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Everything You Need to Know About

Clinical Trials Registration and Results Reporting Requirements

Deborah A. Zarin, M.D.ClinicalTrials.gov

October 2009

Background

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February 27, 2009

Recent Events

February 26, 2009

Kaplan-Meier estimates for ulcer complications according to traditional definition. Results are truncated after 12 months, no ulcer complications occurred after this period. Adapted from Lu 2001.

Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.

Zarin DA, Tse T. Medicine. Moving toward transparency of clinical trials. Science. 2008 Mar 7;319(5868):1340-2.

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Levels of “Transparency”

Zarin DA, Tse T.. Science. 2008 Mar 7;319(5868):1340-2.

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Reasons to Register Clinical Trials and Report Results

• Human Subject Protections– Allows potential participants to find studies– Assists ethical review boards and others to determine

appropriateness of studies being reviewed (e.g., harms, benefits, redundancy)

– Promote fulfillment of ethical responsibility to human volunteers – research contributes to medical knowledge

• Research Integrity– Facilitates tracking of protocol changes– Increases transparency of research enterprise

• Evidence Based Medicine– Facilitates tracking of studies and outcome measures– Allows for more complete identification of relevant studies

• Allocation of Resources– Promotes more efficient allocation of resources

ClinicalTrials.gov—the basics

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History of ClinicalTrials.gov

• FDAMA 113 (1997): Mandates Registry– IND trials for serious and life-threatening diseases or

conditions

• ClinicalTrials.gov Launched in February 2000• Calls for Increased Transparency of Clinical Trials

– Maine State Law; State Attorneys General– Journal Editors (2004)

• ClinicalTrials.gov Accommodates Other Policies• FDAAA 801 (2007): Expands Registry and Adds

Results Database

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New Registrations Continue to Increase

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ClinicalTrials.gov Statistics (as of 10/05/09)

Number Percent

Total 79,605 100%Type of Trial

Observational 12,956 16%Interventional* 66,649 83%– Drug & Biologic 54,208 – Surgical Procedure 8,470 – Behavioral, Gene Transfer, Other 13,369 – Device 4,742

International Sites (172 countries)US only 37,271 47%Non-US only 28,263 35%US & Non-US mixed 5,686 7%Missing 8,385 11%

*231 “delayed posting” device trials included in “total,” but excluded from other statistics

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ClinicalTrials.gov Statistics (cont.)(as of 10/05/09)

User Statistics

Page Views per month 60 Million Unique visitors per month 900,000

Number Percent

Trials by Sponsor

US Federal (including NIH)10,777 14%Industry 25,737 32%University, Other 43,091 54%

Total 79,605

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Value-Added Links

Search Interface

Legal and other requirements

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ICMJE Policy

• Editorial 2004 and updates

• Registration required for manuscript consideration for following:– Interventional studies– Any phase– Any intervention

• ClinicalTrials.gov or WHO Primary registry

• Registration prior to enrollment first participant

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Public Law 110-85Sec.801 Expanded Clinical Trial Registry

• Enacted on September 27, 2007• Requires Trial Registration (Dec 2007)

– Phase II-IV drug and device trials for all diseases– Data elements: ClinicalTrials.gov + ~ WHO/ICMJE

• Requires Results Reporting (Sept 2008)– Trials of FDA-approved or cleared drugs and devices– “Basic” Results: Baseline Characteristics, Primary &

Secondary Outcomes, Statistical Analyses– Adverse Events (Sept 2009)– “Expansion” of results by rulemaking (Sept 2010)

• Added enforcement provisions

Enforcement Provisions

• Notices of non-compliances

• Civil monetary penalties up to $10,000/day

• Withholding of NIH grant funds

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Key Terms

• Applicable Clinical Trials– Interventional trials– Phase 2-4 drug, biologic, device– >= one site in U.S.– Ongoing as of 9/27/07, or later

• Responsible Party– Sponsor, grantee– PI if designated

• Primary Completion Date

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Key Milestones: FDAAA - Sec.801 Expanded Clinical Trial Registry

• December 26, 2007– New registration requirements effective– Linking to existing results

• September 27, 2008– “Basic Results” reporting requirements effective

• April 2009 - Public Meeting

• September 27, 2009 – Adverse Events

• September 27, 2010 – Rulemaking Due

Key Points: Memo from Dr. Kington, Acting Director, to NIH Grant Awardess

• “For grants, NIH is generally not the sponsor … and, as such, NIH would not be the responsible party.”

• “Responsible parties who have not yet registered their clinical trials should do so immediately.”

• “Thank you for your attention to this important matter and your commitment to helping enhance the transparency of NIH funded clinical trials.”

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Basic Results Database

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Basic Results Database: General Characteristics

• Results of “applicable clinical trials” of FDA-approved/cleared medical products

• Generally, submission within 12 months of the earlier of estimated or actual trial completion date (of primary outcome)

• Delayed Submission of Results– Seeking initial approval – Seeking approval of a new use – Extensions for “good cause”

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Adverse Events

• If the Secretary fails to issue regulation by March 2009, default provisions take effect in September 2009

• SERIOUS ADVERSE EVENTS– Table of anticipated & unanticipated serious adverse events – Grouped by organ system– Number and frequency of event in each clinical trial arm

• FREQUENT (other) ADVERSE EVENTS– Table of anticipated & unanticipated adverse events– Exceed a frequency of 5 percent within any trial arm– Grouped by organ system– Number and frequency of event in each trial arm

Basic Results Modules

• Participant Flow • Baseline and Demographic Characteristics• Outcome Measures• Adverse Events (summary data)• Other Information

– “Certain Agreements” Restricting Results Disclosure

– Overall Limitations and Caveats– Results Point of Contact

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Current Status – “Basic Results”(as of 02/06/09)

• Functional Web-based Data Entry System • Launched in September 2008

• 662 Results Records have been submitted• Industry: 449 records from > 100 data

providers• NIH: 24 records

• Rate of submission continues to increase• 40 records per week now• Anticipate about 150 per week

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Sample Posted Results

Participant Flow

“A table ..., including the number of patients who dropped out of the clinical trial and the number of patients excluded from the analysis, if any.”[Sec. 282(j)(3)(C)(i)]

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Reasons Not Completed

An Investigational Drug on Clinical Outcomes in Patients With Aortic StenosisNCT00092677

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Reasons Not Completed

Milestone

Arms

Baseline Measures

“A table of the demographic and baseline data collected overall and for each arm of the clinical trial…”[Sec. 282(j)(3)(C)(i)]

User-SpecifiedMeasure

“Default” RequiredMeasures

Categories

Outcome Measure

“…a table of values for each of the primary and secondary outcome measures for each arm of the clinical trial…”[Sec. 282(j)(3)(C)(ii)]

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Categories

Statistical Analysis

“…a table of values for each of the primary and secondary outcome measures…, including the results of scientifically appropriate tests of the statistical significance of such outcome measures.”[Sec. 282(j)(3)(C)(ii)]

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Statistical Analysis

Statistical Analysis

Statistical Analysis

Serious Adverse Events

“A table of anticipated and unanticipated serious adverse events grouped by organ system, with number and frequency of such event in each arm of the clinical trial.”[Sec. 282(j)(3)(I)(iii)(I)]

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Frequent Adverse Events

“A table of anticipated and unanticipated adverse events that are not included in the [Serious Adverse Events] table … that exceed a frequency of 5 percent within any arm of the clinical trial, grouped by organ system, with number and frequency of such event in each arm of the clinical trial.”[Sec. 282(j)(3)(I)(iii)(II)]

Definition of Adverse Event

• Definition: Unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial.

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Definition of Serious AE

• Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect.

• Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.

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Design Features

• Tables are “constructed” by the data provider– Columns are pre-set as study arms, but can

be changed by the data provider– Rows are measures—some are pre-set,

others are customized for each study– Type of measure determines specific design

of “cells”

• Attempt to balance fixed structure with flexibility

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http://prsinfo.clinicaltrials.gov/fdaaa.html

Issues in Reporting Results

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ICJME

“…will not consider results posted in the same primary clinical trials register in which the initial registration resides as previous publication if the results are presented in the form of a brief, structured (<500 words) abstract or table.”

Who is the Audience?PI and Clinical Research Team

Other Medical Researchers in same field

Other Medical Researchers in other fields

Other Readers of the medical literature

Science Writers

Lay Public (readers of consumer health literature)

Quality Assurance Challenges

• Data tables will be the public representation of the study—must be clear and informative;

• NLM QA Focuses on:– Apparent Validity (when possible)– Meaningful Entries– Internal consistency/logic– Format

What Does QA Address?

• Data must make sense– Measure name, units, and data must match– No invalid entries

• E.g., 823 hours/day; “time to survival”

– No illogical tables– No missing parameters or data

• Tables should convey study design, conduct and analysis

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Tables Must Be Informative

• Scales should include:– Full name– Construct or domain (e.g., pain)– Direction of scores (Best/Worst Value)– Other information as necessary

• Measures Have Useful Descriptions

• Avoid Abbreviations

Measure Information Must be Precise and Accurate

• Avoid misuse of terms, e.g., – proportion– ratio– incidence

• State what is being measured and how– Do not provide results in measure description

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Data in All Tables Must be Internally Consistent and Logical

• Participants must “flow”

• “Number analyzed” must be consistent with participant flow data

• Avoid Illogical Entries

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Drug X, Week 10

Drug X, Change from Week 10 to 18

Number of Participants Analyzed

[units: participants]

88 80

Treatment Satisfaction QuestionnaireAfter 18 Weeks of Treatment

[units: Score]

Mean ± Standard Deviation

81 ± 17.46 7.9 ± 12.16

Illogical Results Table

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Measure Name Time to Disease-Free Survival

Measure Description

Time from date of treatment to date of survival

Time Frame 5 years

Drug A Drug B

Number of Participants Analyzed

[units: participants]

648 645

Time to Disease-Free Survival

[units: participants]

246 277

Unclear Outcome Measure

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Intervention X Control

Number of Participants Analyzed

[units: participants]

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Hours Per Day of Sleep

[units: Average Hours per Day]

Mean ± Standard Deviation

823 ± 92 864 ± 106

Problematic Entry

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Measure Name

Clinician Assessment After Injection

Measure Description

Physician’s assessment of: SIJ pain [5 point-Likert scale], Change of finger to floor [cm] and Schober test [mm]

Time Frame 8 months

Sacroiliac Injection

Number of Participants Analyzed [units: participants]

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Clinician Assessment After Injection

[units: Units on a scale]

100

Problematic Entry

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Measure Name Pregnancy Rate (Pearl Index)

Measure Description

Pearl Index = (100)*(number of pregnancies)*(4 cycles/year)/number of 91-day cycles completed.

Time Frame After the onset of treatment and within 14 days after the last combination pill (approx. 1 year of treatment)

DR-1011

Number of Participants Analyzed 1735

Pregnancy Rate (Pearl Index)

[units: Pregnancies per 100 woman years exposure]

2.74

Informative Entry

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Informative EntryMeasure Name Time to Progressive Disease

Measure Description

Time from study enrollment to the first date of disease progression. Time to disease progression was censored at the date of death if death was due to other cause.

Time Frame Every other 21 day cycle (6-8 cycles) and every 3 months during follow-up

Drug X

Number of Participants Analyzed 50

Time to Progressive Disease

[units: weeks]

Median ( 95% Confidence Interval )

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( 37.9 to 56.9 )

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08Q4 09Q1 09Q2 09Q3

Number of Results Recordswithout Revision by Quarter Posted

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Quarter Posted

Results Posting - Caveats

• Posting does not assure that all review criteria were met

• Data provider is responsible for ensuring that records meet review criteria

• ClinicalTrials.gov may note issues and request revisions after results have been posted publicly

• Additional comments may suggest improvements, but are not necessarily “required” changes prior to posting

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Lessons Learned from Early Submissions of Basic Results

• Data Providers must be able to understand the study design and data analysis– Typically, the investigator and a

statistician will need to be involved

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Interesting Scientific Issues

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Interventional vs. Observational

– Interventional: studies in human beings in which individuals are assigned by an investigator based on a protocol to receive specific interventions. Subjects may receive diagnostic, therapeutic or other types of interventions. The assignment of the intervention may or may not be random. The individuals are then followed and biomedical and/or health outcomes are assessed.

– Observational: studies in human beings in which biomedical and/or health outcomes are assessed in pre-defined groups of individuals. Subjects in the study may receive diagnostic, therapeutic, or other

interventions, but the investigator does not assign specific interventions to the subjects of the study.

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Interventional or Observational?

• Example: Evaluation of PillCam™ Colon Capsule Endoscopy (PCCE) in the Visualization of the Colon– Capsule Endoscopy versus Colonoscopy for

the Detection of Polyps and Cancer– Van Gossum et al. NEJM (2009)

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Interventional (as of 8/3/09)

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Observational (before 8/3/09)

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How Should You Describe the Outcome Measures?

Low

High

Level of Detail

• Anxiety

• Hamilton Anxiety Rating Scale

• Hamilton Anxiety Rating Scale at 12 weeks

• Change in Hamilton Anxiety Rating Scale at 12 weeks from baseline

• Proportion of patients with improvement in Hamilton Anxiety Rating Scale at 12 weeks from baseline

• Proportion of participants with a change of ≥11 points at 12

weeks from Baseline on the Hamilton Anxiety Rating Scale

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Goals for Registration of Outcome Measures

• Inform potential participants

• Provide details to inform other researchers, systematic reviewers, etc.

• Monitor integrity of research– Track additions/deletions– Track significant changes

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Kaplan-Meier estimates for ulcer complications according to traditional definition. Results are truncated after 12 months, no ulcer complications occurred after this period. Adapted from Lu 2001.

Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.

CLASS Study Data by Follow-up Period

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ENHANCE: Prespecified Endpoints

Source: Kastelein JJ et al. Am Heart J. 2005 Feb;149(2):234-9.

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Bottom Line—Reporting Outcome Measures

• Be as specific as possible

• Primary and Secondary outcome measures– Designation should be consistent with

statistical analysis plan

• “Other prespecified” and “post hoc” should be used for measures that are not in the statistical analysis plan

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Outcome Measure Statistics ClinicalTrials.gov (as of 8-27-09)

• 701 Results records posted• 1,592 POMs

– Mean: 2.3– Median: 1– Range: 1-71

• 3,402 “Secondary” OMs– 498 Results records with ≥ 1– Mean: 5– Median: 2– Range: 0-85

“Other Pre-specified”: 43 Records, 156 OMs, Range: 1-31 “Post-Hoc”: 11 Records, 18 OMs, Range: 1-6

Diagnostic Accuracy Studies

• Studies in which the results are generally displayed in a “2 x 2 table” – Columns: “with disease” and “without disease”

based on a reference standard– Rows: “test positive” and “test negative”

based on the experimental diagnostic test.

• ClinicalTrials.gov can be used to create 2 x 2 tables

Applicable Clinical Trials?

• Components involve devices and/or drugs– ImageChecker DMax computer-aided detection

system, version 8.1 (Hologic/R2 Technology)

Gilbert FJ et al. N Engl J Med 2008;359:1675-84.

Device or Procedure?

• What Is the Intervention Type?– Device– Procedure/Surgery

• Example: The Stress Incontinence Surgical Treatment Efficacy Trial – Burch Colposuspension versus Fascial Sling

to Reduce Urinary Stress Incontinence– Albo ME et al. NEJM (2007)

Procedure: Burch Modified TanaghoProcedure: Autologous Fascia Sling

Bottom Line• Determine who is the Responsible Party• Register prior to enrollment (or within 21d):

– Phase 2-4 interventional trials that include a drug, device or biologic

– Regardless of whether or not the trial is being used to support an FDA application

• Report results:– Any trial described above once the drug, device or

biologic has been approved; OR– Within one year of “primary completion date”

• Keep all information up to date!103

Next Steps

• September 27, 2010: Expansion by Rulemaking

• Expect announcement in October about plans for rulemaking

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Key Issues in Expansion

• Expand results reporting to trials of unapproved products?

• Include narrative summaries? Can it be done w/out being promotional and misleading?– Technical– Lay Language

• Data Quality Verification– Process (e.g., Pilot Quality Control Project)– External Sources

• Full protocol versus extract “necessary to help evaluate the results”

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EMEA & Unapproved Products

• Publically Accessible Results Database– Required no later than 6 months after trial

completion (i.e., last patient, last visit)– Applies to EU-regulated clinical trials of

medicines, regardless of authorization status– Applies to trials of pediatric and adult drugs

• Interaction to harmonize EudraCT and ClinicalTrials.gov databases & policies

Resources

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Finding Results at ClinicalTrials.gov

• From Homepage – Go to “Search for Clinical Trials”– Select “Advanced Search”– Select “Studies with Results” from the menu

for the Study Results field– Select study record from results list– Click “Study Results” tab

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Additional Information(at http://prsinfo.clinicaltrials.gov/fdaaa.html)

• "Basic Results" Data Element Definitions• Helpful Hints - tips on entering results

data, including examples of common study models (e.g., crossover design)

• Detailed Review Items - describes items evaluated by the QA/QC staff at NLM

• Common Errors - overview of common types of errors identified in submitted records with "basic results"

Additional Background

• Tse T, Williams RJ, Zarin DA. Update on registration of clinical trials in ClinicalTrials.gov. Chest 2009;136:304-5.

• Tse T, Williams RJ, Zarin DA. Reporting basic results in ClinicalTrials.gov. Chest 2009;136:295-303.

• Zarin DA, Tse T. Moving toward transparency of clinical trials. Science 2008;319:1340-2.

• Wood AJ. Progress and deficiencies in the registration of clinical trials. N Engl J Med 2009;360:824-30.

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Additional Information

• Email LISTSERV and other FDAAA information:– http://prsinfo.clinicaltrials.gov/fdaaa.html

• Other general information:– http://prsinfo.clinicaltrials.gov

• Questions?– register@clinicaltrials.gov