official publication of the drug information association

VOLUME 44, NUMBER 3 M AY 2 0 1 0 ISSN 0092-8615

OFFICIAL PUBLICATION OF THE DRUG INFORMATION ASSOCIATION

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Clinical Trial Registries: An Industry Perspective • LIA MCLEAN • 279

Introduction: Clinical Trial Registries • TRACY J. BECK • BARBARA J. GODLEW • 205

REGULATORY AFFAIRS FDAAA: Unintended Consequences • BARBARA J. GODLEW • 207

Global and Regional Drug Regulatory Harmonization Initiatives • MAHA M. LAKKIS • 289

Clinical Trial Disclosure: Global Overview and Implications of New Laws and Guidelines • KATHY B. THOMAS, ET AL. • 213

Aspects of Modernizing Drug Development Using Clinical Scenario Planning and Evaluation • NORBERT BENDA, ET AL. • 299

The Emergence and Growth of Clinical Trial Information Transparency • PAMELA A. ROSE • 227

Identifying and Rewarding Pharmaceutical Innovation: Application in an EU Member State • PHILIPPE VAN WILDER, ET AL. • 317

ClinicalTrials.gov: A Questionnaire of Industry Experiences and Perceptions • KATIE MCCARTHY • BARBARA J. GODLEW • 233 Clinical Trial Registration and Results Disclosure: Business Process Considerations • PATRICIA TEDEN • 243 Operational Issues in Clinical Trial Disclosure of Global Trials • SHAWN M. PELLETIER, ET AL. • 253 Transparency as a Means to Increase Clinical Trial Enrollment • BARBARA J. GODLEW • PATRICIA FURLONG • 265 Can Clinical Trial Results Databases and Manuscripts Coexist? • TRACY J. BECK • 271

STATISTICS From Adaptive Design to Modern Protocol Design for Drug Development: Part I. Editorial and Summary of Adaptive Designs Session at the Third FDA/DIA Statistics Forum • SUE-JANE WANG • FRANK BRETZ • 325 From Adaptive Design to Modern Protocol Design for Drug Development: Part II. Success Probabilities and Effect Estimates for Phase 3 Development Programs • FRANK BRETZ • SUE-JANE WANG • 333 Primary Efficacy Endpoint in Clinical Trials of Antiepileptic Drugs: Change or Percentage Change • OHIDUL SIDDIQUI • NORMAN HERSHKOWITZ • 343

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Kathy B. Thomas, BSc (Hons), PhD Medical and Scientific Writer (Freelance), Meersburg, Germany Merete Joergensen, MSc (Statistics), MBA Director of Global Clinical Registry, Novo Nordisk A/S, Soeborg, Denmark Gerard Lynch Global Process Owner, Trial Transparency, AstraZeneca, United Kingdom Michael Rubison, PhD President of Flint Hills Consulting, LLC, Lake Bluff, Illinois Brandon D. Porter, Esq., MBA, LLM, RAC Manager of Global Regulatory Affairs, Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California Jacqueline Sayers, MBA, PhD Quality Projects Manager, Product Development Quality, Roche Products Ltd., Welwyn Garden City, United Kingdom

Clinical Trial Disclosure: Global Overview and Implications of New Laws and Guidelines Clinical trial disclosure has received much international attention. The US Congress has enacted the Food and Drug Administration Amendments Act of 2007 (FDAAA), also known as Public Law 110-85. Section 801 of FDAAA requires public registration of new or ongoing clinical trials and disclosure of results for completed clinical trials on the public database ClinicalTrials.gov. FDAAA has provisions for proof of compliance and authorizes penalties for noncompliance; several phases will be implemented over 3 years and completed by 2010. In the European Union (EU), the European Parliament enacted the Clinical Trials Directive (Directive 2001/20/EC of April 4, 2001), which governs public access to information on clinical trials in the European Community. Article 11 of the Clinical Trials Directive, enforced by the European Medicines Agency (EMEA), deals with the exchange of in-

Claudia Tesch Senior Quality Assurance Manager, Nycomed Deutschland GmbH, Konstanz, Germany Key Words Clinicaltrials.gov; EMEA; EudraPharm; EudraCT; FDA Amendments Act of 2007; WHO Correspondence Address Dr. Kathy Thomas-Urban, Medical and Scientific Writer (Freelance), Medical and Scientific Writing and Publication Services, Auf dem Hirtle 14, Meersburg 88709, Germany (email: [email protected]).

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INTRODUCTION Clinical trial disclosure has received much international attention in recent years. Demands for increased public transparency regarding information on clinical trials have been coming from the International Committee of Medical Journal Editors (ICMJE), the World Health Organization (WHO), the World Medical Association, governments, and drug regulatory authorities in many countries around the world as well as patient and consumer groups (1–5). In response to demands for more transparency, the US Congress enacted on September 27, 2007, the Food and Drug Administration Amendments Act of 2007 (FDAAA), also known as US Public Law 110-85, which covers a wide range of topics including public clinical trial registration and results disclosure, postmarketing surveillance, monetary penalties, and expanded FDA enforcement authority. In particular, Section 801 (Title VIII) of FDAAA deals with

formation among the EU member states. In some cases, it also deals with the countries of the European Economic Area. The directive is accompanied by two regulations; one refers to clinical trials in general, and the other applies specifically to trials in the pediatric population. These regulations describe how some of the protocol and results information in the EudraCT database at EMEA will be automatically released to the public through the EudraPharm database. The public release is planned for 2010 and 2011. Requirements for clinical trials disclosure have also been established at the national level in several countries. A summary is presented here of the key global requirements for public disclosure of clinical trial information on drugs, biologics, and medical devices, with a brief overview on the position of various stakeholders involved in this important and evolving topic.

the mandatory disclosure of specific clinical trial information on ClinicalTrials.gov, a public website administered by the US National Library of Medicine. This section of the law specifies requirements for the prospective registration of new or ongoing clinical trials and for the disclosure of results for completed trials. It also contains provisions for proof of compliance and authorizes penalties for noncompliance (6). In the European Union (EU), efforts are also underway to enhance public access to information and avoid unnecessary duplication of clinical trials. In 2001 the European Parliament passed and enacted the Clinical Trials Directive (Directive 2001/20/EC of April 4, 2001) (7), which governs clinical trials in the European Community. Article 11 of the Clinical Trials Directive, promulgated by the European Medicines Agency (EMEA), deals with the exchange of information among EU member states and in some cases also among the countries of the European Economic Area (EEA).1 Two regula-

Drug Information Journal, Vol. 44, pp. 213–225, 2010 • 0092-8615/2010 Printed in the USA. All rights reserved. Copyright © 2010 Drug Information Association, Inc.

Submitted for Publication: January 14, 2010 Accepted for Publication: January 22, 2010

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tions accompany Article 11 of the Clinical Trials Directive; one refers to clinical trials in general (8), and the other applies specifically to trials with children (9). They describe how some of the information in study protocols or results, which is contained in the EMEA’s regulatory database EudraCT,2 will be released to the public through the EudraPharm.3 In addition to the efforts of the US and EU legal authorities and their respective regulatory agencies, requirements for disclosure of information on clinical trials have been established at the national level in several other countries. Clinical trial disclosure is a fast-evolving field, with new information being introduced at a rapid rate. Consequently, a complete overview of the current global situation on this topic is a challenge. In this article, we summarize the key requirements for public disclosure of clinical trial information on drugs, biologics, and medical devices as specified by FDAAA Section 801 and Article 11 of the Clinical Trials Directive, provide an overview of the current situation in some countries outside the United States and EU, and present the position of some stakeholders other than legislative bodies and regulatory authorities.

BACKGROUND UNITED STATES Clinical trial disclosure and registration of clinical trials in the public domain is not new. In the United States, public registration of specific clinical trials was mandated in 1997 by the FDA Modernization Act of 1997 (FDAMA Section 113) (10), which provides patients with serious or life-threatening diseases or conditions and their caregivers or physicians with information on clinical studies with new treatment options for their condition. However, FDAMA left some issues unresolved: (a) it only required sponsors to register trials involving serious and life-threatening diseases and conditions, whereas trials involving nonserious diseases or trials involving medical devices were not covered; (b) it included no penalty provisions for noncompliance; and (c) it did not require disclosure of clinical trial

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results. Consequently, the majority of clinical trials conducted in the United States were not registered; sponsors faced no penalty for noncompliance; and results were not consistently disclosed to the public. In 2007, 10 years after FDAMA, FDAAA of 2007 has revised and expanded FDAMA Section 113. In addition to expanding registration requirements and imposing penalties, FDAAA Section 801 mandates the disclosure of results for some completed trials (6). EUROPEAN UNION AND EUROPEAN ECONOMIC AREA To conduct a clinical trial in the EU and EEA, a sponsor must obtain clinical trial authorization and a unique trial identifier from the EudraCT database at EMEA. The EudraCT database has been operational since 2004 and at present includes trials with at least one site in the EU or EEA. Up to now, the information in EudraCT has been available only to the respective national drug regulatory authorities in EU and EEA member states, but not to the general public. This situation is about to change, making it possible for some of the protocol-related and study results information contained in EudraCT to become public through the EudraPharm database. The legal framework for the public disclosure of clinical trial information is based on Article 11 of Directive 2001/ 20/EC of the European Commission (EC) (7), with two accompanying regulations, one covering all studies (8), and the other specifically applicable to studies involving children (pediatric regulation) (9).

FDA AMENDMENTS ACT OF 2007 SECTION 801 The new law, FDAAA Section 801, requires registration and results posting for all applicable clinical trials on a public database.4 The law applies to trials for medicinal products intended for the US market, for any clinical condition (except phase 1 or small device feasibility studies) that have at least one site in the United States, regardless of who sponsors, finances, or conducts the trial. FDAAA defines

Clinical Trial Results Disclosure: Global Overview

the mandatory information fields for both registration and results posting and the associated timelines. Many interpretations and summaries of FDAAA Section 801 have been published (2,5,12–15). FDAAA Section 801 requires sponsors to submit study information to the National Institute of Health (NIH) for disclosure on the ClinicalTrials.gov database, which is administered by the National Library of Medicine (Bethesda, MD). Company-owned websites or any other disclosure venues (eg, privately sponsored databases, corporate websites, or professional associations’ registries such as the Pharmaceutical Research and Manufacturers of America [PhRMA] Registry) will not satisfy the requirements of FDAAA Section 801. It is noteworthy that, unlike with therapeutic drugs and biologics, information about clinical trials involving medical devices that have not been cleared or approved by the FDA will not be available on the website for public viewing until after the device is cleared or approved. Nevertheless, information on such study protocols must be submitted to ClinicalTrials.gov according to the same timelines as for therapeutic drugs and biologics for entry into the system, where it will be kept in a “lock box” until release. Not complying with FDAAA Section 801 is a prohibited act, subject to civil monetary penalties of not more than $10,000 for all violations adjudicated in a single proceeding. If the violations continue for more than 30 days after notice by NIH, the penalty may increase to $10,000 per day until the violation is corrected. Before the required information can be entered into the ClinicalTrials.gov website, sponsors must formally apply to the Protocol Registration System (PRS) to obtain a companyspecific or individual-specific user name and password. When sponsors log into the data entry section of the PRS, there are guides on how to enter the required information; updates and definitions of the information fields are also available.5 After submitting the study protocol

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information for registration, the entries are checked by the PRS internal Quality Assurance Group and become publicly available (posted) on the website within a few days. In contrast to the registration of trial information, the release of trial results to the public may need several review cycles between the sponsor and the NIH Quality Assurance Group. As such, results disclosure may take several weeks (or even months) before finalization and release of information to the public.

PHASED IMPLEMENTATION OF EXPANSION FDAAA Section 801 includes a phased implementation of additional regulations over 3 years after enactment. As of March 2009, the posting of information on adverse events is in place and postings must include, at a minimum, a table with serious adverse events (by system organ class, number and frequency, and study arm) and a table with frequent adverse events (nonserious anticipated and unanticipated events occurring in more than 5% of patients within any study arm, by system organ class, number and frequency, and study arm). By September 2010, FDAAA Section 801 provisions include the potential for new regulations requiring the posting of technical and nontechnical (lay language) summaries of the clinical trials for all approved products, and full study protocols or related information for these trials. Regulators may also consider whether to expand these requirements to clinical trials of unapproved products. FDAAA Section 801 also contains a preemption clause preventing individual states in the United States from having their own registry and results databases. This preemption, however, does not come into effect until September 2010, when the federal expanded clinical trial registry and results database will be in place. At this writing, Maine is the only US state that has its own rules and regulations regarding clinical trial disclosure for products marketed in Maine.6 It is indeed remarkable that despite

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the existence of a comprehensive federal law on clinical trial disclosure, several US states have nevertheless recently introduced legislation proposing additional requirements for their own clinical trial registry or results database (2).7 REGISTRATION OF NEW AND ONGOING TRIALS Under FDAAA Section 801, the responsibility to register a new or ongoing trial lies with the sponsor. For investigator-initiated trials (phases 2 to 4), however, the investigator may be considered the responsible party for registering the trials as well as posting results. Trials initiated after September 27, 2007, and not completed by December 26, 2007, must be registered within 21 days after the first patient is enrolled (Table 1). Sponsors must review and update the record at least once every 12 months even if no changes are necessary. A notable exception to this rule involves the recruitment status field, which must be updated within 30 days of any change (eg, not yet recruiting, recruiting, no longer recruiting, completed, or terminated). Not all of the study information is visible to the public (eg, a copy of at least one ethics committee approval must be provided but will not be made publicly available). Changes made in each information field are tracked and a history of changes is publicly available. The registry provides a National Clinical Trial (NCT) number, which is unique to each study and may be required when applying for research grants and as proof of study registration for ethics committees,8 regulatory authorities, conference presentations, or manuscript submissions to peer-reviewed journals. The basic elements for registration of new or ongoing trials include the following: • Descriptive information (title, study design, primary/secondary outcome measures) • Administrative information (trial protocol number, Investigational New Drug or Investigational Device Exception number, ethics committee approval) • Recruitment information (eligibility, recruitment status) • Location and contact information (sponsor name,

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responsible party by official title, facility name and contact information, city, zip code for each trial location, or a toll-free number through which such information may be accessed)

RESULTS DISCLOSURE OF COMPLETED TRIALS The timing to disclose results for completed clinical trials depends on the stage of clinical development for the tested product. Results of clinical trials must be posted 12 months after the trial’s estimated or actual completion date,9 whichever is earlier. However, the sponsor may submit a written request to the director of the NIH asking for permission to delay posting the results for a good cause extension (eg, data analysis incomplete) or by certifying that the drug is unapproved and will be part of a future submission package. Currently, good cause has not been defined by the FDA. The process and practical aspects of the certification are currently being established. Temporary instructions on how to proceed with the process of sending of a certification or a request for extension are available on the PRS.10 Briefly, if a clinical trial is for an approved product in an approved indication, the study results must be posted 12 months after the trial’s estimated or actual completion date. For a new and unapproved product, however, a certification may be submitted to indicate that the sponsor is seeking approval of the new product. In this case, the sponsor may delay posting until 30 days after the compound is FDA approved. If the trial is for a new use of an already FDA approved product (ie, new indication), the certification (written request) must indicate that the sponsor is seeking or will seek approval for the new use within one year. In that case, the sponsor must submit results within 30 days after approval, denial, or withdrawal of the application.11 This implies that when the sponsor withdraws an application to the FDA for a new use of an approved product, the disclosure of results for the relevant clinical trials is due within 240 days (210 plus 30 days) of application withdrawal, if there is no resubmission during that period (Table 1).

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FDAAA Section 801: Overview of Requirements

TABLE 1 Posting Requirements Type of clinical trials

Comments All applicable clinical trials subject to FDA regulations (including trials with clinical devices) except phase 1a Clinical trials that were initiated or ongoing on or after September 27, 2007, and completed trials of approved medical products and devices

Responsible party

Sponsor of the clinical trial

Timing for registration (new or ongoing trials)

As of September 27, 2007,b applicable new clinical trials must be registered within 21 days after the first patient is enrolled All applicable ongoing clinical trials involving serious or life-threatening disease or conditionc should have been registered by December 26, 2007d All applicable ongoing clinical trials not involving serious or life-threatening disease or condition should have been registered as of September 27, 2008e Updates of the registry information, if any, must occur at least every 12 months Recruitment status must be updated within 30 days of any change

Timing of posting of results (completed trialsf)

Posting of results for completed trials depends on the FDA approval status of the product: Approved product and approved use/indication: 12 months after trial completion New product with new use/indication: 30 days after approval has been granted Approved product and new use/indication: 30 days after application approval, denial, or withdrawalg

aFor the purpose of FDAAA Section 801, applicable clinical trials are defined as controlled clinical investigations other than phase 1 (subject to section 505 of the Federal Food, Drug, and Cosmetic Act or to section 351 of the Public Health Service Act). Clinical trials, applicable device clinical trials, and applicable drug clinical trials are defined as in CFR title 21, section 312.3 and phases of a clinical investigation in CFR title 21 section 312.21. bFDAAA was signed and enacted on September 27, 2007. cConsistent with current FDA and ClinicalTrials.gov guidance, the NIH interprets “serious and life-threatening disease or condition” to mean: (1) diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and (2) diseases or conditions with potentially fatal outcomes, where the endpoint of clinical trial analysis is survival. Any investigational drug that has received fast-track designation by the FDA is considered a drug to treat a serious disease or condition (http://prsinfo.clinicaltrials.gov section frequently asked questions). dDecember 26, 2007 (90 days after enactment) was the due date to have registered any new trials or update all required information fields for ongoing trials that involved a serious or life-threatening disease or condition. eSeptember 27, 2008 (12 months after enactment) was the due date to register trials that were ongoing as of September 27, 2007, that did not involve a serious or lifethreatening disease or condition. fCompletion date of an applicable trial is defined as the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluded according to the prespecified protocol or was terminated. gFor cases when the sponsor withdraws an application to the FDA, the disclosure of results for the relevant clinical trials is due within 240 days (210 days plus 30 days) of application withdrawal, if there is no resubmission during that period.

The basic elements for results of completed trials include: • Demographic and baseline characteristics. • Number of dropouts (in a table form, equivalent to a CONSORT flow chart). • Primary and secondary outcomes. • Point of contact (name or official title, phone


number, or email address of the designated person). • Certain agreements (between the sponsor and the principal investigator that restrict investigator dissemination of study results). • Results of applicable clinical trials should be electronically linked to any Medline citations of published results.

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LEGACY CLINICAL TRIALS: VOLUNTARY AND REQUIRED DISCLOSURE Voluntary submission of data is possible for legacy clinical trials that were completed prior to the enactment of FDAAA Section 801. In addition, FDAAA Section 801 contains provisions that allow the secretary of the Department of Health and Human Services to request sponsors to disclose information on ClinicalTrials.gov for specific trials that were completed within 10 years prior to the enactment of FDAAA Section 801. CERTIFICATION OF COMPLIANCE To document compliance with FDAAA Section 801, sponsors must provide a certification of compliance with certain applications to the FDA, declaring that applicable registration and database requirements have been fulfilled. This includes abbreviated new drug applications, biologic license applications, investigational new drug applications, humanitarian device exemptions, new drug applications, premarket approvals, medical device exemptions 510(k), and others, as shown on the certification of compliance form available from the FDA website (16).

EUROPEAN UNION AND EUROPEAN ECONOMIC AREA The requirements for clinical trial disclosure in the EU member states and partly for countries of the EEA are governed by two regulations that are provided for in Article 11 of Directive 2001/20/EC (7). The regulation on the public disclosure of clinical trial information for studies with children is being processed faster than for studies with adults. Guideline instructions and a list of data fields that will be made available to the public through the EudraPharm database have been issued by the EC (Table 2). The pediatric regulation defines the fields and format of study protocol-related and results information (9,17), whereas only the protocol-related information has been defined so far for studies in adults (8,18). The protocol-related information is, for the most part, consistent with other international

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initiatives related to clinical trial disclosure in public registries, such as the 20 information elements proposed by the WHO International Clinical Trials Registry Platform and the ICMJE). Data are submitted to EudraCT by the sponsor and released automatically by the authorities. Each clinical trial will be listed as ongoing or ended. This status will be listed for each EU member state with the relevant dates. Clinical trials that have received a decision from the competent authority or a favorable opinion from the ethics committee in the member state in question will be identified in the EudraPharm database. Once the clinical trial has been approved, it will be listed as ongoing. The listing will change to “ended” once the clinical trial has been registered as ended in EudraCT. For pediatric protocol-related information, the guidance specifically states that protocol information will be made public automatically when the data has been entered into EudraCT and the trial has been approved by the National Competent Authority (NCA) concerned. Furthermore, when a negative opinion has been issued by an ethics committee, the information on the trial will still be published, accompanied by the reason for the negative opinion (9). The results information to be included in EudraCT and released to the public may take the format used for the summary of results set out by the ICH E3 guideline,12 although this aspect has not yet been finalized. Nevertheless, the results should contain information according to the proposed list of fields and include a discussion and interpretation of trial results by the sponsor and the competent authority (if available), as well as a declaration by the submitting party on liability for the accuracy of the submitted information. Public release of result-related information takes place automatically once this information has been included by the EMEA in the EudraCT database (8,9). DISCLOSURE OF INFORMATION FOR CLINICAL TRIALS WITH CHILDREN Information regarding clinical trials with pediatric patients (children from birth to less than 18 years of age) applies to studies in phases 1 to

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Comparison of Mandatory Requirements in the EU and United States

TABLE 2 Item Legislation

EU

United States

Article 11 of Directive 2001/20/EC of the EC

FDAAA of 2007, Section 801, Title VIII

Children: Article 41 of Regulation (EC) no. 1901/2006 Guideline (2009/C 28/01); list of fields (ENTR/F/2/ SF/jr D (2009) 3698) Adults: Article 57(2) of Regulation (EC) no. 726/2004 Guideline 2008/C 168/02 List of fields (ENTR/F/2/SF D (2009) 3687) Site

Public website EudraPharm database (registration and results of studies)

Public website ClinicalTrials.gov (registration and results of studies)

Scope

Pediatric: phase 1 to 4 studiesa

Applicable clinical trials: phase 2 to 4

Adult: phase 2 to 4 studies Release (registration)

By authorities (automatically and immediatelya)

By trial sponsor (within 21 days after first subject enrolled)

Content (registration)

Prespecified information fields extracted automatically directly from the information on clinical study protocol, contained in the EudraCTb

Prespecified information fields, entered manually into the PRS ClinicalTrials.gov

Release (results)

Approved and unapproved products

FDA-approved products 12 months after LSLV

Pediatric studies: 6 months after LSLV

Unapproved products: 30 days after FDA approval

Adult studies: 12 months after LSLV

Information supplied by trial sponsor, released to public after formal check

Information supplied by trial sponsor to EudraCT, then automatically released by authorities Content (results)

Synopsis (ICH E3, electronic format)

Prespecified fields

Required: discussion and interpretation of study results by (1) sponsor, (2) competent authority (if available)

Technical (and lay) summaries Not required: discussion of study results

LSLV, last subject last visit. aApplies to all pediatric trials conducted with at least one site in EU or EEA. All pediatric trials conducted with at least one site in a third country and included in an agreed PIP should be entered into EudraCT no later than 1 month after either the EMEA decision agreeing to a PIP or the first approval or positive opinion of the trial by a third country competent authority or third country ethics committee, whichever is the latest. bThe released information will contain: (a) identification of the clinical trial and the sponsor, (b) identification of the medicinal product, (c) identification of the indication under study in the clinical trial and of orphan designation, and (d) general descriptive information on the clinical trial and the patient population included.

4 for both study protocol and study results-related information. Information must be entered into EudraCT when the respective pediatric trial has at least one investigator site in the EEA or is part of an agreed Paediatric Investigation Plan (PIP). This applies to pediatric trials planned, ongoing, or


completed in the EEA. It is also applicable in trials that are planned, ongoing, or completed in any other country (third countries) when these trials are included in an approved PIP. For studies in third countries, the protocol information must be submitted to EudraCT no later than one month after the EMEA decision agreeing to

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a PIP or the first approval or positive opinion of the trial by a third country competent authority or third country ethics committee, whichever is the latest (9,17) (Table 2). Results information must be provided regardless of whether the product has received an approval in the EU. Results-related information for pediatric trials should be submitted (by the PIP holder or marketing authorization holder) to the EMEA, for entry into EudraCT, no more than 6 months after the trial has ended, whether the trial has been completed or prematurely terminated, whichever occurs first. In some circumstances, when it is not possible to uphold the 6-month timeline (for a reason demonstrated by the submitting party), results may be submitted at the latest within 12 months after the trial has ended, whether the trial has been completed or prematurely terminated, whichever occurs first. For the purpose of submitting results-related information, a trial is considered completed when the last visit of the last patient has occurred, as foreseen in the latest version of the protocol; open trial extensions (eg, maintenance treatment) are not considered as part of the trial (9,17). DISCLOSURE OF INFORMATION FOR CLINICAL TRIALS The scope of Article 57(2) of Regulation (EC) 726/2004 specifies the release of information from EudraCT to the public for studies in phase 2 to 4, regardless of whether the medicinal product concerned has already received a marketing authorization in the EU or not. Phase 1 studies are excluded from the disclosure (8). This regulation contains a statement that publication of information on pediatric clinical trials is the subject of a separate regulation, thereby suggesting that Article 57(2) of Regulation (EC) 726/2004 applies to studies with adults (subjects 18 years and older). Protocol-related information data fields from the EudraCT database on medicinal products to be made public for clinical trials are listed in the document (18). A communication from

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the EC regarding this guideline sets out the scope, elements, and guidance on implementation (8). The study protocol-related information is planned for release to the public during 2010. Disclosure of results (both positive and negative) from completed clinical trials will be released to the public database as soon as the information becomes available. The results will need to be submitted by the sponsor not later than 12 months after completion of the trial, according to the guidance on the clinical trial application form and the declaration of the end of a clinical trial form (published by DG ENTR in Volume 10 of EudraLex13) (Table 2).

GLOBAL VIEW To avoid duplication and potential confusion, information on a new study should ideally be entered into only one register. This is, however, not feasible because national law or guidelines in some countries specifically require registration of clinical trials in national registries (see below). Consequently, companies that perform international clinical trials may be required to register a particular study in several respective national clinical trial registries. The WHO International Clinical Trials Registry Platform provides a search capability to locate trials from many registries worldwide.14 Another available search engine for clinical trials (containing information on protocols and results) is administered by the International Federation of Pharmaceutical Manufacturers & Associations.15

REGISTRATION OF NEW CLINICAL TRIALS Currently, registration of new clinical trials is mandatory in, but not limited to the following countries: Argentina, Canada, Croatia, Czech Republic, France, India, Israel, Italy, Hong Kong, South Africa, Taiwan, the UK, and the United States. National guidance on voluntary registration exists in Australia, China, Germany, Iran, Japan, Netherlands, New Zealand, Spain, and Sri Lanka.


RESULTS DISCLOSURE FOR COMPLETED TRIALS Disclosure of results for completed trials is mandated by law in the United States (FDAAA Section 801), and in the EU (Article 11 of Directive 2001/20/EC). In addition to the EU activities, France has its own national register for results disclosure of clinical trials in the French language.

A D D I T I O N A L S TA K E H O L D E R S I N CLINICAL TRIAL DISCLOSURE INTERNATIONAL COMMITTEE OF MEDICAL JOURNAL EDITORS The ICMJE has published several editorial policy statements that have implications for the initial registration as well as the results disclosure of clinical trials (1,4). So that a clinical manuscript may be considered by participating journals, the ICMJE requires that “any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes” must be registered in a nonprofit register before enrollment of the first study subject (1,4). This requirement includes all trials, even phase 1, whereas purely observational trials (those in which the treatment of the individual is solely at the discretion of the investigator and according to normal practice) do not require registration to qualify for future publication. However, in some countries (eg, Germany), the registration of observational trials is required by national industry associations (19). The ICMJE does not restrict its requirements for registration of a clinical study to one registry and has named several public registries that fulfill its criteria (20). Specifications, updates, and a list of participating journals are available on the ICMJE website.16 The international and legislative pressure to disclose results of completed trials in a timely manner has raised questions regarding the publication of clinical trials in peer-reviewed journals, in particular whether editors would still want to publish previously disclosed data. For


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the present, the ICMJE has stated that results posted in the same clinical trial registry in which the initial registration resides will not be considered as prior publication (prepublication) provided the results are presented in a brief structured (