ClinicalTrials.gov

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ClinicalTrials.gov

• Presented by
• Suzanne OShea
• Baker Daniels LLP
• 317-569-4649
• suzanne.oshea_at_bakerd.com

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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

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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)

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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

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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.

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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.

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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)

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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)

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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)

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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)

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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)

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Certification to FDA

• INDs 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

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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)

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NIH

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

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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

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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.

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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)

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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)

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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)

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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

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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)

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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 approved or 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)

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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)

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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)

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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)

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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)

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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)

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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)

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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)

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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)

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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 INDs
• Device applications IDE, 510(k), PMA, HUD.
• 42 U.S.C. 282(j)(5)(B)

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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)

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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)

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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.

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• For specific questions
• wecomply_at_indiana.edu