Registering Clinical Trial Results

Cardiovascular disease (CVD) is the most common cause of death in American women and accounts for a full one-third of all deaths.1 Although the common perception may be that CVD affects mainly men, there is equal prevalence of this disease between the genders by the age of 40, and by the age of 60 more women than men are affected. More women than men have died from CVD causes on a yearly basis since the mid 1980s, and whereas the CVD mortality has steadily declined in men over the past 30 years, it has remained steady in women until very recently when CVD mortality was noted to decrease for both genders.2 See accompanying article on page 277 The impact of cardiovascular disease (CVD) on the health status of American women is gaining more recognition and has become the focus of public education efforts such as the “Go Red for Women” campaign sponsored by the American Heart Association and the “Red Dress” project sponsored by the Department of Health and Human Services, the National Institutes of Health (NIH), and the National Heart Lung and Blood Institute (NHLBI). These programs are, in part, a response to the increasing awareness of cardiovascular disease as a major source of morbidity and mortality in U.S. women. The importance of CVD as a major source of mortality in women was recognized early on by federally funded institutes including the Public Health Service Task Force, which brought attention to concerns about the health information available to women and the historical lack of research focus on women’s health in its 1985 Report of the Public Health Service Task Force on Women’s Health Issues .3 In response to this report, the National Institutes of Health adopted a policy for the inclusion of women in clinical research …

In their editorial entitled “Pediatric Research and Scholarship,” Tobin et al. (1) question whether the Food and Drug Administration (FDA) has taken an acceptably proactive role in efforts to encourage high quality clinical trials of drugs in the pediatric patient population when those studies are performed by individual academic investigators. In particular, they question the obligation of academic investigators to abide by federal regulations when conducting small clinical trials with drugs not yet approved for the pediatric population. In response, we will review the role of the FDA in clinical research conducted by individual academic investigators, summarize recent progress in pediatric drug development, and offer suggestions to academic investigators who wish to perform these types of drug trials. FDA: THE INVESTIGATIONAL NEW DRUG (IND) APPLICATION Most investigational use of drugs is subject to the IND regulations. While these clearly apply to unapproved new drugs, in certain circumstances, federal regulations require that a protocol utilizing an approved drug product must be reviewed by the FDA before a clinical drug trial may proceed. The FDA Web site offers guidance to investigators to help them determine when their proposed study will require FDA review (http://www.fda.gov/cder/guidance/phase1.pdf). When FDA review of a protocol is required, the investigator must submit an IND application. FDA review is always required when the intent of an investigation is to change a product’s label, such as to permit the product’s use in a new, potentially more vulnerable population. For example, the novel use of a product in pediatric patients would require a pharmaceutical company to perform all clinical research under an IND. However, even in the setting of a small-scale academic investigation, an IND would likely be required in a vulnerable population such as pediatric patients, whether or not there is common off-label use of this drug in the pediatric population. If an investigator is uncertain whether an IND application is necessary, he or she should contact the FDA for advice prior to initiating subject recruitment. When an IND application is required, the FDA review process can benefit the investigator and reduce the risk to subjects participating in the clinical study. For example, if there is preliminary evidence that a particular drug is associated with organ toxicity in an animal model of growth and development, the FDA may be able to advise the IND applicant how to safely monitor patients, and provide this information without compromising proprietary work by other investigators. Furthermore, because the FDA is often aware of trials that have failed, the agency can advise an IND applicant when the risk of planned research exceeds the putative benefit. Academic investigators who are not expert in conducting clinical drug research can also receive assistance in developing an appropriate trial design based on FDA experience in the evaluation of previously completed trials (2–4). In contradistinction to statements by Tobin et al. (1), the FDA clearly recognizes the utility of alternative designs to placebo-controlled trials (CFR 314.126) when appropriate. The review of an IND application is conducted by a team consisting of chemists, nonclinical pharmacologists/toxicologists, clinical pharmacologists, statisticians, and physicians, concluding with a determination of whether or not the trial is considered safe to proceed. This process is typically completed within 30 days. When a clinical trial that required an IND review has been conducted without FDA approval, the FDA Division of Scientific Investigations may perform an evaluation at the research site to assess the potential risk that was incurred by subjects during that study. In such cases, the FDA evaluation of the trial and any subsequent regulatory action do not depend on whether the trial data have been or will be published in the medical literature. The magnitude of the risk to research subjects is incorporated into the assessment and can result in a legal action when appropriate. PROGRESS IN PEDIATRIC DRUG DEVELOPMENT Most medications are initially studied and approved in the adult population, which is appropriate given the unknowns of safety and efficacy during initial development. However, this means that children are often treated off-label with these medications prior to the development of well-controlled clinical trials in the pediatric population. Consequently, physicians rely on extrapolating adult experience and on anecdotal information to determine safety and effectiveness of many medications for the treatment of pediatric patients. Congress has enacted several laws intended to directly promote drug development for the pediatric population. These measures have increased the amount of information on the safe and efficacious use of drugs for pediatric patients. The first law, passed in 1997, was the Food and Drug Administration Modernization Act (FDAMA). FDAMA offered pharmaceutical companies a 6-month period of marketing exclusivity if they performed studies in pediatric patients in response to a Written Request (WR) issued by the FDA. Marketing exclusivity incentives attach to a period of existing patent protection or exclusivity and were effective in prompting industry to conduct needed pediatric trials for drugs with existing patent protection or exclusivity. This program did not provide an incentive for the study of off-patent, mostly generic, drugs. The Best Pharmaceuticals for Children Act (BPCA) was signed into law on January 4, 2002, shortly after the pediatric exclusivity provision of FDAMA expired on January 1, 2002. The BPCA reauthorizes the exclusivity incentive enacted originally in FDAMA. Further, section 409I(a)(2) of the BPCA provides a process for the study of off-patent drugs (approved drugs that have no remaining patent protection or exclusivity). This law directs the National Institute of Health (NIH), in consultation with the FDA and experts in pediatric research, to develop and prioritize a list of “off-patent” drugs for which pediatric studies are most urgently needed. The list was originally published in January 2003 and is updated at least annually. WRs for pediatric studies will be issued by the FDA for drugs on the priority list requiring studies to develop adequate pediatric labeling. In turn, the NIH will issue contracts for the studies. Once the trials are performed and the results are analyzed, the data become publicly available for dissemination and incorporation into the label (http://www.fda.gov/cder/pediatric/70FR3937.txt). Since the inception of FDAMA and BPCA, over 450 proposed pediatric study requests from industrial sponsors have been received and more than 300 pediatric WRs have been issued. This has resulted in revisions to more than 100 drug labels to include new pediatric information. The Pediatric Rule, which became effective on April 1, 1999, required that manufacturers of certain new and marketed drugs and biological products conduct studies to provide adequate labeling for the use of these products in children. A District of Columbia federal district court invalidated the Pediatric Rule on October 17, 2002. In December 2003, Congress enacted the Pediatric Research Equity Act (PREA), which requires (retroactively to April 1, 1999) all applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens to contain an assessment of the safety and effectiveness of the product in pediatric patients. PREA is complimentary to BPCA and allows the FDA to obtain pediatric information when applications are submitted. This requirement may be waived or deferred depending on existing labeling, public health benefit, and usefulness of the drug in different pediatric populations. With passage of the BPCA and the PREA, there have been gains in the information available in labeling for the appropriate use of medications in children. While much has been achieved, there are still many drugs that need to be studied for the pediatric population. The anesthesia community can become involved by alerting the leadership of their specialty societies regarding drugs when they feel additional information would benefit the pediatric population. Academic investigators can compete for NIH funding to support pediatric clinical trials. SUGGESTIONS FOR FURTHER RESEARCH IN PEDIATRIC DRUG DEVELOPMENT The editorial by Tobin et al. (1) suggests that a consensus statement by children’s advocacy groups, increased commitment by pharmaceutical companies, and additional resources at FDA are needed to improve pediatric drug development. We concur that all stakeholders should work together to find new ways to advance the development of pediatric drug development. The FDA continues to be active in organizing an increased commitment to this vital area of research. For example, the Newborn Drug Development Initiative: Improving Neonatal Therapeutics workshop, sponsored by the NIH and FDA, included summary recommendations for pain control by members of the academic anesthesia community (5,6). Full-length articles on procedural pain, sedation and analgesia, perioperative pain, and study designs resulting from this effort have also been published (7–10). High-caliber academic investigations, when conducted under an approved IND application, can continue to make valuable contributions to improve the spectrum and quality of therapeutics available to pediatric patients.

The crucial role played by medication use in the elderly is common knowledge in the worlds of health services research, clinical epidemiology, and geriatrics. It is now widely known that although persons over age sixty-five represent only about 13 percent of the population, they consume nearly one-third of all medications in the United States; that medications probably are the single most important health care technology in preventing illness, disability, and death in the geriatric population; that drugs represent one of the largest and fastest-rising out-of-pocket health care expenditures for the elderly; and that the old, because of their high drug usage rate, greater frequency of coexisting illnesses, and diminished physiological reserves, are at greater risk of experiencing adverse drug effects. Yet despite this knowledge, the use of drugs by the elderly and their clinical outcomes have not been prominent research or programmatic priorities for federal government, philanthropic, or corporate grantmakers. Beginning in the mid-1980s, The John A. Hartford Foundation began a grant-making program in the area of medication use and aging, out of an interest in enhancing the therapeutic effect of drugs used by this age group and in reducing the frequency and consequences of adverse drug events. After a number of years of active support in this area, the foundation convened its Expert Panel on Medications and Aging. This panel brought together authorities in the disciplines of geriatrics, gerontology, epidemiology, health services research, public policy, and pharmacology. Its mandate was to provide a consensus report that would critically define the further work needed to make the use of medications by the elderly more effective. This essay represents a synthesis of the work of that panel. The positions and opinions expressed below are extracted from transcripts of the expert panel’s deliberations, a structured survey administered to panel members,

DRUG labeling is of vital importance in guiding the safe and effective use of approved drugs. Drug labels represent the most visible expression of months or years of scientific review by physicians and scientists at the U.S. Food and Drug Administration (FDA), and they are also fundamental to the purpose and mission of the FDA. Creation of the FDA dates to the 1906 passage of the Food and Drugs Act, which prohibited the manufacture and interstate shipment of adulterated and misbranded foods and drugs.†A 1937 disaster, in which more than 100 people died after ingestion of Elixir Sulfanilamide, precipitated the Federal Food, Drug, and Cosmetic Act of 1938, which, for the first time in U.S. history, required demonstration of safety before marketing new drugs. Elixir Sulfanilamide contained diethylene glycol and had never been tested for safety. In 1960, a marketing application for the drug thalidomide was submitted to the FDA. Withstanding enormous pressure from the applicant, FDA reviewers, including Frances Kelsey, M.D., Ph.D., a medical officer at the Center for Drug Evaluation and Research at the FDA (Washington D.C.),‡determined that inadequate data were available to support the safety of the drug product despite its already widespread use throughout the rest of the world. The application was not approved. After thousands of children in 46 countries were born with deformities as a consequence of thalidomide use, leaving the United States relatively unscathed, a political movement for tighter drug controls in the United States gained popular support. The Drug Amendments of 1962 were the first to require demonstration of effectiveness before marketing, recognizing that the assessment of safety must also consider benefit. Since 1962, more than a thousand prescription drugs have had their labeling changed or have been taken off the market to reflect the scientific evidence (or lack thereof) documenting their safety and/or effectiveness.§Section 505 of the Federal Food, Drug, and Cosmetic Act (21 USC 355)∥currently specifies that approved drugs must be safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling.Current regulations stipulate the following labeling requirements1:The Code of Federal Regulations provides the basic skeleton for drug labels,#specifying the section headings and content, as well as the order in which these sections should appear. Regulations have been proposed to improve on the current system of labeling by changing the format of drug labeling to make the information more useful and accessible to practitioners.2This proposal would partition the label into three parts: a Highlights section, an Index, and Comprehensive Prescribing Information.Most typically, the drug manufacturer drafts proposed labeling based on relevant available data. This includes data acquired during drug development, as well as publicly available data on the drug and other related drugs. FDA reviewers carefully scrutinize every phrase in the proposed label for completeness and fair balance and also to ensure that all statements are adequately supported by data.**Scientific experts outside of the FDA and the general public may also be consulted for advice on labeling, particularly in the case of difficult or controversial issues. Commonly, labels undergo one or more rounds of revisions before final approval.Generally, new indications for a drug require evidence of effectiveness based on data submitted from adequate and well-controlled studies (i.e. , generally more than one) conducted in humans under an Investigational New Drug application, under defined standards for data quality and integrity and the reporting of adverse events.††All relevant data must be submitted to a new drug application (NDA), including data from failed trials, along with complete protocols and protocol revisions. Supporting chemistry, pharmacokinetic, and preclinical (in vitro and animal) data are usually required as well. FDA grants indications only after its own internal review and analyses of these data by physicians, statisticians, chemists, clinical pharmacologists, toxicologists, and other relevant scientific and regulatory disciplines within the FDA. In addition, experts external to the FDA, including members of FDA advisory committees, may be consulted as needed. Medical literature, on which much off-label use is based, is usually not accepted as the sole basis for approval of a new drug indication. There are several reasons for this. First, the raw data, along with complete protocols and revisions, are usually unavailable for review. Second, the standards for data quality, integrity, monitoring, and adverse events reporting are often unknown. Last, the study sites are unavailable for inspection. The FDA must also consider the possibility that published literature may present a skewed or incomplete profile of the efficacy and safety of a drug for human use.This regulatory process can be illustrated using the examples of levobupivacaine (Chirocaine; Purdue Pharma LP, Stamford, CT) and of dexmedetomidine hydrochloride (Precedex; Hospira, Lake Forest, IL).‡‡Levobupivacaine (Chirocaine) was approved in 1999 for adult patients for the production of local or regional anesthesia for surgery and obstetrics, and for postoperative pain management. The NDA applicant studied more than 1,400 patients in a total of 27 clinical studies in the United States and Europe. These included 2 pharmacokinetic studies, 4 phase I pharmacodynamic studies examining neurologic and cardiovascular endpoints, 2 studies of epidural administration for cesarean delivery, 2 studies of epidural administration for labor analgesia, 2 studies of epidural infusion for operative procedures, 1 study of intrathecal injection for lower limb surgery, 4 studies of epidural infusion for postoperative pain, 7 studies of peripheral nerve blocks, and 3 pediatric studies, 2 of which were still ongoing at the time of NDA submission. Much of the preclinical support for this application was in the form of animal studies of levobupivacaine and bupivacaine (approved in 1972) that were available in the published literature. Before its approval, the FDA consulted the Anesthetic and Life Support Drugs Advisory Committee, which included a guest cardiac electrophysiology consultant, to discuss the relative safety of levobupivacaine compared with bupivacaine and how the product should be labeled with respect to cardiotoxicity. In addition, FDA chemists and microbiologists reviewed data and information related to the product chemistry, manufacturing, and quality before approval.Dexmedetomidine hydrochloride (Precedex), an α2-adrenoceptor agonist, was approved in 1999 for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. It is to be administered by continuous infusion for not more than 24 h. The NDA applicant submitted full reports of animal pharmacokinetic, toxicology, and teratogenicity studies; two placebo-controlled human studies demonstrating the efficacy of dexmedetomidine; and a total human safety database of more than 3,038 subjects, of whom 1,473 were intensive care unit patients who received the drug by continuous infusion. Only 78 patients received dexmedetomidine for longer than 24 h, and no patient received the drug for longer than 40 h. No safety data in pediatric patients were submitted, and more than 500 patients older than 65 yr were studied, 129 of whom were aged 75 yr or older. Human pharmacokinetic data included evaluation in patients with renal failure after single administration and evaluation of pharmacokinetics with hepatic impairment, as well as analysis of the effects of age on pharmacokinetics in adults. In addition, the FDA inspected clinical trial sites and reviewed information related to the product chemistry, manufacturing, and quality before approval. The NDA applicant also agreed to seven phase IV commitments to address areas in which the FDA desired additional information that might be used to inform future labeling. These included (1) dog studies to evaluate general toxicology, effects on the hypothalamic-pituitary axis, and changes in drug metabolism after 2 weeks of drug infusion; (2) an animal study to evaluate the effects of the three major human metabolites of dexmedetomidine that are absent in rats and dogs; (3) preclinical mutagenicity studies to elucidate findings from studies submitted before approval; and (4) long-term continuous infusion studies in patients to evaluate the pharmacokinetics, safety, and extended effectiveness of dexmedetomidine in the intensive care unit setting and to evaluate the use of long-term infusions in patients with renal failure. To date, these commitments have not been deemed fulfilled in their entirety, and there have not been any labeling changes for dexmedetomidine (Precedex) that are based on these postmarketing commitments.After a drug has been approved for marketing, a supplemental application to the FDA is required to change the labeling to reflect a new indication. The supplemental application must present data to support the safety and effectiveness of the new indication. The data requirements for a supplemental application might not be as extensive as would be expected for a novel NDA application, depending on the nature of the supplement and the indication sought.For example, a supplemental application for ropivacaine (Naropin; AstraZeneca, Wilmington, DE) was approved in 2000 for changes in the labeling, including (1) use of the 0.75% concentration for major nerve block and for epidural administration for cesarean delivery (previously approved concentrations for these indications were 0.2% and 0.5%, respectively); (2) use of 0.2% ropivacaine (Naropin) for up to 72 h for postoperative pain (previously approved for up to 24 h only); and (3) a change in the recommended infusion range for thoracic epidural administration for postoperative pain from 4–8 ml/h of 0.2% ropivacaine (Naropin) to 6–14 ml/h. To support the new labeling recommendations, the NDA sponsor submitted the results of clinical trials in which 324 women received 0.75% ropivacaine by the lumbar epidural route for cesarean delivery, 119 patients received 0.75% ropivacaine for brachial plexus block, and 441 patients received epidural infusions of 0.2% ropivacaine for postoperative pain. Pharmacokinetic data were obtained in 8 of the 20 submitted clinical studies. The FDA also reviewed preclinical (in vitro and animal) studies investigating acute, subchronic, and chronic toxicity; pharmacokinetics; cardiovascular toxicity; reproductive toxicology; and genotoxicology before approval of the supplement.Generally, the FDA requires that indications reflect the likely clinical use of a drug to ensure that a drug is not approved for unrealistically narrow indications. For example, drug company XYZ might propose to develop a novel general anesthetic agent only for "general anesthesia for left foot bunionectomies" and submit data supporting only this indication. In such a case, the company might be asked for more data to support a broader indication that would realistically reflect the likely clinical use, or they would be asked to provide adequate justification that such a limited indication is appropriate. As a corollary, a very broad indication for "maintenance of general anesthesia" would not be supportable by submission of data only from healthy patients undergoing bunionectomy procedures.Food and Drug Administration guidance to industry states that "in general, drugs should be studied prior to approval in subjects representing a full range of patients likely to receive the drug once it is marketed. …"3Therefore, to the extent possible, sponsors are expected to study the full range of patients likely to receive drug for the desired indications. Further, recent legislation stipulates that new drug applications are specifically required to contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred.4In addition, drug product sponsors are generally expected to study elderly patients, and to investigate the effects of metabolic and renal impairment and drug–drug interactions when relevant.5–7In a new drug application, sponsors are also required to present effectiveness and safety data for important demographic subgroups, specifically sex, age, and racial subgroups.Current regulations also require specific labeling in the following subpopulations as applicable: pregnant women (including use during labor and delivery), nursing mothers, pediatric patients, and elderly patients.8However, with the exception of those few special populations defined by regulation or guidance, unless there are data to indicate a need for special study or labeling, it is generally not required, feasible, or even scientifically meaningful, to discuss all potential subpopulations in the label.Therefore, industry is encouraged to study drugs in the range of settings and populations reflecting their likely clinical use, including the range of likely comedications and comorbidities. Labels, in turn, are written to reflect the clinical trials that were performed to support them. However, these clinical trials cannot anticipate or thoroughly study all of the ways that a drug may be used after it is approved. Because every patient and clinical situation is unique in some way, this would truly be an impossible task. In spite of the best efforts of the FDA and the drug industry, neither labels nor the supporting clinical trials can comprehensively describe all potential labeled or off-label uses.What exactly is off-label use, and what are the implications for the anesthesia practitioner? Any use of a drug for a condition or in a manner not appearing in the drug's approved label is considered off-label. This lack of approval is most commonly because data have not been submitted to the FDA to support the safety and efficacy of that use, not necessarily because there has been an adverse finding with respect to safety or efficacy. Off-label use most often describes a deviation from the labeled indication, dosage form, dose regimen, or patient population. However, any significant departure from the approved labeling or any use that is not described in the approved label may be considered to be off-label. When off-label uses are associated with a particular safety hazard, they may be described in the Contraindications, Warnings, or Precautions sections of the label. However, although all contraindicated uses are off-label uses, the Warnings and Precautions sections may discuss both labeled and off-label uses.For example, dexmedetomidine (Precedex) is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. It is to be administered by continuous infusion for not more than 24 h. In this case, the use of dexmedetomidine outside an intensive care setting or in non–mechanically ventilated patients, such as for monitored anesthesia care sedation in the operating room, would be considered off-label. Similarly, infusions of dexmedetomidine lasting longer than 24 h are also off-label, as noted in the Indications and Usage, Precautions, and Dosage and Administration sections of the label. Data have not been submitted to the FDA to support the safe and effective use of dexmedetomidine outside the labeled indications, and for monitored anesthesia care sedation or long-term infusions to be reflected in the FDA-approved labeling, an application would need to be submitted to the FDA with adequate supporting data.The following are additional examples of off-label uses in anesthesiology:Where does that leave the individual anesthesiologist who, based on his or her own knowledge of the medical literature, medical judgment, and experience, believes that a particular off-label use would be safe and effective for the patient at hand? Anesthesiology is unique among medical specialties in the methods by which practitioners administer drugs that they prescribe. Anesthesiologists administer drugs with their own hands and often do not conform to a fixed algorithm. Instead, drug use is tailored to effect and to the individual needs of the patient, as well as to surgical and medical conditions. Anesthesiology is a specialty that prides itself on innovation and resourcefulness. New routes and modes of administration, mixes, doses, and applications for medications are commonly used to solve complex problems.The FDA does not restrict a physician's discretionary use of an approved drug, which is considered the practice of medicine. In fact, it is recognized that off-label use can be essential to medical care, that it is not always investigational or experimental, and that there is no legal or ethical obligation for physicians to discuss FDA regulatory status issues with their patients.9For example, many drugs used in anesthesia have never been approved for use in children. Restricting anesthesiologists only to labeled uses would have a devastating effect on the practice of pediatric anesthesia, and indeed, practitioners restricting their practice in such a way might well be accused of engaging in poor medical practice. It is the physician's prerogative to use legally marketed drugs in a way that he or she believes is best for the individual patient, according to his or her medical judgment (outside of medical research).However, in this context, perhaps understandably, physicians are often unfamiliar with information available in drug labels and even are unaware of basic information the labeling for drugs that they use, such as indications, dosage and administration and are many other reasons that physicians might not have many on their medical practice is and labels may be as to and often cannot the information they are in the label. practitioners may the information contained in the label with and of the for use in drug labeling and practice is illustrated by the drug In 2 yr after it was approved for marketing, a was to the label because of the of related to The label contraindicated use in patients drugs that and the labeling change was by the of a After the of these contraindicated use of in a of practice sites was to in of In the was to other patient at This change was by the of a and of these the of contraindicated use recent history, several effective drugs such as have been from the market because labeling has been in and adverse are very reasons for anesthesiologists to and the of drug labels and to carefully off-label The label much important information that can inform such are the and should what these are and the for in order to inform on when a particular patient may despite an is as important to the label is a particular use is not because data demonstrating safety and effectiveness do not or have never been submitted to the there is no of in the label of a general anesthetic drug, is use in this For the individual who is not to or a drug, the of use in is off-label may be The more relevant is can the drug be used and in and use a of for which the FDA has a that the the in the labeled populations and for individual patients within that the range of and may be even to the extent that some individual patients within the indicated may adverse events that are not by individual benefit. Off-label uses represent a of and unless as would be reflected in a specific labeled or the FDA has not been with adequate data to make a of safety and efficacy for the indication. The label is a to present those conditions in which safety and efficacy have been and to the trials and data that were used to support these As required by regulation and as labeling describes specific and that may for special use is contraindicated in this might be considered a of the adult that was studied to support the drug's indication. However, are not in the it is also likely that they not represent a of the total clinical database to make use of the drug in this should from the adult population. The label describes the important clinical trials and available information on pharmacokinetic, and safety and special this the is expected to clinical judgment in the best use of the drug in the individual patient at may require of dose based on from the general in and of renal and of older drugs for which are available have limited to develop new drug indications. as the clinical use of these drugs clinical use may from the approved labeling, and clinical judgment and ongoing medical may on an important in guiding their of this is the NDA for which was submitted to the FDA in the is approved only for and injection in patients aged 2 yr and older. the widespread use of by intrathecal and epidural and the use of this drug in pediatric patients than 2 data demonstrating the safety and efficacy of these uses have never been submitted to the FDA to support the of these indications to the anesthesiologist should consider several other when off-label use of a data and pharmacokinetic data usually inform labeled Off-label populations and indications have data to indications for new routes of administration and new populations are generally supported by studies in animal In these it is to more the potential profile for drugs in ways that are not in such as by of at the proposed human and data are often unavailable to support the safety of off-label routes of administration or of of or longer than approved and routes of who to administer a drug that is labeled only for use by the or intrathecal route should that the potential for local may not have been thoroughly in those for that Drugs that are used by routes may also have very of than by the approved a situation that may in very drug efficacy and safety for of are often defined by the clinical and preclinical trials from which safety and efficacy data are available only for a limited of may also be limited by specific related to safety or in which case these are usually in the label. may also into For example, assessment of safety for labeling into the potential to drug, and drugs that are approved only for use may in to patients For example, is approved only for of general anesthesia and for of anesthesia during operative infusion of is off-label and has been associated with In addition, many drugs used by pain and or with use of these drugs is not in clinical trials, the may not have adequate information to with use and may not even be of the efficacy of the are also a of and issues of particular to anesthesia For example, drugs approved for epidural or intrathecal use may be to standards than medications with respect to potential to and (including This is a Anesthesiologists commonly use drugs by routes that are not approved for such The and concentrations of and are generally not in the product labeling may the drug is anesthesiologists may to for epidural or intrathecal use, they may not always which drug contain For example, the labels to some of not the of these The had to the to that In addition, drugs can from the product in the of and that the applicant and the and provides information that the do not the safety or efficacy of the drug product for the labeled although the product may contain a or no a of that product may or may not contain that and it may or may not contain a are often in the ways that they and drugs for these are not specifically in the these may be considered off-label The Dosage and Administration section of the label information and administration of the dosage These are supported by data demonstrating and of the drug in the final In addition, drugs are tested for and with with which they into Anesthesiologists and drugs off-label should be of the of and After the FDA received reports of of with FDA a label to Before this the label was on of these drugs. drug labels do not anticipate the range of clinical is the practice of to that contain is a that has been associated with adverse events in particularly to reproductive in in have concentrations under use and conditions. However, is to in into that contain The extent and time for the of of into which is and the potential for to humans related to such have not been Anesthesiologists should be and of drugs outside their not described in the label. When or drugs off-label, practitioners should be in for and for drug When these events do practitioners should are the best of for an individual However, information from trials, the individual may be at a in this Drug effects from patient to patient and from situation to situation in the In addition, relatively adverse events may not be as potential events in clinical practice. This potential is particularly in the and surgical an in which adverse events are and in which there are usually potential for adverse is on individual physicians to be of off-label use and to adverse events when they in the of both labeled and use of adverse reporting is a major by which the FDA can and safety information off-label use of drugs. information the patient, the clinical and the clinical supporting data the are to the effective analysis and of these adverse data. on how to adverse product or can be on the FDA may be submitted or by or after which they are into a database they undergo FDA labeling has implications for and marketing of drugs. Drug generally must conform to labeling and contain information and effectiveness as in the drug label. Drug sponsors are not to off-label uses of although they may medical literature relevant to such uses under some usually submission or a to submit an application for the off-label that the use is not FDA along with the approved labeling for the drug, must also such FDA itself has that a product has been approved for marketing, a may it for uses or in treatment or patient populations that are not included in approved labeling. new uses for drugs already on the market are often first and regulatory with respect to off-label uses of medications may be a of in the literature and in the However, it is that (1) the associated with off-label use represent a broad (2) the of off-label uses may the associated in patients, and (3) off-label use a vital in the practice and of have the to be well the drugs they are and to off-label use on scientific or on medical To best and consider the potential implications and of off-label use, it is that anesthesia practitioners be with the labels for the drugs that they use and the and of these

Drug Development

More transparency for clinical trial data: The decision by the European Medicines Agency to make clinical trial reports publicly available could provide a boon for biomedical research.

T here is welcome news about an old problem. For years, we've been getting only part of the story on clinical drug trials. The successful ones get published and touted, but others that didn't work out so well may never see the light of day. New developments, however, promise a long-awaited exposure of the negative results. Most scientific studies that examine a possible threat or benefit to the public health are repeated, sometimes by several different investigators. When high economic stakes are involved, someone is usually interested enough to perform a meta-analysis, pooling the results of all the published studies to test for significance. That's true for clinical trials, toxicity tests, and other studies designed to assess human risks. So far, so good. But a thoughtful statistician can spoil the fun: “Look, journals and scientists like positive results and get disappointed by negative results. So there's a problem—all the unpublished negative results lurking in those file drawers!” Thus, the fly in the meta-analysis ointment: It's likely that aggregated results from published papers constitute a biased sample. How does the old problem of selection bias relate to new events in the world of clinical trials? Well, pharmaceutical companies often gather favored medical specialists to evaluate, and even tout, the value of a particular drug treatment. Results of clinical trials favorable to the drug and its sponsor are collected, sometimes in the form of a symposium volume or even as a supplement to a specialty medical journal. The U.S. Food and Drug Administration (FDA) has attempted to regulate such sponsored publications in the same way as it regulates advertising in medical or lay journals. ![Figure][1] CREDIT: JOE SUTLIFF But that weapon has been blunted. In a recent lawsuit, the Washington Legal Foundation challenged the FDA's authority to regulate the promotion of drugs for use “off label”—that is, for treating symptoms or diseases for which the drug has not been proven effective by the FDA. The court ruled that the FDA had to permit drug company-sponsored advertisements for off-label use, as long as they were directed at physicians and not consumers. The legal environment now appears to favor the “commercial free speech” doctrine; a position, ironically, that was supported by the FDA's chief counsel on behalf of drug company clients before he came to the agency. The FDA, not surprisingly, is now more hesitant about undertaking enforcement activity against claims made by pharmaceutical firms. The difficulty is that positive claims are sometimes made against a background of unrevealed negative results. A clinical trial that fails to show effectiveness (or indicates safety problems) is required to be submitted to the FDA along with the positive results. But these may not be released, because their proprietary nature is recognized under the law. Back in 1977, an advisory body to the Secretary of Health, Education and Welfare pleaded for public access to these data. Subsequently, consumer groups such as Public Citizen have repeatedly sued to liberate them, with only limited success. In 1997, a new U.S. federal law required companies to register trials at a government database, later called ClinicalTrials.gov. But the FDA has lacked the authority to enforce compliance, and the database remains incomplete. Now a rescue is beginning to take shape. Revisions to the U.S. law regarding the government- enforced registry are now under discussion. The International Committee of Medical Journal Editors is also considering a proposal whereby journals that publish the results of clinical trials would require sponsors to deposit trial-related results in a national registry as a condition of publication. The American Medical Association agrees with this and has recommended that institutional review boards make registration a condition for allowing any trial to proceed. The World Health Organization also plans to propose an international registry of drug trials to national health ministers later this year. These new proposals are promising, and some thanks surely go to the innovative and very public Attorney General of New York, Eliot Spitzer, who made an amazing discovery last month: The First Amendment is not a defense against fraud! He has sued the pharmaceutical complany GlaxoSmithKline for holding back data that may have made the antidepressant drug Paxil look less effective than the successful trials being advertised. That neatly finesses the legal constraints on the FDA, whose scientists should be cheering. And it might finally empty some of those old file drawers. [1]: pending:yes

Labeling refers to the label on the drug container and all printed materials, including the package insert, that accompanies the product. Labeling of a drug indicates that there is substantial evidence from adequate and well controlled clinical trials for the safe and effective use of that drug. Labeling provides important information on clinical pharmacology, indications and usage, contraindications, precautions, adverse effects, dosage, and administration. Unfortunately for children, most drug labeling contains the precautionary disclaimer, because safety and efficacy in children have not been established. The availability of safe and effective drugs has been directly responsible for the improvement in health over the past 50 years. Children essentially have been excluded from the benefit of the many therapeutic advances that have marked pharmaceutic drug development. The failure to include children in clinical trials during drug development leads to delay in implementing potentially effective treatment. Most US food and Drug Administration-approved drugs lack approval for use in all children or are restricted to certain pediatric age groups, primarily older children.1 Only a few of the new drugs released in this country each year are approved for use in children. This lack of information on the safe and effective use of drugs in the most vulnerable patients, infants and neonates, is of greatest concern. Only five of the 80 most frequently used drugs have been approved for use in this population. Another problem is that most drugs are not available in suitable pediatric dosage forms. They are not available in appropriate dosage sizes, lack liquid formulation, and taste peculiar to the child, making compliance difficult. Pharmacies extemporaneously prepare many drugs in liquid dosage forms for use in children. These dosage forms are not sufficiently tested to determine stability, efficacy, or expiration dating. For solid dosage forms, parents often must divide adult tablets …

To the Editor: Phase III clinical trials have been used to provide evidence in support of the approval of most new agents in the treatment of cancer.[1] The selection of the primary endpoint is critical to the outcome of phase III clinical trials and the launch of the cancer drug. In the present study, we performed a cross-sectional study to describe the endpoint information and analyze the trends over time in the research and development of cancer drugs tested in phase III clinical trials in China. The dataset and method used have been previously described.[2] In brief, we performed a cross-sectional study of trials on the National Medical Products Administration (NMPA) Registration and Information Disclosure Platform for Drug Clinical Studies that were registered between January 1, 2013, and December 31, 2019. For trials initiated before 2013 but for which the related new drug application was unfinished, registration was required to be done retrospectively. After searching and screening, 1992 trials of cancer drugs were identified [Supplemental Figure 1, https://links.lww.com/CM9/B476]. First, we excluded those that were not stage III trials (n = 1489). Second, 103 of these 503 phase III anticancer clinical trials were subsequently excluded from this study for various reasons. Third, data correction and reassignment were performed. Primary endpoints were classified as single or multiple endpoints, and overall survival (OS) or surrogate endpoints (including radiology-based endpoints, such as time-to-event endpoints and tumor-response endpoints, pathology-based endpoints, and blood-based endpoints) were classified according to the Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics released by the US Food and Drug Administration (FDA). For descriptive analyses, the number (%) was used for qualitative variables. The χ² test was used for subgroup comparisons of single/multiple endpoints and OS/surrogate endpoints. We analyzed the 12-year trends in our selected indicators, including OS, surrogate endpoints, single endpoints, and multiple endpoints, using the Mann-Kendall test. The annual rate of change was calculated for each indicator. The year of a trial was defined by the date of the first ethical review. All statistical analyses were performed with SAS software 9.4 (SAS Inc., Cary, N.C., USA). From 2008 to 2019, 400 phase III anticancer clinical trials were registered. Of all 400 clinical trials, 336 used a single endpoint as the primary endpoint. Progression-free survival (PFS), OS, objective response rate (ORR), and disease-free survival (DFS) were the top four endpoints, accounting for 44.6% (150/336), 28.9% (97/336), 10.4% (35/336) and 7.1% (24/336), respectively. Among the 64 trials that used multiple endpoints, OS and PFS, ORR and best of response (BOR), and OS and ORR were the top three multiple endpoints, accounting for 73.4% (47/64), 12.5% (8/64) and 6.3% (4/64), respectively [Supplementary Table 1, https://links.lww.com/CM9/B476]. A total of 154 trials (38.5%) used OS as one of the primary endpoints, and 73.8% (295/400) used a surrogate endpoint. Of the 295 trials that used surrogate endpoints, radiology-based endpoints accounted for 70.3% (281/400), pathology-based endpoints accounted for 2.3% (9/400), and blood-based endpoints accounted for 2.0% (8/400). The proportion of trials using a single endpoint as the primary endpoint significantly decreased from 100% (1/1) in 2008 to 78.1% (57/73) in 2019 (average annual growth rate = -2.04%, P <0.01), and the proportion of trials using multiple endpoints as the primary endpoint significantly increased from 0% (0/1) in 2008 to 21.9% (16/73) in 2019 (average annual growth rate = 2.0%, P <0.01) [Figure 1]. As a single endpoint, the proportion of trials using OS as the primary endpoint increased from 0% (0/1) in 2008 to 41.7% (20/48) in 2017 and then decreased to 12.7% (7/55) in 2019 (average annual growth rate = 1.13%, P = 0.11). The proportion of trials using a surrogate endpoint as the primary endpoint decreased from 100% (1/1) in 2008 to 58.3% (28/48) in 2017 and then increased to 87.3% (48/55) in 2019 (average annual growth rate = -1.13%, P = 0.11).Figure 1: Time trends of endpoints of phase III anticancer clinical trials in China from 2008 to 2019. OS: Overall survival.Clinical trials of immunotherapy drugs and targeted drugs preferred multiple endpoints (all P <0.05) [Supplementary Table 2, https://links.lww.com/CM9/B476]. Domestic studies preferred single endpoints more than global studies (P <0.0001). Trials with data and safety monitoring boards preferred multiple endpoints more than trials without data and safety monitoring boards (P <0.0001). Trials of chemical drugs or traditional Chinese drugs/natural drugs preferred single endpoints more than trials of biological products (P <0.0001). Neoadjuvant/adjuvant or first-line treatment trials preferred surrogate endpoints more than second- or subsequent-line treatment trials (P < 0.0001) [Supplementary Table 3, https://links.lww.com/CM9/B476]. Trials for cancers with better prognosis preferred surrogate endpoints more than trials for cancers with poor prognosis (5-year survival rates <26.7%) (P <0.0001). Clinical trials of immunotherapy drugs preferred the OS endpoint (P = 0.01). The most commonly used combination of multiple endpoints was OS and PFS. The reasons why multiple endpoints were used in the primary analysis were to increase the power of statistical tests (or reduce the required sample size) by aggregating information from multiple endpoints and to describe treatment effects more comprehensively in diseases that manifest in a multifaceted way where a single endpoint does not suffice to fully represent the treatment effect.[3] However, the selection of multiple endpoints can significantly increase the complexity of a trial. Finding a balance between trial complexity and efficiency and selecting the appropriate endpoint strategy will maximize study efficiency, advance study progress, and address clinical questions without unduly adding complexity to trial design and execution with multiple endpoints. In 2017, both the FDA and the European Medicines Agency (EMA) released draft guidelines on multiple endpoints in clinical trials. However, each component of the multiple endpoints needs to be fully identified, which is often missing in clinical trials. For diseases with a favorable prognosis, the feasibility of clinical trial protocols may be one of the concerns regarding the primary endpoint chosen. Patients with tumors such as thyroid or breast cancer have prolonged survival, as the average 5-year survival rate is over 80% in China. Extensive follow-up at this time may not only prevent the early reporting of useful drugs but also be time- and cost-consuming. In addition, the subsequent therapy may heavily confound the survival analysis. In this context, using OS as the primary endpoint seems impractical. According to Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, the surrogate endpoints DFS and event-free survival (EFS) used as primary endpoints in the adjuvant setting for breast cancer, colorectal cancer, gastrointestinal stromal tumors, melanoma, and renal cell carcinoma seem to be well accepted by the US FDA. Our analysis provides additional evidence for this strategy, as we found that for trials in the neoadjuvant/adjuvant setting or those on tumors with an average 5-year survival rate of over 60%, approximately 90% of clinical trials used surrogate endpoints as primary endpoints. The guidelines released by the EMA and FDA may have contributed to the increasing application of surrogate endpoints since 2017. It is worth noting that despite the rising trend, surrogate endpoints have not replaced OS in recent studies. The fundamental reason may lie in the heterogeneity of the correlation intensity between surrogate endpoints and OS, which may be attributed to multiple factors, such as the specific disease, context of use, magnitude of the effect, disease setting, location of metastatic sites, available therapy, and risk-benefit relationship. The treatment strategy is one of the essential factors that influence surrogacy. There is limited evidence supporting the use of surrogate endpoints in studies of immunotherapy. Previous reports showed that there were weak correlations between PFS/ORR/disease control rate (DCR) and OS in immune checkpoint inhibitor (ICI)-treated patients,[4,5] which may be partially explained by pseudoprogression, a phenomenon specifically related to immunotherapy.[6] In contrast to chemotherapy, the effect of ICIs is not on tumor cells but on immune cells. Being treated by ICIs, some patients experience immune-related responses, such as an initial increase in the size of tumors or the appearance of new lesions, before a subsequent and sustained reduction in tumor burden occurs. Another explanation might be the residual efficacy of ICIs for a longer duration (delayed treatment effect); these drugs affect OS more than PFS even after treatment discontinuation.[7] The inferior surrogacy explains our results; immunotherapy trials used relatively fewer surrogate endpoints than nonimmunotherapy trials did. In recent years, the NMPA has launched new priority examination and approval processes and initiated multiple actions to prevent the delayed approval of useful drugs. Approving indicated uses supported by data regarding the emerging surrogate endpoints of clinical trials may be one of the strategies to address this concern. For example, in August 2020 and 2021, the NMPA approved radium-223 and darolutamide for use in castration-resistant prostate cancer (CRPC) based on two phase III trials using metastasis-free survival (MFS) as the primary survival endpoint. In addition to radiology-based endpoints, pathology-based endpoints and blood-based endpoints are also promising emerging surrogate endpoints that can be used in trials for patients with certain disease stages or with certain tumor types. Prostate-specific antigen (PSA) is the most well-studied and proven surrogate blood-based endpoint and has been used in an increasing number of global and domestic phase 3 trials (ClinicalTrials.gov Identifier: NCT00653848, NCT04076059, NCT01695135, and NCT00182052). Major pathological response (MPR), defined as ≤10% residual viable tumor in the resected primary lesion and lymph node tissue, is measured in samples obtained surgically after treatment and has been proven to be reliably and significantly associated with survival in multiple tumor types with heterogeneous treatment strategies in the neoadjuvant setting. It has advantages in reflecting treatment-specific antitumor activity independent of pretreatment staging accuracy and can be determined using relatively simple and inexpensive methods.[8] MPR has been accepted by NMPA as the primary endpoint of phase 3 studies to promote the approval of indications (ClinicalTrials.gov Identifier: NCT04158440, NCT04316364, NCT04379635). In conclusion, although favored in terms of feasibility, surrogate endpoints have not replaced OS in all areas of anticancer clinical trials. Surrogate endpoints have wider use in trials in the neoadjuvant/adjuvant setting, in trials of tumors with a favorable prognosis, and in non-immunotherapy trials. The accuracy of surrogate end points and scope of application still need to be verified by high-level evidence. Multiple new non-radiological surrogate endpoints correlated with OS are emerging, which may open up new fields deserving further exploration. Funding The study was supported by the Natural Science Foundation of Henan Province (No. 212300410261) and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Construction and Application of Clinical Trial and Institution Evaluation System 2021-I2M-1-045). Conflicts of interest None.

The total value to society of eliminating all life expectancy disparities attributable to the underrepresentation of minorities for the three common conditions of diabetes, heart disease, and hypertension was approximately $11 trillion based on a commissioned analysis that applied the Future Elderly Model for the National Academies of Sciences, Engineering, and Medicine (NASEM) Committee on Improving the Representation of Women and Underrepresented Minorities in Clinical Trials and Research.1 While older adults experience higher rates of these comorbidities2 and polypharmacy3 than the general population and are the major utilizers of medications,4 they are considerably underrepresented in clinical trials and clinical research overall.5 The prioritization of COVID-19 vaccines for older adults as part of phase 1 by the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices was a prominent example of the importance of studying older adults and, particularly, older adults with chronic disease in clinical trials.6 To address the societally pressing challenge of the lack of older adults, women, and minorities in clinical trials and medical research in general, NASEM hosted a virtual workshop titled "Drug Research and Development for Adults Across the Older Age Span" in 2020. The following year through 2022, NASEM performed a Congressionally mandated consensus study with culminating report titled "Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups." The goal of these NASEM activities was to examine and shed light on the challenges and opportunities in drug research and development for older adults, women, and underrepresented groups and explore hurdles that impair clinical studies in these populations. The NASEM events described the array of consequences due to the underrepresentation of women and minoritized populations as well as the salient conclusions based on the evidence (Table 1). 1. Lack of representation compromises generalizability and relevance of clinical research findings to the whole U.S. population. 2. Lack of representation translates to hundreds of billions of dollars in medical costs in the United States. 3. Lack of representation may hinder innovation and new discoveries. 4. Lack of representation may compound low accrual that causes many trials to fail. 5. Lack of representation may lead to a lack of access to effective medical interventions. 6. Lack of representation may undermine the trust of the clinical research enterprise and the medical establishment. 7. Lack of representation may lead to the absence of determination and measurement of outcomes meaningful to these populations. 8. Lack of representation precludes ascertaining important variations in medication absorption and metabolism, which may be altered by age, sex/gender, and race/ethnicity. 1. Improving representation in clinical research is urgent. 2. Improving representation in clinical research requires substantial investment that must include education and dialogue with patients and communities who may be unfamiliar with clinical trials and may have concerns about potential risks as well as benefits. 3. Improving representation requires transparency and accountability. 4. Improving representation in clinical research is the responsibility of everyone involved in the clinical research enterprise. 5. Creating a more equitable future entails a paradigm shift. Barriers to the necessary representation of underrepresented and excluded populations in clinical research in the current research system have reduced participation by a diverse population in clinical trials and clinical research at multiple levels. Individual research studies, the institutions that conduct research, funders of studies, institutional review boards (IRBs), medical journals, and the broader landscape of national policies and practices that govern research all contribute to barriers of populations historically excluded from clinical research. At the level of an individual research study, the factors and problems that lead to the underrepresentation and exclusion of certain populations in clinical trials and research begin with and follow the life cycle of a project. Understanding and resolving the underrepresentation and exclusion of these populations in research require careful examination of almost every stage in the research process itself. This includes at the time research questions are developed. The composition, training, and attitudes of the research team must also be considered to foster the thoughtful dialogue and insight necessary to maximize representation of needed populations. Research site selection is also a key facet in bolstering access to priority populations for increasing representativeness. Intentionality in "meeting people where they are" has been identified as a key pillar in improving the representativeness and validity of studies. Consideration on participant selection and study protocols in general that includes determination of sampling approaches, recruitment methods, inclusion, and exclusion criteria must also be carefully evaluated. Appropriately performed this includes review of informed consent processes, remuneration for study participants, as well as development and inclusion of multilingual recruitment and consent documents. For older adults, it has been noted that while most older adults with the most common chronic conditions that result in hospitalization in the United States occur in older people with multiple conditions, having multiple conditions was often an exclusion criterion in the National Institutes of Health (NIH) trials. This approach effectively ensured that the representative older population was systematically excluded from the studies. Deliberate considerations of the consequences of inclusion and exclusion criteria decisions on representativeness must be prioritized as fundamental to the research. Institutional structures are also a barrier to appropriate inclusivity. Medical institutions of different types face a range of structural barriers to inclusion in clinical trials. For example, although academic medical centers conduct 55% of the extramural medical research supported by the NIH and operate 98% of the nation's 41 comprehensive cancer centers as of 2019, sustainably and meaningfully engaging underrepresented and excluded populations often does not align with the traditional incentive structures for researchers at these institutions. Recruiting diverse population groups and properly engaging with community members, which is time-consuming and requires investments to build and sustain trust, are only minimally considered in promotion and tenure decisions at academic medical centers. While community health centers serve a much more diverse community than academic medical centers, these institutions also face barriers to clinical trials and research recruitment, which include limited provider knowledge about available research opportunities and challenges with electronic health record (EHR) infrastructure, that can limit providers' ability to query the EHR using study inclusion and exclusion criteria. IRBs can also present barriers to diverse participation in clinical trials by limiting the types and amount of compensation given to research participants to avoid the impression of coercion or undue influence. However, limiting incentives may ultimately compromise beneficence and justice, two of the ethical principles for research with human subjects detailed in the Belmont Report.7 Research funders also have several roles and responsibilities, which can influence the diversity of clinical trials. These include setting funding priorities, deciding which projects ultimately get funded, providing adequate funding to recruit and retain participants, requiring transparent reporting, and evaluating research outputs. Most clinical trials are funded by pharmaceutical firms. These trials present barriers, including out-of-pocket costs for participants, which are often not discussed in the informed consent process, industry pressures to gather data quickly, and the selection of easy-to-recruit samples often being incentivized. It should be noted that some of these barriers are not solely unique to industry-sponsored trials. Peer-reviewed medical journals serve as the gatekeepers to scientific advancements in clinical practice and health. Their editors wield great power for what is, and is not, published in their pages. Lack of representation on editorial boards and other journal leadership positions may contribute to biases in publication. Recent focused efforts have been formalized to improve representation on journal editorial boards. This included the release of The Journal of the American Medical Association priorities to strive for and promote diversity, equity, and inclusion (DEI) that included the following key approaches: update journal mission statements to include inclusivity aims, appoint an editorial director of equity, improve editorial diversity, promote awareness of and responsibility for DEI, formalize process for assessment and reporting, expand editorial fellowship program, hold seminars on excellence in scientific writing, continue to publish articles on DEI, identify and invite peer reviewers and authors of opinion articles with DEI expertise, encourage authors to address systemic and structural problems to advance DEI, review and update inclusive language guidance for authors and editors update statistical analysis guidance, and participate in International Collaboration on Standards and Policies.8 While the JAMA effort is a necessary step, many more journals must plan, execute, and monitor their efforts to ensure representativeness regarding inclusivity. These activities from NASEM developed an array of policy considerations and recommendations to narrow the inclusiveness gap for minorities, women, and older adults in clinical research. In terms of bolstering reporting, transparency, and accountability, the NASEM report recommended that The Department of Health and Human Services (HHS) create a research equity task force within HHS charged with coordinating data collection and designing study subject recruitment and accrual monitoring that would track across federal agencies, including the Food and Drug Administration (FDA), NIH, CDC, Agency for Healthcare Research and Quality (AHRQ), Health Resources Services Administration (HRSA), Indian Health Services (IHS), and the Centers for Medicare & Medicaid Services (CMS). This task force would submit an annual report to Congress on the status of clinical trial and clinical research enrollment in the United States, which would include patient counts recruited into clinical studies by phase and condition. Mandated data would include the study patients' age, sex, gender, race, ethnicity, study location, and recruitment site. The annual report would also describe to what degree the study population was representative of the conditions studied as well as the sponsors of the research. Creating a real-time, data dashboard was offered as an example of a tool to make data more accessible and transparent continuously. The report also recommended clarifying how "representativeness" was determined and evaluated for protocols and product development plans.1 This would serve to not only help discern the older adult representation but allow for stratification of the older adult categories by minority, gender, and location to ensure that studies line up with actual disease prevalence for older adult subpopulations. This was coordinated with a frequent comment that the heterogeneity of older adults must be better tracked with improved tools and technology to enhance knowledge and treatment outcomes to increase the proportion of heterogeneous older adults in clinical trials. The improved use of modern tools was also broached in terms of better use of technology such as social media to improve recruitment of older adults from diverse backgrounds into trials.9 For a path toward equitable compensation to research participants and their caregivers, the NASEM report recommended developing specific guidance that would include systematically modified compensation for those who will experience a financial burden when participating in research activities. Receipt of a detailed recruitment plan should be required by the FDA no later than at the time of Investigational New Drug and Investigational Device Exemption application submission. To facilitate that trial characteristics are consistently labeled throughout the database and can be easily disaggregated, exported, and analyzed by the public, NIH should standardize the submission of demographic characteristics to ClinicalTrials.gov beyond current guidelines. A theme across the NASEM activities was that NIH can better leverage its role as a funder to motivate improved inclusiveness of older adults and minorities. The score-driving criteria that measure the scientific integrity and overall impact of a NIH grant proposal should formally include participant representativeness data. Patient representativeness data should be components of the assessment of the scientific approach, including whether it is appropriate for concluding insights for the populations to whom the results are intended to generalize. In the 2020 NASEM workshop, Alzheimer's disease research was referenced as an area in which representation of older adults would be expected. The concept of requiring a justification for not including older adults was described on several occasions.9 The NIH should also assess in its annual review of progress reports of funded studies whether a given study has met the proposed enrollment goals of representativeness by race/ethnicity, sex, and gender and should establish a plan for remediation that includes criteria for pausing funding that has not met predefined recruitment goals. Journal publisher, editors, and the International Committee on Medical Journal Editors should (1) require information on the representativeness of studies for submissions to their journals in context to the affected population; (2) consider this information in acceptance decisions; and (3) publish this information for manuscripts that are accepted. The overall representativeness of the trial, including how well the study population aligns with the target population, should be evident in the publication. The Office of Human Research Protections (OHRP) and the FDA should advise local IRBs determine and report the representativeness of clinical trials as one measure of sound research design. Study protocols in which the pre-specified enrollment departs markedly from the disease prevalence would trigger a request for a justification statement or possible remediation. The commitment to and value of educating review bodies across the clinical development continuum to incorporate considerations of age, gender, and minority status dimensions was a prevailing theme. In terms of coverage and payment, CMS should revise its guidance for coverage with evidence development to require that study protocols include a plan for recruiting and retaining participants who are representative of the affected beneficiary population in age, race, ethnicity, sex, and gender. Congress should direct the FDA to enforce accountability measures already present, as well as establish a taskforce to study new incentives for new drug applications for trials that achieve representative enrollment. This recommendation has in fact been enacted in the Food and Drug Omnibus Reform Act of 2022 (FDORA)10 that requires sponsors of phase 3 or other pivotal medication studies to submit diversity action plans by the time the study protocol is submitted. A synthesis of the current environment was recently detailed in the special article "Current status of inclusion of older groups in evaluations of new medications: Gaps and implementation needs to fill them" in this journal.11 Incentive programs should be designed to improve representativeness in clinical research and ensure they do not impede access to new therapies. Expedited coverage decisions should be considered for therapies based on clinical programs that achieve representativeness of the populations most affected. To incentivize community providers to enroll participants in trials, CMS should develop reimbursement approaches for the time and infrastructure that is required. Development of new payment codes would allow CMS to reimburse activities associated with clinical trial participation including data collection and personnel to support research education and recruitment endeavors. The Government Accountability Office (GAO) should assess the impact of previously enacted policies reimbursing routine care costs associated with CMS trials. To foster equitable compensation to research participants and their caregivers, federal agencies, including the OHRP, NIH, and FDA, should develop guidance to direct IRBs on appropriate remuneration for study participation. This new guidance should encourage and allow for variable compensation to research participants and their caregivers commensurate with the time commitment and financial burden of participating. There are trial designs tested that offer the prospect of increasing enrollment of older adults, including adaptive platform trial designs, home-based trials, mechanistic modeling, simulations, real-world data, and pragmatic clinical trials. Clinical trials can now be successfully completed in many non-traditional clinical trial environments that have included barber shops and pharmacies.9 Similarly, all sponsors of clinical trials and clinical research (e.g., federal, foundation, private, and/or industry) should ensure that trials provide adequate compensation for research participants. A diverse, inclusive, and representative workforce, particularly in leadership circles, should be maintained for all organizations involved in clinical research. Recognition of research, training, and professional activities to promote community-engaged scholarly efforts and other research to enhance clinical trial representativeness should be included as areas of excellence for promotion or tenure considerations. The HHS should substantially invest in research infrastructure in the community. To bolster the capacity of community health centers and safety net hospitals to participate in clinical research, funding should be directed to agencies such as the HRSA, NIH, AHRQ, CDC, and IHS. These recommendations and recent advances to date in each area are summarized in Table 2. Progress has been made at the government level with the passage of FDORA as well as coordinated efforts to improve representativeness in clinical research by other agencies, academic institutions, foundations, and non-governmental organizations. Yet, recommendations on changing the composition of the workforce and individual academic entities will require a longer timeframe and concerted effort as will building trust across all communities. Bridging the inclusion gaps for older adults, minorities, and women in clinical research is achievable and necessary. However, it will demand intentional and committed policy efforts with coordination from an array of stakeholders. Fortunately, informed guidance now exists that we must immediately harness and apply to reverse our flagging population health outcomes and move us closer to peer nations. Dr. Jonathan H. Watanabe contributed to the concept, design, and preparation of the manuscript. Dr. Jonathan H. Watanabe credits his involvement as a Member of the Forum on Drug Discovery, Development, and Translation of the National Academies of Sciences, Engineering, and Medicine (NASEM), a planning committee member for the Drug Research and Development for Older Adults Across the Older Age Span NASEM Workshop, and a prior National Academy of Medicine Emerging Leader in Health and Medicine Scholar. He would like to thank Dr. Janice Schwartz for her insightful feedback that strengthened this manuscript. The information or contents are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by NASEM or NAM. Jonathan H. Watanabe has received research funding from the National Institutes of Health and the National Academies of Sciences, Engineering, and Medicine. These organizations played no role in the design, development, writing, or review of this manuscript. None. None.

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Last week the drug industry was shown, twice, to have suppressed trial results that were commercially unfavourable—an all too familiar tale.1 2 But from September 2008, a new US law...