Development and Application of a Liquid Chromatography-Mass Spectrometry Method for Residual Iodixanol Quantification in AAV-Based Gene Therapy Product Development.

Adeno-associated viruses (AAVs) are nonenveloped viruses that have become popular gene transfer vectors to deliver DNA to target cells in clinical gene therapy. Iodixanol-based density gradient is one of the widely used purification methods for serotype-independent AAVs. However, residual iodixanol in AAV could be a safety concern, and further purification to remove this process-related impurity is typically needed. An analytical assay with high sensitivity is essential for the detection of residual iodixanol to ensure the safety of AAV products. We developed a liquid chromatography-mass spectrometry method with the limit of quantification of 0.01 µg/mL for residual iodixanol measurement in AAVs. The method also demonstrated linearity over four orders of magnitude that allows quantifying a high iodixanol concentration in in-process samples with excellent recovery and accuracy. In addition, we further explored a highly efficient purification method for removal of the residual iodixanol, to minimize the safety concern from iodixanol as a process impurity.

A New Approach to the Development of Disease-Modifying Therapies for PD; Fighting Another Pandemic.

A disease-modifying therapy that slows disease progression and development of disability is the major unmet need in the treatment of Parkinson's disease. Recent scientific advances suggest many promising and exciting new interventions. However, despite these opportunities, the cost, time and uncertainty of being able to receive an indication as a disease-modifying therapy has caused many pharmaceutical companies to abandon development of potentially disease-modifying drugs. We propose a new approach to development of these agents that will reduce the cost and facilitate approval of putative disease-modifying drugs that should prove acceptable to pharmaceutical companies and regulatory agencies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Challenges, solutions, and recommendations for Alzheimer's disease combination therapy.

Given the complex neuropathology Alzheimer's disease (AD), combination therapy may be necessary for effective treatment. However, scientific, pragmatic, regulatory, and business challenges need to be addressed before combination therapy for AD can become a reality. Leaders from academia and industry, along with a former member of the Food and Drug Administration and the Alzheimer's Association, have explored these challenges and here propose a strategy to facilitate proof-of-concept combination therapy trials in the near future. First, a more integrated understanding of the complex pathophysiology and progression of AD is needed to identify the appropriate pathways and the disease stage to target. Once drug candidates are identified, novel clinical trial designs and selection of appropriate outcome assessments will be needed to enable definition and evaluation of the appropriate dose and dosing regimen and determination of efficacy. Success in addressing this urgent problem will only be achieved through collaboration among multiple stakeholders.

Building a roadmap for developing combination therapies for Alzheimer's disease.

Combination therapy has proven to be an effective strategy for treating many of the world's most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer's disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition, the Critical Path Institute and the Alzheimer's Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.

Charting a path toward combination therapy for Alzheimer's disease.

It is acknowledged that progress in combined therapeutic approaches for Alzheimer's disease (AD) will require an unprecedented level of collaboration. At a meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer's Disease Coalition and the Critical Path Institute, investigators from industry, academia and regulatory agencies agreed on the need for combinatorial approaches to treating AD. The need for advancing multiple targets includes recognition for novel adaptive trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination. A combination trial now being planned may test drugs targeting different pathogenic pathways or multiple targets along a common pathway. Collaborations and consortia-based strategies are pivotal for success and a regulatory framework is recommended for success.

Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Coalition Against Major Diseases: Precompetitive Collaborations and Regulatory Paths to Accelerating Drug Development for Neurodegenerative Diseases.

Precompetitive collaborations have been successful in several disease areas and industries. Such collaborations are critical to address the gaps and challenges in therapeutic development for chronic neurodegenerative diseases. On November 5, 2012, members of the scientific community, advocates, regulators, industry, and government officials met at the US Food and Drug Administration to develop tools to expedite drug development and maximize the potential for success in future drug trials for Alzheimer disease and Parkinson disease. The meeting established that multiple collaborative approaches are essential for accelerating drug development. Such approaches include precompetitive data sharing, regulatory qualification of biomarkers and clinical outcome assessments, implementation of data standards, and development of quantitative drug disease trial models. While challenges to collaboration among industry partners are formidable, they are not insurmountable. The Coalition Against Major Diseases (CAMD) has several positive examples to highlight. This review represents proceedings from CAMD's annual conference and discusses the key themes that are being advanced by the Critical Path Institute.

Considerations in the design of clinical trials for cognitive aging.

What will it take to develop interventions for the treatment of age-related cognitive decline? Session V of the Summit provided perspectives on the design of clinical trials to evaluate promising but unproven interventions, and some of the steps needed to accelerate the discovery and evaluation of promising treatments. It considered strategies to further characterize the biological and cognitive changes associated with normal aging and their translation into the development of new treatments. It provided regulatory, scientific, and clinical perspectives about neurocognitive aging treatments, their potential benefits and risks, and the strategies and endpoints needed to evaluate them in the most rapid, rigorous, and clinically meaningful way. It considered lessons learned from the study of Alzheimer's disease, the promising roles of biomarkers in neurocognitive aging research, and ways to help galvanize the scientific study and treatment of neurocognitive aging.

Development and regulatory strategies for drug and diagnostic co-development.

At the 5th FDA-Drug Industry Association (DIA) Workshop on 'Pharmacogenomics in Drug Development and Regulatory Decision Making', track four focused on the current thinking and issues in the co-development of therapeutic drugs or biologics, and their companion diagnostic products. Identification and validation of genomic and other biomarkers are becoming important components of drug-development strategies, and recent successes show the power of personalized approaches to change the benefit-risk paradigm for new drugs.

Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.

Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified release products: workshop summary report.

Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified-release products: workshop summary report.

Modified-release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to discuss current regulatory expectations and industry practices for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: Workshop summary report.

BACKGROUND: Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. OBJECTIVE: This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1-2, 2009, in Baltimore, Maryland. METHODS: The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical equivalence and bioequivalence of oral MR products. RESULTS: In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioequivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioequivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioequivalence limits may be set based on the known within-subject variability for the reference product. CONCLUSIONS: The current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioequivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response.

Maximizing the Alzheimer's Disease Neuroimaging Initiative II.

The Alzheimer's Disease Neuroimaging Initiative is the largest public-private partnership on brain research underway at the National Institutes of Health. This 6-year study tracks cognitive and brain changes in normal subjects, those with mild cognitive impairment, and individuals with Alzheimer's disease. It was designed to provide better tools for performing effective clinical trials, and is slated to run until 2010. While data are being generated and analyzed, researchers involved in the study are developing an extension, i.e., the Alzheimer's Disease Neuroimaging Initiative II. The Foundation for the National Institutes of Health and the Alzheimer's Association convened a meeting to review the progress, evaluate future directions, and obtain the United States Food and Drug Administration's perspective on how the Alzheimer's Disease Neuroimaging Initiative could affect the drug-approval process.

FDA update.

This report addresses: (1) a general update of FDA activity in areas relevant to AED development; (2) an update on issues relevant to the development of AEDs in the pediatric population; and (3) an update on the Agency's approach to the evaluation of AEDs as monotherapy. FDA ACTIONS: Since January 2002, 47 Approval actions for 10 AEDs were issued, but none for a new chemical entity. Nine of the ten Approvable actions taken were relatively minor changes to existing applications. An Approvable letter was issued for Lyrica (pregabalin) for the treatment of post-herpetic neuralgia, painful diabetic neuropathy, and partial seizures in adults. The primary issue to be addressed in the face of post-marketing reports of adverse events is one of causality. The FDA has requested that sponsors search their databases for selected problems under review (e.g., suicidality). PEDIATRICS: The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) require studies in pediatric patients for those indications granted for adults that are relevant for the pediatric population. Current FDA policy asks sponsors to undertake a development program in pediatric patients essentially analogous to that for adults. MONOTHERAPY TRIALS: Establishing the effectiveness of AEDs as monotherapy continues to be desirable, but problematic. Problems include the difficulty of performing monotherapy trials, ethical issues, designation of patients as "newly diagnosed," and endpoints. Historical controls may be acceptable if: (a) there is a consensus that it is essentially impossible to conduct controlled trials designed to demonstrate a difference between treatments; (b) there is an adequate historical database against which the seizure rate seen with the new drug can reasonably be compared; and (c) there is evidence from adequate and well-controlled trials that the treatment is effective as adjunctive therapy. FDA is Agency is reviewing analyses describing historical controls.

Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized.

BACKGROUND: The most severe sequela of measles virus infection is subacute sclerosing panencephalitis (SSPE), a fatal disease of the central nervous system that generally develops 7-10 years after infection. From 1989 through 1991, a resurgence of measles occurred in the United States, with 55,622 cases of measles reported. The purpose of the present study was to identify cases of SSPE that were associated with the resurgence of measles and to calculate the risk of developing SSPE. METHODS: Brain tissue samples obtained from 11 patients with a presumptive diagnosis of SSPE were tested for the presence of measles virus RNA. Measles virus genotypes were determined by reverse-transcription polymerase chain reaction (RT-PCR) and by analysis of the sequences of the PCR products. A search of the literature was conducted to identify reports of cases of SSPE in persons residing in the United States who had measles during 1989-1991. RESULTS: The measles virus sequences derived from brain tissue samples obtained from 11 patients with SSPE confirmed the diagnosis of SSPE. For 5 of the 11 patients with SSPE who had samples tested by RT-PCR and for 7 patients with SSPE who were identified in published case reports, it was determined that the development of SSPE was associated with the measles resurgence that occurred in the United States during 1989-1991. The estimated risk of developing SSPE was 10-fold higher than the previous estimate reported for the United States in 1982. CONCLUSIONS: Vaccination against measles prevents more cases of SSPE than was originally estimated.