Lot-to-lot reproducibility, stability and life cycle management of antibody reagents for flow cytometry

The increasing number of biopharmaceuticals, gene and cell therapies in development has seen a growing use of flow cytometry to measure biomarkers, generate pharmacokinetic data, assess immunogenicity and investigate target engagement. The importance of these data types and their inclusion in regulatory submissions mean that flow cytometry analyses are now expected to demonstrate robust performance and comply with both regulatory and scientific recommendations during their validation and subsequent use in sample analysis. The control of the ‘critical reagents’ commonly used in flow cytometry presents some specific challenges, particularly when an assay is required for use over a long period of time across different phases of a drug development program, or where it is deployed in complex, multisite clinical studies. This paper highlights some key challenges in flow cytometry reagent management with some of the strategies employed to control and monitor flow cytometry critical reagents.

Estimating Probabilities of Success of Clinical Trials for Vaccines and Other Anti-Infective Therapeutics

A key driver in biopharmaceutical investment decisions is the probability of success of a drug development program. We estimate the probabilities of success (PoS) of clinical trials for vaccines and other anti-infective therapeutics using 43,414 unique triplets of clinical trial, drug, and disease between January 1, 2000, and January 7, 2020, yielding 2,544 vaccine programs and 6,829 non-vaccine programs targeting infectious diseases. The overall estimated PoS for an industry-sponsored vaccine program is 39.6%, and 16.3% for an industry-sponsored anti-infective therapeutic. Among industry-sponsored vaccines programs, only 12 out of 27 disease categories have seen at least one approval, with the most successful being against monkeypox (100%), rotavirus (78.7%), and Japanese encephalitis (67.6%). The three infectious diseases with the highest PoS for industry-sponsored non-vaccine therapeutics are smallpox (100%), CMV (31.8%), and onychomycosis (29.8%). Non-industry-sponsored vaccine and non-vaccine development programs have lower overall PoSs: 6.8% and 8.2%, respectively. Viruses involved in recent outbreaks—MERS, SARS, Ebola, Zika—have had a combined total of only 45 non-vaccine development programs initiated over the past two decades, and no approved therapy to date (Note: our data was obtained just before the COVID-19 outbreak and do not contain information about the programs targeting this disease.) These estimates offer guidance both to biopharma investors as well as to policymakers seeking to identify areas most likely to be undeserved by private-sector engagement and in need of public-sector support.

Predicting the Need for a Tier II Ototoxicity Study From Early Renal Function Data

History has established that many drugs, such as the antibiotics, chemotherapies, and loop diuretics, are capable of inducing both nephrotoxicity and ototoxicity. The exact mechanisms by which cellular damage occurs remain to be fully elucidated. Monitoring the indices of renal function conducted in the Food and Drug Administration’s prescribed set of early investigational new drug (IND)–enabling studies may be the first signs of ototoxicity properties of the new drug candidate. In developing improved and efficacious new molecular entities, it is critically necessary to understand the cellular and molecular mechanisms underlying the potential ototoxic effects as early in the drug development program as possible. Elucidation of these mechanisms will facilitate the development of safe and effective clinical approaches for the prevention and amelioration of drug-induced ototoxicity prior to the first dose in man. Biomarkers for nephrotoxicity in early tier I or tier II nonclinical IND-enabling studies should raise an inquiry as to the need to conduct a full auditory function assay early in the game to clear the pipeline with a safer candidate that has a higher probability of continued therapeutic compliance once approved for distribution.

P57 Filling the gap for children with heart failure: the EU-funded drug development program LENA (labeling of enalapril from neonates up to adolescents)

BackgroundACE-inhibitors are first choice treatment for adult and paediatric patients with heart failure. Since there are no systematic data on pharmacokinetics and safety in the young heart failure population, the EU funded a drug development program1 to fill those gaps for the ACE-inhibitor enalapril. An age appropriate paediatric formulation was also required.MethodsA paediatric patient cohort with heart failure was recruited to fulfil the paediatric investigation plan (PIP) requirements. The PIP required a total of 85 evaluable patients from birth to less than 12 years of age with a subset cohort of 25 patients with heart failure due to dilated cardiomyopathy and a subset of 60 heart failure patients of congenital heart disease. Out of these, 54% of patients must be aged below 12 months to provide a substantial amount of young patients.ResultsThe LENA consortium recruited 102 children from birth to 12 years. Out of those, 89 patients fulfilled relevant protocol criteria and could be regarded as evaluable. Of these, 26 demonstrated heart failure due to cardiomyopathy and 63 due to congenital heart disease. Sixty five patients (73%) were below 12 months of age. Moreover, 22 patients were below 3 months of age, 26 patients from 3 months to less than 6 months and 17 patients from 6 months up to 12 months of age.ConclusionsThe LENA consortium had recruited the PDCO required number of paediatric patients for the drug development program LENA. As more than 2/3 of patients belong to the most vulnerable patient population below the age of 12 months, relevant data can be generated to fill gaps for the safe and reliable treatment with ACE-inhibitors of children with heart failure.ReferencesThe research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)Disclosure(s)Nothing to disclose