From the Lister Hill National Center for
`Biomedical Communications, National
`Library of Medicine, National Institutes
`of Health, Bethesda, MD (D.A.Z., T.T.,
`R.J.W., N.C.I.); and Duke Translational
`Medicine Institute, Duke University, Dur-
`ham, NC (R.M.C.). Address reprint re-
`quests to Dr. Zarin at the National Library
`of Medicine, Bldg. 38A, National Institutes
`of Health, 8600 Rockville Pike, Bethesda,
`MD 20894, or at dzarin@mail.nih.gov.
`
`N Engl J Med 2011;364:852-60.
`Copyright © 2011 Massachusetts Medical Society.
`
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Special article
`
`The ClinicalTrials.gov Results Database —
`Update and Key Issues
`Deborah A. Zarin, M.D., Tony Tse, Ph.D., Rebecca J. Williams, Pharm.D., M.P.H.,
`Robert M. Califf, M.D., and Nicholas C. Ide, M.S.
`
`A bs tr ac t
`
`Background
`The ClinicalTrials.gov trial registry was expanded in 2008 to include a database for
`reporting summary results. We summarize the structure and contents of the results
`database, provide an update of relevant policies, and show how the data can be used
`to gain insight into the state of clinical research.
`
`Methods
`We analyzed ClinicalTrials.gov data that were publicly available between September
`2009 and September 2010.
`
`Results
`As of September 27, 2010, ClinicalTrials.gov received approximately 330 new and
`2000 revised registrations each week, along with 30 new and 80 revised results
`submissions. We characterized the 79,413 registry and 2178 results of trial records
`available as of September 2010. From a sample cohort of results records, 78 of 150
`(52%) had associated publications within 2 years after posting. Of results records
`available publicly, 20% reported more than two primary outcome measures and 5%
`reported more than five. Of a sample of 100 registry record outcome measures, 61%
`lacked specificity in describing the metric used in the planned analysis. In a sample
`of 700 results records, the mean number of different analysis populations per study
`group was 2.5 (median, 1; range, 1 to 25). Of these trials, 24% reported results for
`90% or less of their participants.
`
`Conclusions
`ClinicalTrials.gov provides access to study results not otherwise available to the
`public. Although the database allows examination of various aspects of ongoing
`and completed clinical trials, its ultimate usefulness depends on the research com-
`munity to submit accurate, informative data.
`
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`CLINICALTRIALS.GOV RESULTS DATABASE — UPDATE AND ISSUES
`
`HE CLINICALTRIALS.GOV TRIAL REGIS-
`
`try was launched more than a decade ago.
`. Since that time, it has been evolvinginre-
`sponseto various policy initiatives. The registry
`now contains information on more than 100,000
`clinical studies and has emerged as a key element
`of many public health policy initiatives aimed at
`improving the clinical research enterprise. In
`2008, a database for reporting summary results
`was addedto theregistry. In this article, we pres-
`ent an update on relevantpolicies, summarize the
`structure and contents ofthe results database, and
`show howClinicalTrials.gov data can be used to
`gain insightinto the state of clinical research.
`
`
`KEY TRIAL-REPORTING POLICIES
`
`for noncompliance. The law’s scopeis not limit-
`ed to industry-sponsoredtrials intended to sup-
`port marketing applications but includes studies
`not intended to inform FDAaction(e.g., compar-
`ative-effectiveness trials of approved drugs or
`devices), regardless of sponsorship. Table 1 sum-
`marizes the scope of key reporting requirements
`of the FDAAAand twootherpolicies: the regis-
`tration policy of the International Committee of
`Medical Journal Editors® and regulations being
`implemented by the European Medicines Agency
`for registration and results reporting ofclinical
`drugtrials conducted in the European Union.?°
`
`
`DESCRIPTION
`OF CLINICALTRIALS.GOV
`
`Section 801 of the Food and Drug Administration
`Amendments Act (FDAAA)* expanded the legal
`requirements fortrial reporting at ClinicalTrials
`-gov. It was passed into law amid concerns about
`ethical andscientific issues affecting the design,
`conduct, and reporting ofclinical trials,” includ-
`ing the suppression and selective reporting of
`results based on the interests of sponsors,? unac-
`knowledged alterations of prespecified outcome
`measures,* “offshoring” of human-subjects re-
`search,> and failure to report relevant adverse
`events.° Among other things, the FDAAA man-
`dates the submission ofsummary results data for
`certain trials of drugs, biologics, and devices to
`ClinicalTrials.gov, whether the results are pub-
`lished or not,” and imposessubstantial penalties
`
`Data in ClinicalTrials.gov are self-reported by
`trial sponsors or investigators by means of a
`Web-based system.” Registration information is
`generally reported attrial inception. Each record
`contains a set of mandatory data elements that
`describe the study’s purpose, recruitment status,
`design, eligibility criteria, and locations, as well
`as other key protoco] details.+? Additional in-
`formation may be provided with the use of op-
`tional data elements. Before public posting,
`ClinicalTrials.gov conducts a quality review of
`the submitted information. Eachtrial (regardless
`of the numberofstudysites) is represented by a
`single record, which is assigned a unique identi-
`fier (i.e., NCT number). Each record is expected
`to be corrected or updated throughoutthe trial’s
`
`Table 1. Scope of Interventional Studies Covered by Major Reporting Policies.*
`
`Policy Requirements;
`
`Registration
`
`Results Reporting
`
`4; at least one European Union site
`
`FDAAA?*
`
`ICMJE®
`
`EMA®?°
`
`Interventionalstudies of drugs,biologics, or
`devices (whetheror not approved for mar-
`keting); phases2 through 4; at least one
`U.S. site or IND or IDE
`
`Sameasregistration scope,but interventional
`studies ofdrugs, biologics, or devices only
`after FDA-approved for any use
`
`Interventional studies of any interventiontype,
`phase,or geographic location
`Interventional studies of drugs and biologics
`(whetheror not approved for marketing);
`phase 1 (pediatrics only); phases 2 through
`
`Notapplicable
`
`Sameasregistration scope
`
`* For complete descriptions of policy requirements, see the references cited. EMA denotes European Medicines Agency,
`FDAAA Food and Drug Administration Amendments Act, ICMJE International Committee of Medical JournalEditors,
`IDEinvestigational device exemption, and IND investigational new drug application.
`{ ClinicalTrials.gov allows the reporting of interventional and observational studies that are in conformancewith any ap-
`plicable human subject or ethics review regulations (or equivalent) and any applicable regulations of the national (or
`regional) health authority (or equivalent).
`
`N ENGL) MED 364;9 NEJM.ORG MARCH 3, 2011
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`life cycle, and all changes are tracked on a public
`archive site that is accessible from each record
`(through a “History of Changes” link). Summary
`results data are entered in the results database
`after a trial is completed or terminated (Table 2).
`Once posted, results records are displayed with
`corresponding registry (summary protocol) in-
`formation for each study. Resources and links to
`additional information are inserted by the Na-
`tional Library of Medicine to enhance the overall
`usefulness of the database. ClinicalTrials.gov is
`designed to benefit the general public by expand-
`ing access to trial information, but different parts
`of the database are likely to be of more or less
`direct use to different audiences.
`
`Quality Assurance
`ClinicalTrials.gov uses automated business rules
`to alert data providers when required informa-
`tion is missing or when certain data elements are
`internally inconsistent. After passing automated
`validation, all submissions are individually re-
`viewed before public posting to assess whether
`entries are complete, informative, internally con-
`sistent, and not obviously invalid; specific crite-
`ria for this assessment are described on the Web
`site.15 Although the review of summary protocol
`information is generally straightforward, that of
`results submissions is more complex. The goal,
`at a minimum, is to determine whether entries
`provide an accurate depiction of the study design
`
`and whether the results can be understood by an
`educated reader of the medical literature. Some
`invalid data can be detected by ClinicalTrials.gov
`staff; however, other data cannot be verified be-
`cause ClinicalTrials.gov does not have an inde-
`pendent source of study data (e.g., “624 years” is
`clearly an invalid results entry for mean age,
`whereas “62.4 years” may or may not be the true
`mean age). Submissions are not posted on the
`public site until quality requirements are met; if
`any important problems are detected (Table 3),
`results records are returned to the data providers
`for revision. However, individual record review
`has inherent limitations, and posting does not
`guarantee that the record is fully compliant with
`either ClinicalTrials.gov or legal requirements.
`
`Relation to Publication
`ClinicalTrials.gov is designed to complement, not
`replace, journal publication. The results database
`provides public access to a complete set of sum-
`mary results in a structured system that supports
`search and analysis. These data are primarily tab-
`ular in format and lack significant narrative por-
`tions. The database facilitates identification of
`acts of omission (e.g., incomplete reporting of
`outcome measures) and acts of commission (e.g.,
`unacknowledged changes to prespecified out-
`come measures). Journals select research articles
`for publication on the basis of their target audi-
`ences, and the articles supplement reported data
`
`Table 2. Summary Objectives and Description of Requirements for the ClinicalTrials.gov Results Database.
`
`Objectives
`Satisfy legal requirements
`Promote objective, standardized reporting by capturing key trial features in the form of tabular data while minimizing
`potentially subjective narrative text
`Facilitate “good reporting practices,” including accommodation of publishing12 and regulatory13 guidelines
`Provide structured data entry to ensure complete reporting, efficient quality review, and consistent display of both
`required and voluntary data elements
`Support detailed searches with the use of the database structure and other National Library of Medicine functions14
`Description of scientific modules (in tabular format)
`Participant flow: Progress of research participants through each stage of a trial according to group, including the num-
`ber of participants who dropped out of the clinical trial
`Baseline characteristics: Demographic and baseline data for the entire trial population and for each group
`Outcome measures and statistical analyses: Aggregate results data for each primary and secondary outcome measure
`according to group; statistical analyses as appropriate
`Adverse events: List of all serious adverse events; list of other (not including serious) adverse events in each group that ex-
`ceed a frequency threshold of 5% within any group; both lists include adverse events, whether anticipated or unantici-
`pated, and grouped by organ system
`Administrative information
`Key dates and contact information
`Description of agreements, if any, between the sponsor and the principal investigator that would restrict dissemination
`of results by the principal investigator
`
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`ClinicalTrials.gov Results Database — Update and Issues
`
`Table 3. ClinicalTrials.gov Quality Review Criteria.
`
`Quality Review Criterion
`
`Description
`
`Example
`
`Comment
`
`Lack of apparent
` validity
`
`Data are not plausible on the basis
`of information provided
`
`Outcome measure data: mean value of
`263 hours of sleep per day
`
`Measure of mean hours per day can
`have values only in the range of
`0 to 24, so value of 263 is not valid
`
`Data are uninformative; unclear
`what counts of 100 and 96 par-
`ticipants refer to; description of
`outcome measure not sufficient
`for an understanding of the spe-
`cific outcome
`
`A time-to-event measure requires a
`unit of time (e.g , days or months)
`
`Outcome measure: description states
`“clinical evaluation of adverse events,
`laboratory parameters, and imag-
`ing”; data reported as 100 and 96
`participants in each group
`
`Outcome measure is described as “time
`to disease progression”; data re-
`ported as 42 and 21 participants in
`each group
`
`Meaningless entry
`
`Information is too vague to permit
`interpretation of data
`
`Data mismatch
`
`Data are not consistent with descrip-
`tive information
`
`Internal inconsistency
`
`Trial design unclear
`
`Information in one section of record
`conflicts with or appears to be
`inconsistent with information in
`another section
`
`Structure of tables and relevant group
`names and descriptions do not
`permit a reader to understand
`the overall trial design or do not
`accurately reflect the design
`
`Study type is “observational,” but study
`title includes the word “randomized”
`
`Randomized studies are interven-
`tional, not observational
`
`Results modules: participant flow and
`baseline characteristics entered as a
`two-group study with a total of 400
`participants; outcomes entered for
`three comparison groups with 600
`participants
`
`If there is a third group, this should
`be reflected in the description
`of participant flow and baseline
`characteristics
`
`with peer-reviewed discussions of background, ra-
`tionale, context, and implications of findings.
`Journal editors who abide by the standards set by
`the International Committee of Medical Journal
`Editors recognize these complementary roles and
`consider manuscripts for publication even when
`the results of a trial have already been posted on
`ClinicalTrials.gov.8
`
`Descriptive Data about Trials
`in ClinicalTrials.gov
`Table 4 provides summary data on registry and
`results records for interventional studies that
`were publicly available on September 27, 2010. As
`of this date, approximately 330 new registrations
`and 2000 revised registrations had been submit-
`ted each week.
`
`Results Database
`All studies registered at ClinicalTrials.gov are eli-
`gible for results submission; however, submission
`of results is required only for trials covered by the
`FDAAA (Table 2). Approximately 30 new and 80
`revised records had been received each week; we
`estimate that full compliance with the FDAAA
`would lead to results submission for approxi-
`mately 40% of newly registered studies, or over
`100 new records per week.
`
`The results of 3284 registered trials had been
`submitted by 666 data providers. Of these trials,
`2324 had been posted publicly; the remainder
`either were undergoing quality-assurance review
`by ClinicalTrials.gov staff or were returned for
`correction.
`Of 2178 clinical trials with posted results re-
`cords, 20% had more than two reported primary
`outcome measures and 5% had more than five.
`For some studies, posted results include more
`than 100 primary and secondary outcome mea-
`sures. The FDAAA requires the reporting of all
`primary and secondary outcome measures, and
`ClinicalTrials.gov does not limit the number of
`primary and secondary outcome measures that
`can be listed. Other prespecified and post hoc
`outcome measures may also be listed.
`Of the 2324 posted results entries, 14% were
`linked to a PubMed citation through an indexed
`NCT number16; other publications that may exist
`could be found only through focused PubMed
`searches. We randomly selected a sample of 150
`posted results records in September 2009 and
`conducted manual searches in an attempt to
`identify all associated publications. Using all
`available data, we found that 38 of these studies
`(25%) had an associated citation in September
`2009, and 78 (52%) by November 2010. Although
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`this percentage may continue to increase, it is
`unlikely that all outcomes from these studies
`will be published.17
`
`Seconda r y Findings from
`Clinic a lTr i a l s.g ov Data
`
`A growing number of researchers are using
`ClinicalTrials.gov data to examine various aspects
`
`of the clinical research enterprise. For example,
`recent studies evaluated registration records to
`analyze trends in the globalization of the clinical
`research enterprise,5,18 the level of selective pub-
`lication of study results,19,20 and the degree of
`correspondence between registered and published
`outcome measures.19­21 Scoggins and Patrick re-
`viewed registration records to identify the types
`of trials for which patient-reported outcomes were
`
`Table 4. Characteristics of Interventional Study Records Posted at ClinicalTrials.gov as of September 27, 2010.*
`
`Variable
`
`Lead sponsor class — no. of records (no. of sponsors)
`
`Industry
`
`Nonindustry
`
`Recruitment status — no. of records
`
`Registry Records
`(N = 79,413)
`
`Results Records
`(N = 2178)
`
`28,264 (2880)
`
`51,149 (4372)
`
`1802 (200)
`
`376 (196)
`
`22,696
`
`12,343
`
`34,549
`
`3,551
`
`6,274
`
`56,580
`
`9,636
`
`6,012
`
`16,771
`
`9,359
`
`20,023
`
`13,822
`
`7,890
`
`38,813
`
`21,765
`
`6,543
`
`1,524
`
`10,768
`
`Recruiting
`
`Active, not recruiting
`
`Completed
`
`Terminated†
`
`Other‡
`
`Intervention type — no. of records§
`
`Drug or biologic
`
`Medical procedure
`
`Device
`
`Other¶
`
`Study phase — no. of records‖
`
`0 or 1
`
`1–2 or 2
`
`2–3 or 3
`
`4
`
`Intervention model — no. of records
`
`Parallel assignment
`
`Single group assignment
`
`Crossover assignment
`
`Factorial assignment
`
`Missing data
`
`Data monitoring committee — no. of records/total no.
`with responses (%)
`
`By study phase
`
`0 or 1
`
`1–2 or 2
`
`2–3 or 3
`
`4
`
`Phase not available
`
`By enrollment**
`
`0
`
`74
`
`1883
`
`221
`
`0
`
`1935
`
`69
`
`127
`
`185
`
`271
`
`393
`
`844
`
`375
`
`1321
`
`497
`
`331
`
`18
`
`11
`
`359/1509 (24)
`
`12/221 (5)
`
`113/314 (36)
`
`142/520 (27)
`
`45/298 (15)
`
`47/156 (30)
`
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`ClinicalTrials.gov Results Database — Update and Issues
`
`Table 4. (Continued.)
`
`Variable
`
`≤500 participants
`
`>500 participants
`
`By lead sponsor
`
`Industry
`
`Nonindustry
`
`Outcome measures reported per trial — no.
`
`Primary
`
`Median
`
`Interquartile range
`
`Full range
`
`Secondary
`
`Median
`
`Interquartile range
`
`Full range
`
`Registry Records
`(N = 79,413)
`
`Results Records
`(N = 2178)
`
`291/1299 (22)
`
`67/209 (32)
`
`195/1164 (17)
`
`164/345 (48)
`
`1
`
`1–2
`
`1–71
`
`3
`
`1–7
`
`0–122
`
`* The posted registry records totaled 96,026 (which include 16,506 observational studies and 107 expanded-access rec-
`ords). The posted results records totaled 2324, of which 146 were observational studies. In addition, there were 320
`registry records for trials of devices not previously cleared or approved by the FDA.
`† Terminated means that “recruiting or enrolling participants has halted prematurely and will not resume; participants
`are no longer being examined or treated” (http://prsinfo.clinicaltrials.gov/definitions.html).
`‡ Other recruiting status categories are as follows: enrolling by invitation (937 records), not yet recruiting (4181), sus-
`pended (508), and withdrawn (648).
`§ A study record may include more than one type of intervention.
`¶ Other interventions might be a behavioral intervention or a dietary supplement.
`‖ These data are limited to posted interventional study records with at least one drug or biologic intervention. Information
`about the study phase was missing in 5486 posted registry records and 52 posted results records.
`** One study record did not provide enrollment information.
`
`most likely to be reported and the specific in-
`struments used.22 Some authors of systematic
`reviews have also integrated ClinicalTrials.gov
`into their search strategies.23 The integrity of
`trial reporting is a common theme among these
`studies, which generally focus on whether pre-
`specified procedures in the study protocol (and
`any subsequent amendments) are appropriate and
`were followed. This interest has been fueled by
`highly publicized cases in which trial protocols
`were not followed, and the subsequent publica-
`tion of partial results was considered to be mis-
`leading.24 The requirement for registering out-
`come measures at trial inception is designed to
`address two problems: publication of only some
`measures and unacknowledged changes in pre-
`specified measures.17,21,25
`We used ClinicalTrials.gov data to examine
`two data fields that are integral to the interpre-
`tation of study results: outcome measure and
`analysis population. These can be considered the
`
`“numerator” (outcome measure) and “denomina-
`tor” (analysis population), respectively, of a study
`result (e.g., the number of events per number of
`participants in each group studied). The accu-
`racy and specificity of the information within
`these fields partly determine their usefulness to
`a reader as well as their usefulness for assessing
`the fidelity of published reports to prespecified
`protocols. (Summaries of the methods used in
`these analyses are available in the Supplemen-
`tary Appendix, available with the full text of this
`article at NEJM.org.)
`
`Specification of Outcome Measures
`ClinicalTrials.gov instructs data providers to re-
`port the specific measure and time frame for
`each primary and secondary outcome measure at
`registration, reflecting the current international
`standard for trial reporting.26,27 Experience with
`reporting outcomes in a tabular format in the
`results database has emphasized the need for the
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`The NEW ENGLAND JOURNAL of MEDICINE
`
`statistical analyses and allowing for cherry-
`picking of results. Some argue that the method
`of aggregation (level 4) is part ofthe statistical
`analysis plan and may properly be specified later
`— after data accrual but before unblinding. The
`archive feature of ClinicalTrials.gov enables
`those viewing such recordsto see the originally
`registered outcome measure andthe full time-
`line of changes(if relevant).
`
`REPORTING OF RESULTS IN ANALYSIS POPULATION
`
`description of a measure to bespecific in order
`to sufficiently form the rowsfor the results table
`(with comparison groups as columns). In addi-
`tion to time frame, a fully specified outcome
`measure includes information about the follow-
`ing: domain(e.g., anxiety), specific measurement
`(e.g., Hamilton Anxiety Rating Scale), specific
`metric used to characterize each participant’s re-
`sults (¢.g., change from baseline at specified
`time), and method of aggregating data within
`each group (e.g., a categorical measure such as
`proportion of participants with a decrease great-
`The analysis population is another source of
`potential bias in results reporting. Substantial
`er than or equal to 50%) (Fig. 1).
`distortion of results can occur if all data are not
`Wereviewed thefirst primary outcome mea-
`accounted foror if missing data are not handled
`sure, as initially registered, from 100 randomly
`selected non—phase 1 clinical trials in August
`appropriately. The use of different analysis pop-
`ulations for different outcomes may not be no-
`2010. Entries were assessed for whether a spe-
`ticed by many readers, but it can exert a strong
`cific time frame was provided and were catego-
`rized according to level of specification (Fig. 1).
`effect on reported results. In a sample of 700
`We categorized 36% as level 1 (i.e., domain
`records (representing 1749 study groups and
`only), 25% as level 2, 26% as level 3, and 13% as
`5160 outcome measures), the mean number of
`different analysis populations per study group
`level 4; of these, 72% included a specific time
`with at least one participant was 2.5 (median, 1;
`frame. When only a specific measurement or
`range, 1 to 25). The magnitude ofthe difference
`domain is registered, as occurred in 61% of the
`across groups and outcomesvaried. To further
`entries in our sample, post hoc choices of the
`explore the magnitude of these differences, we
`specific metric or method of aggregation could
`evaluated the percentage of participants who
`mask the fact that multiple comparisons were
`conducted, potentially invalidating the reported
`started the study and were analyzedforthefirst
`
`
`Description of Measure
`at Specified Time
`Level 1
`Domain
`
`Depression
`
`Schizophrenia
`
`Level 2
`Searle’ Rierarere
`
`Beck Anxiety Inventory
`
`Hamilton Anxiety Rating Scale
`
`Fear Questionnaire
`
`—
`——
`[>Jce
`Ja
`
`Figure 1. An Example ofthe Four Levels of Specification in Reporting Outcome Measures.
`
`Level 3
`Specific Metric
`
`Change from baseline
`
`Timeto event
`
`Level 4
`MethodofAggregation
`
`Continuous
`
`Categorical
`
`Proportion ofparticipants
`with decrease =>50%
`
`Proportion of participants
`with decrease =8 points
`
`858
`
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`DR. REDDY’S LABORATORIES, INC.
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`ClinicalTrials.gov Results Database — Update and Issues
`
`primary outcome measure in a sample of 684
`eligible studies (representing 1706 groups). Ap-
`proximately 31% of trials included 100% of
`participants in the analysis, and 24% of trials
`reported results for 90% or less of their partici-
`pants (see the Supplementary Appendix). Deter-
`mination of the appropriateness of the analysis
`population for any specific outcome analysis
`would require a detailed methodologic review of
`each study and would potentially involve subjec-
`tive judgments.
`
`Discussion
`
`In the past 5 years, prospective registration of clin-
`ical trials has become standard practice. Public
`reporting of summary results, independent of the
`interests of the trial sponsor, represents the next
`step in this international experiment in system-
`atic disclosure of clinical trial information. It has
`been 2 years since the launch of the ClinicalTrials
`.gov results database, and people can now access
`summary trial data that were not previously
`available publicly. Researchers, policymakers, and
`others can now examine features and trends of
`the clinical research enterprise that were previ-
`ously difficult to study. For example, methodolo-
`gists may evaluate the appropriateness of design-
`ing trials with many primary outcome measures.
`Policymakers may consider how current patterns
`in the use of data monitoring committees might
`affect the quality and safety of the resulting re-
`search. Others may use the data to monitor
`trends in the clinical research enterprise and
`raise questions about the portfolio of trials rela-
`tive to public health needs. The ultimate useful-
`ness of the registry and results database will be-
`come apparent as more trial information and
`results are posted and as persons with different
`interests and needs incorporate these data into
`their analyses. ClinicalTrials.gov is continually
`adding features and linkages to facilitate the use
`of the data by different audiences, and other
`groups repackage these data for more specific
`audiences. For example, BreastCancerTrials.org
`(www.breastcancertrials.org) augments registry
`data to serve the breast-cancer community. The
`Clinical Trials Transformation Initiative is lead-
`ing an effort to develop a publicly accessible re-
`search-quality data set in order to facilitate ex-
`amination of the clinical research enterprise.28
`When one is using the data in ClinicalTrials
`.gov, however, certain limitations should be kept
`
`in mind. First, there are undoubtedly trials that
`are not registered in ClinicalTrials.gov or any
`other publicly accessible registry. Coverage in
`ClinicalTrials.gov is likely to be most complete
`for trials of drugs or devices that are sponsored
`by U.S.-based or multinational organizations
`(e.g., major pharmaceutical companies). Second,
`some records are missing information (e.g., op-
`tional data elements) or contain imprecise en-
`tries. We are not able to impose requirements
`beyond those of the prevailing federal law; trials
`registered since the passage of the FDAAA have
`to meet more requirements than do older trials,
`but investigators who use all ClinicalTrials.gov
`data will encounter many records with missing
`fields. In addition, given the demands of indi-
`vidual record review, some problematic entries
`will find their way onto the public site. Third,
`new registry and registration policies are being
`implemented in specific regions and countries
`around the world. The World Health Organiza-
`tion has established a search portal that includes
`data from ClinicalTrials.gov and 11 other regis-
`tries, totaling more than 123,500 records as of
`November 23, 2010. However, overlapping scope
`and inadequate coordination internationally have
`contributed to the difficulty in determining the
`precise number of unique trials being conducted.
`Disclosure requirements for clinical trials con-
`tinue to evolve. In the United States, the FDAAA
`calls for the expansion of the basic results data-
`base through rulemaking “to provide more com-
`plete results information” and mandates the
`consideration of issues such as requiring results
`reporting for trials of drugs and devices that have
`not been approved by the FDA, the inclusion of
`narrative summaries, and the submission of full
`study protocols. In general, a guiding principle
`is that expansion of the registry and results data-
`base should only improve on, not reduce, the
`functionality and usefulness of ClinicalTrials.gov.
`Information about the status of the rulemaking
`process, including notification of the opportu-
`nity to provide comments, can be found at http://
`prsinfo.clinicaltrials.gov/fdaaa.html. Internation-
`ally, the European Medicines Agency is planning
`to make summary protocol and results informa-
`tion publicly available for clinical trials of ap-
`proved and unapproved drugs conducted in the
`European Union. Efforts are under way to ensure
`the compatibility of the European Medicines
`Agency database with ClinicalTrials.gov, thus
`potentially minimizing reporting burdens for
`
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`859
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`DR. REDDY’S LABORATORIES, INC.
`IPR2024-00009
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`ClinicalTrials.gov Results Database — Update and Issues
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`those conducting multinational trials and sup-
`porting seamless access to results from many
`parts of the world.29
`Despite the change in cultural expectations
`regarding trial disclosure and the fact that many
`trial sponsors and investigators are successfully
`meeting the requirement to submit summary re-
`sults, our experience to date indicates that others
`are still struggling. In addition, the poor quality
`of some submitted entries is troubling. As Beecher
`observed in 1966, a “truly responsible investigator
`[emphasis in the original]” is essential if the
`
`rules governing clinical research are to have the
`intended effect.30 Similarly, the usefulness of
`ClinicalTrials.gov ultimately depends on wheth-
`er responsible investigators and sponsors make
`diligent efforts to submit complete, timely, accu-
`rate, and informative data about their studies.
`Disclosure forms provided by the authors are available with
`the full text of this article at NEJM.org.
`We thank Drs. Alastair J.J. Wood, Harlan M. Krumholz, and
`Joseph S. Ross for comments on earlier versions of this manu-
`script; Sarah O. Kornmeier and Annice M. Bergeris for help with
`data analysis; and Jonathan McCall for editorial assistance.
`
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