FDA Decisions Research Articles

Intellectual Property of Psychedelics for Addiction Treatment: Enabling Access and Protecting Innovation Opportunities Through Preserving the Public Domain.

Recent research has shown potential for psychedelic therapeutics as addiction treatments; however, some academic institutions, commercial entities, and individuals are attempting to monopolize psychedelic compounds through exploiting the patent process. This Perspective article describes efforts that have been devised to mitigate exclusionary patent practices pertinent to psychedelic therapeutics for addiction. The nonprofit Porta Sophia has identified 170 patent documents focused on treating addiction through psychedelics, and many of these patents could threaten to privatize public domain knowledge and severely limit or increase the cost of research if granted. Patent examiners who determine if a patent application should be granted must negate false claims to innovation. Yet, given the unique history of psychedelics, prior knowledge can be difficult to find. As a result, overreaching patents may be granted, causing dramatic shifts in access to addiction-focused psychedelic research, treatments, and funding. As the field of psychedelics approaches this crucial inflection point of U.S. Food and Drug Administration decisions, it is imperative for all stakeholders--including university investigators, academic and commercial patent seekers, and policymakers--to use available tools for determining prior knowledge. Maintaining an informed awareness of legal patent eligibility and limitations is crucial for establishing an ethical patent landscape and ensuring subsequent access to these potential life-altering psychedelic therapeutics for addiction.

Perceived threat and fear responses to e-cigarette warning label messages: Results from 16 focus groups with U.S. youth and adults.

A warning on e-cigarette packaging is one way the U.S. government can inform the public of known harms of e-cigarette use. Currently, the only required warning on these products is: "WARNING: This product contains nicotine. Nicotine is an addictive chemical." This exploratory study aims to inform potential future investigations and FDA decisions regarding alternative warnings that may generate fear in addition to being intentionally informational. Data were obtained from responses by 16 online focus groups with adult (N = 47, age range = 18-64) and youth (N = 32, age range 14-16) participants with various smoking and vaping experiences. We showed each focus group a set of hypothetical e-cigarette warning labels to determine how they respond to currently existing public statements that communicate information on the toxicity of ingredients in e-cigarettes, potential health risks, addiction to nicotine, and the uncertainty of the science regarding health effects of using these products. The focus group interviews were audio recorded and transcribed. Transcripts were subjected to a multiphase coding process to identify common response themes. Codes derived from the Extended Parallel Processing Model were then applied to understand impact of potentially fear-inducing language by warning category and age group. For adults, all warnings-except those about addiction-gave rise to spontaneous danger control (intended) responses, such as quit intentions. Warnings highlighting cognitive and uncertain effects may be particularly promising for adult consumers of tobacco products because both gengerated danger control and response efficacy without evidence of fear control. However, responses also suggest that warnings risk discouraging some adults who use combustible cigarettes from transitioning to e-cigarettes for harm reduction. For youth, while evidence of response efficacy and danger control emerged among youth exposed to messages in all warning categories but one-addiction-unproductive reactions indicative of fear control were also prevalent among youth respondent across most warning types. On average, youth were more skeptical than adults about the harms of using e-cigarettes. Implications of study findings for the development of future effective e-cigarette warning messages are explored.

Clinical practice guideline descriptions of oncologic drugs granted FDA accelerated approval: A cross-sectional study.

1590 Background: The Food and Drug Administration’s (FDA's) accelerated approval (AA) pathway allows drugs to be approved using surrogate endpoints, while requiring that sponsors complete postmarketing requirement (PMR) studies verifying clinical benefit. Subsequently, FDA determines whether AA can be converted to standard approval or be withdrawn. It is unclear whether clinical practice guidelines reflect PMR results or FDA regulatory decisions. As most drugs granted AA are cancer therapies, we investigated whether and how National Comprehensive Cancer Network (NCCN) guidelines reflect underlying evidence supporting AAs and subsequent FDA decisions. Methods: In this cross-sectional study, we used Drugs@FDA to identify drug indications granted AA by FDA for oncologic indications from 2016-2018, PMR status and results, and whether AA was converted to regular approval or withdrawn. We excluded pediatric and tumor-agnostic indications. PMR studies were classified as positive if the results from primary efficacy endpoint were statistically significant ( P<0.05) favoring the drug. For each AA indication, we searched relevant NCCN guidelines for their recommendations and examined if AA status, PMR results, and updated FDA decisions were reflected. Results: Among 36 oncology drug indications granted AA from 2016 to 2018, 29 (81%) NCCN guidelines did not mention that the drug was approved via AA pathway or had not yet verified clinical benefit. For all 36 (100%) indications, NCCN guidelines did not state that approval was based on surrogate endpoints. As of December 31, 2022, among 16 drug indications that were converted to standard approval, 13 (81%) guidelines reflected FDA’s updated decisions. Among 8 indications withdrawn after AA, 5 (63%) guidelines reflected the withdrawn status. Of 6 drug indications with negative PMR study results that were withdrawn, 2 (33%) were still recommended in NCCN guidelines thereafter. Conclusions: NCCN guidelines do not consistently reflect FDA regulatory status or PMR study results, highlighting the need for more up-to-date and accurate information to guide clinical practice.[Table: see text]

Using real-world evidence (RWE) in regulatory decision making: A study of 6 oncology approvals with RWE included in the product label.

6611 Background: The 21st Century Cures Act in 2016 enhanced the FDA’s ability to include the use of real-world data (RWD) and consideration of RWE in the development and approval of new medical products. Currently, limited assessments of the use of RWE in FDA approved oncology product reviews exist in the literature. This study was conducted to determine how RWE was used in FDA decisions for oncology drug approvals between 2015 and 2022. Methods: A systematic review of FDA submission documents and product labels available on the FDA website from 2020 to 2022, in addition to an exhaustive manual search of grey literature and the results of a targeted literature search from 2015 to 2019 were used to identify RWE that were included in FDA submission documents and in approved product labels. Results: In total, 124 oncology product evaluations were reviewed in the 2020 to 2022 literature search. Twenty-nine oncology product NDAs and BLAs included RWE to support efficacy, safety, or indication, of which the majority (n=26) ultimately had RWE accepted as evidence by the FDA for the submission. In these cases, RWE was used to add context (n=16), to support the indication or safety (n=7), to provide substantial basis for indication or safety (n=2), as a statistical comparison (n=2), or for informational purposes only (n=1). Feedback from the FDA reviewers for reasons RWE studies were not considered during product approval reviews included methodology issues, sample size concerns, and omission of patient level data. Ultimately, across the 2015 to 2019 targeted literature review and the 2020 to 2022 FDA submission document review, 6 oncology product labels incorporated RWE: palbociclib, uridine triacetate, lutetium Lu 177 DOTATATE, bevacizumab-adcd, naxitamab-gqgk, and decitabine/cedazuridine. RWE was used to support the initial indication for the majority of products (n=5) and also supported label expansion (n=1). RWE was incorporated in the product label postmarketing experience section (n=3), the clinical studies section (n=2), and the warnings/precautions section (n=1). Conclusions: These results suggest that RWE has become an important part of regulatory decision-making for oncology drug approval. Twenty-six of 29 RWE studies were accepted as evidence for the submission. For the 6 oncology products that include RWE in the product label, RWE was most frequently used to support the initial indication and was included in the postmarketing experience section. These examples show consistent use of RWE since the approval of the 21st Century Cares Act and provide evidence of a promising new direction with the creation of the FDA guideline/program for RWE.

FDA preemption of conflicting state drug regulation and the looming battle over abortion medications.

Over the past 25 years, Congress and the FDA have determined the safest and most beneficial way to regulate the use of mifepristone (Mifeprex), the medication that accounts for the majority of abortions in the United States. The Dobbs decision has renewed the importance of those scientific determinations, especially FDA's decisions implementing the Risk Evaluation and Mitigation Strategy (REMS) provisions of the Federal Food Drug and Cosmetic Act (FDCA), that mifepristone may be taken by patients outside the presence of any healthcare provider (often through telemedicine prescription and shipment across state lines). Now that Dobbs has been decided, state officials have indicated that they will seek to enforce state statutes which conflict with FDA's regimen for the proper use of mifepristone, by banning its use entirely, prohibiting telemedicine prescription, or imposing other requirements which FDA has specifically considered and now rejected as contrary to the congressional mandate that FDA-approved drugs be as accessible as safety considerations allow. Litigation has already been filed to invalidate such statutes on the grounds that they are preempted by the doctrine that state law which conflicts with, or undermines the purposes of, FDA actions with respect to approved drugs are preempted under the Supremacy Clause of the Constitution. This article examines the Supreme Court caselaw and FDA actions which will dictate the outcome of that litigation. Part I details the statutory basis for FDA preemption of conflicting state law and the four decisions by the Supreme Court over the last 13 years (Levine, Mensing, Bartlett and Albrecht) which enunciate the governing legal standards for FDA preemption. We pay particular attention to the opinions of Justice Alito and the other conservative justices, which hold that such FDA preemption should be robust to ensure that there is one consistent, national policy for the distribution and regulation of drugs, under the science-based decisions of the FDA, rather than the 'parochialism' of differing state standards. Part II details FDA's comprehensive program for the balanced, though appropriately restricted, use of mifepristone, and the 22 years of FDA actions that brought that about. It then catalogs the state statutes limiting the use of the drug which, in material ways, conflict with those FDA determinations. Part III outlines the arguments made in one early lawsuit seeking preemption of the statutes of one state (Mississippi)-a law suit which previews the wider litigation to come. It then sets forth the strong arguments for FDA preemption of each type of state restriction and responses to the 'defenses' of those statutes that have been offered in an effort to avoid FDA preemption under the Supremacy Clause. That review shows that a straight-forward application of the FDCA and the Supreme Court caselaw should result in the preemption of the state restrictions that squarely conflict with the relatively free access to abortion medications which FDA has mandated.

FDA decisions on new oncological drugs.

FDA decisions on new oncological drugs.

FDA decisions on new oncological drugs.

Division of Hematology and Oncology, Department of Medicine, University of California, Irvine, CA, USA (DJB); Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA (VP); Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK (MPL) Importing oncology trials from China: a bridge over troubled waters?On Feb 10, 2022, the US Food and Drug Administration's Oncologic Drugs Advisory Committee will convene to discuss ORIENT-11, a clinical trial comparing chemotherapy plus sintilimab, an anti-PD-1 monoclonal antibody and member of the checkpoint inhibitor class, with chemotherapy alone as an initial treatment for metastatic non-small-cell lung cancer (NSCLC).1 Done exclusively in China, the trial's design, patient population, and statistical analysis closely resembles landmark NSCLC trials that established checkpoint inhibitors as part of initial treatment regimens several years ago. Full-Text PDF FDA decisions on new oncological drugsGuanqiao Li, Yang Liu, Ruyi He, Ling Su, *Xiaoyuan Chen Full-Text PDF

Easing Medical Device Regulatory Oversight: The FDA and Testing Amidst the COVID-19 Pandemic.

The FDA already subjects most medical devices to much less stringent approval requirements than drugs and biologics, and attempts to speed up rollout during the COVID crisis have been problematic. Agency decisions, including to allow antibody test marketing without emergency use authorization or review, and the back-and-forth guidance on laboratory-developed tests, have met harsh criticism and unreliable results. Though the long-term results of these decisions are unclear, the FDA's credibility, reliability, and commitment to safety are threatened by even further lessening medical device regulatory oversight during the coronavirus pandemic. The relaxed and fix-it-later approach to many of the FDA's public health emergency decisions regarding medical devices reflect the ongoing criticisms of medical device regulation in general, specifically the 510(k) process and laboratory developed test regulation, offering a point of reflection towards reform. Adaptive legislation and a risk-based and evidentiary approach to premarket and postmarket review can begin to address these issues both generally and in an emergency context.

FDA Decisions on Measures of Hypoactive Sexual Desire Disorder in Women: A History, With Grounds to Consider Clinical Judgment.

In 2000, the FDA began issuing advice about treatments for hypoactive sexual desire disorder (HSDD) in women. How its recommendations have evolved has not been reviewed. Its consistent preference for self-rating by patients over evaluation by an examining clinician has not been addressed. Recount the changes in FDA's proposals about patient-reported outcomes and diagnostics. Compare the value of patient-reported measures and clinical interviews. Historical review is based on draft guidances, publications, meetings, and prescribing information. The FDA has avoided clinician input into diagnosis and evaluation of the severity of HSDD in women. It abandoned its initial (2000) insistence on counts of satisfying sexual events to define efficacy in favor of symptom-related scales to evaluate desire and distress with daily self-ratings. By 2015, the FDA accepted the self-rated Female Sexual Function Index-Desire Domain (FSFI-D) to measure desire and the most relevant item of the Female Sexual Distress Scale-Revised (FSDS-R) to measure distress; retrospection for both is one month. TheFDA rejected the one clinician-rated broad measure of HSDD, the Sexual Interest and Desire Inventory (SIDI-F), although well-validated and treatment-sensitive. Since 2005, the FDA has accepted the Decreased Sexual Desire Screener (DSDS) to diagnose HSDD by non-expert clinicians using self-ratings and exploring them in more depth in a clinical interview. FDA's decisions on how to measure HSDD in women may have stabilized on accepting 2 co-primary measures: the FSFI-D and the FSDS-R item on bother about low desire, and on accepting the DSDS for diagnosis. FDA's rejection of clinician ratings of severity through interviews in clinical trials seems unsound because interviews can give broader assessments than (brief) self-ratings, although the agency's logic was to avoid diagnostic controversies and help avoid overcommercialization. Semistructured clinical interviews for diagnosis (DSDS) and severity-rating (SIDI-F) are well validated and are recommended for clinical practice. Pyke RE. FDA Decisions on Measures of Hypoactive Sexual Desire Disorder in Women: A History, With Grounds to Consider Clinical Judgment. Sex Med Rev 2021;9:186-193.

Role of real-world evidence for oncology product registration in the United States: A review of approvals by the U.S. Food and Drug Administration from 2015 to 2019.

e14130 Background: There are few concrete examples of real world evidence (RWE) used to support clinical development in regulatory filings despite growing interest in this field. This study systematically reviewed FDA oncology approvals to identify use cases of RWE. Methods: FDA’s new drug application (NDA) and biologics license application (BLA) approvals for oncology products from 2015-2019 were systematically reviewed. Among cases with RWE, data characterizing the submission and RWE details (data source, study design, FDA comments) were synthesized. Results: 93 approved NDAs and BLAs were identified; 6 included RWE in support of efficacy (see Table), approved on or after 2017, and were largely retrospective studies that contextualized results to pivotal trial, with primary endpoints overall survival (OS), overall response rate (ORR), and time to treatment discontinuation (TTD). Flatiron data were used in 3 of these as database analyses, 1 was an expanded access program (EAP), 1 was a meta-analysis, and 1 was a retrospective chart review. Conclusions: In the past 5 years, few FDA decisions incorporated RWE in oncology drug approvals. When used, RWE has been a complement rather than a supplement for clinical trial data. Early engagement, a priori protocol development, and robust research design (adjusting for bias, comparability to clinical trial population) remain key determinants for successful use of RWE in FDA decision making. [Table: see text]

PHP40 - Trends in Approval of Therapeutic Biologic Approved by the US Food and Drug Administration (1986–2017)

This study assessed the trends in new therapeutic biologic license applications (BLA) and new molecular entities (NME) regulated by the Center for Drug Evaluation and Research and approved by the FDA in the period 1980–2017. The following information was collected from FDA online databases: date of approval; orphan designation; market status; discontinuation reasons; risk evaluation and mitigation strategy (REMS), black-boxed warning, medication guide, and date of first generic/biosimilar approval. The Anatomical Therapeutic Chemical (ATC) classification was collected from the WHO. Descriptive statistics, t-test and chi-square tests were performed in the analysis (α=0.05). The FDA approved 132 BLA and 949 NME in the period of analysis. The annual average±standard deviation of approvals was 3.5±3.2 for BLA and 25.0±7.9 for NME. The approvals of BLA increased from 0.9±1.4 in the 1980s to 7.1±3.9 in the period 2010-2017. BLA represented 4.0%, 7.7%, 15.9%, and 21.5% of the approvals in the 1980s, 1990s, 2000s, and 2010-2017, respectively. 88.6% of the BLA and 85.0% of the NME were marketed as of 31-Dec-2017. The main ATC was antineoplastic and immunomodulating agents (69;52.3%) for BLA, and antiinfectives for systemic use (135;14.2%) for NME. BLA (48.5%) were more likely than NME (22.7%) to have orphan designation (p<0.001), REMS (14.4% vs. 4.4%, p<0.001), black-boxed warning (43.2% vs. 25.8%), and medication guide (30.3% vs. 17.1%). A lower percentage of BLA (6;4.5%) than NME (413;43.5%) experienced market competition (p<0.001). The average number of years without market competition was higher for BLA (17±3.9 years) than for NME (12.6±4.2 years). The number of BLA licensed by the FDA increased overtime. In the period 2010-2017, BLA represented more than 1 in 5 new drugs approved by the FDA. BLA were more likely than NME to have an orphan designation, and safety-related FDA decisions.

Time to Converge FDA Decisions and Evidence Syntheses for Long-Acting Muscarinic Antagonists and SMART in Guidelines for the Treatment of Asthma

Time to Converge FDA Decisions and Evidence Syntheses for Long-Acting Muscarinic Antagonists and SMART in Guidelines for the Treatment of Asthma

Migraine drug race turns its final corner, FDA decisions in sight.

Migraine drug race turns its final corner, FDA decisions in sight.

A Benefit-Risk Analysis Approach to Capture Regulatory Decision-Making: Multiple Myeloma.

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision-making about new drugs to treat multiple myeloma (MM). MM assessments have been based on endpoints such as time to progression (TTP), progression-free survival (PFS), and objective response rate (ORR) which are different than benefit-risk analysis based on overall survival (OS). Twenty-three FDA decisions on MM drugs submitted to FDA between 2003 and 2016 were identified and analyzed. The benefits and risks were quantified relative to comparators (typically the control arm of the clinical trial) to estimate whether the median benefit-risk was positive or negative. A sensitivity analysis was demonstrated using ixazomib to explore the magnitude of uncertainty. FDA approval decision outcomes were consistent and logical using this benefit-risk framework.

Find your own path

Are you doing things because that’s “the way we’ve always done it?” If so, I’d like you to consider “The Calf-Path.” That’s a poem by Sam Walter Foss that describes how many of today’s roads follow the winding paths originally carved by calves of centuries ago. It reads in part: Each day a hundred thousand rout Followed that zigzag calf about, And o’er his crooked journey went The traffic of a continent. A hundred thousand men were led By one calf near three centuries dead. They follow still his crooked way, And lose one hundred years a day, For thus such reverence is lent To well-established precedent. In a June 14 article in the New York Times, Judge Edward R. Korman mentioned this poem in explaining his decisions in the Plan B case discussed on page 58. Precedent is critical in judicial decisions, but he added, “I think judges don’t stop often enough to think about whether the path should be followed. I try and straighten the calf’s path.” Korman has certainly set a new path when it comes to judicial review of FDA decisions. Randee Bowder is also developing new paths through an innovative medication therapy management (MTM) program in Oregon. Read her story in this month’s MTM profile (pages 34–36) and think about how you could be coaching patients all over the country who need MTM. Then turn to a new section of Pharmacy Today on specialty pharmacy (pages 39–44). Jennifer Hagerman and her colleagues at Diplomat Specialty Pharmacy will provide news and information about this growing practice segment on a quarterly basis. Regardless of where you practice, specialty pharmaceuticals are important because they are expensive and complex. In addition, they are growing in number as medical research produces increasingly specific therapies for human disease. On page 47, we begin a three-part series on MTM programs that address the recommendations made by the IMS Institute for Health Informatics report, The Responsible Use of Medicines: Applying Levers for Change. Consider how you can better serve older patients in your practice based on the MTM innovations developed by Vanita K. Pindolia of Detroit’s Henry Ford Health System Health Alliance Plan. Implications of the Affordable Care Act will be detailed in another series beginning this month. We begin on page 56 with opportunities for pharmacists as 2014 brings implementation of major provisions of this landmark law, for better or worse. It’s a new day, one that calls for breaks from the past. Creativity will be as important as business acumen as health care is reformed, and following the path of long-dead calves won’t get us there. Enjoy your July Today!

Access to Levonorgestrel Emergency Contraception: Science versus Federal Politics

Past US FDA decisions about emergency contraception (EC) have been subject to undue political influence, and last year's barring of over-the-counter access to Plan B One-Step(®) for those under the age of 17 years is no exception. The US Department of Health and Human Services cited insufficient data on EC use for females aged 11-12 years. These youngest adolescents, however, rarely need EC: data from California (USA) show that in 2009, fewer than one in 10,000 females under the age of 13 years received EC. Maintaining barriers to safe and effective EC is not medically necessary and conflicts with national goals to decrease teenage and unintended pregnancies.

Electroconvulsive Therapy in the Spotlight

The FDA's Neurological Devices Advisory Panel recently recommended keeping electroconvulsive therapy (ECT) devices in class III, the highest risk category. The FDA's regulatory decisions about the devices could determine the future of ECT in the United States.

A Summary of FDA Decisions on Propoxyphene-Containing Products

Topics in Pain Management: February 2011 - Volume 26 - Issue 7 - p 9 doi: 10.1097/01.TPM.0000394229.06620.88

FDA and EMA decisions on Avastin use in breast cancer

FDA and EMA decisions on Avastin use in breast cancer

The impact of randomized trial results and altered regulatory policies on ESA use, transfusions, and thrombosis: A longitudinal analysis over a 3-year period of resource utilization data from a large comprehensive oncology program

6611 Background: Recent randomized trials and meta-analyses demonstrated unexpected findings with ESA use with chemotherapy. Results revealed an overall increase in thrombosis rates with the use of ESAs as well as decrements in survival in some malignancies, particularly with breast and head and neck cancers (Bohlius, JNCI, 2006; Raftopoulos, Proc ASCO, 2008; Bennett, JAMA 2008). Benefits with ESA use have resulted in an average 1–1.5g/dl rise in hemoglobin. The impact on quality of life and fatigue remains controversial. Toxicity issues have led to restricted labeling by the FDA and reimbursement decisions by the Centers for Medicare and Medicaid Services (CMS). Despite these risks associated with the use of ESAs, concerns regarding increased use of transfusions remain prominent. A longitudinal study to assess the impact of these ESA policies was conducted to assess the demand on transfusion services and ESA use over time. Methods: Our center comprises a large comprehensive combined hematology and oncology program and has a non- restrictive transfusion policy, allowing physician discretion and the capacity to accommodate all out-patient transfusions. We analyzed ESA use over the 3 year period, 2006–2008. 2006 functioned as our baseline; 2007 was the year of initial FDA and CMS changes; 2008 allowed us to see if practice changes would persist. Results: We present in the table below, our data on ESA use and transfusion resource utilization. Conclusions: With over 60,000 patient visits during 3 years, longitudinal assessment reveals a continued, marked decrease in ESA use. Despite liberal transfusion policies, there has been little effect on transfusion rates. Increases in transfusions are commensurate with a rise in patient visit volume. We are now evaluating whether this marked decrease in ESA use translates into decreased thrombosis rates over this 3-year period at our cancer center. [Table: see text] No significant financial relationships to disclose.