Food And Drug Administration Draft Research Articles

Regulatory and Clinical Expert Perspective of the 2022 FDA Draft Guidance “Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet”

Regulatory and Clinical Expert Perspective of the 2022 FDA Draft Guidance “Celiac Disease: Developing Drugs for Adjunctive Treatment to a Gluten-Free Diet”

Real-world data: Assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products.

Real-world data: Assessing electronic health records and medical claims data to support regulatory decision-making for drug and biological products.

Analysis: Intravascular Devices with a Higher Risk of Polymer Emboli: The Need for Particulate Generation Testing.

Hydrophilic polymer coatings on intravascular devices lower friction between the device and vasculature, thereby reducing trauma during interventional procedures. Polymer coating embolism-the detachment and downstream embolism of polymer particles-has been reported as an iatrogenic complication of coated interventional devices affecting the vasculature and various organs. The Food and Drug Administration (FDA) acknowledges this complication and continues to work with stakeholders to close gaps in performance testing and standards related to polymer coating integrity. Recent innovations within interventional technologies have led to development of new hydrophilic-coated devices with expanded indications for use. The 2018 FDA draft guidance for intravascular guidewires expands the application of particulate generation testing to most devices and recommends labeling changes to increase industry awareness. This article highlights current procedural trends where the phenomenon of polymer coating embolism may be more prevalent. It describes the mechanisms of polymer separation, reported clinical sequelae, and risk factors for relevant indications. These procedural trends and associated risk factors articulate the need for particulate testing and support the FDA's draft guidance recommendations for performance testing of applied coatings. If standardized, particulate assessments may allow characterization and comparisons of coating integrity among devices from various manufacturers, and are an important foundation for setting particulate limits. As hydrophilic coatings enable endovascular treatment for a range of patient populations, setting particulate limits or finding alternative solutions without compromise to device function may be essential. Particulate testing is relevant to physicians, regulators, and manufacturers for the purposes of product development and quality improvement of interventional devices.

The “Science” of Policy Development During Administrative Rulemaking

The legitimacy of government agencies rests in part on the premise that public administrators use scientific evidence to make policy decisions. Yet, what happens when there is no consensus in the scientific evidence—i.e., when the science is in conflict? I theorize that scientific conflict yields greater policy change during administrative policymaking. I assess this claim using data from the U.S. Food and Drug Administration (FDA). I identify policy change—what I refer to as “policy development” in this article—between the FDA's draft and final rules with a novel text analysis measure of shifts in regulatory restrictions. I then go on to find that more policy development does occur with scientific conflict. Moreover, using corresponding survey data, I uncover suggestive evidence that one beneficiary of such conflict may be participating interest groups. Groups lobby harder—and attempt to change more of the rule—during conflict, while an in‐survey experiment provides evidence of increased interest group influence on rule content when scientific conflict is high.

ALS drug development guidances and trial guidelines: Consensus and opportunities for alignment.

The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community's views on key topics. In parallel to this effort, there was an independent effort to revise and update the ALS Clinical Trial Guidelines. We discuss the areas of agreement of these 3 documents and the areas that provide opportunities to improve the efficiency of drug development in ALS. It is likely that further research into biomarkers, efficacy endpoints, and predictive algorithms will provide greater alignment among community stakeholders and increase clarity on drug development efforts going forward. Continued patient engagement and inclusion of patient experience data in every aspect of the drug development process will further facilitate the approval of new treatments.

3381 Reducing Problem Records in the Johns Hopkins University ClinicalTrials.gov Protocol Registration and Results System (PRS)

OBJECTIVES/SPECIFIC AIMS: The Johns Hopkins University Clinicaltrials.gov (CT.gov) Program has previously reported on a study showing reduction of “Late Results – per FDAAA” from 111 to 0. What we hope to do here is to focus on non-late results records. Over the years, some institutions spend their efforts solely on late results in order to avoid any penalties from the Food and Drug Administration (FDA). However, there are a number of variables that labels “problem records” within the Protocol and Registration System (PRS). These records are also subject to penalties. Our goal has been to minimize problem records and establish processes to improve and maintain our institutional compliance in regards to regulations governing clinical trials registration and results reporting. METHODS/STUDY POPULATION: The Johns Hopkins University implemented a Clinicaltrials.gov program solely mandated to assist Principal Investigators (PIs) and other study team members with clinical trial registration and results reporting. The program has developed processes in its duty towards reducing problem records in the PRS. Full-time staff have been assigned to assist research teams with registration and results reporting, while ensuring compliance with all relevant regulations. Several methods have been utilized to track metrics, such as monthly reports and internal databases. Features within the PRS have also been used to draw attention to newly-identified problem records on a daily basis in order to rectify these issues with the study team promptly. In order to ensure compliance, our office communicates with study teams regarding the problems within their CT.gov record that requires attention. In challenging cases, our program will also collaborate with the CT.gov PRS Team at the NIH to facilitate the process and avoid multiple review cycles, which can delay registration or the posting of results. Our Program has also formed internal collaborations with the Institutional Review Board (IRB) which allows us to verify study status and view active study team members. This is especially useful in cases where the study team members who are listed on the CT.gov record cannot be reached or the contact information is outdated (a common occurrence with older studies). With access in the IRB, we can contact the current study team members who may not be listed in CT.gov and assist them to resolve any outstanding issues of non-compliance within their CT.gov record. RESULTS/ANTICIPATED RESULTS: From September 2015 (before our program was established) to September 2016 (three months after the institution of our program), the total amount of problem records increased from 44% (339/774) to 45% (383/852). Since then, the processes we have developed resulted in a decline in problem records to 30% (282/955) in September 2017, and a further decline to 8% (83/1075) as of September 2018. The short rise that was observed in 2016, was a potential indicator that if our program was not instituted, it would have been more difficult to maintain compliance. DISCUSSION/SIGNIFICANCE OF IMPACT: According to the FDA Draft Guidance released in September 2018 referring to the Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank, there are a number of ways to violate the FDA regulations, resulting in potential monetary penalties, which include “failing to submit required clinical trial information or submitting clinical trial information that is false or misleading”. These regulations apply to results as well as registration and study status updates. By paying attention to all problems that are identified by the PRS, institutions can rectify errors and remain complaint with all regulations that govern clinical trial registration and results reporting.

Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

The US Food and Drug Administration (FDA) recently released a draft guidance for industry titled “Drug Products, Including Biological Products, that Contain Nanomaterials.” The FDA’s attention to the unique safety and efficacy aspects of drugs containing nanomaterials is commendable. This Draft Guidance succeeds in acknowledging the complexity of these products, as well as the challenges associated with approving safe and therapeutically equivalent complex generic versions. However, the challenge posed by the manufacturing process for drugs containing nanomaterials is insufficiently addressed. The critical quality attributes of such products cannot be properly defined, and therefore it is not possible to design informative comparative physicochemical assessments for equivalence. As a consequence, the 505(j) Abbreviated New Drug Application (ANDA) pathway, currently advised as the standard from the FDA, is not suitable for the approval of complex generic products. Drawing from the successful story of biologics, we propose instead a stepwise totality-of-evidence approach, demonstrating similarity and including clinical studies when deemed necessary, as an appropriate alternative to the 505(j) ANDA pathway.

Implications of the US Food and Drug Administration draft guidance for mitigating septic reactions from platelet transfusions.

In March 2016, the US Food and Drug Administration (FDA) issued the second draft guidance entitled “Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion.”1 This draft guideline addresses the residual risk of bacterial contamination of platelet products, which may result in septic transfusion reactions. Among blood products, platelet products are most frequently associated with septic transfusion reactions, as they are stored at room temperature. Since 2004, multiple steps have been implemented to decrease the risk of contamination. These include skin cleansing, diversion pouch, and bacterial screening. These steps have decreased the rate of septic reactions from a reported range of 10 to 400 to 7 to 25 per 1 000 000, and the rate of fatal septic reactions from a reported range of 2 to 63 to 2 to12 per 1 000 000 apheresis platelet products transfused.2 Thus, the overall risk has decreased by approximately two thirds. In the last couple of years, additional steps to decrease risk of septic reactions have been FDA approved, including pathogen-reduction technologies (PRT) and point-of-issue (POI) (also known as point-of-release) testing capabilities. At the New York Blood Center (NYBC), the residual risk as reported from hospitals is septic reaction rate of 1 per 250 065.3 Recent data using prospective testing report 20 per 51 400 (1/2570) platelet products contaminated resulting in 4 per 51 400 (1/12 800) reactions (1 being fatal [1/51 400]).4 PRT decreases most bacteria load by >4 logs. Hemovigilance data have not reported septic transfusion cases with pathogen-reduced (PR) platelets.5 Prospective screening of apheresis platelets using the Pan Genera Detection (PGD) test (Verax Biomedical, Marlborough, MA), a POI test, demonstrated a residual bacterial contamination risk of 1 per 2302 (75% detected with PGD) apheresis platelets. The PGD has a false positive rate of 0.51% and a false negative rate of 1 in 9206.6 The FDA-reported fatality rates due to bacteria contamination of platelets (both pooled and apheresis) range from 1 to 4 per year from 2011 to 2015 in ∼2.1 million annual platelets transfused.7,8 Staphylococcus aureus was the contaminant in the majority of contaminated apheresis platelets. The FDA draft guidance asks for implementation of PRT, POI testing, or a second bacterial culture, or to shorten the shelf life of the platelet product from 5 to 3 days. Each of these methods has considerable logistical and clinical issues. In June 2016, during the open comment period, the NYBC, as well as other blood centers, including AABB (formerly known as the American Association of Blood Banks) and ABC (America’s Blood Centers), expressed their opinions regarding the impact of implementing the draft guidance as written (https://www.regulations.gov/docket?D=FDA-2014-D-1814). We have recently submitted additional comments and have urged the FDA to reopen the comment period to encourage a broader community to remark. Options for meeting these new guidelines based upon days from collection are shown in Table 1. Once the guidance is finalized, there is a proposed 1-year implementation date. Table 1. Platelet product shelf-life and draft guidance options

Clinical Pharmacology and Translational Aspects of Bispecific Antibodies.

Clinical Pharmacology and Translational Aspects of Bispecific Antibodies.

Bioequivalence Demonstration for Ω-3 Acid Ethyl Ester Formulations: Rationale for Modification of Current Guidance

The US Food and Drug Administration (FDA) draft guidance for establishing bioequivalence (BE) of ω-3 acid ethyl esters (containing both eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] as ethyl esters), used to treat severe hypertriglyceridemia, recommends the conduct of 2 studies: one with participants in the fasting state and one with participants in the fed state. For the fasting study, the primary measures of BE are baseline-adjusted EPA and DHA levels in total plasma lipids. For the fed study, the primary measures of BE are EPA and DHA ethyl esters in plasma. This guidance differs from that established for icosapent ethyl (EPA ethyl esters) in which the primary measure of BE is baseline-adjusted total EPA in plasma lipids for both the fasting and fed states. The FDA guidance for ω-3 acid ethyl esters is not supported by their physiologic characteristics and triglyceride-lowering mechanisms because EPA and DHA ethyl esters are best characterized as pro-drugs. This article presents an argument for amending the FDA draft guidance for ω-3 acid ethyl esters to use baseline-adjusted EPA and DHA in total plasma lipids as the primary measures of BE for both fasting and fed conditions. This change would harmonize the approaches for demonstration of BE for ω-3 acid ethyl esters and icosapent ethyl (EPA ethyl esters) products for future development programs and is the most physiologically rational approach to BE testing.

Content and compliance of pharmaceutical social media marketing

Purpose The purpose of this paper is to explore ethical issues related to pharmaceutical marketers’ social media efforts including the prevalence and forms of direct-to-consumer web 2.0 advertising (eDTCA) and corporate social responsibility (CSR) messages across social networking sites (SNSs). One goal is to determine if these eDTCA posts comply with draft guidelines issued by the Food and Drug Administration (FDA). Design/methodology/approach Content analysis of ten pharmaceutical marketers’ SNS posts documented the frequency and types of posts devoted to eDTCA, drug risks and benefits, CSR, and other purposes. Findings eDTCA represents about 35 percent of all pharmaceutical firm SNS posts and primarily communicates help-seeking messages via Facebook, Twitter, and YouTube. Firms also promote their ethical image through CSR-related posts. These posts primarily highlight employee-focussed and community-focussed initiatives. Analysis of consumer behavior in response to each post shows that eDTCA affects only liking of YouTube videos, but CSR increases behavior responses on all SNSs except LinkedIn. Social implications Despite absence of final guidance, pharmaceutical marketers seem to abide by FDA draft social media guidance. In line with the FDA’s draft fair-balance regulations, almost all product-claim eDTCA posts state both benefit and risk information. Nevertheless, the FDA should issue final eDTCA guidance without delay consistent with traditional media direct-to-consumer advertising guidance. This should benefit consumers through consistency with their existing advertising literacy competencies. Originality/value The study represents an initial attempt to document ethical issues in the current state-of-the-practice of pharmaceutical social media marketing related to eDTCA and CSR.

Regulatory Forum Opinion Piece: Review of FDA Draft Guidance Testicular Toxicity-Evaluation during Drug Development Guidance for Industry.

In July 2015, the U.S. Food and Drug Administration (FDA) posted a new draft guidance entitled "Testicular Toxicity: Evaluation during Drug Development Guidance for Industry," with a 90-day public comment period. As the nonclinical assessment of testicular toxicity often relies on the expert interpretation of pathology affecting the male reproductive tract, this draft guidance is considered directly relevant to the toxicologic pathology community. Therefore, a working group was formed through the Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathologists (STPs) to provide a detailed review of the draft guidance. Specific comments on the guidance were submitted to the FDA by the STP. The draft guidance and all comments received are currently under review with the FDA. This commentary provides a summary of the components of the draft guidance and the comments submitted by the STP with acknowledgment of different perspectives reflected in comments from other respondents.

How do we implement Day 6 and Day 7 platelets at a hospital-based transfusion service?

Regulations surrounding blood components are designed to maintain safety, purity, and potency of products used for transfusion and further manufacture. These regulations evolve in response to risks and available options to reduce risk. Recent updates to the Code of Federal Regulations require transfusion services to take steps to control bacterial contamination of platelets (PLTs) using Food and Drug Administration (FDA)-approved or cleared devices and to identify contaminating organisms and notify the donor if the organism is likely to represent an endogenous infection. The recently published FDA draft guidance describing bacterial testing to enhance the safety and availability of PLTs outlined the steps for hospital transfusion services to extend apheresis PLT dating for up to 7 days. Newly cleared storage containers and a bacterial detection device labeled as a "safety measure" now provide the opportunity for hospital transfusion service to implement routine use of Day 6 and Day 7 PLTs. As one of the first adopters of this approach, we provide a detailed description of our own implementation process including the required update to our FDA registration, supplier agreement modification, laboratory information system changes, and process modifications necessary to support this practice change.

FDA's draft guidance on laboratory-developed tests increases clinical and economic risk to adoption of pharmacogenetic testing.

The US Food and Drug Administration (FDA) notified Congress July 31, 2014,1 of its intent to regulate laboratory developed tests. These encompass thousands of clinical assays currently used in medical practice including most pharmacogenetic tests. This guidance has the potential to impact the innovation and sustainability of pharmacogenetic research and its clinical implementation.

Pharmacodynamic Studies to Demonstrate Bioequivalence of Oral Inhalation Products.

In the session on "Pharmacodynamic studies to demonstrate efficacy and safety", presentations were made on methods of evaluating airway deposition of inhaled corticosteroids and bronchodilators, and systemic exposure indirectly using pharmacodynamic study designs. For inhaled corticosteroids, limitations of measuring exhaled nitric oxide and airway responsiveness to adenosine for anti-inflammatory effects were identified, whilst measurement of 18-h area under the cortisol concentration-time curve was recommended for determining equivalent systemic exposure. For bronchodilators, methacholine challenge was recommended as the most sensitive method of determining the relative amount of β-agonist or anti-muscarinic agent delivered to the airways. Whilst some agencies, such as the Food and Drug Administration (FDA), do not require measuring systemic effects when pharmacokinetic measurements are feasible, the European Medicines Agency requires measurement of heart rate and serum potassium, and some require serial electrocardiograms when bioequivalence is not established by pharmacokinetic (PK) studies. The Panel Discussion focused on whether PK would be the most sensitive marker of bioequivalence. Furthermore, there was much discussion about the FDA draft guidance for generic fluticasone propionate/salmeterol. The opinion was expressed that the study design is not capable of detecting a non-equivalent product and would require an unfeasibly large sample size.

Quality Assurance Test of Delivered Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products

The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products–Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.

A Note on Breast Cancer Trials With pCR-Based Accelerated Approval

Accelerated approval by the Food and Drug Administration (FDA), under the agency’s Fast Track review designation, allows early approval of drugs to treat serious diseases and fill an unmet medical need based on a surrogate endpoint. In May 2012, FDA issued a draft Guidance for Industry on the accelerated approval of breast cancer drugs based on the surrogate endpoint “pathologic complete response” (pCR). The research reported in this article investigates potential issues in designing clinical studies for pCR-based accelerated approval. The correlation between pCR and long-term survival was investigated. Two sample comparisons based on a conditional survival model under different assumptions were performed and are discussed along with simulation results. The findings from this research may shed some light on the implementation of the FDA draft guidance.

Adaptive Design: Results of 2012 Survey on Perception and Use.

Adaptive designs are increasingly used in clinical trials. The Drug Information Association's Adaptive Design Scientific Working Group (ADSWG) works to foster collaboration among regulatory agencies, academia, and pharmaceutical and biotech companies to further the science of adaptive clinical development. The ADSWG Survey Subteam has collected data on the usage of adaptive designs in clinical research from multiple sources, including a recent ADSWG survey regarding the perception and usage of adaptive designs in academia and industry for studies between 2008 and 2011, as well as barriers to usage; a literature review examining publications of adaptive design methodology and usage between 2000 and 2011; and a trial registry review of adaptive design references from 1996 to 2011. The comprehensive results of the ADSWG 2012 survey are provided in this article with comparisons to our previous 2008 survey, the literature and registry reviews, and recent surveys carried out by the US Food and Drug Administration (FDA) and the European Medicines Agency. Results of the ADSWG 2012 survey illustrate that industry and academia are showing more enthusiasm for adaptive trials, accompanied by an increase in the number of trials using designs described as less well understood in the FDA draft guidance on adaptive designs, published in 2010. The increased use of these methods in exploratory trials is consistent with the FDA draft guidance. The survey also identified several examples of successful marketing applications supported by confirmatory trials utilizing adaptive designs that were considered, at least at the time of the draft guidance, as less well understood. While some of the technological barriers to adaptive design usage identified in the 2008 survey are now less common, there are several important persistent barriers to usage. Organizations can help overcome these barriers through education, preplanning, and early engagement in discussions with the regulators.

Estimating the incremental net health benefit of requirements for cardiovascular risk evaluation for diabetes therapies.

PurposeTo evaluate the advantages and disadvantages of pre-approval requirements for safety data to detect cardiovascular (CV) risk contained in the December 2008 U.S. Food and Drug Administration (FDA) guidance for developing type 2 diabetes drugs compared with the February 2008 FDA draft guidance from the perspective of diabetes population health.MethodsWe applied the incremental net health benefit (INHB) framework to quantify the benefits and risks of investigational diabetes drugs using a common survival metric (life-years [LYs]). We constructed a decision analytic model for clinical program development consistent with the requirements of each guidance and simulated diabetes drugs, some of which had elevated CV risk. Assuming constant research budgets, we estimate the impact of increased trial size on drugs investigated. We aggregate treatment benefit and CV risks for each approved drug over a 35-year horizon under each guidance.ResultsThe quantitative analysis suggests that the December 2008 guidance adversely impacts diabetes population health. INHB was −1.80 million LYs, attributable to delayed access to diabetes therapies (−0.18 million LYs) and fewer drugs (−1.64 million LYs), but partially offset by reduced CV risk exposure (0.02 million LYs). Results were robust in sensitivity analyses.ConclusionThe health outcomes impact of all potential benefits and risks should be evaluated in a common survival measure, including health gain from avoided adverse events, lost health benefits from delayed or forgone efficacious products, and impact of alternative policy approaches. Quantitative analysis of the December 2008 FDA guidance for diabetes therapies indicates that negative impact on patient health will result. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

A new paradigm for obtaining marketing approval for pediatric-sized prosthetic heart valves

Congenital heart valve disease is one of the most common abnormalities in children. There are limited technological solutions available for treating children with congenital heart valve diseases. The aim of this study is to provide the details of the consensus reached in terms of pediatric definitions, design approach, invitro testing, and clinical trials, which may be used as guidance for developing prosthetic heart valves for the pediatric indication. In stark contrast to the various designs of adult-sized replacement valves available in the market, there are no Food and Drug Administration (FDA)-approved prosthetic heart valves available for use in the pediatric population. There is a pressing need for FDA-approved pediatric valve devices in the United States. The pediatric patient population has been typically excluded from replacement heart valve trials for several reasons. In January 2010, heart valve manufacturers and pediatric clinicians collaborated with academicians and FDA staff in a workshop to suggest ways to successfully evaluate pediatric prosthetic valves and conduct pediatric clinical trials to provide acceptable heart valve replacement options for this patient population. Recommendations, derived from ISO 5840:2005 and the 2010 FDA Draft Replacement Heart Valve Guidance, are provided for hydrodynamic, durability, and fatigue testing. The article specifically addresses invitro and premarket and postmarket approval clinical studies that should be considered by a heart valve manufacturer for obtaining regulatory approval of pediatric sizes of prosthetic heart valve designs that are already approved for adult clinical use.