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current August 2006

FDAMA Section 113: Analysis of Cancer Trials Submitted May - July, 2005

Department of Health and Human Services
Food and Drug Administration
Office of Special Health Issues

June 2006

TABLE OF CONTENTS

I.    INTRODUCTION

II.   OBJECTIVES

III.  METHODS

A. Data collection
B. Data extraction
C. Documenting trial listings in ClinicalTrials.gov
D. Follow-up telephone calls

IV. RESULTS

A.Protocols by sponsor type
B.Follow-up telephone calls
C.Comparison of 2002, 2004, and 2005 cancer data
D. Process used to determine the compliance rate

V. DISCUSSION

VI. CONCLUSION

I. INTRODUCTION

In 1997, the U.S. Congress addressed the needs of patients and their advocates by adding a provision to the Food and Drug Administration Modernization Act (FDAMA) that mandated the establishment by the National Institutes of Health (NIH) of a publicly-accessible clinical trials data bank and required sponsors to list eligible trials in the data bank. The NIH, through its National Library of Medicine (NLM), developed the Clinical Trials Data Bank called ClinicalTrials.gov.  This service was made available to the public in February 2000 at www.clinicaltrials.gov.

On March 18, 2002, FDA issued a final guidance to industry to address statutory and procedural issues related to Section 113 of FDAMA.¹ The guidance states that a trial is required to be listed in the data bank if it is intended to treat a serious or life-threatening disease or condition and is a phase 2, 3 or 4 trial with efficacy endpoints.

In January 2002, the Food and Drug Administration (FDA) Office of Special Health Issues (OSHI) undertook a program to educate private-sector sponsors about the statutory reporting requirements under Section 113 of FDAMA and to assess sponsor compliance with the law.  In 2003, the results of this study stimulated questions about whether the number of clinical trial listings submitted by sponsors to the clinical trials data bank was increasing over time.  Consequently, in May 2004 another project was initiated to further assess compliance and, if possible, identify sponsors’ reasons for not complying. The report describing these two studies is available at http://www.fda.gov/oashi/clinicaltrials/section113/113report/default.htm. 

In May 2005, FDA initiated another study similar to the one initiated in 2004.  Details of the study are provided below.

II. OBJECTIVES

The objectives of the study were as follows:

1.   To determine the regulatory compliance by comparing the number of cancer trials listed in ClinicalTrials.gov by sponsors to the number of cancer protocols submitted to the Center for Drug Evaluation and Research’s (CDER’s) Division of Oncology Drug Products (DODP) during the three-month period of May 1, 2005 through July 31, 2005.²

2.    To assess changes in compliance by comparing the number of cancer trials listed in ClinicalTrials.gov that were submitted to CDER’s DODP during the three-month period of May 1 – July 31 in 2002, 2004, and 2005.

3.    To determine reasons why some sponsors are not listing their trials in ClinicalTrials.gov.

III. METHODS

Data were obtained from two primary sources within the agency: Center ORACLE Management Information System (COMIS), and paper protocol records submitted by investigational new drug (IND) sponsors.  New commercial protocols submitted to CDER's DODP between May 1 and July 31, 2005 were identified from a search of the COMIS database.³ The COMIS search included both new protocols and new INDs because it was assumed each new IND submitted contained at least one protocol.  We selected cancer protocols and the May-July timeframe for evaluation to maintain consistency of methods with previous projects examining compliance data.

A. Data collection

• OSHI received from CDER two electronic Microsoft Excel™ spreadsheets: one containing original IND applications and one containing new protocols for existing INDs submitted to DODP.  The following protocol information was contained in the Excel spreadsheets:
  • IND number
  • Serial number
  • Submission date (indicates the date the sponsor filed the submission)
  • Stamp date (indicates the date the FDA received the submission)
  • Sponsor name
  • Drug name (brand and generic)
• The Excel spreadsheets were downloaded into a Microsoft Access™ database.

• OSHI received copies of the paper INDs from the CDER document room staff.

• OSHI organized the paper documents in individual folders labeled with the corresponding IND number.  Documents were sorted numerically by IND number.

B.  Data extraction

The following key data elements were extracted from 122 protocols and entered into the OSHI database:

• Indication: The indication provided by COMIS was revised using NLM's controlled vocabulary thesaurus known as Medical Subject Headings (MeSH) (http://www.nlm.nih.gov/mesh/MBrowser.html).
• Sponsor type: Industry (pharmaceutical company), NIH, Other Government, Physician, Medical Center, Other
• Number of protocols within the submission
• Protocol number(s): Sponsor designated protocol identifier
• Protocol title(s): Title of protocol
• Phase: 1, 1/2, 2, 2/3, 3, 3/4, 4, Not Specified (NS)

If the phase was not mentioned in the title or protocol synopsis then the phase listed on FDA Form 1571, the cover sheet for an IND submission, was used.  We used FDA Form 1571 to identify the phase in approximately 5% of all protocols.

Although 21 CFR 312.21 states that a clinical investigation of a previously untested drug is divided into three phases (1, 2, 3), we included transitional phases (1/2, 2/3, 3/4) to reflect how sponsors categorize protocol submissions.

• Is the protocol indicated for a serious or life-threatening disease or condition? Yes or No
• Does the study test effectiveness? Yes, No or NS. If the study listed efficacy endpoints as primary or secondary objectives, then "yes."
  • Did the study list primary efficacy endpoints?  Yes, No or NS
  • Did the study list secondary efficacy endpoints?  Yes, No or NS

If the protocol listed efficacy endpoints as either primary or secondary, the protocol was considered for purposes of this study as one to test effectiveness.

• Comments:  The name of the sponsor's regulatory affairs person (contact person) responsible for the protocol in the event of follow-up phone calls to the sponsor.

C.  Documenting trial listings in ClinicalTrials.gov

NLM prepared weekly reports to provide an update on sponsor trial listings in ClinicalTrials.gov.  The reports were used to verify whether IND protocols submitted to CDER were listed in ClinicalTrials.gov.  The NLM reports contained the date the trial was released into ClinicalTrials.gov, sponsor name, official representative, IND number, serial number, sponsor protocol ID, NLM identifier, title, condition, and drug name.

• The IND number, serial number, and sponsor protocol ID from the NLM report were compared to data in the OSHI database to verify whether the protocol had been submitted to CDER within the 3-month period of May 1 - July 31, 2005. Because protocols generally would be listed in ClinicalTrials.gov after they are submitted to CDER, the comparison process began on May 1, 2005 and continued until December 31, 2005.

• A final comparison was conducted in February 2006 to verify whether trials contained in the OSHI database met the criteria for inclusion in ClinicalTrials.gov and were listed there.  

• If the protocol was listed in the OSHI database, the date the trial was listed in ClinicalTrials.gov and the assigned NLM identifier were recorded in the database.

D.  Follow-up Telephone Calls

Follow-up telephone phone calls were placed to 18 different sponsors who appeared not to have listed cancer trials that met the criteria for inclusion. The follow-up call was an attempt to gather information about why the sponsor had not listed the trial.

IV. RESULTS

A. Protocols by sponsor type

One hundred twenty-two commercial protocols were submitted to CDER's DODP between May 1, 2005 and July 31, 2005.  Of the 122 cancer protocols submitted to DODP, 100 (82%) were sponsored by pharmaceutical companies, 21 (17%) by NIH, and 1 (1%) by Other. 

Table 1 shows the number of protocols submitted to DODP by sponsor type that met the inclusion criteria for listing in ClinicalTrials.gov.  Upon initial review, approximately 37 percent (45 / 122) of trials submitted to DODP met the guidance criteria for listing in ClinicalTrials.gov.

Table 1.  Trials meeting guidance criteria for listing in ClinicalTrials.gov

¹ Inclusion criteria is defined as a phase 2, 3, or 4 protocol with efficacy endpoints to treat a serious or life-threatening disease or condition.

Upon initial review of required trial listings in ClinicalTrials.gov it appeared that 19 out of 34 pharmaceutical company protocols and 1 out of 11 NIH/NCI protocols were not listed.  We followed-up with sponsors and learned that only 24 trials sponsored by pharmaceutical companies and 10 trials sponsored by NIH were required to be listed.

B.  Follow-up telephone calls

Follow-up telephone calls were made to eighteen different sponsors, representing 20 trials (one sponsor had 3 protocols), who had trials that met the criteria for inclusion yet could not be located in ClinicalTrials.gov.  Reasons given by the sponsors for not listing the 20 protocols are as follows:

• Protocol was not finalized. (n=3)
• Protocol was not active and more than likely would remain inactive. (n=3)
• IND was terminated. (n = 2)
• Protocol was withdrawn from IND. (n=2)
• Protocol was listed in ClinicalTrials.gov in June 2003 under a different IND. (n = 1)
• Protocol recently opened for enrollment. Information was entered into the PRS and would be posted in ClinicalTrials.gov shortly. (n=2)
• Protocol information was being reviewed internally and would be released to ClinicalTrials.gov. (n=2)
• Listing of the trial was overlooked.  Trial would be listed as a result of the phone call. (n=1)
• Contract research organization (CRO) recently acquired the foreign sponsor from another CRO.  Current CRO would notify the company about listing the trial. (n=1)
• Protocol was submitted to NCI’s cancer trial listing, the Physician’s Data Query (PDQ) found on Cancer.gov.  Due to time delay of often 4-5 weeks, protocol has not appeared in ClinicalTrials.gov. (n=1)
• Lack of knowledge about the law and guidance. (n=1)
• Sponsor was not aware that trials with only international sites needed to be listed in ClinicalTrials.gov. (n=1)

It was determined that eleven out of 45 trials were not required to be listed for the following reasons: withdrawal of protocol from the IND, delayed enrollment, study not finalized, study was not active, IND was terminated, or study was listed in ClinicalTrials.gov under a different IND number. Table 2 shows the compliance rates by sponsor type that resulted after the follow-up telephone calls were made.

Table 2.  Compliance by Sponsor Type After Follow-up

C.  Comparison of 2002, 2004, and 2005 cancer data

Table 3 compares the compliance rates by sponsor type during the three-month period of May 1 - July 31 in 2004 and 2005.  Compliance rates were 81% and 76%, respectively.  Compliance data were collected during the same three-month period in 2002.  Compliance rates for pharmaceutical companies, NIH/NCI, and Other were 50%, 85%, and 50%.  A direct comparison can not be made between the 2002, 2004, and 2005 data because the methods used in 2002 differed from those employed in 2004 and 2005.  Follow-up with sponsors was not conducted in 2002.  

Table 3.  Cancer Trials Submitted to CDER's DODP and Listed in ClinicalTrials.gov

D. Process used to determine the compliance rate

Figure 1 below describes the process used to determine how many protocols met the guidance criteria for listing in ClinicalTrials.gov.

Figure 1.  Number of Oncology Trials Listed in ClinicalTrials.gov

V. DISCUSSION

Several observations can be derived from OSHI’s discussions with sponsors.  Follow-up proved to be an important part of the project since it revealed that 11 out of 45 (24%) trials were not initiated, and therefore were not required to be listed in ClinicalTrials.gov.  As stated in Section IV B (follow-up telephone calls), a total of eight sponsors said they would list their trial or were in the process of listing their trial and those listings were to appear in the Data Bank within one to two weeks.  We continued to monitor the listings in ClinicalTrials.gov until the end of February 2006, at least seven months after the protocol was submitted to the IND.  Three of the eight sponsors did not list their trials.  There was no further follow-up with these companies. 

We learned from follow-up that one company submitted their trial information to PDQ rather than ClinicalTrials.gov.  Even though the databases share information, the trials submitted to PDQ may take several weeks to appear in ClinicalTrials.gov.  While the FDA guidance states that all information for cancer protocols that meet the requirements of section 113 of the Modernization Act must be submitted to ClinicalTrials.gov rather than PDQ, it also states that the sponsor may use an intermediary to provide their information to ClinicalTrials.gov.  Some sponsors may use NCI as the intermediary and data provider for ClinicalTrials.gov.  In these cases, NCI has agreed to ensure that these trials are promptly listed in ClinicalTrials.gov.

Reasons provided by industry sponsors for not listing trials in 2004 were similar to those stated in 2005 with the exception of concerns about availability of information to the public and to competitors.  In 2004 one company representative stated its trial would not be listed due to confidentiality concerns.  However, in 2005, none of the seventeen company representatives mentioned confidentiality as a reason for not listing a trial in ClinicalTrials.gov.

As indicated in Table 3, compliance by pharmaceutical companies was similar in 2004 and 2005 (70% in 2004 and 67% in 2005) and may have increased from 2002.  A direct comparison can not be made between the 2002, 2004, and 2005 data because the telephone follow-up with sponsors was not conducted in 2002.

Of note, sponsors voluntarily listed 24 out of 77 trials (31%) that did not meet the criteria for inclusion during the May-July 2005 time period.  This represents an increase in voluntary listing from 22% (19 out of 85) in 2004. 

We expect that the number of industry-sponsored trials submitted to ClinicalTrials.gov may continue to increase for two reasons.  First, as a result of the Pharmaceutical Research and Manufacturers of America (PhRMA) voluntary disclosure policy announced in January 2005, PhRMA members will voluntarily post information about ongoing hypothesis-testing trials for all diseases to ClinicalTrials.gov by September 13, 2005. Second, as of July 1, 2005 the International Committee of Medical Journal Editors (ICMJE) requires trials be registered (i.e. listed in ClinicalTrials.gov) in order to be considered for publication.

VI.  CONCLUSION

Pharmaceutical industry listing in ClinicalTrials.gov of cancer-related trials required to be listed under Section 113 of FDAMA continues at a rate of 66-70%.  Continued FDA monitoring and initiatives by PhRMA and ICMJE may further improve pharmaceutical industry compliance with requirements for participation in ClinicalTrials.gov.  These efforts should help expand patient access to information about opportunities to participate in trials of investigational new treatments for serious or life-threatening diseases and conditions, as was intended by the statutory reporting requirements under Section 113 of FDAMA.
 

Food and Drug Administration Modernization Act (FDAMA) Section 113 and ClinicalTrials.gov

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