How debunking biases in research and development decisions could lead to more equitable healthcare?

Decades of research have demonstrated that a variety of cognitive biases can affect our judgment and ability to make rational decisions in personal and professional environments. The lengthy, risky, and costly nature of pharmaceutical research and development (R&D) makes it vulnerable to biased decision-making. Moreover, cognitive biases can play a role in regulatory and clinical decision-making, the latter impacting diagnostic and treatment decisions in the therapeutic use of medicines. These inherent and/or institutionalized biases (e.g., in assumptions, data, or decision-making practices) could conceivably contribute to health inequities. In this mini-review, we provide a broad perspective on how cognitive biases can affect pharmaceutical R&D, regulatory evaluation, and therapeutic decision-making. Example approaches to mitigate the effect of common biases in the development, approval, and use of new therapeutics, such as quantitative decision criteria, multidisciplinary reviews, regulatory and treatment guidelines, and evidence-based clinical decision support systems are illustrated. Mitigating the impact of cognitive biases could increase pharma R&D efficiency, change the perspective and prioritization of unmet medical needs, increase representativeness and quality of evidence generated through clinical trials and real-world research, leading to higher quality insights and more effective medication use, and as such could eventually contribute to more equitable healthcare.

Using Machine Learning to Determine a Suitable Patient Population for Anakinra for the Treatment of COVID-19 Under the Emergency Use Authorization.

A randomized, double-blind, placebo-controlled study (SAVEMORE trial) provided data to support an Emergency Use Authorization (EUA) of anakinra in hospitalized adults with positive results of direct severe acute respiratory syndrome-coronavirus 2 viral testing with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR). Currently, the suPAR assay is not commercially available in the United States. An alternative method was needed to identify patients that best reflect the population in the clinical trial selected based on suPAR level ≥ 6 ng/mL at baseline. A machine learning approach based on data from the SAVEMORE trial was used to develop a scoring rule to identify patients who are likely to have a suPAR level ≥ 6 ng/mL at baseline. External validation of the scoring rule was conducted with data from a different trial (SAVE). This clinical scoring rule with high positive predictive value, high specificity, reasonable sensitivity, and biological relevance is expected to identify patients who are likely to have an elevated suPAR level ≥ 6 ng/mL at baseline. As such, it is included in the EUA to identify patients that fall within the authorized population for whom the known and potential benefits outweigh the known and potential risks of anakinra.

Statin Drug-Drug Interactions: Pharmacokinetic Basis of FDA Labeling Recommendations and Comparison Across Common Tertiary Clinical Resources.

Statins are widely prescribed and highly susceptible to pharmacokinetic (PK)-based drug-drug interactions (DDIs). To date, there has not been a comprehensive analysis of the basis upon which statin DDI recommendations in US Food and Drug Administration (FDA) prescribing information (PI) are derived. We have conducted such an analysis. We also assessed the degree of concordance of statin DDI recommendations in FDA PI and those provided in common tertiary clinical resources. We catalogued statin DDI information, including PK data and management recommendations, for statin precipitant drugs approved from 2010 to 2021, available from FDA PI and tertiary clinical resource databases. Recommendations were categorized and mapped with associated PK data to assess consistency in the PK basis for labeling recommendations. From the 80 precipitant drugs evaluated, 180 statin DDIs were identified in FDA PI. Dedicated clinical DDI studies were conducted for 54% (n = 97) of these DDIs and 34% (n = 61) of DDI recommendations were extrapolated from clinical data with other statins. Overall, we found that PK-based statin recommendations were consistent across PI. These findings highlight regulatory precedence for translating information across statins without conducting dedicated clinical DDI studies, which may support future efforts toward streamlining the approach to investigation and labeling of statin DDIs. In addition, with the exception of some notable discrepancies, general concordance was observed between FDA and tertiary resources regarding "Dose Adjustment" and "Avoid Coadministration" recommendations. However, further analyses are warranted across other DDI pairs to determine whether discordance can routinely lead to different clinical recommendations depending on the drug information resource.

Intranasal Naloxone Repeat Dosing Strategies and Fentanyl Overdose: A Simulation-Based Randomized Clinical Trial.

Importance: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl). Objective: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose. Design, Setting, and Participants: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023. Intervention: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference). Main Outcomes and Measures: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics. Results: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes. Conclusions and Relevance: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting. Trial Registration: ClinicalTrials.gov Identifier: NCT04764630.

Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins.

Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model-informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK-based bridging) or pharmacodynamic (PD) responses (PD-based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK- and PD-based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate.

A Multistakeholder Perspective on Advancing Individualized Therapeutics.

Precision medicine has evolved from the application of pharmacogenetic biomarkers to the prospective development of targeted therapies in patients with specific molecular/genetic subtypes of disease to truly "N-of-1" medicines targeted to very small numbers of patients - in some cases, a single identified patient. This latter iteration of precision medicine presents unprecedented opportunities for patients with severe, life-threatening, or life-limiting diseases. At the same time, these modalities present complex scientific, clinical, and regulatory challenges. To realize the promise of individualized medicines, a multistakeholder approach to streamlining medical diagnoses, advancing the technologies that enable development of these therapeutic modalities, and re-envisioning collaborative environments for access and evidence generation is of critical importance. Herein, we highlight some of these challenges and opportunities.

US FDA Postmarketing Requirements and Commitments: A Systematic Assessment of Clinical Pharmacology Studies and Their Impact on US FDA Prescribing Information.

Many of the conditions for the safe and effective use of new molecular entities (NMEs) are understood at the time of initial drug approval. However, some remaining knowledge gaps can be addressed after drug approval through postmarketing requirements (PMRs) or commitments (PMCs) established by the US Food and Drug Administration (FDA). Our objective was to conduct an assessment of clinical pharmacology-related PMRs and PMCs established at the time of approval and evaluate the impact of fulfilled PMRs and PMCs on prescription information (PI). This analysis included clinical pharmacology-related PMRs and PMCs established for NMEs approved between 2009 and 2020. Of the 1171 PMRs and PMCs, over one-third were clinical pharmacology-related. Of these, 46% were to evaluate drug interactions, 16% were to evaluate drug dosing in patients with hepatic impairment, and 10% were related to dose. The majority (57%) of PMRs and PMCs were fulfilled at the time of analysis, with a median time to fulfillment of approximately 2.3 years. The majority (94%) of the fulfilled PMRs and PMCs, either with or without a PI revision, resulted in new or modified instructions for use or supported existing instructions for use. This is the first time that clinical pharmacology-related PMRs and PMCs have been catalogued and analyzed to understand their impact on PI. An understanding of the knowledge gaps that exist at the time of drug approval could inform the most effective and efficient methods for evidence generation prior to and after new drug approval.

Model-Based Approach to Selecting Pegfilgrastim Dose for Pharmacokinetic and Pharmacodynamic Similarity Studies in Biosimilar Development.

This study applied modeling and simulation (M&S) approaches to evaluate the sensitivity of pegfilgrastim pharmacokinetics (PKs) and pharmacodynamics (PDs) to changes in dose amount, and linear or nonlinear clearance (CL) over pegfilgrastim subcutaneous dose of 2-6 mg. A previously published model was adapted to better describe pegfilgrastim PK and PD data in healthy subjects and used in simulation. Nonlinear CL accounts for 98% and 77%, respectively, of the total CL of pegfilgrastim at 2 and 6 mg. The sensitivity analyses showed: (i) PK of 2 and 6 mg doses are similarly sensitive to detect differences for a 5% change in dose; (ii) PK of 2 mg dose is more sensitive to changes in receptor binding affinity, a model parameter for nonlinear CL, and a product quality attribute characterized with orthogonal methods as part of demonstrating analytical similarity between products; (iii) PK of approved 6 mg dose is more sensitive to changes in linear CL, which has not been associated with any specific product quality attributes, and (iv) the PDs are not sensitive to changes in linear or nonlinear CL. Taken together, our analyses support that the approved pegfilgrastim dose of 6 mg is appropriate for detecting differences between a biosimilar and the reference products in pegfilgrastim PK and PD similarity studies. The described M&S approaches can be adopted to support dose selection for biosimilars with nonlinear PK and complex PK-PD interplay.

Pharmacodynamic Biomarkers Evidentiary Considerations for Biosimilar Development and Approval.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from a US Food and Drug Administration (FDA)-approved reference product. The development and approval of biosimilars is critical to enhancing the availability of safe, effective, and affordable treatment options for patients. Utilization of pharmacodynamic (PD) biomarkers can help streamline biosimilar development programs as the current process can be costly and time-consuming. Whereas PD biomarkers have not been prominently used across biosimilar approvals to date, moving forward, there is ample opportunity to increase the use of PD biomarkers in biosimilar development programs in place of comparative clinical studies with efficacy end point(s). This includes utilizing PD biomarkers that were not used as surrogate end points in approval of reference products. This mini-review summarizes how PD biomarkers have been used in biosimilar development programs to date and then discusses evidentiary considerations for PD biomarkers. In addition, study design considerations for clinical pharmacokinetic and PD assessment of proposed biosimilars are discussed. Finally, the FDA's applied regulatory science activities related to PD biomarkers for biosimilars conducted in support of the FDA's Biosimilars Action Plan are reviewed. This included conducting three clinical studies to address information gaps about PD biomarkers for biosimilars and inform general methodological best practices. In summary, enhancing our understanding of key evidentiary considerations and optimal study designs for incorporating PD biomarkers in the evaluation of proposed biosimilars can help bring more treatment options to patients faster.

Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development - (I) A Randomized Trial with PCSK9 Inhibitors.

US Food and Drug Administration (FDA) guidance outlines how biosimilars can be developed based on pharmacokinetic (PK) and pharmacodynamic (PD) similarity study data in lieu of a comparative clinical efficacy study. There is a paucity of PD comparability studies in biosimilar development, leaving open questions about how best to plan these studies. To that end, we conducted a randomized, double-blinded, placebo-controlled, single-dose, parallel-arm clinical study in healthy participants to evaluate approaches to address information gaps, inform analysis best practices, and apply emerging technologies in biomarker characterization. Seventy-two healthy participants (n = 8 per arm) received either placebo or one of four doses of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors alirocumab (15-100 mg) or evolocumab (21-140 mg) to evaluate the maximum change from baseline (ΔPDmax ) and the baseline-adjusted area under the effect curve (AUEC) for the biomarkers low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in serum. We investigated approaches to minimize variability in PD measures. Coefficient of variation was lower for LDL-C than apoB at therapeutic doses. Modeling and simulation were used to establish the dose-response relationship and provided support that therapeutic doses for these products are adequately sensitive and are on the steep part of the dose-response curves. Similar dose-response relationships were observed for both biomarkers. ΔPDmax plateaued at lower doses than AUEC. In summary, this study illustrates how pilot study data can be leveraged to inform appropriate dosing and data analyses for a PK and PD similarity study.

Concentration-Response Model of Immediate Release Oxycodone Drug Liking by Different Routes of Abuse.

OBJECTIVE: To understand the correlation between oxycodone concentration and drug liking response for immediate-release formulations as they relate to different doses and different routes of administration following manipulation involved in opioid misuse and nontherapeutic use. METHODS: Concentration-response and noncompartmental analyses of drug liking and plasma oxycodone data from Category 3 human abuse potential studies (n = 15-29 per study) were conducted, using Phoenix 6.0 software. Time to onset of a set threshold of subjective effects (Tonset) and offset of subjective effects (Toffset) were estimated based on a baseline pharmacodynamic response set at 50 on a bipolar Drug Liking visual analog scale of 0-100 and the threshold for drug liking set at ≥65, based on study qualification criteria. Partial Area Under the Concentration (AUCTonset-Toffset) and Effect (AUETonset-Toffset) profiles were calculated and their correlation with individual partial AUE vs partial AUC was assessed. RESULTS: The oxycodone concentration-response (drug liking) was best described by a sigmoidal-effect Emax model (S-shaped). Using a defined threshold, drug liking was closely associated with the rate of rise in concentration and the onset of action for oxycodone administered via oral or intranasal route. Partial AUCTonset-Toffset and AUETonset-Toffset showed a strong linear correlation. CONCLUSIONS: Results indicate that oxycodone concentration-response and duration of drug liking following manipulation via different routes of administration may be an approach for further exploring drug liking effects of opioids.

Association of partial systemic exposure and abuse potential for opioid analgesics with abuse deterrence labeling claims supporting product-specific guidance.

BACKGROUND: Over the past decade, U.S. FDA has approved 10 opioid analgesics in abuse-deterrent formulations (ADFs). ADFs are intended to reduce abuse of a prescription opioid through manipulation of the product to use one or more routes of abuse. Although it is critically needed for evaluation of the abuse deterrent properties of an opioid product, the relationship between systemic exposure and likelihood of abuse of the opioid has not been fully characterized. To fill the current knowledge gap, we have evaluated the association of subjective measures predictive of abuse potential (e.g., scores of "drug liking," "take drug again"), which are referred to as 'pharmacodynamic (PD)' responses for measuring abuse potential, with systemic exposure of the opioid using the data from all the clinical abuse potential trials submitted to FDA in support of the approval of innovator ADFs. METHODS: Extensive pharmacokinetic (PK) and subjective response data from 11 clinical abuse potential trials in recreational opioid users following oral and nasal administration of intact and manipulated oxycodone, hydrocodone and morphine products from the FDA internal database were utilized for the present analysis. This retrospective study used data collected from January 11th, 2010 until March 25th, 2015. The potential relationship between PK metrics, especially those for early exposure measures, and the subjective measures of drug liking and take drug again as PD metrics of abuse potential were explored using linear and logistic regression analyses. Heterogeneity analysis was conducted to assess study-to-study variation and multi-level logistic regression analysis was used to affirm the identified PK-PD relationship based on pooled data. FINDINGS: Following oral and nasal administration of intact and manipulated opioids, the maximum visual analogue scale (VAS) for Drug Liking was generally achieved no later than the time to peak plasma drug concentration. Both heterogeneity analysis and multi-level logistic regression indicated insignificant inter study variability for the evaluated PK-PD relationships. Duration of Drug Liking response (i.e., VAS ≥ 65) lasted for 2 to 4 h after drug administration. The early portion of the systemic area under the plasma concentration-time curve (AUC), e.g., partial AUCs in the first 3 h and 4 h were found to be associated with abuse potential measures including maximum Drug Liking VAS and maximum Taking Drug Again VAS. Neither a formulation factor (e.g., immediate-release vs. extended-release, intact vs. manipulated) nor a route of administration was identified as a significant factor together with early partial AUCs to predict the probability of maximum Drug Liking or maximum Take Drug Again responses being greater than or equal to 65. INTERPRETATION: Our assessment indicates that the measure of early systemic drug exposure of opioids is the best predictor of the abuse potential response in recreational opioid users following oral or nasal administration of a single dose of an intact or manipulated abuse deterrent opioids. Our findings support FDA's recommendation of comparative PK studies with early partial AUCs as a supportive PK metric for the assessment of abuse deterrent properties of generic opioid drug products in the general and product-specific guidance's of ADFs. FUNDING: The study was partially funded by Fiscal Year 2017 Critical Path of the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration.

Evaluating Patients With Impaired Renal Function During Drug Development: Highlights From the 2019 US FDA Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting.

Patients with multiple chronic conditions, including more advanced chronic kidney disease (CKD), are often excluded from clinical trials, creating challenges in deriving appropriate dosing information and labeling. This article summarizes the May 7, 2019, US Food and Drug Administration Pharmaceutical Science and Clinical Pharmacology Advisory Committee Meeting, which solicited expert opinions on how to enroll patients with more advanced CKD into clinical trials as well as the assumptions behind and different approaches of exposure-matching.

A Systematic Assessment of US Food and Drug Administration Dosing Recommendations For Drug Development Programs Amenable to Response-Guided Titration.

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end-of-phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response-guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA-sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.