ClinicalTrials.gov

1. ClinicalTrials.gov Presented by: Suzanne O’Shea Baker & Daniels LLP 317-569-4649 suzanne.oshea@bakerd.com

2. Clinical Trial Databases • Food and Drug Administration Amendments Act enacted September 27, 2007 • Expanded database includes drugs and devices • Nearly all clinical trials • Registration and Results • No Federal funding unless registered • Civil Penalties for failure to register

3. The Responsible Party • Sponsor (as defined in § 21 CFR 50.3) is default responsible party • Principal Investigator may be responsible party under certain circumstances: 42 U.S.C. 282(j)(1)(A)(ix)

4. Principal Investigator May be designated as responsible party by sponsor, grantee, contractor or awardee when: • Responsible for conducting trial • Has access to and control over data from the clinical trial • Has the right to publish the results of the trial • Has the ability to meet all the requirements for submission of information

5. Important! Be sure to determine if YOU are the Responsible Party for your trial! • If you are a sponsor – investigator, you are most likely the Responsible Party, unless that role has been delegated to a Principal Investigator meeting all criteria. • If you are the IND or IDE “holder,” you may be considered the sponsor. • If you are the Principal Investigator, you may have been designated as the Responsible Party by the sponsor.

6. 21 CFR § 50.3 (d) Investigator means an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject, or in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. (e) Sponsor means a person who initiates a clinical investigation, but who does not actually conduct the investigation, i.e., the test article is administered or dispensed to or used involving, a subject under the immediate direction of another individual. (f) Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject. The term does not include any person other than an individual, e.g., corporation or agency.

7. Registration Purpose: to enhance patient enrollment and provide a mechanism to track subsequent progress of clinical trials. Information must be submitted to www.clinicaltrials.gov within 21 days after the first patient is enrolled. 42 U.S.C. § 282(j)(2)(C)(ii)

8. Registration transition period • Studies of drugs for serious or life-threatening disease or condition in which last patient will receive intervention before December 26, 2007 – no new registration required. • Studies of drugs for serious or life threatening disease or condition still ongoing on December 26, 2007 – submit new required information by December 26, 2007. • Applicable clinical trials were ongoing on September 27, 2007 – submit new required information by September 27, 2008. • Applicable clinical trials that enroll first patient between September 27, 2007 and December 6, 2007 – submit required information by December 26, 2007. 42 U.S.C. § 282(j)(2)(C)

9. What is an Applicable Clinical Trial? Now includes drug and device trials. Previously, only trials of drugs for serious or life threatening diseases or conditions were required to register. 42 U.S.C. 282(j)(1)(A)(i)

10. Applicable Clinical Trials-- Devices • Prospective clinical study of health outcomes • Comparing a device intervention against a control in human subjects • When device is subject to 510(k), PMA, Humanitarian Use Device (HUD), or • Pediatric postmarket surveillance studies • Excludes: small clinical feasibility trial or trial of prototype where primary outcome measure relates to feasibility rather than health outcomes. 42 U.S.C. § 282(j)(1)(A)(ii)

11. Applicable Clinical Trials -- Drugs • Controlled clinical investigations (Phases II, III, and IV) of drugs subject to: • new drug provisions of Food, Drug and Cosmetic Act, including generics, (21 U.S.C. § 355) or • licensing provisions of Public Health Service Act, e.g., blood, blood derivatives, virus, vaccine, toxin, antitoxin, allergenics, cell and gene therapy. (42 U.S.C. § 351) • Excludes Phase I trials as defined in 21 CFR 312.21 42 U.S.C. § 282(j)(1)(A)(iii)

12. Certification to FDA • IND’s submitted to FDA, including amendments, must include a certification that all requirements of clinicaltrials.gov have been met. • FDA will issue a form to use to certify. 42 U.S.C. § 282(j)(5)(B) see also slide 31

13. Voluntary Submissions Responsible party for a trial that is: • not an applicable clinical trial (e.g. Phase I trial, see slides 10 and 11) or • not required to register (see slides 7 and 8) May submit complete clinical trial information as long as all required information is submitted. 42 U.S.C. § 282(j)(4)(A)

14. NIH NIH encourages registration of ALL trials whether or not required by law. NIH notice number: NOT-OD-08-014

15. ICMJE Note: ICMJE recently adopted a recent expanded definition of “clinical trial” to include essentially all clinical trials, including Phase I trials, but excluding purely observational studies. Under this expanded definition, if your trial begins enrollment on or after July 1, 2008, an ICMJE journal will consider it for publication only if it is registered. www.icmje.org

16. Note on Informed Consent • FDA regulations to be updated to require inclusion in informed consent documents and process a statement that clinical trial information has been or will be submitted to clinicaltrials.gov 21 U.S.C. § 505(i)(4) • Probably a good idea to include same information in informed consent documents in device trials.

17. Updates • Updates to reflect changes to clinical trial information must be submitted at least once every 12 months, unless there were no changes. • Date of change must be identified. • Changes in recruitment status must be reported within 30 days. • Completion of trial must be reported within 30 days. 42 U.S.C. § 282(j)(4)(C)(i) With the exception of recruitment status, individual site status, location, and contact information, updates to registration will not result in removal of information from the data base. 42 U.S.C. § 282(j)(4)(C)(ii)

18. Completion The term ‘completion date’ means the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome….. 42 U.S.C. § 282(j)(1)(A)(v)

19. Registration Information • Descriptive information • title, summary, design, phase, disease or condition, start date, expected completion date, target number of subjects, primary and secondary outcome measures • Recruitment information • eligibility criteria, gender, age, healthy volunteers, overall recruitment status, individual site status, availability of treatment IND • Location and contact information • Administrative data (publicly available only as necessary) 42 U.S.C. § 282(j)(2)(A)(ii)

20. Expanded RegistrationSearch Categories • Disease or condition • Name of the intervention • Location of trial • Age group being studied (including pediatric) • Study phase • Sponsor • Recruitment status • National Clinical Trial number • Safety issue being studied as primary or secondary outcome(by March 27, 2009) • Other categories deemed necessary 42 U.S.C. § 282(j)(2)(B)(i) • Current search categories: condition, drug intervention, sponsor, and location

21. Results • Applicable clinical trials (see slides 10 and 11) • Required to submit registration information (see slides 7 and 8) • Basic results information must be submitted within 1 year of the earlier of the estimated completion date, or the actual completion date. 42 U.S.C. § 282(j)(3)(E)(i)

22. Delay of Submission of Results Information • Director of NIH may provide extension of deadline for submission of results information for “good cause.” • If applicable trial is completed before drug, biologic or device is approved or cleared, results information must be submitted within 30 days of approval or clearance. Responsible party must submit certification to Director of NIH. • If applicable clinical trial supports a new use of already approvedor cleared drug, biologic or device, results information must be submitted within 30 days of approval or clearance of new use. Responsible party must submit certification to Director of NIH. 42 U.S.C. § 282(j)(3)(E)(iii), (iv), (v), and (vi)

23. Results Information Waiver Upon written request from responsible party, the Secretary may waive the requirement that results information be submitted if: • extraordinary circumstances justify the waiver and • the waiver is consistent with the public health or • the waiver is in the interest of national security. Within 30 days of any waiver, the Secretary must notify the appropriate Congressional committee of the waiver and provide an explanation for why the waiver was granted. 42 U.S.C. § 282(j)((3)(H)

24. Basic Results Information • Demographic and baseline characteristics of patient sample. Includes number of subjects who dropped out or were excluded. • Table of values for primary and secondary outcome measures for each arm, including results of scientifically appropriate tests of statistical significance. • Point of contact for further scientific information. • Information whether an agreement exists between sponsor and principal investigator that restricts ability of principal investigator to discuss results of the trial in a public or private forum, or to publish results. 42 U.S.C. § 282(j)(3)(C)

25. Additional Results Information • By September 27, 2010, FDA required to issue new regulations pertaining to the submission of additional results information. • Regulations must pertain to applicable clinical trials for drugs, biologics, and devices that are approved, licensed or cleared. • FDA must decide whether new regulations apply to applicable clinical trials for drugs, biologics, and devices that are not approved, licensed or cleared (whether or not approval, licensure or clearance was sought). • FDA must decide effective date of new regulations – e.g., whether additional results information must be submitted on applicable clinical trials completed more than a year prior to issuance of regulations. 42 U.S.C. § 282(j)(3)(D)

26. Additional Results Information • New regulations will require summary of clinical trial and results in non-technical language and technical language, if Secretary determines that such summaries can be included without being misleading or promotional • Full protocol or information about the protocol as would be helpful to evaluate results of trial • Other • FDA required to hold public meeting by March 27, 2009 to get input from interested parties on these regulations. 42 U.S.C. § 282(j)(3)(D)(iii) and (vii)

27. Adverse Event Information • By March 27, 2009, FDA required to issue regulations determining best method for including information on serious and frequent adverse events for drugs (not devices). • Frequent adverse event exceeds 5 percent within any arm of trial. • Regulation is to require information in a form useful to and not misleading to patients, physicians, and scientists. • Information on adverse events will be considered basic results information. 42 U.S.C. § 282(j)(3)(I)

28. Specifically Required Studies When necessary to protect the public health, the Secretary may require registration and results information about: • specific applicable trials completed between September 27, 1997 and September 27, 2007 or • an applicable clinical trial on a drug, biologic or device that has not been approved, licensed, or cleared. 42 U.S.C. § 282(j)(4) (B)

29. Compliance – Federal Funding • Funding agencies within Department of Health and Human Services (e.g., NIH, FDA, AHRQ) will verify that required information submitted for applicable clinical trials. • All required registration and results information must be submitted before funding released. • Grantee has 30 days to remedy non-compliance by submitting required information. • Secretary to consult with other funding agencies (e.g. Veterans’ Administration) to develop comparable procedures. 42 U.S.C. 282(j)(5)(A)

30. Compliance -- Public Notice If responsible party fails to submit required registration or results information, Director of NIH shall include in the database a statement that responsible party is not in compliance for: • failing to submit information, or primary or secondary outcomes information. “This may or may not have any bearing on the accuracy of the information in the entry.” • submitting false or misleading information. Database will be searchable on such notices 42 U.S.C. § 282(j)(5)(E)

31. Certification in Marketing Applications Certification that all database requirements have been fulfilled required in: • New drug applications, including INDs, ANDAs for generic drugs • Biologic License Applications, including IND’s • Device applications: IDE, 510(k), PMA, HUD. 42 U.S.C. § 282(j)(5)(B)

32. Food, Drug, and Cosmetic Act Prohibited Acts • Failing to certify in drug, biologic or device marketing application that all required information has been submitted • Failing to submit required information to database • Submission of information that is false or misleading in any particular 21 U.S.C. § 331(jj)(1)

33. Food, Drug, and Cosmetic Act Civil Money Penalties Any person who commits a prohibited act is subject to a civil money penalty of not more than $10,000 for all violations adjudicated in a single proceeding. If violation is not corrected within 30 days, responsible party may be subject to a civil money penalty of not more than $10,000 for each day violation is not corrected. 21 U.S.C. § 331(jj)(2)

34. Preemption • No state or political subdivision of a state may require registration of clinical trials or inclusion of information relating to clinical trials in a database. • Submitting information to database about use of drug, biologic or device not included in approved or cleared labeling is not evidence of a new intended use, and is not considered labeling, adulteration or misbranding.

35. For specific questions: wecomply@indiana.edu