10093_Impact Of Fdaaa On Registration, Results Reporting, And Publication Of Clinical Trials Evaluating

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Yale Medicine Thesis Digital Library
School of Medicine
January 2019
Impact Of Fdaaa On Registration, Results
Reporting, And Publication Of Clinical Trials
Evaluating New Neuropsychiatric Drugs Approved
Between 2005 And 2014
Constance Xuanyi Zou
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Recommended Citation
Zou, Constance Xuanyi, “Impact Of Fdaaa On Registration, Results Reporting, And Publication Of Clinical Trials Evaluating New
Neuropsychiatric Drugs Approved Between 2005 And 2014” (2019). Yale Medicine Thesis Digital Library. 3547.
https://elischolar.library.yale.edu/ymtdl/3547

Impact of FDAAA on Registration, Results Reporting, and
Publication of Clinical Trials Evaluating New
Neuropsychiatric Drugs Approved between 2005 and 2014

A Thesis Submitted to the Yale University School of Medicine in Partial
Fulfillment of the Requirements for the Degree of Doctor of Medicine

by
Constance Xuanyi Zou

Class of 2019
Abstract

IMPACT OF FDAAA ON REGISTRATION, RESULTS REPORTING, AND
PUBLICATION OF CLINICAL TRIALS EVALUATING NEW
NEUROPSYCHIATRIC DRUGS APPROVED BETWEEN 2005 AND 2014

Constance X. Zou, Jessica E. Becker, Adam T. Phillips, James M. Garritano, Harlan M.
Krumholz, Jennifer E. Miller, Joseph S. Ross

Center for Outcome Research and Evaluation, Department of Medicine, Yale University
School of Medicine and Yale-New Haven Hospital, New Haven, Connecticut

Evidence-based medicine (EBM) promotes the use of randomized controlled trials
(RCTs) published in peer reviewed medical journals as the “gold standard”. However, up
to 50% of the completed clinical trials are never published and trials with results in favor
of studied interventions are 2-4 times more likely to have been published then those with
non favorable results. Publication bias seems to be a particularly severe problem for
RCTs evaluating newly approved brand-name neuropsychiatric drugs. Mandatory trial
registration, and later results reporting, were proposed to mitigate selective clinical trial
publication and outcome reporting. Congress enacted the FDA Amendments Act
(FDAAA) on September 27, 2007 requiring the registration of all non-phase I clinical
trials involving FDA-regulated medical interventions and results reporting for FDA
approved drugs. It’s been 10 years since FDAAA enactment, the impact of FDAAA on
the selective publication of clinical trials has not been studied. Our objective is to
determine whether FDAAA enactment is associated with improvements in trial

2

registration and results reporting, as well as with decreased publication bias of clinical
trials evaluating new neuropsychiatric drugs. We conducted a retrospective cohort study
of all efficacy trials supporting FDA new drug approval between 2005 to 2014 for
neuropsychiatric indications. Trials were categorized as pre- or post-FDAAA based on
initiation and/or completion dates as outlined by the statue. The main outcomes were the
proportions of trials registered, proportions reported results in ClinicalTrials.gov, and the
degree of publication bias. Publication bias was estimated using the relative risks pre- and
post-FDAAA of both the publication of positive vs non-positive trials, as well as of
publishing positive vs. non-positive trials without misleading interpretations. Registration
and results reporting proportions were compared pre- and post-FDAAA using two-tailed
Fisher Exact Test and the degrees of publication bias were compared by calculating the
ratio of relative risks (RRR) for each period. Our study sample included 101 Pre-FDAAA
and 41 Post-FDAAA efficacy trials supporting the FDA approval of 37 new drugs for
neuropsychiatric indications between 2005 and 2014. Post-FDAAA trials were
significantly more likely to be registered (100% vs 64%; P<0.001) and report results (100% vs 10%; P<0.001) than pre-FDAAA trials. Pre-FDAAA, positive trials were more likely to be published (RR=1.52; 95% Confidence Interval [CI]=1.17-1.99; P=0.002) and published without misleading interpretations (RR=2.47; Cl=1.57-3.73; p<0.001) than those with non-positive results. In contrast, post-FDAAA positive trials were equally likely to have been published (RR=1; Cl=1-1, p=NA), and published without misleading interpretations (RR=1.20; Cl=0.84-1.72; p=0.30). The likelihood of publication bias pre- FDAAA vs. post-FDAAA was greater for publication of positive vs. non-positive trials (RRR=1.52; Cl=1.16-1.99; p=0.002) and for publication without misleading interpretations (RRR=2.06, Cl=1.17-3.61, p=0.01). The enactment of FDAAA was followed by significantly higher proportions of trials that were registered and reported 3 results on ClinicalTrials.gov, and with significantly lower degrees of publication bias among trials supporting recent FDA approval of drugs for neuropsychiatric indications. 4 Acknowledgement We would like to thank Dr. Vinay Rathi (Yale University School of Medicine Class of 2015) for his outstanding peer mentorship. We thank the organizers of the Eighth Inter- national Peer Review Congress (PRC) for giving us the opportunity to present our work,1 and the editors and reviewers who helped us publish our manuscripts in Trials. 1 Video recording of Ms. Zou’s presentation has been made available by the meeting or- ganizer through Youtube. https://youtu.be/yDKwxE81Tk4 2 Zou CX, Becker JE, Phillips AT, et al. Registration, results reporting, and publication bias of clinical trials supporting FDA approval of neuropsychiatric drugs before and after FDAAA: a retrospective cohort study. Trials. 2018;19(1):581. 1 Table of Contents INTRODUCTION ...........................................................................................................................1 The Role of Randomized Controlled Trials in Modern Medicine ....................................................1 RCT, Gold Standard with an Achille’s Heel. ...................................................................................2 RCT, Gold Standard or Gold Trojan Horse?.................................................................... ...............4 FDAAA: Mandatory Registration and Results Reporting ...............................................................5 STATEMENT OF PURPOSE .........................................................................................................7 METHOD ........................................................................................................................................9 Data Sources .....................................................................................................................................9 Novel Therapeutics Approved for Treating Neurological and Psychiatric Disorders, 2005-2014 ...9 Efficacy Trials Supporting FDA New Neuropsychiatric Drug Approval .......................................10 Determination of FDAAA Status ...................................................................................................11 Determination of Registration and Results Reporting Status on ClinicalTrials.gov ......................11 Determination of Publication Status ...............................................................................................12 Interpretation of Trial Results: Publication vs. FDA ......................................................................12 Validating the Published Interpretations .........................................................................................13 Calculating the Degree of Publication Bias ...................................................................................14 Data Collection and Data Validation .............................................................................................14 Data Analysis .................................................................................................................................15 RESULTS ......................................................................................................................................16 Characteristics of the Neuropsychiatric Drugs Approved between 2005-2014 ..............................16 Table 1. New Drug Applications (NDA) Approved by the FDA between 2005 and 2014 with Indications for Neurologic and Psychiatric Conditions .................................................................16 Clinical Trials Supporting FDA Approval .....................................................................................18 Clinical Trial Registration and Results Reporting .........................................................................18 Publication and Published Interpretations .....................................................................................19 Table 2. Characteristics of 142 Efficacy Trials Supporting FDA Approval of NDA for neuropsychiatric conditions, 2005-2014 .........................................................................................19 Table 3. Publication and Publication-FDA Agreement of Trials Supporting FDA Approval of NDAs with Neuropsychiatric Indications with Positive, Equivocal, and Negative Results ...........20 Box 1 Examples of Trials Published with Interpretations Disagreeing with the Interpretations of the FDA medical reviewers. ...........................................................................................................21 Publication Bias .............................................................................................................................25 DISCUSSION ................................................................................................................................26 Study Findings & Prior literature ....................................................................................................26 Implication for Understanding the Impact of FDAAA ...................................................................27 Implications for Future Policy Development ..................................................................................28 Implications for the Practice of Medicine .......................................................................................28 Limitations ......................................................................................................................................29 Conclusions ....................................................................................................................................30 2 REFERENCE .................................................................................................................................31 FIGURES, TITLES, AND LEGENDS ..........................................................................................31 Figure 1. Identification of Trials Reviewed by the FDA for New Drug Applications with Neuropsychiatric indications, 2005-2014 .......................................................................................37 Figure 2 Registration and Results Reporting Status of Trials Supporting FDA Indications by FDAAA applicability, 2005-2014 ..................................................................................................38 Figure 3. Publication Status and Publication-FDA Agreement of Neuropsychiatric Trials by FDAAA Applicability and by Trial Results ...................................................................................39 1 Introduction The Role of Randomized Controlled Trials in Modern Medicine Randomized controlled trials (RCT) started to have profound impacts on the prac- tice of medicine today since the rise of evidence-based medicine (EBM) , which has been defined as “the conscientious, explicit, and judicious use of current best evidence in mak- ing decisions about the care of individual patients.” (1) However, it is difficult, to put one’s finger on what made EBM the haute couture, based on its name and such a defini- tion. Some find it difficult to distinguish the phrase EBM from the word medicine itself. (2, 3) (3)(4–7)If one were to summarize the teaching of how-to-EBM textbooks and guides(14–18), EBM method describes an RCT based formula to answer hypothetical questions involving hypothetical patients with hypothetical diseases related to clinical care. The main agenda of the EBM campaign is to make sure that RCTs are the best evi- dence and that only the RCT are good enough to rely on as the “gold standard” for “judging whether a treatment does more good than harm” (19)because they are “so much more likely to inform clinicians and so much less likely to mislead them” (than the alter- natives).(20)(3)(21) The success of EBM campaign has resulted in many parts of medicine being gov- erned by RCTs through the Practice Guidelines, which are usually issued by medical pro- fessional societies outlining best practices. These practice guidelines are welcomed by physicians who are believers of the power of RCT but find themselves incapacitated by the complexity of the method and the volume of the work involved in full EBM style in- vestigation and calculation. The proponents of EBM may object to the idea that EBM en- courages mindless following of practice guidelines, after all, the physician can and should 2 learn to speak the EBM fluently themselves and use it to guide their day to day practice. That could happen if the United States suddenly required graduate degrees in statistics for all medical school graduates; if the physicians have at least days between each appoint- ment to perform one round of rituals in full as outlined by the 500-hundred page long EBM bible; (21) and if there is a sudden change of US malpractice law. The truth is the physicians cannot afford the time or the effort to perform EBM on their own. When they do try, it usually means a quick PubMed search followed by skimming through the ab- stracts of a few randomly selected publications of RCTs. They could not afford the lux- ury sometimes to disobey the order of the “best practice” as outlined in the practice guidelines, even when they have good reasons to believe it inappropriate for a given set- ting. They may lose bonuses tied to meeting “quality measures”, which are frequently based on guidelines, or worse, they can be sued for transgressing the norm as definied by their professional societies even though it was suppose to be a suggestion. Practice guidelines are being used in the malpractice arena to define a credible standard of care to measure the accused physician for an alleged problem addressed. This may occur despite a medical society's disclaimer that they are not intended, nor devised, for that purpose. (22) RCT, Gold Standard with an Achille’s Heel The EBM formula relies on RCTs published in the literature. The problem is as many as 50% of completed clinical studies were never published (23–42)What’s more, trials with non-positive results were significantly more likely to remain unpublished than trials with positive results and negative results were often manipulated to appear positive. (39, 43–46) Experience has shown that such study reports do not always contain a complete, or en- tirely accurate, representation of study plans, conduct and outcomes. Outright fraud (i.e., 3 deliberate deception) is unusual. However, incompleteness, lack of clarity, unmentioned deviation from prospectively planned analyses, or an inadequate description of how criti- cal endpoint judgments or assessments were made are common flaws. (47) Because studies were usually considered positive when whatever proposed new in- tervention works better than a control, publication bias leads to perceived efficacy. EBM informed clinical practice based on half of the whole truth can result in inappropriate en- thusiasms for what’s new. Many considered the problems of nonpublication and untruth- ful publication to be particularly severe among trials evaluating newly approved brand name neuropsychiatric drugs.(48) Clinical studies supporting approved drugs for neuro- psychiatric indications, such as paroxetine (Paxil) (49), reboxetine (Edronax ) (50)gabapentin (Neurontin) (51), and lamotrigine (Lamictal) (52), have been identified as being subject to underreporting. Data demonstrating these drugs to be potentially ineffec- tive for approved indications or suggesting harm were not publicly disclosed until the pharmaceutical companies’ internal documents were reviewed during legal proceedings (53, 54) Ten years ago, if a psychiatrist were to use the EBM method to calculate and com- pare the effect size of any of the one dozen antidepressants approved in the previous sev- eral decades, he or she would find only good news—all of the published trials showed the drugs to be effective, but in fact only half of the completed trials were. The physician would overestimate the effect size of each drug for about 30%. (28)Take one of these an- tidepressants Serzone (nefazodone) for example, which was approved by the FDA in 1994. When the drug was just approved, Bristol-Myers called it a "significant" addition to the numerous antidepressants with an “additional boost, fewer side-effects—and a lower price.”(55) It was speculated that the sales of this drug contributed to the fact that Bristol-Myers Squibb “posted record results for 1996.” (56) While its effective size based 4 on FDA documents was only 0.26. Effect size measures the magnitude of difference be- tween a given drug and the placebo. 0.2-0.5 is small difference, 0.5-0.8, medium, and 0.8-1, high. 0.26 means the difference between nefazodone and sugar pills are small. Be- cause its effective size based on the published trials was 69% higher, EBM practice based on published RCTs would conclude that the drug seem to have a moderate effect. (28) It is also worth noting this drug was associated with severe liver toxicity and death and was pulled from the market in 2004. (57–59) Similarly, among trials evaluating drugs indicated for anxiety (23), and psychotic disorders (60) that were first approved by the U.S. Food and Drug Administration (FDA) in recent decades, 80-90% of trials with negative or equivocal results were either not pub- lished or were published in a misleading manner to suggest a positive result, while nearly 100% of trials with positive results were published. RCT, Gold Standard or Gold Trojan Horse? Many feel that this new paradigm brought by EBM based on RCT is doomed to fail because the industry can and will harness the power of RCT for the benefit of the few. (2, 3, 61–73) In the perfect world pictured by the proponents of EBM, RCTs are performed by disinterested researchers who are driven only by the desire to further truth,to improve care, and to reduce waste. In reality, most large RCT are sponsored by the industry as business strategy. It is unrealistic to expect that they will always choose to protect the public interest even at the cost of getting a smaller share of the $3 Trillion that United 5 States spends on healthcare each year, of which 17% were for prescription drugs. (74) Because of high cost of new drug development, high risk of failure, and high poten- tial financial gain, conflicts of interest is a particularly serious problem for RCT evaluat- ing new drugs. With few exceptions, for profit industry are the primary funders of clinical trials because of the high cost associated with conducting early phase clinical trials to evaluate drugs that had never been used in humans: Phase II trials can cost up to $20 mil- lion dollars, while Phase III, up to $50 million each. On average, the cost to run clinical trials to support the FDA approval of a new drug for a single indications is about 200 mil- lions dollars. In order for the drug company to profit, not only they need to recover the astronomical cost invested in the drug targest that received approval, but also those that did not, which happens 2 to 50 times more often. (75, 76) (77) FDAAA: Mandatory Registration and Results Reporting What can be done to prevent the results of completed trials from being swept under the rug? Publication has always been and will likely remain voluntary, but if the proto- cols and results of all clinical trials can be found through a publicly accessible, central- ized trial registry, it would be difficult for the sponsors to withhold trials with unfavora- ble results or to introduce post hoc analysis to encourage positive interpretations of the results. Additionally, Journal editors, peer reviewers, and interested members of the pub- lic could cross reference the results submitted by the sponsors and investigators for publi- cation. In 1997, Congress passed the FDA Modernization Act (FDAMA), which mandated the first U.S.-based public registry ClinicalTrials.gov in 2000 by the National Institute of Health (NIH) . In 2005, the International Committee of Medical Journal Editors (ICMJE) 6 issued a policy requiring trial registration as a condition of publication in member jour- nals.De Angelis et al., 2009, #257} Nonetheless, FDAMA only required registration of a small number of trials, while the ICMJE recommendation was only followed on a volun- tary basis and still permitted publication of unregistered trials. (78) (79) In 2007, Congress passed the FDA Amendments Act (FDAAA). At the time FDAAA was applicable to essentially all non-phase I interventional studies involving FDA-regulated drugs, biological products, or devices with manufacture site or trial site based in the United States. FDAAA mandated that sponsors and investigators register all applicable trials in ClinicalTrials.gov prior to subject enrollment, and report results to ClinicalTrials.gov within 30 days post approval of the indication being studied. FDAAA is applicable to trials that began after September 27th, 2007 and to earlier trials that were still ongoing as of December 26th, 2007. Inappropriately delayed registration and results reporting, as well as reporting of false results, are punishable by fines of up to $10,000 per day and can lead to withholding of funding from studies receiving federal support. It has now been ten years since FDAAA was enacted. Its impact on clinical trial registration, results reporting, and publication bias has largely remained undetermined. (41)Recently we demonstrated that FDAAA was associated with increased registration and publication of clinical studies in another study involving new drugs approved to treat cardiovascular disease and diabetes (CXZ performed data validation and contributed to the final editing of the manuscript for publication). (80)However, no study has focused on trials involving drugs treating neurological and psychiatric conditions, an area for which concern for selective publication and outcome reporting remain. 7 Statement of Purpose We conducted a retrospective cohort study using efficacy trials that were submitted to and reviewed by the FDA for the approval of new drug applications (NDA) between 2005 and 2014 for the treatment of neurologic and psychiatric conditions. Our objective is to compare the rate of registration, results reporting, and the degree of publication bias for efficacy trials involving newly approved drugs treating neurologic and psychiatric conditions before and after the enactment of FDAAA. For each trial, we determined whether a trial is pre- or post-FDAAA based on trial initiation and/or completion dates, as well as their registration, results reporting, and publication status, Prior to conducting this study, we put forth the following hypotheses: 1. There is an association between the FDAAA status, and the likelihood of trial registration on ClinicalTrials.gov. 2. There is an association between the FDAAA status, and the likelihood of trial results reported to ClinicalTrials.gov. 3. There is an association between the FDAAA status and the degree of publica- tion bias. The aim of this study was three fold: (1) to assess the impact of FDAAA on selective reg- istration and publication of efficacy trials supporting new drugs approved by the FDA to treat neurologic and psychiatric conditions, (2) to assess the degree of publication bias 8 among trials evaluating newly approved neuropsychiatric drugs, and (3) to inform ongo- ing efforts to regulate clinical trials registration and results reporting. 9 Method Data Sources Data were obtained from three sources: Drugs@FDA , ClinicalTrials.gov and PubMed’s listing of Medline-indexed journals. Drugs@FDA is a public database maintained by the FDA, providing access to regulatory actions and documents issued for each drug approved by the agency. ClinicalTrials.gov is a public clinical trial registry database maintained by the National Library of Medicine at the NIH (U.S. National Library of Medicine 2018). PubMed’s list of Medline-indexed journals includes more than 5,500 biomedical journals. Novel Therapeutics Approved for Treating Neurological and Psychiatric Disorders, 2005-2014 The Center of Drug Evaluation and Research (CDER), which is part of the FDA, provides annual reports summarizing all New Drug Applications (NDAs) approved in each year (U.S. Food and Drug Administration). We downloaded the reports from 2005 to 2014, when available, and otherwise searched Drugs@FDA for those NDAs that were approved to treat neurologic and psychiatric disorders. Our study sample began with drugs approved in 2005 to align with our prior work (Downing, Aminawung et al. 2014) and because an earlier seminal study on the topic examined all antidepressants approved through 2004 (Turner, Matthews et al. 2008); we chose to exclude drugs approved after December 2014 to ensure that at least 24 months had passed between drug approval date and the date when we concluded the final search for the registration record, reported results and publication, which was March 2017. For each NDA, we recorded its 10 indication, orphan status, priority review status, accelerated approval status, sponsor, and approval date. CXZ performed all of the above data collection in the summer of 2016. JSR, as the principle investigator, reviewed with CXZ the lists of approved NMEs and BLAs between 2005 and 2014 to ensure that all new drugs approved with neuropsychiatric indications were included in our sample. JSB, randomly selected 4 drugs using an online randomizer and validated the data collected for those 4 drugs. Efficacy Trials Supporting FDA New Neuropsychiatric Drug Approval As described in a comprehensive tutorial for how to use the Drugs@FDA (Turner 2013), we downloaded the relevant FDA files for each NDA from Drugs@FDA, including the approval letters, summary reviews, clinical reviews, and statistical reviews. Among these files, we searched for clinical trials evaluating the efficacy of the drugs under review. We included only trials for which the FDA discussed and characterized results, based on the assumption that these trials influenced the FDA’s decision to approve the study drug for the proposed indication. We excluded ongoing trials, phase I/safety-only trials, expanded access trials, terminated and withdrawn trials without enrollment, and trials evaluating indications different than that for which the drugs were originally approved. We also excluded failed trials. Failed trials were determined by the FDA and the results of failed trials are invalid. For each included trial, we recorded the following characteristics: pivotal status, phases, sponsors, study sites, trial length, randomization, blinding, types of control, description of the treatments, arms of the investigational drugs, enrollment numbers, and the primary efficacy endpoints. A pivotal study is defined by the FDA as “a definitive study in which evidence is gathered to 11 support the safety and effectiveness evaluation of the medical product for its intended use” (2013). Pivotal status was frequently assigned prospectively by FDA, occasionally assigned retrospectively by the FDA, or at times not assigned by FDA and thus determined using a previously described method. (Downing, Aminawung et al. 2014) All searches and data collection were done by CXZ between June 2015 and October 2015. JSB validated the data collected associated with previously randomly selected 4 NDAs. Determination of FDAAA Status At the time when. FDAAA was enacted in 2007, it applied to trials that were initiated after September 27th, 2007, as well as to trials initiated earlier but still ongoing as of December 26th, 2007. Based on this, FDAAA applicable trials were categorized as post-FDAAA, while trials that were initiated or completed prior to the cut-off dates were categorized as pre-FDAAA. All coding was done by CXZ in the summer of 2015. JSB validated the data collected associated with previously randomly selected 4 NDAs. Determination of Registration and Results Reporting Status on ClinicalTrials.gov To determine whether trials were registered and reported results on ClinicalTrials.gov, one investigator (CXZ) performed the initial search using the following terms and their combination: generic, or brand names of the study drugs, drug indications, trial IDs, trial acronyms, numbers of participants randomized, comparators, and study time frames. All searches were done by CXZ between the summer of 2015. JSB validated the data collected associated with previously randomly selected 4 NDAs. For trials that were not able to be matched with any registration record, a second 12 investigator (JEB) independently performed a second round of searches. No new records were identified. Determination of Publication Status To determine whether trials were published, we searched PubMed for full-length publications using the same terms as we did for the registration record. Among identified publications, abstracts and conference reports were excluded. Publications reporting multiple trials, such as reviews and meta-analyses were also excluded unless the results of each trial were analyzed and discussed individually in the level of detail as one would expect from a full-length publication. When the search terms returned too many similar entries in PubMed, we used Google Scholar to narrow the results. Google Scholar has the advantage that it can search among the full texts of publications hosted by a variety of online database or platforms, while for many journals, especially those that require paid access, PubMed searches only among the title and abstracts. All searches were done by CXZ between the summer of 2015 and the spring of 2016. JSB validated the data collected associated with previously randomly selected 4 NDAs. For trials that were not able to be matched with any registration record, a second investigator (JEB) independently performed a second round of searches. No new records were identified. Interpretation of Trial Results: Publication vs. FDA Trials were classified as positive, negative, or equivocal based on the FDA’s interpretation of the results as described in Additional File 1. The classification was based on whether the primary outcome(s) achieved statistical significance while taking into consideration the summary statements made by the FDA medical reviewers 13 regarding whether or not the findings provide support for the efficacy claim of the study drugs. Published trial results were categorized similarly based on whether the primary outcomes achieved statistical significance according to the authors’ analysis while taking into considerations the authors’ conclusions in the abstract section. Trials with equivocal or negative results were grouped together as non-positive trials for purposes of calculating publication bias. All data collection was done by CXZ between the summer of 2015 and the spring of 2016. JSB validated the data collected associated with previously randomly selected 4 NDAs. For trials that were not able to be matched with any registration record, a second investigator (JEB) independently performed a second round of searches. No new records were identified. Validating the Published Interpretations We validated the interpretations of the trial results made by the study investigators for each publication using the interpretations made by the FDA medical reviewers found in the FDA approval package as the gold standard. Both the conclusions in the abstract and the main text of the publications were validated. The two were considered in agreement if the interpretations were both categorized as positive, negative or equivocal, and no major contradictions existed between the two statements. As an example of contradiction between two sources: the published interpretation of trial 02 of milnacipran (Savella) concluded that “both doses (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms.” (81) This was considered different from the statement made by the FDA in the summary review documents, which stated that “[the] analysis of the ‘pain only’ responders does not indicate that there is a significant effect of MLN 14 (Savella) on pain….(treatment effect) was driven by the patient global response outcome rather than the pain or function outcome…when studied in isolation, statistically significant treatment effects for pain and function were not demonstrated.” (82) All coding was done by CXZ in the summer and fall of 2016. JSB validated the coding associated with the previously selected 4 drugs. Due to the interpretive nature of this comparison, two additional investigators (JEB and JSR) reviewed all instances where there was disagreement between the FDA’s and the authors’ interpretation. Calculating the Degree of Publication Bias We calculated and compared two different measures of publication bias between pre- and post-FDAAA trials. First, we estimated the relative risk of publication of positive vs non-positive trials in each period. Second, we estimated the relative risk of publishing positive vs non-positive trials without misleading interpretations in each period. Thus, publication bias was calculated as the ratio of relative risks (RRR) pre- FDAAA vs post-FDAAA. CXZ completed the data analysis in fall 2017 and JSR performed validation of the analysis. Data Collection and Data Validation Registration status, results reporting status, publications status, and publication- FDA interpretation agreement were validated as described previously. We performed a quality control for the rest of the data set, many of which were collected but not reported for purposes of this study. A second investigator (JEB) re-collected all data elements obtained for a random 10% sample of the included new drug approvals, using an online randomization tool to randomly select 4 out of the 37 drugs. Among the 676 unique data 15 elements collected by the two investigators, the rate of agreement was 99.6% and disagreements were resolved through consensus. Data Analysis We used descriptive statistics to characterize the proportions of trials that were registered and reporting results on ClinicalTrials.gov. We used two-tailed Fisher Exact tests to compare the proportions among pre- and post-FDAAA trials. Analysis was performed using Epi Info Companion App for iOS (3.1.1) (Centers for Disease Control and Prevention [CDC]; Atlanta, GA) , as well as with MedCalc online statistical software (2016), supplemented using an online program written by Hutchon (Hutchon 2015) to calculate the RRRs to estimate both measures of publication bias. All data analysis was completed by CXZ, JSR independently validated the analysis. 16 Results Characteristics of the Neuropsychiatric Drugs Approved between 2005-2014 Between January 1st, 2005 and December 31st, 2014, 37 new drugs were approved by the FDA for the treatment of neuropsychiatric conditions, of which 23 (62%) were approved for neurological conditions and 14 (38%) for psychiatric disorders, which included 3 drugs for substance-use related conditions (Table 1). Among the 37 approved drugs, 34 (92%) were pharmacologic therapies, 3 (8%) were biologics; orphan status was granted for 9 (24%), priority review status for 6 (17%), and accelerated approval for 1 (3%) Table 1. New Drug Applications (NDA) Approved by the FDA between 2005 and 2014 with Indications for Neurologic and Psychiatric Conditions. Brand Name INN Name NDA Ap- plicant Indication Ap- proval Year Rozerem Ramelteon Takeda Global Insomnia 2005 Chantix Varenicline Tartrate Pfizer Smoking cessation 2006 Azilect Rasagiline Mesylate Teva Parkinson’s disease 2006 Invega Paliperidone Janssen, L.P. Schizophrenia 2006 Vyvanse Lisdexamfeta- mine Dimesyl- ate New River Attention deficit hyperactivity disorder 2007 Neupro Rotigotine Schwarz Bi- oscience Parkinson’s disease 2007 Pristiq Desvenlafax- ine Succinate Wyeth Major depressive disorder 2008 Relistor Methylnaltrex- one Bromide Progenics Opioid-induced constipation 2008 Xenazine Tetrabenazine Prestwick Huntington's disease 2008 Vimpat Lacosamide Schwarz Bi- oscience Partial-onset seizure disorder 2008 17 Banzel Rufinamide Eisai INC Seizures associated with Lennox-Gastaut syndrome 2008 Nucynta Tapentadol Hydrochloride Ortho Mcneil Janssen Acute Pain 2008 Lusedra Fospropofol Disodium Eisai Medi- cal Anesthesia 2008 Savella Milnacipran Hydrochloride Cypress Bi- oscience INC Fibromyalgia 2009 Dysport Abobotuli- numtoxina Ipsen Bio- pharm Lim- ited Cervical dystonia 2009 Fanapt Iloperidone Vanda Phar- maceuticals Inc Schizophrenia 2009 Saphris Asenapine Maleate Organon USA INC Bipolar I disorder 2009 Sabril Vigabatrin Lundbeck Inc Complex partial seizure disorder 2009 Qutenza Capsaicin Neurogesx Inc Neuropathic pain 2009 Ampyra Dalfampridine Acorda Therapeu- tics Inc Multiple sclerosis 2010 Xeomin Incobotuli- numtoxina Merz Phar- maceuticals GMBH Cervical dystonia and Blepharospasm 2010 Gilenya Fingolimod Novartis Pharmaceu- ticals Corp Multiple sclerosis 2010 Latuda Lurasidone Hydrochloride Sunovion Pharmaceu- tical INC Schizophrenia 2010 Viibryd Vilazodone Hydrochloride Trovis Phar- maceuticals LLC Major depressive disorder 2011 Horizant Gabapentin Enacarbil Glaxo Group LTD DBA Glax- oSmithKline Restless legs syndrome 2011 Potiga Ezogabine Glax- oSmithKline Partial seizure disorder 2011 Onfi Clobazam Lundbeck INC Seizures associated with Lennox-Gastaut syndrome 2011 Aubagio Teriflunomide Sanofi Aventis US LLC Multiple sclerosis 2012 Fycompa Perampanel Eisai INC Partial seizure disorder 2012 Dotarem Dimethyl Fumarate Biogen Idec INC Multiple sclerosis 2013