A framework enabling LLMs into regulatory environment for transparency and trustworthiness and its application to drug labeling document.

Regulatory agencies consistently deal with extensive document reviews, ranging from product submissions to both internal and external communications. Large Language Models (LLMs) like ChatGPT can be invaluable tools for these tasks, however present several challenges, particularly the proprietary information, combining customized function with specific review needs, and transparency and explainability of the model's output. Hence, a localized and customized solution is imperative. To tackle these challenges, we formulated a framework named askFDALabel on FDA drug labeling documents that is a crucial resource in the FDA drug review process. AskFDALabel operates within a secure IT environment and comprises two key modules: a semantic search and a Q&A/text-generation module. The Module S built on word embeddings to enable comprehensive semantic queries within labeling documents. The Module T utilizes a tuned LLM to generate responses based on references from Module S. As the result, our framework enabled small LLMs to perform comparably to ChatGPT with as a computationally inexpensive solution for regulatory application. To conclude, through AskFDALabel, we have showcased a pathway that harnesses LLMs to support agency operations within a secure environment, offering tailored functions for the needs of regulatory research.

FDA Initiative for Drug Facts Label for Over-the-Counter Naloxone.

BACKGROUND: The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use. METHODS: In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval. RESULTS: The results for performance on six primary end points met or exceeded thresholds, including the steps "Check for a suspected overdose" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and "Give the first dose" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of "Call 911 immediately," but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of "Check, give, and call 911 immediately" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9). CONCLUSIONS: Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales.

A Legislative/Legal History of Prescription Drug Advertising and Promotion Regulation.

PURPOSE: The communication by pharmaceutical companies of promotional messages about their products has long been controversial, but deemed to be necessary by the pharmaceutical industry so that health care professionals and in some cases patients/consumers can be made aware of the latest developments through the communication vehicles they are accustomed to seeing - in the case of health care professionals, through medical advertising, direct mail, visits by company representatives, and attendance at medical meetings, and in case of patients, through the news media and television advertising. On the other hand, critics argue that such promotion, which sometimes reduces complex medical issues to advertising slogans, is inappropriate for products intended to treat and cure diseases, and that health care professionals should learn about new products from peer-reviewed medical literature.  Consequently, advertising, and promotional programs are heavily regulated by the U.S. Food and Drug Administration (FDA). However, the laws themselves raise constitutional issues of infringement on free speech.  Over the past few years, a number of lawsuits have been decided that help clarify the role of the FDA and the extent of its authority in regulating what companies or their employees say about their products. These court decisions are important because they help define how health care professionals and patients/consumers receive medical information. METHODS: This overview is intended to identify, in non-technical language, some of the more controversial and challenging issues involved in the FDA's efforts to regulate marketing communications by drug companies and how the courts view them. RESULTS: The recent lawsuits often involve complex and far-reaching legal issues.  But when examined in toto, as this paper does, they have reflected a view by the courts that truthful and non-misleading statements by drug companies about their products can be legally communicated even when the medical information is not formally approved by the FDA and included in the FDA-approved labeling.  The lawsuits thus have led to an environment in which the FDA continues to oversee with great fervor the activities of drug companies in communicating medical information but at the same time having some flexibility in keeping health care professionals and patients up to date with th latest information about medical research and new therapeutic products. CONCLUSION: How pharmaceutical products are marketed has been deemed by the U.S. Congress to be important enough to need to be subject to federal regulation.  The issues create a tension between the need for medical information to be accurate and balanced, and the guarantees of free speech.  This review provides an important perspective on how this tension is being resolved, even as dramatic advances in both medical products and technology create new challenges.

Analytical survey of tattoo inks-A chemical and legal perspective with focus on sensitizing substances.

BACKGROUND: Tattoo inks have been reported to elicit allergic contact dermatitis. OBJECTIVES: To investigate the labels and the contents of metals and pigments in tattoo inks, considering restrictions within the European Union. METHODS: Seventy-three tattoo inks currently available on the market, either bought or donated (already used), were investigated for trace metals and pigments by inductively coupled plasma mass spectrometry and by matrix-assisted laser desorption/ionization time of flight tandem mass spectrometry. RESULTS: Ninety-three percent of the bought tattoo inks violated European, legal requirements on labeling. Fifty percent of the tattoo inks declared at least one pigment ingredient incorrectly. Sixty-one percent of the inks contained pigments of concern, especially red inks. Iron, aluminium, titanium, and copper (most in green/blue inks) were the main metals detected in the inks. The level of metal impurities exceeded current restriction limits in only a few cases. Total chromium (0.35-139 µg/g) and nickel (0.1-41 µg/g) were found in almost all samples. The levels of iron, chromium, manganese, cobalt, nickel, zinc, lead, and arsenic were found to covary significantly. CONCLUSIONS: To prevent contact allergy and toxic reactions among users it is important for tattoo ink manufacturers to follow the regulations and decrease nickel and chromium impurities.

Safety-Related Postmarketing Modifications of Drugs for Hematological Malignancies.

The prevalence of safety-related postmarketing label modifications of medications for hematological malignancies is unknown. We identified 35 new drugs indicated for hematological malignancies approved by the US Food and Drug Administration between January 1999 and December 2014. Characteristics of supporting trials and safety-related label modifications from approval to December 2017 were collected from drug labels. Regulatory review and approval pathways were also collected. New drug approvals were supported by trials with a median of 167 patients (interquartile range 115-316). All drugs were approved based on surrogate endpoints. Twenty-seven drug approvals (77%) were not supported by randomized controlled trials. All drugs received orphan drug designation, and most were granted fast track designation, priority review, and accelerated approval (83, 74, and 60%, respectively). A total of 28 drugs (80%) had postmarketing safety-related label modifications. Additions to black box warnings, contraindications, warnings and precautions, and common adverse reactions were identified in 31, 11, 77, and 46% of drugs, respectively. Five drugs (14%) were permanently or temporarily withdrawn from the US market. Drugs for hematological malignancies are often approved based on limited evidence through expedited regulatory pathways with incomplete safety profiles. Hematologists should be vigilant for unrecognized side effects when prescribing newly approved drugs.

FDA postmarketing safety labeling changes: What have we learned since 2010 about impacts on prescribing rates, drug utilization, and treatment outcomes.

PURPOSE: Prior literature reviews have identified gaps in understanding of how postmarketing safety labeling changes and related FDA communications impact key clinical and behavioral outcomes. We conducted a review of newly published studies on this topic to determine what new evidence exists and to identify which gaps may still remain. We believe that this information can support FDA as it develops and implements future risk communication approaches. METHODS: We searched PubMed and Embase for studies published between January 1, 2010, and August 7, 2017 that examined the impact of labeling changes or associated FDA safety-related communications. For each study, we extracted information on research design and findings for key clinical outcomes and behaviors. We also conducted a ROBINS-I review to identify potential for bias in the research design of each study. RESULTS: We found that the estimated impacts of FDA labeling changes on several key outcomes-including adverse events-varied. Labeling changes also yielded unintended consequences on drug prescribing in some cases, despite low provider adherence. Finally, some studies we reviewed exhibited potential for bias due to confounding, among other factors. CONCLUSIONS: The new studies we reviewed contain many of the same limitations identified in previously published reviews. While there are several challenges to conducting this research there is substantial room for improvement in the quality of the evidence base. More information, particularly with respect to the types of populations and medications affected by labeling changes, is needed to support the development of more effective and targeted safety communications.

Biosimilars: The US Regulatory Framework.

With the passage of the Biologics Price Competition and Innovation Act of 2009, the US Food and Drug Administration established an abbreviated pathway for developing and licensing biosimilar and interchangeable biological products. The regulatory framework and the technical requirements of the US biosimilars program involve a stepwise approach that relies heavily on analytical methods to demonstrate through a "totality of the evidence" that a proposed product is biosimilar to its reference product. By integrating analytical, pharmacological, and clinical data, each of which has limitations, a high level of confidence can be reached regarding clinical performance. Although questions and concerns about the biosimilars pathway remain and may slow uptake, a robust scientific program has been put in place. With three biosimilars already licensed and numerous development programs under way, clinicians can expect to see many new biosimilars come onto the US market in the coming decade. [Note added in proof: Since the writing of this article, a fourth biosimilar has been approved.].

Future of the drug label: Perspectives from a multistakeholder dialogue.

Regulating drugs does not end when market access has been granted. Monitoring drugs over the life cycle has become state of the art, inherent to evolving legislation and societal need. Here, we explore how the drug label could move along in a changing playing-field and become a sustainable label for the future. A dialogue between academia, government, the pharmaceutical industry and patient/societal organizations was organized by the Regulatory Science Network Netherlands. This is their view.

A Review of Patient-Reported Outcomes Labeling for Oncology Drugs Approved by the FDA and the EMA (2012-2016).

OBJECTIVES: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies. METHODS: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication. RESULTS: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation. CONCLUSIONS: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews.

Secret safety warnings on medicines: A case study of information access requests.

PURPOSE: There has been less attention to the transparency of postmarket evidence of harmful effects of medicines than of premarket clinical trial data. This is a case study of requests for Australian "direct health professional communications" (DHPCs). These letters are used by regulators and manufacturers to inform clinicians of emergent evidence of harm. DHPCs are not made public by Australia's Therapeutic Goods Administration (TGA). METHODS: We requested all DHPCs sent out in Australia from 2007 to 2016 inclusive for 207 drugs that were subject to safety advisories over this decade in Canada, the United Kingdom, and/or the United States. We contacted 39 manufacturers (February to May 2018), with repeat requests to nonrespondents, and a follow-up freedom-of-information (FOI) request to the TGA. RESULTS: Fifteen companies provided information, either sending DHPCs (n = 4, on five drugs) or affirming none were sent out (n = 11). The remaining 24 of 39 (62%) companies did not provide DHPCs: nine (23%) refused the request, often citing commercial confidentiality; the rest provided no answer despite repeat requests. In total, we had no information for 170 of 207 (82%) of the drugs. Our FOI request to the TGA was unsuccessful. CONCLUSIONS: Our experience highlights unacceptable secrecy concerning safety warnings previously sent to thousands of Australian clinicians. In the absence of explicit regulatory policy supporting disclosure, companies differed in their response. These letters warn of serious and often life-threatening harm and guide safer care; full ongoing public access is needed, ideally in searchable online databases.

Fosamax Fractures-Justice Has Not Been Served.

This Viewpoint discusses the ongoing lawsuit between plaintiffs who had been affected by atypical femoral fractures while receiving alendronate and the drug manufacturer.

The new FDA labeling rule: impact on prescribing rheumatological medications during pregnancy.

After several decades of deliberation, the US Food and Drug Administration updated the Pregnancy and Lactation Labeling Rule in 2015, eliminating the prior A, B, C, D, X grading system for medication use in pregnancy. Although physicians and patients liked the relative ease of use of this system, it was often misconstrued and not updated to include new data suggesting greater compatibility of medications with pregnancy. The new label is designed to include more clinically relevant data, including data from human studies and registries, and fewer animal data. A key goal of the new label is to assist physicians and patients as they weigh the risks and benefits of medications vs the risks of pregnancy in a woman with a chronic, untreated illness. As such, each label now includes a section outlining the pregnancy risks of the diseases that the medication treats. This review includes a historical perspective on the label change and a guide to the interpretation of the new label. It also includes an assessment of the baseline risk of pregnancy in women with SLE and RA, to help balance the consideration of medication risks and benefits in pregnancy.

Drugs in Lactation.

One impediment to breastfeeding is the lack of information on the use of many drugs during lactation, especially newer ones. The principles of drug passage into breastmilk are well established, but have often not been optimally applied prospectively. Commonly used preclinical rodent models for determining drug excretion into milk are very unreliable because of marked differences in milk composition and transporters compared to those of humans. Measurement of drug concentrations in humans remains the gold standard, but computer modeling is promising. New FDA labeling requirements present an opportunity to apply modeling to preclinical drug development in place of conventional animal testing for drug excretion into breastmilk, which should improve the use of medications in nursing mothers.

Disgust but not Health Anxiety Graphic Warning Labels Reduce Motivated Attention in Smokers: A Study of P300 and Late Positive Potential Responses.

Background: Graphic health warning labels (GHWLs) on tobacco products attempt to leverage avoidance-promoting emotions, such as anxiety and disgust, to encourage cessation. Prior studies have relied on self-report or attentional metrics that may not accurately illuminate GHWLs' ability to motivate change. This report evaluates the impact of disgust- and anxiety-based GHWLs on electroencephalograph (EEG) measures of motivated attention among two groups of smokers-those that report higher versus lower cigarette dependence. We hypothesized that both anxiety and disgust GHWLs would reduce appetitive attention, as indexed by lowered P300 (P3) and late positive potential (LPP) activations. Methods: Sixty-one smokers provided demographic and smoking history before completing an oddball paradigm consisting of three counterbalanced stimuli blocks. Each block (100 trials) contained a neutral, GHWL-anxiety, or GHWL-disgust frequent image and a smoking cue as the oddball image (20%). Oddball trials for each block were averaged, P3 and LPP were identified at midline electrode positions (Fz, Cz, and Pz), and mean amplitude was analyzed. Results: Separate mixed-model ANOVAs of P3 and LPP reactivity revealed disgust-focused GHWLs reduced motivated attentional processing. Conversely, the anxiety-focused GHWL appeared to increase the salience of the smoking cue (Fz only). Less-dependent smokers showed lower P3 reactivity than those with higher dependence at Fz, but greater P3 reactivity at Cz and Pz. Conclusion: These results extend prior work in demonstrating that disgust, but not anxiety-based GHWLs, may reduce EEG-assessed motivated attention to smoking cues. Disgust may thus represent a more fruitful target for public health cessation efforts. Implications: Most GHWL evaluations have focused on fear (or anxiety) elicitation rather than disgust, an emotion that may have a unique link to smoking, having evolved specifically to facilitate the avoidance of contaminants via oral incorporation. Analyses of P300 and LPP responses to GHWLs suggest that disgust-focused images interfere with the EEG-indexed attentional processing of smoking cues and do so better than health anxiety-focused messages. However, interaction effects at different electrode sites indicated that GHWLs have complex effects in more versus less-dependent smokers and that an understanding of how smoking cues and anti-smoking imagery become associated over time is needed to identify relevant targets for public health efforts.

Factors distinguishing important identified risks from important potential risks in orphan and nonorphan drugs: An analysis of safety specifications of Japan and European Union risk management plans.

PURPOSE: The purposes of the study are to compare safety specifications between Japan and the European Union (EU) and to identify the factors affecting categorization of important identified or potential risks. METHODS: Safety specifications were collected from orphan and nonorphan drugs approved in Japan between 2014 and 2016, and in the EU as of October 2017. Outcome was defined dichotomously as listed as important identified risks or potential risks. A mixed-effects logistic regression was performed to estimate odds ratios of being listed as important identified risks. RESULTS: This study included 20 orphan and 33 nonorphan drugs. The number of safety specifications per drug and the distribution of risk categories were significantly different between Japan and the EU regardless of orphan status. In orphan drugs, the occurrence of serious adverse events (AEs) during clinical trials for new drug applications was associated with a higher probability of being listed as important identified risks in Japan, while AE rate (%) was positively associated with being listed as important identified risks in the EU. For nonorphan drugs in Japan, AE occurring at a high rate, adverse drug reactions (ADRs) listed as important identified risks in EU risk management plans, and clinically significant ADRs known in similar drugs were likely to be listed as important identified risks, whereas a ≥1.4 risk ratio was associated with a higher probability of being listed as important identified risks in the EU. CONCLUSIONS: Factors affecting risk categories were different between Japan and the EU, which might contribute to the difference in safety specifications between these 2 regions.

Effect of European Medicines Agency's restrictions on trimetazidine utilization in Portugal.

PURPOSE: Following safety concerns regarding trimetazidine, the European Medicines Agency (EMA) recommended restrictions on its use. Our objective was to determine the impact of regulatory actions on trimetazidine utilization in Portugal. METHODS: Retrospective interrupted time-series analysis of monthly ambulatory pharmacy reimbursement records for the Portuguese National Health Service between January 2006 and December 2015. Regulatory actions were identified by searching the EMA, Portuguese Medicines Authority, and European Commission's websites. Concurrent factors in the same period were also identified. The main outcome was the dispensing of trimetazidine-containing products per month in Portugal. RESULTS: Two interruption periods were defined in the series: May 2011, when EMA announced it would review trimetazidine safety, and June 2012 to January 2013, when EMA announced it had reached a final opinion recommending restrictions; the European Commission approved EMA's recommendation; the Portuguese Medicines Authority issued safety alerts, changed the summary of product characteristics, and approved a direct health-care professional letter; and a regional bulletin was issued. Interruption 1 had no effect on trimetazidine use, but interruption 2 resulted in decreases in level and trend-from 8.3 million defined daily doses in 2010 to 2.8 million in 2015. After interruption 2, trimetazidine use tended towards a lower steady state. CONCLUSIONS: There was a significant decrease in trimetazidine use in Portugal following a complex intervention that included safety alerts, changes to the summary of product characteristics, a direct health-care professional letter, and a regional drug bulletin. No effect was seen when EMA announced its review of trimetazidine safety.

Do FDA label changes work? Assessment of the 2010 class label change for proton pump inhibitors using the Sentinel System's analytic tools.

PURPOSE: To pilot use of the US Food and Drug Administration's (FDA's) Sentinel System data and analytic tools by a non-FDA stakeholder through the Innovation in Medical Evidence Development and Surveillance system of the Reagan Udall Foundation. We evaluated the US FDA 2010 proton pump inhibitor (PPI) class label change that warned of increased risk of bone fracture, to use PPIs for the lowest dose and shortest duration, and to manage bone status for those at risk for osteoporosis. METHODS: The cohort consisted of adults aged 18 years or older prescribed PPIs without fracture risk factors. We evaluated incident and prevalent uses of the 8 PPIs noted in the label change. Outcomes evaluated before and after label change were PPI dispensing patterns, incident fractures, and osteoporosis screening or interventions. Consistent with FDA use of descriptive tools, we did not include direct comparisons or statistical testing. RESULTS: There were 1 488 869 and 2 224 420 incident PPI users in the before [PRE] and after [POST] periods, respectively. Users with 1 year or more of exposure decreased (8.4% vs 7.5%), as did mean days supplied/user (130.4 to 113.7 d among all users and 830.8 to 645.4 d among users with 1 y or more of exposure). Osteoporosis screening and interventions did not appear to increase, but the proportion of patients with fractures decreased (4.4% vs 3.1%). Prevalent user results were similar. CONCLUSIONS: This analysis demonstrated the ability to use Sentinel tools to assess the effectiveness of a label change and accompanying communication at the population level and suggests an influence on subsequent dispensing behavior.

Schedules of Controlled Substances: Temporary Placement of N-Ethylpentylone in Schedule I. Temporary amendment; temporary scheduling order.

The Acting Administrator of the Drug Enforcement Administration is issuing this temporary scheduling order to schedule the synthetic cathinone, 1- (1,3-benzodioxol-5-yl)-2-(ethylamino)- pentan-1-one (N-ethylpentylone, ephylone) and its optical, positional, and geometric isomers, salts, and salts of isomers in schedule I. This action is based on a finding by the Acting Administrator that the placement of Nethylpentylone in schedule I of the Controlled Substances Act (CSA) is necessary to avoid an imminent hazard to the public safety. As a result of this order, the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances will be imposed on persons who handle (manufacture, distribute, reverse distribute, import, export, engage in research, conduct instructional activities or chemical analysis, or possess), or propose to handle N-ethylpentylone.

Exclusive Drug Labeling Rights as a New Incentive for Contribution to a Communal Biomarker Resource.

Biomarkers are an important tool in modern drug development. The FDA has posited that increased use of biomarkers in clinical trials can accelerate pharmaceutical industry productivity, ushering new drugs to market. Accordingly, the FDA has created two pathways for evaluation of biomarker utility. Biomarkers incorporated into clinical trials, the traditional pathway, are effectively private to a therapeutic sponsor and to the scope of the trial. By contrast, in Biomarker Qualification ("BQ"), the second pathway, a biomarker is certified as a publicly available tool. The FDA has hoped that academic, non-profit, and industry stakeholders would work together in consortia to qualify biomarkers, cumulatively generating a common resource of broad utility. In practice, utilization of Biomarker Qualification has been paltry. Incentives for BQ that align with the interests of industry resource holders are necessary to fuel increased utilization of biomarkers in clinical trials and create the communal biomarker toolkit envisioned by the FDA. A blanket extension of exclusivity for any drug successfully paired with a companion biomarker would diminish public access to medicine by encouraging spurious biomarkers and correspondingly narrowed clinical trials. As a measured alternative, an exclusive right to include a qualified companion biomarker on an FDA drug label would balance public access externalities. This exclusivity would waylay label approval, and thus marketability, of later drugs relying on the qualified biomarker for clinical safety or efficacy. Accordingly, sponsors would find no incentive to portage an ineffective or unnecessary biomarker through clinical trials, as there would be no benefit to securing exclusive rights in a tool others saw no value in using.