FDA Perspective Research Articles

US FDA Perspective: preparing for a bright and busy future for cell & gene therapy

US FDA Perspective: preparing for a bright and busy future for cell & gene therapy

Nonparametric estimation for SDE with sparsely sampled paths: An FDA perspective

We consider the problem of nonparametric estimation of the drift and diffusion coefficients of a Stochastic Differential Equation (SDE), based on n independent replicates Xi(t):t∈[0,1]1≤i≤n, observed sparsely and irregularly on the unit interval, and subject to additive noise corruption. By sparse we intend to mean that the number of measurements per path can be arbitrary (as small as two), and can remain constant with respect to n. We focus on time-inhomogeneous SDE of the form dX(t)=μ(t)X(t)αdt+σ(t)X(t)βdB(t), where α∈{0,1} and β∈{0,1/2,1}, which includes prominent examples such as Brownian motion, Ornstein–Uhlenbeck process, geometric Brownian motion and Brownian bridge. Our estimators are constructed by relating the local (drift/diffusion) parameters of the SDE to its global parameters (mean/covariance, and their derivatives) by means of an apparently novel Partial Differential Equation (PDE). This allows us to use methods inspired by functional data analysis, and pool information across the sparsely measured paths. The methodology we develop is fully non-parametric and avoids any functional form specification on the time-dependency of either the drift function or the diffusion function. We establish almost sure uniform asymptotic convergence rates of the proposed estimators as the number of observed paths n grows to infinity. Our rates are non-asymptotic in the number of measurements per path, explicitly reflecting how different sampling frequency might affect the speed of convergence. Our framework suggests possible further fruitful interactions between FDA and SDE methods in problems with replication.

S-11-02 Regulatory considerations for non-clinical studies for COVID-19 vaccines: US FDA perspective

S-11-02 Regulatory considerations for non-clinical studies for COVID-19 vaccines: US FDA perspective

PCR27 The Voice of the Regulator: How FDA Appraises Clinical Outcome Assessments in Supplemental Submissions for Expanded Indications

FDA makes significant public information accessible through its website and databases. In particular, to learn about the role of clinical outcome assessments (COA) data in regulatory review and approval of marketing applications, [email protected] is a comprehensive source. The limitation is that while all updates to the label are posted, typically only the medical reviews of the original marketing application are accessible. Reviews covering label expansion data from supplemental submissions are not readily available. The aim of this project is to review and compare multiple methods to better understand current FDA perspectives on patient experience data.

Development and regulation of cellular and gene therapy products: FDA perspective

Development and regulation of cellular and gene therapy products: FDA perspective

Pentosan associated retinal pigmentary changes: FDA's perspective on an emerging postmarketing safety finding.

Recent publications describe pigmentary changes in the retina associated with the use of pentosan polysulfate sodium, the only FDA-approved oral agent for relief of bladder pain or discomfort associated with interstitial cystitis. To evaluate this association, we reviewed data from the FDA Adverse Event Reporting System and published case reports and observational studies. The totality of clinical and epidemiology evidence does not resolve the question of causation between pentosan use and retinal pigmentary changes; however, several elements support a potential association. Here, we provide our perspective on the available evidence the agency weighed when retinal pigmentary changes were added to pentosan labeling. It is important for urogynecologists prescribing pentosan to be aware of this potential association and be vigilant about assessing eye health in pentosan users.

US FDA perspective: getting back into high gear – driving cell and gene therapy forward through 2022 and beyond

<div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://bioinsights.blob.core.windows.net/uploads/Peter Marks_3765 copy.jpg" data-image="1"></div><div class="author-det"> Peter Marks, MD, PhD, is the director of the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. The center is responsible for assuring the safety and effectiveness of biological products, including vaccines, allergenic products, blood and blood products, and cellular, tissue, and gene therapies. </div></div></div>

FDA perspective on the preclinical development of cell-based immunotherapies

FDA perspective on the preclinical development of cell-based immunotherapies

Abstract IA08: Use of liquid biopsy to facilitate drug development in early-stage disease—FDA perspective

Abstract Background: With advances in precision oncology, liquid biopsies have shown promise as a minimally invasive means to potentially diagnose cancer, detect resistance mutations and monitor tumor evolution, predict relapse, provide prognosis, and guide treatment decisions. One unique setting for the use of liquid biopsy to facilitate drug development is in early-stage disease where there is the potential for use in patient selection, prognostication, and drug activity demonstration. Discussion: From the regulatory and clinical trial perspective, liquid biopsies can be used as prognostic biomarkers to identify the likelihood of disease recurrence in early-stage cancer. For example, circulating cell-free tumor DNA (ctDNA) in an adjuvant cancer setting affords the potential to select a high-risk population that could be utilized as a stratification factor, or selection of an enriched high-risk population in which specific drug development could be pursued. Use of liquid biopsy as a putative surrogate endpoint or efficacy-response biomarker, in this setting, would require a large body of evidence demonstrating biologic plausibility, demonstration of studies of prognostic value of the surrogate endpoint for the clinical outcome, and evidence from clinical trials (or meta-analysis) that the treatment effects on the biomarker correlate to the long-term outcome. Another use of liquid biopsy as an efficacy-response biomarker could allow for go or no-go decision making earlier on in drug development, which could also be applied in the adjuvant setting. Conclusions: Liquid biopsies will continue to play a role in the clinical management of malignancies and have the potential to support drug approval and become more broadly incorporated and utilized in early-stage clinical trials. Citation Format: Julia A. Beaver. Use of liquid biopsy to facilitate drug development in early-stage disease—FDA perspective [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA08.

Scientific and Regulatory Approach to Botanical Drug Development: A U.S. FDA Perspective.

The United States FDA has received over 800 botanical investigational new drug applications (IND) and pre-IND meeting requests (PIND) in the years preceding 2018. The current data show that indications for submitted INDs cover nearly every review division of the FDA. Despite increasing global interest in the investigation of botanical mixtures as drug products, only two botanical new drug applications (NDA) have been approved in the U.S.: Veregen in 2006 and Fulyzaq (also known as Mytesi) in 2012. Given botanicals' chemical and biological complexity, efforts in characterizing their pharmacology, demonstrating therapeutic efficacy, and ensuring quality consistency remain scientific and regulatory challenges. The FDA published a revised Botanical Drug Development Guidance for Industry document in December 2016 to address developmental considerations for late-phase trials and to provide recommendations intended to facilitate botanical drug development. Herein, we present an analysis of botanical INDs showing their variety of botanical raw materials (e.g., coming from different geographic regions, single vs multiple herbs), the varied levels of previous human experience, and therapeutic areas, as well as provide an overview of experience and challenges in reviewing botanical drugs.

ES10.01 US Food and Drug Administration

Dr Blumenthal will provide the US FDA Oncology Center of Excellence perspective on Oncology Drug Approval: Challenges and Opportunity. With the recent influx of novel targeted therapies, immunotherapy and chemotherapy to treat patients with lung cancers, there are increased challenges to ensuring that safe and effective therapies are available to patients as efficiently as possible while ensuring that the evidence generated is robust and reliable. This talk will discuss FDA's perspective on global drug development. regulation, development, access

Preclinical considerations for assessment of cellular & gene therapy products: FDA perspective

Preclinical considerations for assessment of cellular & gene therapy products: FDA perspective

Introduction of ICICJ 15years.

Introduction of ICICJ 15years.

Regulatory aspects of the development of drugs for metabolic bone diseases – FDA and EMA perspective

Regulation of medicines involves complex scientific and public health policies which are reflected in the regulatory approaches used by the European Medicines Agency and the United States Food and Drug Administration for the approval of products developed for metabolic bone diseases. For osteoporosis therapies, utilized by many patients, the approaches and existing guidance for product development of both agencies are similar; confirmatory studies for the approval of osteoporosis products can rely on well-defined efficacy outcome parameters. Therapeutics for rare bone diseases, a rapidly expanding area, often require an individualized regulatory approach. This review outlines key aspects of these regulatory approaches applied by the two agencies for products for metabolic bone diseases.

An FDA Perspective on the Regulatory Implications of Complex Signatures to Predict Response to Targeted Therapies.

As technologies evolve, and diagnostics move from detection of single biomarkers toward complex signatures, an increase in the clinical use and regulatory submission of complex signatures is anticipated. However, to date, no complex signatures have been approved as companion diagnostics. In this article, we will describe the potential benefit of complex signatures and their unique regulatory challenges, including analytic performance validation, complex signature simulation, and clinical performance evaluation. We also will review the potential regulatory pathways for clearance, approval, or acceptance of complex signatures by the FDA. These regulatory pathways include regulations applicable to in vitro diagnostic devices, including companion diagnostic devices, the potential for labeling as a complementary diagnostic, and the biomarker qualification program. Clin Cancer Res; 23(6); 1368-72. ©2016 AACR.

An FDA perspective on the assessment of proposed biosimilar therapeutic proteins in rheumatology.

Biologic products have revolutionized the management of many rheumatic diseases, but access to these products might be limited by their relatively high costs. The US Biologics Price Competition and Innovation Act of 2009, which is contained within the Patient Protection and Affordable Care Act, established an abbreviated pathway for licensure by the FDA of biologic products that are demonstrated to be biosimilar to or interchangeable with FDA-licensed biologic products, termed reference products. This law allows for the approval of biosimilar biologic products, which are expected to increase access to treatment for patients, and ensuring the implementation of this Act is a high priority for the FDA. In this Perspectives article we describe the considerations for approval of proposed biosimilar products, including those to treat rheumatological conditions, by describing the FDA's rigorous approach to assessment of biosimilarity.

The Gradually Expanding Scope for Biowaivers of Oral Products: An Overview.

The regulatory paradigm is relaxing gradually without compromising the safety, efficacy and the quality of the drug product and, most importantly, a perceptible scientific consensus is maturing towards the need of affordable medicines. The establishment of bioequivalence (BE) is no longer being considered to be accomplished only by in vivo studies in oral drug products. The potential use of in vitro dissolution testing in lieu of BE studies has now been regulatory adopted and is commonly referred to as "biowaiver". Further, the advent of biopharmaceutics classification system (BCS) and in vitro-in vivo correlation (IVIVC) proves to be sound milestones and signifies that we are incessantly forwarding towards a scenario that would reduce regulatory burden, save time and make the drug products more affordable while ensuring their quality. This review outlines, the current and pertinent regulatory environment for biowaiver based on in vitro drug dissolution, primarily as per the FDA perspective. The rationale used for qualification of biowaiver for different strengths, post-approval changes and multi-source products are discussed along with the role of BCS and IVIVC.

Enrollment of older adults on oncology trials: An FDA perspective.

Enrollment of older adults on oncology trials: An FDA perspective.

Expanded Access of Investigational Drugs: The Experience of the Center of Drug Evaluation and Research Over a 10-Year Period.

The purpose of this study was to describe the experience of the Center of Drug Evaluation and Research (CDER) with expanded access of investigational drugs. Multiple searches of CDER's document tracking system were performed to identify the number, type, and indication for all expanded access requests over the 10-year time period of January 2005 through December 2014. An additional search was performed to identify all active commercial investigational drug development programs during that time period and whether or not the clinical program was placed on hold. The two searches were then cross-referenced to identify those commercial investigational drug development programs placed on clinical hold due to serious adverse events occurring within expanded access programs. CDER receives over 1000 applications for expanded access each year. The majority are for single patients, roughly evenly split between emergency and nonemergency use. The vast majority, 99.7%, are allowed to proceed. The incidence of clinical holds for all commercial investigational drug development programs is 7.9%, as compared to only 0.2% related to adverse events observed in patients receiving drug treatments under expanded access. The expanded access program is viewed as a success from FDA's perspective based on the large number of applications processed and allowed to proceed each year. However, the actual number of patients and their health care providers that desire drug treatments available under expanded access is not known. It is exceedingly rare for a serious adverse event under expanded access to affect the development program for that drug.

An FDA perspective on preclinical development of cell-based regenerative medicine products.

An FDA perspective on preclinical development of cell-based regenerative medicine products.