May 2008 1

Expansion of Clinical Trial Registration and Results Reporting

Requirements

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

National Library of Medicine

May 2008 2

History of ClinicalTrials.gov

• FDAMA 113: Mandates Registry (1997)• ClinicalTrials.gov Launched in Feb 2000• Calls for Increased Transparency of Clinical Trials

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

• ClinicalTrials.gov Accommodates Other Policies• PL 110-85, Sec. 801: Expands Registry (2007)

May 2008 3

Steady Growth

May 2008 44

ClinicalTrials.gov Statistics(from 4/3/2008)

Number Percent

Total 53,956 100%Type of Trial*

Observational 8,171 15%Interventional 45,737 85%– Drug & Biologic 34,903 – Medical Procedure 11,200 – Behavioral, Gene Transfer, Other 5,484 – Device 2,839

International SitesIn the US only 27,056 50%At least 1 site in the US 4,141 8%

Outside the US 17,229 32%Missing 5,530 10%

* 48 Missing Study Type Information

May 2008 55

ClinicalTrials.gov Statistics Cont.(from 4/3/2008)

Trials by Data Provider

University, other 21,480 40%US Federal (including NIH)16,808 31%

Industry 15,668 29%

User Statistics

Page Views per month 20 Million Unique visitors per month 500,000

Number Percent(N = 53,956)

May 2008 6

Search Engine

• 56,000 trials in Registry• Search Engine makes it useful• Features

– Spelling correction/relaxation• Alzimers = Alzheimer’s

– Synonymy from UMLS• Heart attach = myocardial infarction

– Search within a field– Hierarchy from MeSH

• Crohn’s is a type of IBD

May 2008 7

Overview of New Requirements

FDAAA

PL 110-85

9/27/07

May 2008 8

Key Milestones

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

• September 27, 2008– BASIC Results reporting requirements effective

• September 27, 2009 – Adverse Events

• September 27, 2010 – ENHANCED results implemented

May 2008 9

New Registration Requirements

• Drug and device trials – Exclude “phase 1”

• 12 Previously optional data elements now required

• 4 new data elements are required

• Registration due within 21 days of first enrollment

• Penalties for non-compliance

May 2008 10

Other Registration Issues

• Trials for devices that are not approved/cleared are not posted publicly (“lock box”)

• Updates– As necessary to keep information accurate– Within 30 days of recruitment status change– At least every 12 months for other changes– Changes are date stamped and tracked

publicly

May 2008 11

Who Must Register?“Responsible Party”

• The sponsor of the clinical trial

-- OR --

• The principal investigator (PI) of such clinical trial if so designated by a sponsor, grantee, contractor, or awardee, so long as the PI is responsible for conducting the trial and has sufficient data rights.

May 2008 1212

May 2008 13

Requirements for Results Reporting

May 2008 14

Links to Existing Results

• December 26, 2007 (90 days after enactment)• FDA Information, including

– Advisory Committee summary document– Posted assessment of drug clinical trial results– Public health advisories regarding drug or device– Drug action package for approval document– Safety and effectiveness summary (devices)

• NIH Information– MEDLINE - Citation of published results– DailyMed – FDA structured product labels

May 2008 15

Basic Results Database

• Which trials? – trials of approved drugs/devices

• When? – 12 months after “completion date” if approved

product– or later if submitting an sNDA– or 30 days after product approval

May 2008 16

Basic Results: Statutory Requirements

• Demographic and baseline characteristics

• Primary and secondary outcomes

• Point of contact

• Certain agreements– Restrictions on PI to discuss or publish results

May 2008 17

Basic Results Tables

• Participant flow

• Demographic and baseline characteristics– Overall and by arm

• Values for primary and secondary outcomes– By arm– Scientifically appropriate tests of statistical

significance

May 2008 18

Overall Approach to Collecting Results Information

• Results tables are similar to those found in journal articles

• Data entry systems will use terms familiar to investigators

• Technical items (e.g., statistical tests) would be necessary for any official study report

• Multiple modalities of user support services will be important (e.g., online, telephone)

May 2008 1919

Published Participant Flow

Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

May 2008 2020

Published Baseline Data

Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

May 2008 2121

Published Primary Outcome

Source: Kimmick GG et al. Breast J. 2006 Mar-Apr;12(2):114-22.

May 2008 22

Challenges and Goals for Data Entry System

• Need to accommodate full range of study designs and data types

• Need for structure to optimize data quality and search capabilities, and to allow for control over data display

• Need to be usable by full range of international trial community– Large data providers (e.g., drug companies, NIH ICs)– Academic medical centers– Individual investigators

• Desire to promote “good trial practices”, but must accommodate all practices

May 2008 23

Data Entry Mechanisms

• Electronic Data Interchange – upload data in XML format

• Manual Data Entry – enter data using a Web-based Results Registration System (RRS)– analogous to the Protocol Registration

System (PRS) for the registry

May 2008 24

Basic Results Data Entry System

• Prepopulates certain data elements from registry, if provided (e.g., Arm Description)

• Lists some prespecified baseline demographics (e.g., gender, ethnicity)

• Allows users to enter and edit tables– Column labels: e.g., Arms– Row labels: e.g., demographics, outcome

measures– Cells: e.g., measurement values

May 2008 25

Measurement Types

Dichotomous

Continuous (Years)

Multiple Categories

May 2008 26

Time To Event

May 2008 2727

Participant Flow

• Number entered study

• Number completed study

• Number not completed study

• Other details– Phase specific information– Study specific information– Number achieved milestones, as specified by

registrant

May 2008 2828

Demographic & Baseline Characteristics

• Commonly used measures– Age (continuous and categorical)– Gender– Race/Ethnicity– Region of enrollment

• Measures specific to each trial• For each measure

– Name of measure– Value, total and by arm– Names and values of categories, if categorical– Measure of dispersion, if continuous– Other details, if time-to-event

May 2008 2929

Outcomes

• Pre-specified primary and secondary outcome measures from registry

• For each measure– Description– Units– Value by arm or other comparison group

• Names and values for categories, if categorical• Measure of dispersion, if continuous• Other details if time to event

– Statistics (cont. next slide)

May 2008 3030

Outcomes

• Statistics (cont.)– Test of non-inferiority? (y/n)

• If yes, other details

– For each p-value provided• Name of test (e.g., Chi-squared, ANOVA)• Other details/comments

– For each confidence interval provided• % (e.g., 95% confidence interval)• Name of estimate (e.g., OR, RR)• Value of estimate• Other details/comments

May 2008 3131

Issues to Consider in Developing Public Display

• Simple, tabular format (“just the facts”)• Provide context

– Study design– Background information– Display links to other similar trials

• Consider linking to systematic reviews and other resources

• Link to published articles and FDA reviews, when available

May 2008 32

Data Display Mechanisms

• Summary result records displayed in a Results Database at ClinicalTrials.gov

• Results records linked to registry records via NCT number

• Similar search engine and “look and feel”

• Details to be determined

May 2008 33

How to Facilitate Rational Use of Data

• Provide context– Study design

– Background information

• Consider linking to systematic reviews

• Link to other resources

May 2008 34

Seeking Public Input

• Updated information on status of implementation

– http://prsinfo.clinicaltrials.gov/fdaaa• Public comment on early versions is critical• Short timeline for development – May to September 2008

– Describes rulemaking process for expanded registry and results database

• Public Meeting by March 2009 to inform rulemaking for “expanded” results database

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