting safety database must inform a favorable benefit-risk assessment for the intended use of the medicinal product. While extrapolation from adults can be used to support efficacy of drugs in children, there may be a reluctance to use the same approach in safety assessments, wiping out potential gains in trial efficiency through a reduction of sample size. To address this reluctance, we explore safety review in pediatric trials, including factors affecting these data, specific types of safety assessments, and precision on the estimation of event rates for specific adverse events (AEs) that can be achieved. In addition, we discuss the assessments which can provide a benchmark for the use of extrapolation of safety that focuses on on-target effects. Finally, we explore a unified approach for understanding precision using Bayesian approaches as the most appropriate methodology to describe/ascertain risk in probabilistic terms for the estimate of the event rate of specific AEs

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Background & Aims: There is little information regarding the extent to which difficult to cure patients with advanced liver fibrosis, due to hepatitis C virus genotype-1 (HCV-1) can successfully and safely be treated with triple therapy with telaprevir (TVR), pegylated interferon alpha (P) and ribavirin (R). In the TVR early access program HEP3002 we aimed to explore treatment safety and efficacy, and identify predictors of sustained virological response at week 24 (SVR24). Methods: 1078 patients with bridging fibrosis (n = 552) or cirrhosis (n = 526) diagnosed by either liver biopsy or non-invasive markers, with compensated bone marrow (neutrophils >1500/ mm3, Hb >12/13 g/dl) and liver function (Albumin >3.3 g/dl, Platelets >90,000/ml) received TVR PR for 12 weeks, followed by a PR tail according to label. Results: Overall, 614 (57%) achieved SVR24 by intention-to-treat analysis. The SVR24 rate was 68% in 221 treatment naïve patients (62.8% F4), 72% in 356 prior relapsers (64.4% F4), 55% in 139 partial responders (53.2% F4), and 34% in 294 null responders (28.6% F4). The SVR24 rate to response-guided therapy (24 weeks treatment duration if undetectable viremia at weeks 4 and 12) was 84% in 222 naïve/relapser F3 patients. Independent predictors of response were: (A) F3 (odds ratio (OR) = 1.51, 95% CI 1.31- 2.00, p = 0.005), (B) subtype 1b (OR = 1.63, 95% CI 1.18-2.24, p = 0.0029), (C) alpha-fetoprotein <10 ng/ml (OR = 2.50, 95% CI 1.87-3.36, p <0.0001) and (D) any prior response other than null (OR = 3.29, 95% CI 2.40-4.52, p <0.0001). SVR24 rose for patients who had more of these predictive factors: 6/32 (19%) for none, 38/139 (27%) for 1, 129/260 (50%) for 2, 202/329 (61%) for 3, and 194/235 (83%) for 4 factors. Grade 2-4 treatment-related adverse events (AE) were experienced by 719 (67%) patients; 169 (16%) discontinued therapy for AE and 7 (0.6%) died during the PR tail. Conclusions: Naïve and experienced patients with advanced fibrosis or cirrhosis due to HCV-1 who have compensated bone marrow and liver function, can effectively and safely be treated by TVR triple therapy. Baseline predictors of outcome have been identified to optimize pre-treatment counselling.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Final results of the telaprevir access program: Fibroscan values predict safety and efficacy in hepatitis c patients with advanced fibrosis or cirrhosis

Background: Liver stiffness determined by transient elastography is correlated with hepatic fibrosis stage and has high accuracy for detecting severe fibrosis and cirrhosis in chronic hepatitis C patients. We evaluated the clinical value of baseline FibroScan values for the prediction of safety and efficacy of telaprevir-based therapy in patients with advanced fibrosis and cirrhosis in the telaprevir Early Access Program HEP3002. Methods: 1,772 patients with HCV-1 and bridging fibrosis or cirrhosis were treated with telaprevir plus pegylated interferon-α and ribavirin (PR) for 12 weeks followed by PR alone, the total treatment duration depending on virological response and previous response type. Liver fibrosis stage was determined either by liver biopsy or by non-invasive markers. 1,282 patients (72%) had disease stage assessed by FibroScan; among those 46% were classified as Metavir F3 at baseline and 54% as F4. Results: Overall, 1,139 patients (64%) achieved a sustained virological response (SVR) by intentionto- treat analysis. Baseline FibroScan values were tested for association with SVR and the occurrence of adverse events. By univariate analysis, higher baseline FibroScan values were predictive of lower sustained virological response rates and treatment-related anemia. By multivariate analysis, FibroScan was no longer statistically significant as an independent predictor, but higher FibroScan values were correlated with the occurrence of infections and serious adverse events. Conclusions: FibroScan has a limited utility as a predictor of safety and efficacy in patients treated with telaprevir-based triple therapy. Nevertheless it can be used in association with other clinical and biological parameters to help determine patients who will benefit from the triple regiments. © 2015 Lepida et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in North and South America

Background: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor. Methods: Patients from 48 sites in the United States, Canada, Mexico, and Brazil with at least six months of previous treatment with agents in three classes of antiretroviral drugs, resistance to drugs in these classes, or both, and with at least 5000 copies of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio to receive enfuvirtide plus an optimized background regimen of three to five antiretroviral drugs or such a regimen alone (control group). The primary efficacy end point was the change in the plasma HIV-1 RNA level from base line to week 24. Results: A total of 501 patients underwent randomization, and 491 received at least one dose of study drug and had at least one measurement of plasma HIV-1 RNA after treatment began. The two groups were balanced in terms of the median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both groups), median CD4+ cell count (75.5 cells per cubic millimeter in the enfuvirtide group, and 87.0 cells per cubic millimeter in the control group), demographic characteristics, and previous antiretroviral therapy. At 24 weeks, the least-squares mean change from base line in the viral load (intention- to-treat, last observation carried forward) was a decrease of 1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of 0.764 log10 copies per milliliter in the control group (P<0.001). The mean increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells per cubic millimeter, respectively (P<0.001). Reactions at the site of the injections were reported by 98 percent of patients receiving enfuvirtide. There were more cases of pneumonia in the enfuvirtide group than in the control group. Conclusions: The addition of enfuvirtide to an optimized antiretroviral regimen provided significant antiretroviral and immunologic benefit through 24 weeks in patients who had previously received multiple antiretroviral drugs and had multidrug-resistant HIV-1 infection

Holographic data storage using azobenzene polymer

It is well known that holographic data storage can significantly increase data storage capacity. However, the technological maturity of holographic data storage is believed to be impeded by the lack of good holographic material that can be erased and recorded optically with almost unlimited rewriting cycles, large index modulation for large capacity multiplexed data recording, long lifetime, and immunity to destructive readout for archival applications. The performance of an azobenzene polymer is presented for holographic data storage applications. Initial experiments demonstrated that it is capable of satisfying many of above requirements. Recording of holograms without follow-up processing and being stable in application environment are its most attractive features. Applications of such material to other adaptive structures are possible

Holographic data storage on azobenzene photopolymer film using nanosecond laser pulses

A new photopolymer has been developed as a material candidate for high-density holographic data storage applications. Holographic gratings have been recorded on the polymer film using nanosecond laser pulses at 532 nm wavelength with diffraction efficiency measured up to 20%. Further studies have shown 14 line pairs/mm as the material resolution of our photopolymer films at the current development stage. Combined with the erasability results published earlier, the results presented in this paper suggest the possibility of both types of recording (rewritable with low-power CW laser recording and read-only with high-energy pulse laser recording) on this new photopolymer film

Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve. Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve. Results. Overall, 272 patients received DRV/r OD n=135 or BID n=137 plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was 4.10 log10⁡ copies/mL; median CD4 cell count was 258 cells/μL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load <50 copies/mL. No patient developed primary PI RAMs. Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression <50 copies/mL in 82% of NNRTI-experienced, PI-naïve patients by week 48