Use of US Food and Drug Administration Expedited Drug Development and Review Programs by Orphan and Nonorphan Novel Drugs Approved From 2008 to 2021.

Importance: The US Food and Drug Administration (FDA) has 4 programs that can be used alone or in combination to expedite drug availability: Accelerated Approval, Breakthrough Therapy, Fast Track, and Priority Review. Drugs using these programs can include novel drugs, which do not contain a previously FDA-approved active moiety, and orphan drugs, intended for diseases or conditions affecting fewer than 200 000 people; to date, no comprehensive evaluation of how these programs have been used in combination has been published. Objective: To assess how often and in what combinations expedited programs are used in the development and review of approved novel biologics and small-molecule drugs, stratified by orphan drug status and indication. Design, Setting, and Participants: This cross-sectional study evaluated all novel drugs that were FDA approved between January 1, 2008, and December 31, 2021. Main Outcomes and Measures: The main outcome was the frequency with which expedited programs were used and in what combinations, stratified by orphan drug status and drug type (small molecule vs therapeutic biologic). The unit of analysis was the novel drug-indication pair because a drug can be approved for multiple indications, each of which may use a different expedited program or differ in orphan drug status. Results: The study included 581 novel drug-indication pairs approved during the 14-year study period; 252 (43.4%) were orphan drugs, 139 (23.9%) were therapeutic biologics, and 442 (76.1%) were small-molecule drugs. Use of at least 1 expedited program increased from 11 of 26 drug-indication pairs (42.3%) in 2008 to 41 of 55 (74.5%) in 2021. Of the 363 approved drug-indication pairs using at least 1 expedited program, 225 (62.0%) were orphan drugs; at least 1 expedited program was used by 97 of the 139 approved biologic drugs (69.8%) and by 266 of the 442 approved small-molecule drugs (60.2%). Eighty-two of the 581 novel drug-indication pairs (14.1%) used the Accelerated Approval Program; of those, 65 (79.3%) were oncology drugs and 70 (85.4%) had an orphan designation. Conclusions and Relevance: The study showed that use of the FDA's expedited programs to bring novel drugs to market in the US increased from 2008 to 2021. The findings suggest that this trend is likely to continue.

Participation of Older Adults in Clinical Trials for New Drug Applications and Biologics License Applications From 2010 Through 2019.

Importance: Older age may be accompanied by changes in the pharmacokinetics or pharmacodynamics or both of medications that can result in altered safety and efficacy profiles. Objective: To assess representation of older adults in clinical trials of new drug applications (NDAs) and biologics license applications (BLAs). Design, Setting, and Participants: This cross-sectional study analyzed US Food and Drug Administration (FDA) data for NDAs and BLAs approved from 2010 through 2019. Age distribution of clinical trial participants was compared with age distribution of the US population with the disease or disorder (prevalent population). Data were from adults enrolled in registration trials for depression, heart failure, insomnia, non-small cell lung cancer (NSCLC), nonvalvular atrial fibrillation (NVAF) stroke prevention, osteoporosis, and type 2 diabetes or adults sampled from US prevalent population in community-dwelling health data. Data were analyzed from November 2020 to February 2021. Exposures: Trial enrollment. Main Outcomes and Measures: Representativeness of trial populations was assessed by the participation to prevalence ratio (PPR) defined as the percentage of patients by age group among clinical trial participants to the percentage of patients by age group among US prevalent population. Results: Data from 166 clinical trials (229 558 participants) for 44 NDAs and BLAs were analyzed. The most consistent finding was the limited enrollment of the oldest age groups, namely those 75 years and above for type 2 diabetes and NSCLC, and 80 years and above for NVAF stroke prevention, insomnia, heart failure, and osteoporosis. Adults aged 60 to 74 years were enrolled in equal or greater proportion than the US prevalent population. Conclusions and Relevance: In this cross-sectional study, underrepresentation of the oldest adults existed during evaluation of new drugs and biologics, yet the older adults may represent significant proportions of the treatment population. Closing the representation gap between clinical trial enrollment and potential treatment populations is essential for safe and effective use of new drugs and biologics.

Effect of Mailing Educational Material to Patients With Atrial Fibrillation and Their Clinicians on Use of Oral Anticoagulants: A Randomized Clinical Trial.

Importance: Only about half of patients with atrial fibrillation (AF) who are at increased risk for stroke are treated with an oral anticoagulant (OAC), despite guideline recommendations for their use. Educating patients with AF about prevention of stroke with OACs may enable them as agents of change to initiate OAC treatment. Objective: To determine whether an educational intervention directed to patients and their clinicians stimulates the use of OACs in patients with AF who are not receiving OACs. Design, Setting, and Participants: The Implementation of a Randomized Controlled Trial to Improve Treatment With Oral Anticoagulants in Patients With Atrial Fibrillation (IMPACT-AFib) trial was a prospective, multicenter, open-label, pragmatic randomized clinical trial conducted from September 25, 2017, to May 1, 2019, embedded in health plans that participate in the US Food and Drug Administration's Sentinel System. It used the distributed database comprising health plan members to identify eligible patients, their clinicians, and outcomes. IMPACT-AFib enrolled patients with AF, a CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) score of 2 or more, no evidence of OAC prescription dispensing in the preceding 12 months, and no hospitalization-related bleeding event within the prior 6 months. Interventions: Randomization to a single mailing of patient and/or clinician educational materials vs control. Main Outcomes and Measures: Analysis was performed on a modified intention-to-treat basis. The primary end point was the proportion of patients with at least 1 OAC prescription dispensed or at least 4 international normalized ratio test results within 1 year of the intervention. Results: Among 47 333 patients, there were 24 909 men (52.6%), the mean (SD) age was 77.9 (9.7) years, mean (SD) CHA2DS2-VASc score was 4.5 (1.7), 22 404 patients (47.3%) had an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more, and 8890 patients (18.8%) had a history of hospitalization for bleeding. There were 2328 of 23 546 patients (9.9%) in the intervention group with initiation of OAC at 1 year compared with 2330 of 23 787 patients (9.8%) in the control group (adjusted OR, 1.01 [95% CI, 0.95-1.07]; P = .79). Conclusions and Relevance: Among a large population with AF with a guideline indication for OACs for stroke prevention who were randomized to a mailed educational intervention or to usual care, there was no clinically meaningful, numerical, or statistically significant difference in rates of OAC initiation. More-intensive interventions are needed to try and address the public health issue of underuse of anticoagulation for stroke prevention among patients with AF. Trial Registration: ClinicalTrials.gov Identifier: NCT03259373.

Roadmap to 2030 for Drug Evaluation in Older Adults.

Changes that accompany older age can alter the pharmacokinetics (PK), pharmacodynamics (PD), and likelihood of adverse effects (AEs) of a drug. However, older adults, especially the oldest or those with multiple chronic health conditions, polypharmacy, or frailty, are often under-represented in clinical trials of new drugs. Deficits in the current conduct of clinical evaluation of drugs for older adults and potential steps to fill those knowledge gaps are presented in this communication. The most important step is to increase clinical trial enrollment of older adults who are representative of the target treatment population. Unnecessary eligibility criteria should be eliminated. Physical and financial barriers to participation should be removed. Incentives could be created for inclusion of older adults. Enrollment goals should be established based on intended treatment indications, prevalence of the condition, and feasibility. Relevant clinical pharmacology data need to be obtained early enough to guide dosing and reduce risk for participation of older adults. Relevant PK and PD data as well as patient-centered outcomes should be measured during trials. Trial data should be analyzed for differences in PK, PD, effectiveness, and safety arising from differences in age or from the presence of conditions common in older adults. Postmarket evaluations with real-world evidence and drug labeling updates throughout the product lifecycle reflecting new knowledge are also needed. A comprehensive plan is needed to ensure adequate evaluation of the safety and effectiveness of drugs in older adults.

U.S. racial and ethnic participation in global clinical trials by therapeutic areas.

WHAT IS KNOWN AND OBJECTIVE: The discussion about health equity in the United States frequently involves concerns over racial and ethnic minority under-representation in clinical trials and particularly in trials conducted in support of product approvals. The FDA has long worked to encourage diverse participation in clinical trials and through its Drug Trials Snapshots (DTS) program, the U.S. Food and Drug Administration (FDA) has moved to make trial demographic data more accessible and transparent. We conducted a demographic study of U.S. participants in clinical trials for FDA-approved new drugs (new molecular entities [NMEs], and original Biologics License Applications [BLAs]) from 2015 to 2019, as reported in DTS database with a purpose of understanding the extent to which U.S.-based trials used to support product approvals represent the racial and ethnic diversity of the U.S. population by therapeutic area. METHODS: Participant-level trial data were collected by accessing the FDA electronic common technical document (eCTD), for the applications used to publish each Snapshot. The therapeutic area (TA) for each drug was determined by review division assignment. The demographic data were analysed and compared to U.S. census data. RESULTS AND DISCUSSION: We examined 102,596 U.S. participants in trials of new drugs that were approved and presented in Drug Trials Snapshots between 2015 and 2019. White participation ranged from 51% in psychiatric trials to 90% in cardiovascular (CV) trials; Black or African American participation ranged from 5% in medical imaging to 45% in psychiatric trials; Asian participation ranged from 0.75% in CV to 4% in dermatologic trials; and Hispanic or Latino participation ranged from 1% in medical imaging to 22% in infectious diseases and gastroenterology trials. WHAT IS NEW AND CONCLUSION: Our data showed variable representation of racial and ethnic minorities across therapeutic areas at the U.S. sites. Blacks or African Americans were represented at or above U.S. census estimates across most therapeutic areas, while Asians and American Indian or Alaska Natives were consistently underrepresented. Hispanic or Latino participation across most therapeutic areas was below U.S. census estimates, however, more variable, and a sizable proportion of data was missing. The next step is a comparison of trial participation based on disease prevalence and epidemiology, which is a more accurate assessment of trial diversity.

Encouragement of subgroup assessment by the FDA.

Responses to a drug treatment can differ among subgroups of the population, including demographic subgroups, groups with different disease characteristics, and groups with different metabolic or excretory functions. The differences can be pharmacokinetic (PK) or pharmacodynamic (PD) affecting toxicity or effectiveness. In recent years wide availability of drug blood level data, including metabolite data, has made PK differences in subgroups very readily detectable, but PD differences are more difficult to detect and need to be carefully examined by assessment of effectiveness and toxicity in demographic and other subgroups, as illustrated by the forest plots examining multiple subgroups typically presented for cardiovascular outcome studies. Such examinations and presentations would probably be more broadly useful and informative if used to examine pooled outcome and toxicity data for symptomatic treatments.

Contents of US Food and Drug Administration Refuse-to-File Letters for New Drug Applications and Efficacy Supplements and Their Public Disclosure by Applicants.

Importance: Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts "filing reviews" to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown. Objectives: To quantitatively analyze the FDA's reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents. Design and Setting: This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019. Main Outcomes and Measures: Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA's refusal reasons were also assessed. Results: The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters. Conclusions and Relevance: This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants' disclosure of those reasons was incomplete. This work sheds light on the FDA's regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.

The efficient Lamarckian spread of life in the cosmos.

In this Chapter we discuss the various mechanisms that are available for the possible transfer of cosmic microbial living systems from one cosmic habitat to another. With the 100 or so habitable planets that are now known to exist in our galaxy alone transfers of cometary dust carrying life including fragments of icy planetoids/asteroids would be expected to occur on a routine basis. It is thus easy to view the galaxy as a single connected "biosphere" of which our planet Earth is a minor component. The Hoyle-Wickramasinghe Panspermia paradigm provides a cogent biological rationale for the actual widespread existence of Lamarckian modes of inheritance in terrestrial systems (which we review here). Thus the Panspermia paradigm provides the raison d'etre for Lamarckian Inheritance. Under a terrestrially confined neoDarwinian viewpoint such an association may have been thought spurious in the past. Our aim here is to outline the main evidence for rapid terrestrial-based Lamarckian-based evolutionary hypermutation processes dependent on reverse transcription-coupled mechanisms among others. Such rapid adaptation mechanisms would be consistent with the effective cosmic spread of living systems. For example, a viable, or cryo-preserved, living system traveling through space in a protective matrix will of necessity need to adapt rapidly and proliferate on landing in a new cosmic niche. Lamarckian mechanisms thus come to the fore and supersede the slow (blind and random) genetic processes expected under neoDarwinian Earth centred theories.

Experiments to prove continuing microbial ingress from Space to Earth.

A wide range of evidence for pointing to our cosmic origins is close to the point of being overwhelming. Yet the long-entrenched paradigm of Earth-centered biology appears to prevail in scientific culture. A matter of crucial importance is to carry out a decisive experiment that is long overdue-establishing empirically beyond any doubt that extraterrestrial microbiota reaches the surface of the Earth at the present day. Such an experiment may of course happen naturally by the appearance of pandemics of new disease as discussed in an earlier chapter.

Origin of new emergent Coronavirus and Candida fungal diseases-Terrestrial or cosmic?

The origins and global spread of two recent, yet quite different, pandemic diseases is discussed and reviewed in depth: Candida auris, a eukaryotic fungal disease, and COVID-19 (SARS-CoV-2), a positive strand RNA viral respiratory disease. Both these diseases display highly distinctive patterns of sudden emergence and global spread, which are not easy to understand by conventional epidemiological analysis based on simple infection-driven human- to-human spread of an infectious disease (assumed to jump suddenly and thus genetically, from an animal reservoir). Both these enigmatic diseases make sense however under a Panspermia in-fall model and the evidence consistent with such a model is critically reviewed.

Classification of aerosol-generating procedures: a rapid systematic review.

In the context of covid-19, aerosol generating procedures have been highlighted as requiring a higher grade of personal protective equipment. We investigated how official guidance documents and academic publications have classified procedures in terms of whether or not they are aerosol-generating. We performed a rapid systematic review using preferred reporting items for systematic reviews and meta-analyses standards. Guidelines, policy documents and academic papers published in english or french offering guidance on aerosol-generating procedures were eligible. We systematically searched two medical databases (medline, cochrane central) and one public search engine (google) in march and april 2020. Data on how each procedure was classified by each source were extracted. We determined the level of agreement across different guidelines for each procedure group, in terms of its classification as aerosol generating, possibly aerosol-generating, or nonaerosol-generating. 128 documents met our inclusion criteria; they contained 1248 mentions of procedures that we categorised into 39 procedure groups. Procedures classified as aerosol-generating or possibly aerosol-generating by ≥90% of documents included autopsy, surgery/postmortem procedures with high-speed devices, intubation and extubation procedures, bronchoscopy, sputum induction, manual ventilation, airway suctioning, cardiopulmonary resuscitation, tracheostomy and tracheostomy procedures, non-invasive ventilation, high-flow oxygen therapy, breaking closed ventilation systems, nebulised or aerosol therapy, and high frequency oscillatory ventilation. Disagreements existed between sources on some procedure groups, including oral and dental procedures, upper gastrointestinal endoscopy, thoracic surgery and procedures, and nasopharyngeal and oropharyngeal swabbing. There is sufficient evidence of agreement across different international guidelines to classify certain procedure groups as aerosol generating. However, some clinically relevant procedures received surprisingly little mention in our source documents. To reduce dissent on the remainder, we recommend that (a) clinicians define procedures more clearly and specifically, breaking them down into their constituent components where possible; (b) researchers undertake further studies of aerosolisation during these procedures; and (c) guideline-making and policy-making bodies address a wider range of procedures.

Endpoints in Heart Failure Drug Development: History and Future.

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients.

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

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

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

Nonrandomized Real-World Evidence to Support Regulatory Decision Making: Process for a Randomized Trial Replication Project.

Recent legislation mandates that the US Food and Drug Administration issue guidance regarding when real-world evidence (RWE) could be used to support regulatory decision making. Although RWE could come from randomized or nonrandomized designs, there are significant concerns about the validity of RWE assessing medication effectiveness based on nonrandomized designs. We propose an initiative using healthcare claims data to assess the ability of nonrandomized RWE to provide results that are comparable with those from randomized controlled trials (RCTs). We selected 40 RCTs, and we estimate that approximately 30 attempted replications will be completed after feasibility analyses. We designed an implementation process to ensure that each attempted replication is consistent, transparent, and reproducible. This initiative is the first to systematically evaluate the ability of nonrandomized RWE to replicate multiple RCTs using a structured process. Results from this study should provide insight on the strengths and limitations of using nonrandomized RWE from claims for regulatory decision making.

Technology-Enabled Clinical Trials: Transforming Medical Evidence Generation.

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.