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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 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

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.

The development of a neuroprotective or disease-modifying therapy is the major unmet need in the management of Parkinson's Disease (PD) and the goal of much clinical and scientific research. However, despite enormous efforts and expense, no disease-modifying therapy for PD has been approved to date. Historically attempts to define such a therapy have been limited by confounding symptomatic/pharmacologic effects of the study intervention and the lack of a clear and well-defined regulatory and clinical development pathway that leads to a disease-modifying indication. Further, the costs of the development program average 1 billion dollars with a duration of 10 to 13years. As a consequence, many pharmaceutical companies are reluctant to test novel therapies despite the recent scientific advances and promising candidate targets and approaches. In the present review we describe previous studies aimed at defining a disease-modifying drug and discuss their limitations. We also consider some of the modern approaches and trial design for drug development that will hopefully pave the way toward identifying and gaining regulatory approval for a disease-modifying therapy in a relatively efficient and cost-effective manner.

Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer’s disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer’s disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias.

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.

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.

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 vari- ability 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.

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.

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.

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.

For Alzheimer’s disease treatment trials that focus on the pre-dementia stage of disease, outcome measures are needed that will enable assessment of disease progression in patients who are clinically normal. The EU/US CTAD Task Force, an international collaboration of investigators from industry, academia, non-profit foundations, and regulatory agencies, met in Philadelphia, Pennsylvania, USA, on November 19, 2014 to discuss existing and novel outcome assessments that may be useful in pre-dementia trials. Composite measures that assess changes in episodic memory, executive function, global cognition, and global function have recently been developed by a number of groups and appear to be sensitive at this stage. Functional measures that involve real-life complex tasks also appear to capture early subtle changes in pre-dementia subjects and have the advantage of representing clinically meaningful change. Patient reported outcomes and novel CSF and imaging biomarkers have also shown promise. More studies are needed to validate all of these tests in the pre-dementia population. Many of them have been incorporated as exploratory measures in ongoing or planned trials.

The focus of drug development in Alzheimer's disease has increasingly been on earlier disease stages, before overt dementia, when it is difficult to assess cognitive impairment. The FDA has now developed guidance for the design and execution of relevant clinical trials.

Summary: The United States Food and Drug Administration is charged with approving drug treatments that have been shown to be safe and effective. Relevant statutes and regulations provide a legal framework for establishing safety and effectiveness that is sufficiently flexible to ensure that appropriate scientific data are collected for specific treatments targeted to particular diseases. Nonetheless, all clinical trials proposed to establish effectiveness must incorporate common elements in order for the appropriate legal and scientific standards of drug approval to be met. This article will discuss the relevant laws and regulations pertaining to the current effectiveness standard and will discuss the most important clinical trial design elements currently considered acceptable for applications for treatments of neurologic and psychiatric illness.

Russell Katz is the director of the Division of Neurology Products in the US FDA’s Center for Drug Evaluation and Research. Katz’s division is responsible for regulating research with investigational treatments for neurologic diseases, including epilepsy, as well as making decisions about which treatments should be approved. He has written and lectured extensively about all aspects of the development of treatments for neurologic diseases. Katz speaks to Laura Harvey at the journal, on the difficulties facing antiepilepsy drug trials today.

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.

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.

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.

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.

The Gravity Probe B spacecraft, developed, integrated, and tested by Lockheed Missiles & Space Company and later Lockheed Martin Corporation, consisted of structures, mechanisms, command and data handling, attitude and translation control, electrical power, thermal control, flight software, and communications. When integrated with the payload elements, the integrated system became the space vehicle. Key requirements shaping the design of the spacecraft were: (1) the tight mission timeline (17 months, 9 days of on-orbit operation), (2) precise attitude and translational control, (3) thermal protection of science hardware, (4) minimizing aerodynamic, magnetic, and eddy current effects, and (5) the need to provide a robust, low risk spacecraft. The spacecraft met all mission requirements, as demonstrated by dewar lifetime meeting specification, positive power and thermal margins, precision attitude control and drag-free performance, reliable communications, and the collection of more than 97% of the available science data.

There is significant interest in the development of new drugs to treat vascular dementia. However, before US approval of new drugs for this entity is possible, certain issues with regulatory implications need to be addressed. Is vascular dementia a distinct clinical syndrome with valid diagnostic criteria? Can this entity be distinguished from Alzheimer's disease (AD) and other causes of dementia? What design features are important for clinical trials in this disorder? The US Food and Drug Administration (FDA) convened a special meeting of the Peripheral and Central Nervous System Advisory Committee in an attempt to answer these questions. The conclusions from this meeting indicate that vascular dementia (VaD) is a pathologically heterogeneous disorder but appears to be reasonably distinguishable from AD dementia. The NINDS-AIREN diagnostic criteria are suitable as entry criteria for vascular dementia trials. Trials should be similar in duration to AD dementia trials and should employ a dual outcome strategy (cognitive + global/functional measures). For drugs that are believed to have a disease-modifying effect, clinical trials should study specific vascular dementia subtypes and would need to employ substantially different designs from those used currently. The term “vascular dementia” may not be entirely appropriate to describe this population.

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.

Summary: Interest is increasing rapidly in the use of surrogate markers as primary measures of the effectiveness of investigational drugs in definitive drug trials. Many such surrogate markers have been proposed as potential candidates for use in definitive effectiveness trials of agents to treat neurologic or psychiatric disease, but as of this date, there are no such markers that have been adequately “validated,” that is, shown to predict the effect of the treatment on the clinical outcome of interest. While the current law and regulations permit the United States Food and Drug Administration to base the approval of a drug product on a determination the effect of the drug on an unvalidated surrogate marker (that is, one for which it is not known that an effect on the surrogate actually predicts the desired clinical benefit), there are a number of difficulties in interpreting trials that use surrogate markers as primary measures of drug effect. In this article, the relevant regulatory context will be discussed, as well as the epistemological problems related to the interpretation of clinical trials in which unvalidated surrogate markers are used as primary outcomes.

As disease-modifying therapies near realization, there are concerns about the criteria by which these therapies will be judged. It is not yet clear what kind of evidence (clinical, biomarker, or otherwise) will be required to support a disease-modifying claim. When such a drug is approved, regulators must be certain that the claims in the label are factual and unambiguous, yet a definition for “disease modification” remains to be established. One strong potential definition is: “a therapy that affects the underlying pathology and structure of the disease”. However, this is only one possibility, and a consensus definition must be codified before criteria to evaluate it can be determined.There is room for informed speculation, however. Criteria to evaluate disease-modifying effects have been proposed, and typically involve one of two approaches (neither of which has yet been endorsed by regulators). The first is a clinical approach, in which clinical designs are employed that would ideally force a conclusion that a drug has a disease-modifying effect. In one proposed design, patients would be randomized to drug or placebo for an appropriate duration. At the end of that period, and if a difference in outcome between drug and placebo on an appropriate clinical measure or measures has been achieved, patients originally randomized to drug would then be treated with placebo, while patients originally treated with placebo would remain on placebo.

In the February 2004 issue of Diabetes Care , the American Diabetes Association (ADA) published a summary of their conclusions drawn from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes (1). Although the ADA ranked the diabetes risk for second-generation antipsychotics (SGAs), the U.S. Food and Drug Administration’s Division of Neuropharmacological Drug Products (DNDP) does not believe that the evidence currently available allows such a ranking. The ADA concluded that aripiprazole and ziprasidone have no effect on the risk of diabetes. The ADA notes that because these two drugs have not been included in epidemiological studies, this conclusion is solely based on data from clinical trials that did not …

While this chapter is primarily concerned with describing the perspective of the Food and Drug Administration (FDA) about what constitutes appropriate controlled trials of drugs in patients with epilepsy, it is impossible to fully understand the Agency’s viewpoint without some understanding of the legal and regulatory foundation of the Agency’s decision-making process. For this reason, it is important to describe in some detail the relevant law and regulations that the Agency is charged with enforcing.

Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [ 18 F]fluorodopa PET, (+)-[ 11 C]dihydrotetrabenazine PET, [ 123 I]β-CIT SPECT, and [ 18 F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.