Food And Drug Administration Modernization Act Research Articles

Clinicaltrials.gov: Is the Glass Half Full?

Clinicaltrials.gov: Is the Glass Half Full?

A survey of individuals in US-based pharmaceutical industry HEOR departments: attitudes on policy topics

We surveyed US-based leaders in health economics and outcomes research (HEOR) departments in drug and device companies to examine their views on the state of the field. We created a questionnaire that was emailed to 123 US-based senior HEOR professionals at 54 companies. Of the 123 recipients, 74 (60%) completed the survey. Most respondents (92%) expected their company’s HEOR use to increase, and 80% reported that their organization’s senior management viewed HEOR work as critical. Approximately 62% agreed that Academy of Managed Care Pharmacy (AMCP) dossiers are useful to US health plans, and 55% stated that Food and Drug Administration Modernization Act (FDAMA) Section 114 is useful. Approximately 49% believed the US government should use cost-effectiveness analysis in coverage and reimbursement decisions, but only 31% expected this to occur within 3 years. The findings suggest strong support for the function at senior management levels and optimism about the field.

Off-Label Drug Use in the Pediatric Cardiac Intensive Care Unit

Off-label drug use in pediatrics has challenged the U.S. Food and Drug Administration (FDA). Historically, pharmaceutical companies have been willing to fund pediatric safety and efficacy trials but only for medications with a large market (vaccines and antibiotics). In the field of pediatric cardiac intensive care, the small number of patients and the widely varying physiologies challenge prospective clinical drug trials. There is a limited, if any, return on investment for the pharmaceutical company. However, in the past decade, there has been an increase in pediatric safety and efficacy trials as a result of the 1997 FDA Modernization Act (FDAMA) that was extended in 2002 under the Best Pharmaceutical for Children Act. The FDAMA allows companies performing an FDA-approved pediatric drug trial to extend their patent for an additional six months. Unfortunately, even well-run exclusivity clinical trials under the FDAMA do not necessarily result in a FDA-approved pediatric drug label. An example is milrinone, that has been shown to decrease low cardiac output syndrome in young infants following biventricular repair but remains off-label. Of perhaps greater challenge are drugs that are available in generic form (dopamine for example), where the incentives of the FDAMA do not apply. Maltz and associates, in a study published in this issue of World Journal for Pediatric and Congenital Heart Surgery, investigated off-label drug use in a pediatric cardiac intensive care unit (PCICU). They found that 36% of the prescribed drugs were off-label, with 94% of the patients receiving at least one off-label drug and 46% of the patients receiving greater than three off-label drugs. This is an important educational point, as most practitioners are likely unaware of which pharmaceutical agents are FDA approved for pediatrics. Not surprising, patients at higher risk were shown to receive more medications and more off-label medications. Other publications have described the off-label drug use in pediatric anesthesia and intensive care and in hospitalized children with congenital and acquired heart disease. Offlabel drug use is not confined to the pediatric critical care population but has also been described in adult critical care units. The report by Maltz and associates offers a description of the frequency of off-label drug use in one PCICU. It is important to discount any conclusion that off-label drug use was a causative factor for increased length of stay. Increased length of stay has been shown to be a surrogate for complexity of disease and intensity of care. In the study by Maltz and associates, there are far too many risk variables that were not included in the analysis. In addition, the number of patients enrolled in their study was small. It is primarily an observational study. The descriptive analysis does not control for severity of illness and complexity of disease. One should not conclude that the off-label drug use was unsafe or contributed to harm. The field of pediatric cardiac critical care has evolved since its infancy three decades ago. Due in part to advancements in pharmaceutical options, survival following neonatal heart surgery has improved, hospital length of stay has become shorter, and our ability to recover a patient from a significant event has improved. Many drugs used in pediatric cardiac critical care are brought into our environment through the expertise of other specialties (pediatric critical care, neonatology, adult critical care, anesthesiology), with modifications in their dosage and indications over time. A current example is the rapidly increasing use of dexmedetomidine, despite limited trials evaluating dose ranging or efficacy, complications, or potential drug interactions. Thus, safety and efficacy for many drugs used in pediatric cardiac critical care are a result of years of experience rather than clinical trials. The use of off-label medications is to benefit the individual patient, and the FDA is very clear that practitioners are able to use their professional judgment to determine these uses. Offlabel drug use is therefore common in both pediatric and adult critical care settings. Does this mean patients are at risk? There is no plausible data to support such a contention. Obviously, we all want to prescribe drugs that have been adequately tested so that we understand their safety and efficacy. We also want protection from litigation if there is an adverse event perceived to be related to off-label use of a medication. How do we get this data? Clinical trials are the gold standard for changes in

Direct-to-Consumer Television Advertising: Time to Turn Off the Tube?

Direct-to-Consumer Television Advertising: Time to Turn Off the Tube?

The Future of USP Monographs for PET Drugs

Section 121 of the 1997 FDA Modernization Act (FDAMA) required that PET drugs be prepared according to U.S. Pharmacopeia (USP) compounding standards and PET drug monographs until the Food and Drug Administration (FDA) established appropriate approval processes and good manufacturing practice (GMP)

The Evolution of Trial Registries and Their Use to Assess the Clinical Trial Enterprise

THE ORIGINAL PURPOSE OF REGISTRIES OF CLINICAL trials was to reveal the existence of all trials, published or not, to investigators and systematic reviewers. Trials left unpublished because results were unfavorable to their sponsors, or simply because investigators never submitted them to journals for publication, could then be discovered, the trial investigators contacted, and the available trial evidence involving medical interventions could then be assessed. This would help eliminate publication bias, shown originally in the 1980s, demonstrated by Simes to affect the treatment of patients, and later revealed to be widespread by the expanding efforts of the Cochrane Collaboration. A seemingly arcane statistical point became a pressing clinical problem. Although the 1997 US Food and Drug Administration Modernization Act (FDAMA) established a US-based trial registry, ClinicalTrials.gov, the mandated content was narrowly defined by law, and trial investigators, whether funded by commercial sponsors, government agencies, or academic institutions, largely ignored any legal requirement to register. In the United States, the lines were drawn at a small invitational meeting in April 2000 that we both attended when pharmaceutical company executives stated emphatically that they would resist any effort to have a public registry of trials registered at inception. By that year, 2000, the US ClinicalTrials.gov registry was made publicly available (FIGURE), and in addition, more than 200 individual trial registries existed. Some investigators registered trials before the first patient was randomized, others when the trials were complete. The proliferation of registries by hospitals and academic centers was at least in part because their leaders could see the importance of trial enrollment as a way of attracting both grant funding and patients to their centers. Pharmaceutical companies established their own registries and contributed to existing registries as well. Many of these early trial registries were selective in the information they displayed and in their public accessibility, and they were remarkably limited on facts (eg, a drug might simply have been listed as “investigational drug”) at a time when developments in the techniques of systematic review and meta-analysis were demanding easier and fuller access to more uniform registries. Acknowledging that many others, chiefly in the United Kingdom, Europe, and elsewhere, had been pushing for trial registration, we responded with an explanatory editorial in 2003 designed to build the scientific, clinical, and ethical case for such registries and to secure support from academic leaders and journal editors, particularly in the United States. Two key events occurred in 2004. First, the New York State Attorney General Eliot Spitzer sued GlaxoSmithKline (GSK) for failing to reveal the results of trials that showed an antidepressant might be harmful. Within a matter of days, GSK and several other pharmaceutical companies announced that they would henceforth register their trials and had intended to do so all along. Shortly thereafter, the International Committee of Medical Journal Editors (ICMJE) announced that their journals, which included those regarded as among the most prestigious, would not publish reports of trials unless they had been registered, adding to their definition of trials and medical interventions the necessity of a concurrent control group and concentrating on phase 3 trials. For many, including the pharmaceutical industry and those in academia, the ICMJE decision was the most important motivator to register their trials, given the substantial gain to investigators and sponsors from positive results published in high-profile journals. The World Health Organization declared support for clinical trials registration and in 2006 launched the WHO International Clinical Trials Registry Platform (ICTRP), a portal through which more than a dozen major trial registries from around the world can now be accessed. They include ClinicalTrials.gov; ISRCTN; the Australian New Zealand

US FDA Modernization Act, Section 114

Section 114 of the 1997 US FDA Modernization Act (FDAMA) is an important vehicle for pharmaceutical companies to promote the economic value of their drugs to formulary decision makers, but little is known about how the Section has been interpreted and used. We conducted a web-based survey of a convenience sample of 35 outcomes directors of major pharmaceutical and biotechnology companies. We asked them about their interpretation of, and experiences with, Section 114, as well as their views regarding the FDA's role in the matter, and whether the advent of comparative effectiveness research (CER) will affect the use of Section 114 promotions. Of the 35 experts, 16 (46%) completed the survey. 81% stated they always or frequently consider using Section 114 when making promotional claims for drugs. 75% stated that the FDA should issue guidance on how to make such promotions to payers, especially what qualifies as "healthcare economic information" and "competent and reliable scientific evidence." Most expected to use Section 114 to a greater extent in the future, and agreed that the increased focus on CER would increase Section 114 use. The survey suggests strong awareness about Section 114 among the outcomes directors and some use of the Section for promotional purposes. It also reflects a belief that CER will increase use of Section 114 promotions, and that guidance from the FDA is needed. More clarity - and, ideally, flexible interpretation - from the FDA is warranted, especially given the rise of CER.

Break in the silence around FDAMA section 114

Break in the silence around FDAMA section 114

Patent Extension Policy for Paediatric Indications

The Food and Drug Administration Modernization Act (FDAMA) of 1997, Best Pharmaceuticals for Children Act (BPCA) of 2002 and Pediatric Research Equity Act of 2007 provide an extended period of 6 months of marketing exclusivity (i.e. patent extension) to prescription drug manufacturers that conduct paediatric studies. Branded drugs in the statin, ACE inhibitor and selective serotonin reuptake inhibitor (SSRI) classes were three of many classes with drugs granted patent extensions. We estimated the cost impact of the 6-month exclusivity extension policy on the Utah Medicaid drug programme by comparing actual costs to projected costs had the 6-month exclusivity extension not been granted for these drugs and thus less expensive generic alternatives been available sooner. Using these results, we then projected the cost impact of this policy on Medicaid programmes in the US during the 18 months following patent expiration. The Utah Medicaid prescription claims obtained for statins, ACE inhibitors and SSRIs included reimbursement amount, number of units dispensed, days supplied, date of service and drug strength. Actual expenditures for each drug were calculated for the 6 months before and 12 months after generic availability. The percentage difference between the brand name prescription reimbursement amount to Medicaid in the last 2 months of the 6-month extension and the generic prescription reimbursement amount to Medicaid in the first 2 months following exclusivity expiration was then calculated for each drug. This was done using data from the 5 months surrounding the exclusivity expiration by regressing the log-transformed Utah Medicaid reimbursement amount on an indicator for patent expiration, controlling for number of units, volume of sales, month filled and strength. This was used to estimate what the initial generic prescription price would have been without the 6-month patent extension and what costs would have been in the 18 months following the original expiration date if the patent extension had not been granted. Medicaid rebates were assumed to be 15.1% for branded products and 11% for generics. The 6-month extension policy was estimated to cost Utah's Medicaid $US2.2 (95% CI 1.9, 2.4) million for these three drug classes over the 18 months following the original patent expiration date (year 2007 values). Projected to the US Medicaid population, this cost was $US430 (95% CI 371, 475) million. For the individual drugs that we examined, the percentage cost decrease in reimbursement amount resulting from exclusivity expiration and generic entry ranged from 24.4% (p < 0.001) for enalapril to 3.8% (p = 0.0951) for pravastatin sodium. Makers of the branded drugs evaluated were given market exclusivity extensions for conducting studies of their medications in children. The costs found in this study are just a small portion of the total paid, which include those born by other payers. Whether the benefits of this policy outweigh these costs is an open question, but these results suggest that the costs to Medicaid and thus taxpayers are substantial.

Política de medicamentos en Estados Unidos de América

The USA federal prescription drug policies are inconsistent. The federal government regulates the development, production, marketing and safety of prescription drugs in the country through various legal mechanisms as well as private and governmental institutions. Patent laws also play an important role in this process protecting the pharmaceutical industry. The government has no direct mechanism to control prices of prescription drugs nor does it have a policy to cover the whole US population with a prescription drug benefit. The FDA is the agency charged with regulation of medicines. Various laws have been enacted over the years to improve quality control, safety and ensure efficacy of prescription drugs as: Prescription Drug User Fee Act (PDUFA) and Food and Drug Administration Modernization Act (FDAMA), as well as increase patient access to prescription drugs (Fast Track; Orphan Drug Act, Pediatric exclusivity). The Hatch-Waxman Act, named for its authors, has played an important role in the development of generic drugs with much success and a significant effect on drug prices. The insurance health system is voluntary and also inconsistent offering various forms of insurance that range from the individual applying for insurance personally, through employer financed health insurance, to government run health insurance systems. All health insurance may or may not have a prescription drug benefit.

Drug company advertising in medical journals about the health-economic advantages of their products for 2000-2006 versus 1990-1999.

Section 114 of the 1997 Food and Drug Administration Modernization Act (FDAMA) effective February 19, 1998, permitted some additional flexibility for drug companies to provide "health care economic information" to "a formulary committee or other similar entity" and may have caused a decline in economic messages used in print advertisements in medical journals. We previously investigated the promotional claims made by pharmaceutical companies about the economic advantages of their prescription products in print advertisements in 6 leading medical journals from 1990-1999. To examine the hypotheses that (1) economic promotion in journals declined after the effective date of Section 114 of the FDAMA, and (2) increased calls for U.S. Food and Drug Administration (FDA) scrutiny of health-economic information was associated with an increase in the reporting of supporting information for economic advertisements in 2000- 2006 compared with the 1990s. Two researchers independently reviewed all pharmaceutical print advertisements in 3 issues each year of 3 general medical and 3 specialty journals (totaling 18 issues each year) from 2000 through 2006. The type of economic claim (e.g., advertisements using the words "price," "costs less," "value") as well as the presence of supporting information for an advertisement's claims (e.g., published studies) were tabulated using a standardized data collection form. The research method was similar to that used in previous research of economic claims in advertisements in the same 6 medical journals from 1990-1999, and we compared the results from previous research for 1990-1999 with the new findings for 2000-2006. The list of health economic terms was expanded in the 2000-2006 research to include "less hospitalization"/"less treatment," "formulary"/"coverage," "co-pay"/"cost-sharing," and "in community longer." Our results are derived from 2,144 pharmaceutical advertisements from the 10-year period 1990-1999 and 1,372 from the 7-year period 2000-2006. Economic content occurred in 11.1% (237/2,144) of advertisements in the 1990s, and 7.6% (104/1,372) in 2000-2006 (P < 0.001). The frequency of economic advertisements rose in the 1990s to a peak in 1997 at 16.2% (31/191) (test for trend: P < 0.001) and declined thereafter, reaching a low of 3.9% (9/234) in 2002 (test for trend: P < 0.001) before rising again to 13.7% (25/182) in 2006 (test for trend: P=0.030). Economic claims centered mainly on direct costs (i.e., "less expensive") and benefit design (i.e., "one co-pay") and less on cost-effectiveness (i.e., "value"). The percentage of economic advertisements that included any supporting information was similar in the 1990s and 2000s (63.7% [151/237] vs. 61.5% [64/104], P = 0.70). The source of information to support an advertisement's economic claims shifted away from price information (e.g., "average wholesale price" or "Red Book") towards published studies and "data on file." Drug companies continue to advertise the economic advantages of their products in medical journals, though the practice declined somewhat after the 1997 FDAMA Section 114 legislation. Use of supporting references in the body of advertisements has not improved over time. The promotion of health economic information warrants more scrutiny by regulators and medical journal editors.

Pediatric Hypertension: Recent Trends and Accomplishments, Future Challenges

Publication of the Fourth Report on high blood pressure (BP) in children and adolescents by the National High BP Education Program (NHBPEP) in 2004 has been followed by a remarkable increase in interest in pediatric hypertension. New data have emerged on the epidemiology of hypertension in the young, the influence of the childhood obesity epidemic on BP, how ambulatory BP monitoring (ABPM) can be used in evaluating elevated BP and the extent of hypertensive target-organ damage in the pediatric age group. Exciting new information on drug treatment of pediatric hypertension has been produced by industry-sponsored clinical trials of antihypertensive medications spurred by the FDA Modernization Act (FDAMA) and successor legislation. Despite these trends, recognition of elevated BP in children and adolescents by primary care providers remains problematic. This article will highlight these and other aspects of pediatric hypertension, hopefully providing a snapshot of where we are in early 2008, and pointing out areas where further work is needed in order to reduce the future burden of adult cardiovascular disease.

Future of Pediatric Therapeutics: Reauthorization of BPCA and PREA

Clinical Pharmacology & TherapeuticsVolume 81, Issue 4 p. 477-479 Macroscopy Future of Pediatric Therapeutics: Reauthorization of BPCA and PREA Correction(s) for this article Future of Pediatric Therapeutics: Reauthorization of BPCA and PREA R M Ward, R Kauffman, Volume 81Issue 6Clinical Pharmacology & Therapeutics pages: 910-910 First Published online: April 11, 2007 R M Ward, Corresponding Author R M Ward [email protected] Pediatric Pharmacology Program, University of Utah, Salt Lake City, Utah, USASearch for more papers by this authorR Kauffman, R Kauffman Medical Research Department, Children's Mercy Hospital, University of Missouri, Kansas City, Missouri, USASearch for more papers by this author R M Ward, Corresponding Author R M Ward [email protected] Pediatric Pharmacology Program, University of Utah, Salt Lake City, Utah, USASearch for more papers by this authorR Kauffman, R Kauffman Medical Research Department, Children's Mercy Hospital, University of Missouri, Kansas City, Missouri, USASearch for more papers by this author First published: 21 February 2007 https://doi.org/10.1038/sj.clpt.6100109Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume81, Issue4Maternal and Child HealthApril 2007Pages 477-479 RelatedInformation

Why were we abandoned? Orphan drugs in paediatric pain

Why were we abandoned? Orphan drugs in paediatric pain

Stimulation programs for pediatric drug research – do children really benefit?

Most drugs that are currently prescribed in pediatrics have not been tested in children. Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act (FDAMA) that grants patent extensions when pediatric labeling is provided. We investigated the effectiveness of these programs in stimulating drug research in children, thereby increasing the evidence for safe and effective drug use in the pediatric population. All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or, if these were unavailable, the labeling information as provided by the manufacturer. A systematic search of the literature was performed to identify drug utilization patterns in children. From July 1998 to August 2006, 135 drug entities were granted pediatric exclusivity. Most frequent drug groups were anti-depressants and mood stabilizers, ACE inhibitors, lipid-lowering preparations, HIV antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs. The distribution of the different drugs closely matched the distribution of these drugs over the adult market, and not the drug utilization by children. Many drug studies in children have been performed since the introduction of the FDAMA. However, children infrequently use the drugs granted pediatric exclusivity. The priorities for pediatric drug research should be set by the need of the patients, not by market considerations.

Pediatric Drug Development in Anesthesiology: An FDA Perspective

Bob A. Rappaport, MD 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.

New Pathways for Evaluating Potential Acute Stroke Therapies

Pharmacological therapy for acute ischemic stroke remains limited to one successful, approved treatment: tissue plasminogen activator within 3 h of stroke onset. Many neuroprotective drugs and a few other thrombolytics were evaluated in clinical trials, but none demonstrated unequivocal success and were approved by regulatory agencies. The development paradigm for such therapies needs to provide convincing evidence of efficacy and safety to obtain approval by the Food and Drug Administration (FDA). The FDA modernization act of 1997 stated that such evidence could be derived from one large phase III trial with a clinical endpoint and supportive evidence. Drugs being developed for acute ischemic stroke can potentially be approved under this act by coupling a major phase III trial with supportive evidence provided by a phase IIB trial demonstrating an effect on a relevant biomarker such as magnetic resonance imaging or computed tomography assessment of ischemic lesion growth. Statistical approaches have been developed to optimize the design of such an imaging-based phase IIB study, for example approaches that modify randomization probabilities to assign larger proportions of patients to the 'winning' strategy (i.e. 'pick the winner' strategies) with an interim assessment to reduce the sample size requirement. Demonstrating a treatment effect on a relevant imaging-based biomarker should provide supportive evidence for a new drug application, if a subsequent phase III trial with a clinical outcome demonstrates a significant treatment effect.

FDA perspectives on health claims for food labels

The U.S. Food and Drug Administration's regulatory authority over health claims was clarified in 1990 legislation known as the Nutrition Labeling and Education Act (NLEA). This law established mandatory nutrition labeling for most foods and placed restrictions on the use of food label claims characterizing the levels or health benefits of nutrients in foods. NLEA set a high threshold for the scientific standard under which the U.S. Food and Drug Administration (FDA) may authorize health claims, this standard is known as the significant scientific agreement (SSA) standard. Subsequent legislation known as the Food and Drug Administration Modernization Act (FDAMA) provided an alternative to FDA review of the health claim where an U.S. government scientific body other than FDA concluded that there is SSA for a substance/disease relationship. Courts have since extended the scope of health claims to include qualified health claims (QHC) that are health claims not substantiated on evidence that meets the level of SSA standard, but include a qualifying statement intended to convey to the consumer the level of evidence for the claim. FDA has responded by developing an evidence-based ranking system for scientific data to determine the level of evidence substantiating a health claim. The following is an overview of FDA's regulations and evidence-based method for evaluating health claims.

Medication Studies Increase For Children, Adolescents

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessMedication Studies Increase For Children, AdolescentsJim RosackJim RosackSearch for more papers by this authorPublished Online:19 Sep 2003https://doi.org/10.1176/pn.38.18.0016As the body of efficacy evidence continues to grow, clinical trials of adult medications in children are adding strength to a long-held scientific secret: Children are not simply adults hiding in a smaller package, at least not when it comes to medications.In 1997 the Food and Drug Administration Modernization Act (FDAMA) required the agency to promote research into pediatric use of adult medications through a “pediatric exclusivity” incentive program.The program promised drug manufacturers an additional six months of patent protection for their branded medications in exchange for research on the use of those medications in children.The FDAMA instructed the FDA to develop a list of medications approved for use in adults that were commonly used in children but had not been studied for safety or efficacy in pediatric populations. From that list, the FDA was to make written requests to the manufacturers of the drugs on the list asking for clinical data on at least the safety of the medications in children and adolescents. Efficacy studies were not required.According to information posted on the FDA Web site, as of August 22, 88 medications had been studied in children, resulting in labeling changes to 58 and the granting of pediatric exclusivity to 53. To date, the FDA has issued 242 written requests for pediatric data.While the FDA requested pediatric data on numerous psychotropic and related medications, only two antidepressant, one antiseizure, and two antianxiety medications have undergone pediatric labeling changes.In 1998 midazolam (Versed) was relabeled to include data on effective dosing and time of onset and adverse-event information specific to pediatric populations. In 2000, fluvoxamine (Luvox) was relabeled to reflect data on dosing and the requirement for a dose adjustment in adolescents (increased dose) and girls aged 8 to 11 (decreased dose). Also that year, gabapentin (Neurontin) was relabeled to reflect neuropsychiatric adverse events in children aged 3 to 12.Late in 2000, Lilly submitted data showing fluoxetine’s safety and efficacy in children and adolescents for both obsessive-compulsive disorder and major depression. To date, it remains the only antidepressant labeled as indicated for children and adolescents (Original article: see related article on page 2). The fluoxetine studies documented decreased weight gain in children and the potential for switching of children into mania or hypomania. Specific dosing information was also included in the revised label.Recently, studies of paroxetine (Paxil) created a stir when they failed to show efficacy in children and adolescents with major depression and raised significant safety concerns about suicidal thoughts and behaviors in pediatric populations. Those studies were prompted by the pediatric exclusivity provision.In 2001 Bristol-Myers Squibb submitted data showing that the safety and efficacy of buspirone (Buspar) were not shown in patients aged 6 to 17 for generalized anxiety disorder. In addition, the studies found variable pharmacodynamic parameters that differed from those in adults. In many cases, including those above, studies prompted by the pediatric exclusivity clause of FDAMA (which was reauthorized by Congress in 2002) have found significant differences in the use of the medication in children and adolescents compared with adults.A study in the August 20 Journal of the American Medical Association highlights those differences. The study, by four staff members of the FDA’s Office of Counter-Terrorism and Pediatric Drug Development, concluded that the FDAMA “has stimulated pediatric clinical studies, resulting in improved understanding of the pharmacokinetics of drugs prescribed in pediatric medicine, important dose changes, and improved safety for children taking certain drugs.”Dianne Murphy, M.D., director of the FDA’s Office of Pediatric Therapeutics and a co-author of the report, noted in a press release that while the pediatric exclusivity program “has led to improvements, it is voluntary and cannot solve the problem alone.”Indeed, the FDA has supported the Pediatric Research Equity Act (S 650), which was passed by the Senate and awaits action by the House of Representatives. The bill would restore a 1998 FDA regulation known as the pediatric rule under which the FDA could require drug companies to undertake clinical trials of medications in pediatric populations and submit data on safety and efficacy.The pediatric rule was struck down by a U.S. District Court decision in October 2002. The court ruled that the FDA did not have legislative authority from Congress to require pediatric testing. S 650, which would give the agency that authority, has been supported by APA, the American Academy of Pediatrics, American Academy of Child and Adolescent Psychiatry, and AMA.Murphy’s study is posted on the Web at http://jama.ama-assn.org/cgi/content/full/290/8/1033. The text of the Pediatric Research Equity Act can be accessed at http://thomas.loc.gov by searching on the bill number, S 650. ▪ JAMA 2003 290 1033 ISSUES NewArchived

Policy developments in regulatory approval.

Although radical changes in drug regulation are rare (e.g., the Federal Food, Drug and Cosmetic Act of 1938 and the 1962 amendment to the Act creating an effectiveness requirement), regulations and guidance do evolve significantly in the face of new problems and accumulating experience. Recent changes have been driven by the Food and Drug Administration Modernization Act (FDAMA), user fee legislation, the International Conference on Harmonization, recent safety related drug withdrawals, and concerns about trial ethics and investigator conflict of interest. FDAMA and guidance developed in response to it has helped circumstances in which FDA would rely on a single study to support effectiveness and the circumstances in which surrogate endpoints could support approval. An ICH Document 'Choice of control group and related design issues in clinical trials' focussed attention on the ethics of placebo controls (acceptable, even if there is existing therapy, when the placebo-treated patient will suffer no irreversible injury) and the design of 'equivalence' or 'non-inferiority' trials. There has been greatly increased attention to obtaining good dose-response information and to assessing need for modifying treatment in demographic (age, gender, race) and concomitant disease (renal or hepatic function abnormalities) subgroups, and in assessing drug-drug interactions. Other important trends are increasing reliance on non-U.S. data, increasing numbers of FDA-industry meetings during drug development, and new focus on risk assessment and risk management.