# Presentation: 075696

## Session 2Expanded Clinical Trials RegistryDeborah A. Zarin, M.D.

- NLM Accomplishments
- Impact to Date
- Specific Data Element Issues

## Expanded Clinical Trial Registry

**Enactment**

- 1 yr

- 2 yr

- 3 yr

- 18 m

- Linking to existing results information at FDA and NIH

- Launch Basic Results Database

- Expansion by Rulemaking: Final Rule

- Additional Adverse Events Data

**REGISTRY**

**RESULTS**

- 90 d

- Public Meeting

**9/27/07**

- Pilot Quality Control Project
- Recommendation to Secretary – Narrative Summaries

**12/26/07**

**9/27/08**

**3/27/09**

**9/27/10**

- New Administration
- Transition Phase

## Accomplishments To Date

- ClinicalTrials.gov registration system (PRS) modified to enable compliance with expanded registration requirements (11/27/07)
- Links established from registry to NIH/NLM and FDA results information
- Information developed for affected communities
- NLM Data Element Definitions and Fact Sheet
- NIH Guide Notices (2) and FAQs – including instructions for initial NIH grantee/contractor compliance

## Slide 4

## Slide 5

## Slide 6

## Enforceability of Data Elements 

- Need to collect information not explicitly listed in the law
- More detail required than specified in law (e.g., “study design”)
- Additional information necessary to comply with law (e.g, data required to implement search requirements)
- Competing concerns
- Congressional intent to establish registry quickly
- Difficulty of enforcing all necessary data elements without regulation
- HHS is considering rulemaking

## Revisions to Registry

- “Data providers” are alerted to items that (may be) required by the FDAAA
- Omission of these items does not block acceptance of the record, and an NCT # is assigned
- Items in question include those with some complexity, those that are required to implement the law, and one that reflects NIH policy
- HHS is considering rulemaking

## Study Record

## Slide 10

## Slide 11

## Slide 12

## Sept

**New Records:**
**2007 ****vs. ****2006**

**New Accounts:**
**2007**** ****vs. ****2006**

**~45%**

- Oct

- Nov

- Dec

## Enhanced Registry Activity (12/1/07-1/20/08)

- New** **Study Submissions: 2,932
- 419 records/week
- Updated** **Studies: 10,558
- 1,508 records/week
**Overall Studies: 13,490**
**1,927 records/week;  100% increase**
**New PRS Accounts: 252 **
**36/week;   64% increase**
- Current Backlog: ~600 records (~10 days)

## Overall Characteristics: New Studies (12/1/07-1/20/08)

**Total**				 2,932 (100%)
- Type of Trial*
-     Observational		    628 (22%)
**    ****Interventional****	**	 2,281 (78%)
-        - Drug, Biologic		 1,492
-        - Behavioral, Gene
-          Transfer, Other 	    479
-       - Medical Procedure	    290
-       - Device		    	    227
- 			(+*27 delayed posting*)

- * 23 records missing “Study Types” information

## Overall Characteristics: New Studies (12/1/07-1/20/08)

**Total – Interventional Studies               **2,281 (100%)
**Studies by Registrant Type**
- 	University, Other			1,397 (61%)
- 	Industry				   645 (28%)
- 	US Federal (including NIH)		   239 (11%)
**Studies by Facility Location**
- 	US sites only				 1,436 (63%)
- 	Non-US only				    569 (25%)
- 	US & non-US mixed			      73 (  3%)
- 	Missing				    203 (  9%)

## Overall Characteristics: Updated Studies (12/1/07-1/20/08)

- *4 records missing “Study Types” information

**Total**				10,558 (100%)
- Type of Trial*
-     Observational		  1,019 (10%)
**    ****Interventional****	**	  9,535 (90%)
-        - Drug, Biologic		  8,080
-        - Behavioral, Gene
-          Transfer, Other 	     776
-       - Medical Procedure	  4,282
-       - Device		    	     329

## Overall Characteristics: Updated Studies (12/1/07-1/20/08)

**Total – Interventional Studies               **9,535 (100%)
**Studies by Registrant Type**
- 	University, Other			1,947 (21%)
- 	Industry				2,997 (31%)
- 	US Federal (including NIH)		4,591 (48%)
**Studies by Facility Location**
- 	US sites only				 5,746 (60%)
- 	Non-US only				 2,006 (21%)
- 	US & non-US mixed			 1,158 (12%)
- 	Missing				    625 (  7%)

## Delayed Posting of Device Trial Registrations

- Law appears to prohibit public posting of trials of devices that have not been approved/cleared by FDA – *even when* desired by registrant
- Would therefore:
- Require removal from current database of some device trials voluntarily posted prior to passage of law
- Preclude use of ClinicalTrials.gov for recruitment
- Preclude use of ClinicalTrials.gov to comply with registration policy of journal editors (ICMJE)
- Limit transparency of such trials funded by NIH or other gov’t agencies
- Complaints received from some companies; some registrants are omitting approval/clearance status of devices to circumvent
- HHS is studying possible options

## Device Studies:Delayed Posting

- Must answer “yes” to following: Indicate whether this is an unapproved or uncleared device trial for which posting to ClinicalTrials.gov should be delayed in accordance with US Public Law 110-85, Title VIII, Section 801.
- 32 studies in “lock box” as of 2/7/08

## Overall Interventional Device Studies (12/1/07-1/20/08)

| Delayed? | Records | Registrant Type |  |  | Overall Status |  |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Industry | University, Other | Federal (incl. NIH) | Active | Not Active |
| Yes |   27 (  5%) |   23 (10%) |     4 (  2%) |   0 (0%) |   26 |     1 |
| No | 127 (24%) |   75 (34%) |   38 (15%) | 14 (22%) | 110 |   17 |
| Missing | 377 (71%) | 123 (56%) | 204 (83%) | 50 (78%) | 272 | 105 |
| Total | 531 (100%) | 221 (100%) | 246 (100%) | 64 (100%) |  |  |

## Delayed Posting General Characteristics

- Total: 32 studies (as of 2/7/08)
- Provider Type
- 27 Industry
-   5 Other
- Study Type
- 27 Interventional
-   4 Expanded Access
-   1 Observational

## Analysis of Response:OVERALL 

**Data Completion Statistics for**** **_**Overall**_**Active Phase II-IV Drug/Device Interventional Trials Submitted**** ****(12/1/07 - 1/20/08)**

|  |  | Completed Data |  |  |
| --- | --- | --- | --- | --- |
| 
Registrant Type | 

Total | Primary Outcome Measure | 
Number of
Arms | 
Responsible Party |
| Industry |  2,029 | 1,947 (96%) |  1,601 (90%) |  1,576 (78%) |
| Federal (incl. NIH) |  2,539 | 1,964 (77%) |     227 (  9%) |     220 (  9%) |
| University, Other |  1,208 | 1,200 (99%) |  1,199 (99%) |  1,118 (93%) |

## Top Device Companies

- ** All device interventional and observational studies registered at ClinicalTrials.gov as of 2/4/08
- *** Active, phase II-IV device interventional trials
- ****Includes: BiosenseWebster, ConorMedsystems, Cordis, Dupuy*, Ensure, Ethicon*, LifeScan, Visioncareinc

## Top Pharmaceutical Companies

- * Source: Top 10 Companies by U.S. Sales. IMS Health, IMS National Sales Perspective.3/2007
- ** All interventional and observational studies registered at ClinicalTrials.gov as of 2/4/08
- *** Active, phase II-IV drug/biologic interventional trials

## Specific Data Element Issues

- Public Law 110-85, Section 801
- PL 110-85 Implementation
- NIH Policy

## Evolution of Data Elements

- ClinicalTrials.gov has included data elements necessary to accommodate many policies
- FDAMA
- ICMJE
- Specific wording and structure of data elements has evolved with experience
- FDAAA has incorporated previously optional ICMJE data elements—usually identified by overall title (without details)

## NIH Policy – “Board Approval”

- Submitted studies should have approval from a human subjects review board prior to the recruitment of the first patient
- Studies may be registered prior to board approval, if status is “Not yet recruiting”
- Data Elements
- Board Approval Status (e.g., “Submitted, exempt”)
- Board Name
- Board Affiliation
- Board Contact

## Interventional “Study Design”

- Each of the following elements is required
- Intervention Model – intervention assignments (e.g., parallel arms)
- Number of Arms – number of comparative groups
- Masking – knowledge of intervention assignments (e.g., double blind)
- Allocation – participant assignment to intervention arm (e.g., randomized)
- Sources: ICH E3, 21 CFR 314.126

## “Intervention Name”

- Provides sufficiently detailed description of the intervention(s) and to link intervention(s) to arm(s)
- Data Elements
- Intervention Name: generic name for drugs; for others, sufficient detail to distinguish from similar interventions (e.g., devices)
- Intervention Description: e.g., dosage
- Arm Name or Label: way to identify arm
- Arm Type: e.g., experimental, active comparator
- Arm Description: if different from intervention description

## ENHANCE TrialNCT00552097 

- ENHANCE TrialNCT00552097

## CATIENCT00014001

## “Outcome Measure”

- Specific measurement that will be used to measure the effect of experimental variables in a study
- Requires the following
- Outcome Measure: Description of the specific measure
- Outcome Time Frame: Time point(s) at which outcome measure is assessed
- [Safety Issue? (yes/no)]

## PL 110-85 Implementation

**Safety Issue?** – “the safety issue, if any, being studied in the clinical trial as a primary or secondary outcome”
**Facility Contact** – location information (e.g., city, state, country) to be able to search by “location of the clinical trial”
**Applicable Clinical Trial?**
- FDA Regulated Intervention? (Yes/No)
- Section 801 Clinical Trial? (Yes/No)
- Delayed Posting? (Yes/No)

## Other Questions to Address

- Cut-off for modifying registry records?
- Estimated completion date
- Outcome measures
- Target enrollment
- Good enough outcome measure?
- How should changes be displayed?