Clinical Trial Applications (CTAs)

1
Clinical Trial Applications (CTAs)

• PRA700

2
Overview

• History of the CTA and the regulations/guidelines
• Pre-CTA Consultation Meetings
• CTA and CTA-Amendment Requirements
• Additional CTA related requirements

3
History

• Prior to September 2001 INDs were filed in Canada
  for investigational products
• INDs had a 60-day default review time
• Clinical Trial Review and Approval Policy (1997)

4
History (continued)

• Canada Gazette Part I - Schedule 1024 Clinical
  Trials
• Anticipated to appear in Canada Gazette, Part II
  - April 2000
• Initially Proposed Effective date - September 1,
  2000
• Implementation date - September 1, 2001

5
Expectations of New Clinical Trial (CT)
Regulations

• Shorten clinical trial application review times
• Improve safety mechanisms for clinical trial
  participants,
• Be more involved in the monitoring and follow-up
  of conduct of clinical trials
• Remove obstacles to additional research and
  development in Canada
• Ensure that Canadians have improved access to
  innovative therapies and advice from Canadian
  physicians with research expertise in these new
  therapies

6
Where are the new regulations located?

• Part C, Division 5
• Schedule 1024 of Gazette II

7
CTA Reference Materials

• Schedule 1024
• CTA Guidance Document
• Quality Guidance for CTAs ?
• Quality Overall Summary - Chemical Entities
  (QOS-CE)?
• Quality Information Summary - Biologics (QIS-B) ?
• Quality Information Summary - Radiopharmaceuticals
  (QIS-R) ?
• Revised Application Form (3011) ?
• Clinical Trial Site Information form ?

8
CTA Reference Materials (continued)

• Qualified Investigator Undertaking Form ?
• Research Ethics Board Attestation Form ?
• ADR Expedited Reporting Summary Form ?
• Electronic Clinical Trials Application

9
CTA Guidance Document

• PRA700

10
CTA Guidance Document

• Supercedes the Clinical Trials Review and
  Approval Policy
• Used in conjunction with HPFB Guidances
• Good Clinical Practice Consolidated Guideline
• General Considerations for Clinical Trials
• Clinical Safety Data Management Definitions and
  Standards for Expedited Reporting

11
When do you file a CTA?

• To conduct Phase I to III clinical trials in
  Canada for a
• New drug prior to a Notice of Compliance (NOC)
• Marketed drug investigating anything outside the
  parameters of the NOC/DIN
• EXAMPLES
• indication
• target patient population
• route of administration
• dosage regimen
• dosage form

12
Do NOT File a CTA

• Post-marketing trials within the parameters of
  the NOC or DIN, i.e., Phase IV trials
• For example
• Pharmacoeconomic evaluations
• Additional drug-drug interactions
• Dose-response and safety trials
• Use of a marketed drug by a HCP for an individual
  patient

13
Pre-CTA Meeting

• PRA700

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PRE-CTA CONSULTATION

• Requested by sponsor
• Not mandatory
• Recommended for first-time CTA submission with
  new chemical entity (NCE) or applications with
  complex issues

15
PRE-CTA CONSULTATION

• Opportunity to present relevant data, discuss
  concerns and resolve issues with drug development
• Brief summary of data, toxicology discussion,
  adverse events and discussion of potential safety
  problems
• Qualified Investigators may be invited to attend
• Recommendations will be made and should be
  followed

16
PRE-CTA INFO PACKAGE

• Your request for a consultation
• Five copies of Pre-CTA package
• propose four dates and times for meeting
• 30 days notice required

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What will the package contain?

• Product information
• Global clinical plan (regulatory status in other
  countries)
• Proposed clinical trials to be conducted in
  Canada within CTA
• Chemistry and Manufacturing summary
• Physicochemical properties and structure
• Development Pharmaceutics

18
Meeting Record

• Sponsor will take meeting minutes and summarize
  significant discussions/conclusions
• Provide to Directorate within 7-10 days
• Central Registry

19
Pre-CTA Meeting

• Group I Work
• It is September 2004 and your head office wants
  to have a pre-CTA meeting for an NCE in December
  2004.
• What do you do?
• What do you need?

20
Pre-CTA Meeting

• Group II Work
• You are the other Regulatory Associate and have
  been asked to plan the logistics of the meeting
  in Ottawa.
• What do you do?
• Plan the meeting

21
CTA Requirements

• PRA700

22
CTA Requirements

• Filed directly to appropriate Directorate (TPD or
  BGTD)
• Outer label - Clinical Trial Application

23
CTA Requirements (continued)

• Module 1 Administrative/Clinical Information
• Table of Contents
• Comprehensive list for all Modules
• Application Information
• HC/SC 3011
• Prior Related Applications
• IB/Product Monograph

24
CTA Requirements (continued)

• Protocol Synopsis
• PCERT for drugs
• submission rationale/brief summary for biologics
  radiopharmaceuticals
• Study Protocol
• Informed Consent (IC)
• Clinical Trial Site Information Form (List of
  Proposed Clinical Trial Sites)

25
CTA Requirements (continued)

• Pre-CTA Meeting Record (if applicable)
• Information related to REB refusals
• Labels (for biologics and radiopharmaceuticals
  only)
• Letters of Access

26
CTA Requirements (continued)

• Module 2 Common Technical Document (CTD)
  Summaries
• Table of Contents
• Module 2 3 (if applicable)
• Quality Overall Summary (QOS)
• DOES NOT APPLY
• if the drug has DIN and/or NOC
• if the quality information previously submitted
  to HPFB has not changed

27
CTA Requirements (continued)

• Depending on the phase of the clinical trial, the
  completed applicable Quality Overall Summary -
  Chemical Entities (QOS-CE) template, as well as
  additional Quality information as outlined in the
  template, should be submitted
• Clinical Trial Applications - Phase I QOS-CE
  (CTA - Phase I)
• Clinical Trial Applications - Phase II or III
  QOS-CE (CTA - Phase II or III)

28
CTA Requirements (continued)

• Module 3 Quality - Chemistry Manufacturing
• Table of Contents
• Module 3 only
• Body of Data
• Where there is additional supporting Quality
  information to that provided in Module 2.3, this
  information should be provided separately in the
  appropriate Module 3 section and cross-referenced
  under Module 2.3.

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CTA Requirements (continued)

• For Biologics Radiopharmaceuticals only
• Executed batch records
• Literature References
• For Biologics and Radiopharmaceuticals only
  Literature references related to Quality
  information should be provided here if
  applicable.

30
CTA Requirements (continued)

• Module 3 Quality (Chemistry Manufacturing)
• BIOLOGICS (Schedule D)
• Draft QIS-B acceptable
• RADIOPHARMACEUTICALS (Schedule C)
• Draft QIS-R is acceptable

31
CTA Review Process

• PRA700

32
CTA Review Process

• 30-day default period
• Target to review Phase I and comparative
  bioavailability trials in healthy adult
  volunteers in 7 days

33
CTA Review Process

• Exceptions to 7-day review for Phase I trials
  include
• somatic cell therapies
• xenografts
• gene therapies
• prophylactic vaccines or
• reproductive and genetic technologies

34
CTA Screening

• All CTAs and CTA-amendments are screened for
  acceptability
• Deficiencies addressed by either
• Clarifax (request for clarification of
  information)
• Screening Deficiency/Rejection

35
CTA Review

• Clarifax response required within 2 calendar days
• Not Satisfactory Notice (NSN) issued if
• there are significant deficiencies or
• if sponsors fails to respond to clarifax within 2
  calendar days
• No Objection Letter (NOL) issued if no
  deficiencies are identified

36
Amendments

• PRA700

37
Changes to an Accepted CTA

• Filed when there are amendments to a approved
  Protocol or Changes to Clinical Trial Supplies
  (C.05.008)
• Approved prior to implementation
• Cannot submit an amendment with CTA or while CTA
  is under review
• If amendment eliminates an immediate hazard it
  does not need to be approved prior to
  implementation

38
Clinical Amendment

• Where a sponsor wishes to make changes to the CTA
  under review, the sponsor should withdraw the
  active CTA and submit a new CTA.
• Filed directly to appropriate Directorate (TPD or
  BGTD)
• Outer label - Clinical Trial Application -
  Amendment

39
Clinical Amendment

• Sponsors must file a CTA-A when the proposed
  changes to the protocol
• affect the selection, the criteria for selection,
  monitoring, or dismissal of a clinical trial
  subject
• affect the evaluation of the clinical efficacy of
  the drug
• alter the risk to health of a clinical trial
  subject
• affect the safety evaluation of the drug or
• extend the duration of the clinical trial.

40
Quality Amendments

• Sponsors must file a CTA-A to a previously
  approved application when changes that may affect
• the quality or safety of the clinical trial drug
  supplies are proposed.
• Changes to the Quality summary subsections of
  Module 2.3 and Module 3 (if applicable)
  including, but not limited to those listed below,
  warrant the filing of a CTA-A.

41
Quality Amendments

• Changes affecting the quality or safety of the
  clinical trial supplies
• Pharmaceuticals
• Changes to QOS sections S 2.2, S 3.2, S 4.1, P
  3.2, P 3.3, P 5.1
• Biologics
• Changes to QIS-B sections S 2.4, S 3.1, P 3.3, P
  5.1, P 7.1, 0 1.0

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Quality Amendments (continued)

• For Biologics and Radiopharmaceuticals any of the
  items listed in CTA Guidance Section 5.2 are
  considered beyond the scope of a Quality Amendment

43
Quality Amendment Requirements

• Filed directly to appropriate Directorate (TPD or
  BGTD)
• Outer label - Clinical Trial Application -
  Amendment

44
Miscellaneous CTA Items

• PRA700

45
Filing Trial Commencement Information

• After NOL and prior to commencing trial sponsors
  must
• complete and submit CT Site Information forms
• Added to HPFB file (w/o acknowledgement letter)

46
Notification

• Sponsors must notify HPFB of the following with
  15 calendar days of the day of the change
• changes to protocol that do not affect the safety
  of trial participants
• discontinued trials
• changes to quality
• Updated information should be submitted
• Change may then be implemented immediately

47
Labelling Requirements

• Labels must include the following in both
  official languages
• Statement Investigational Drug To Used By
  Qualified Investigators Only
• Name, number or identifying mark of the drug
• Expiry date
• Recommended storage conditions

48
Labelling Requirements (continued)

• Labels must include the following in both
  official languages
• Lot number
• Name and address of the sponsor
• Protocol code or identification and
• Radiopharmaceuticals only radiation symbol and
  statement Caution - Radioactive Material

49
Continuous Assessment

• Following regulatory approval of a CTA or CTA-A,
  information regarding refusals by other
  regulatory authorities or Research Ethics
  Board(s), should be submitted as a notification.
• This information will be added to the file, but
  will not be subject to an acknowledgement letter,
  nor will a (NOL) be issued.

50
Premature Discontinuation

• In the event of the premature discontinuation of
  a trial in its entirety or at a clinical trial
  site for which a CTA or CTA-A has been filed in
  Canada, the responsible Directorate must be
  notified as soon as possible, but no later than
  15 calendar days after the date of discontinuance
  C.05.015(1).

51
Premature Discontinuation

• Adverse Events
• Only adverse drug reactions that are both serious
  and unexpected are subject to expedited reporting
  to Health Canada.

52
Expectedness / Unexpectedness?

• To determine the expectedness of an adverse
  event/reaction
• Company's Investigator's Brochure (IB/IDB)
• Reports which add significant information on
  specificity or severity of a known, already
  documented serious ADR constitute unexpected
  events, e.g., hepatitis with a first report of
  fulminant hepatitis.

53
Expectedness / Unexpectedness?

• If expectedness is not straightforward, submit in
  expedited manner and the relevant issues
  addressed in a covering letter

54
Reporting Timelines?

• Fatal or life-threatening, unexpected ADRs should
  be notified as soon as possible but no later than
  7 calendar days followed by a complete report
  within 8 additional calendar days
• Serious, unexpected (ADRs) that are not fatal or
  life-threatening must be filed as soon as
  possible but no later than 15 calendar days

55
Report to TPP

• Each case of ADR which is subject to expedited
  reporting should be reported individually
• A completed summary form (ADR Expedited Reporting
  form) should be attached to the front of the
  report (CIOMS)

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Addendum to Investigators Brochure

• ADRs reported to HPFB should simultaneously be
  conveyed to investigators and their REBs through
  updated IB or as an addendum
• IBs should be updated annually and submitted
  annually highlighting changes and additional
  information

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Records

• PRA700

58
Records

• As per CTA Guidance Section 13.0, sponsors must
  maintain the following for a period of 25 years
• all versions of IB
• all AEs
• Enrollment records to CT subjects
• CT documentation records
• Undertaking from investigators that GCP was
  followed (completed Qualified Investigators Form)

59
Records (continued)

• As per CTA Guidance Section 13.0, sponsors must
  maintain the following for a period of 25 years
• Copies of protocol, IC and any amendments to
  either approved by REB
• Signed REB attestations

60
Records (continued)

• As per CTA Guidance Section 13.0, sponsors must
  maintain the following
• Brief summary of significant foreign marketing
  developments during the past year
• Self-auditing of an institution must be kept on
  file and available upon request

61
Records (continued)

• Available within 2 days if there is a concern
• Available within 7 days under other circumstances

62
REB Review

• REB approval required prior to CT initiation
• REB member must meet expertise as outlined in
  regulations
• Submit prior to CT commencement
• REB approval
• Attestation from REB that approved protocol at
  each site follows GCPs
• Any REB refusal for any reason

63
Internationally

• PRA700

64
Internationally.

• Approximately 20 annual increase in the number
  of trials worldwide
• Over 60 of all clinical trials are performed
  overseas with the majority conducted in the
  United Kingdom
• Canada ranks 3rd behind the EU and US
• Global pressures to harmonize requirements, and
  expedite trial reviews

65
Internationally.

• Electronic data
• Increased ethical concerns about human safety
• Need to conduct clinical trials in specific
  patient populations
• Clarify the roles responsibilities of the
  various players clinical trial review

66
Coming Up.

• e-CTA - ????

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Summary

• History of the CTA and the regulations/guidelines
• Pre-CTA Consultation Meetings
• CTA and CTA-Amendment Requirements
• Additional CTA related requirements