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SOCRA 2024 > ICH E6 > Flashcards

ICH E6 Flashcards

1
Q

ICH E6 Investigator Obligations

A
  1. Investigators must be qualified to run the trial (education, training, experience)
  2. Thoroughly familiar with the appropriate use of the IP
  3. Aware of and comply with GCP
  4. Permit monitoring & auditing by the sponsor and reg. authorities
  5. Maintain a list of appropriately qualified persons they’ve delegated significant duties to.
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2
Q

What constitutes adequate site resources for running a trial per ICH E6?

A
  • Potential for recruiting required # of subjects in the recruitment period
  • Sufficient time
  • Adequate staff and facilities
  • All persons assisting with the trial are adequately informed on the protocol, the IP, and trial related duties and functions
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3
Q

Per ICH E6 - who should be informed about a subject’s trial participation?

A

If the subject agrees, the investigator should inform the subject’s primary physician. The FDA does not have this requirement

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4
Q

What does ICH stand for?

A

International Council for Harmonization

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5
Q

Per ICH E6 - what should an investigator do when a subject withdraws from a trial?

A

Make a reasonable effort to ascertain the reason(s), though subjects are not required to answer.

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6
Q

What evidence must an investigator provide to prove they are qualified to properly conduct a trial?

A

An up-to-date CV

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7
Q

What documents does ICH E6 require be submitted to the IRB?

A

Protocol, informed consent, investigator’s brochure, subject recruitment materials, and any written information to be provided to subjects

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8
Q

How must changes to source data be handled?

A

Changes to source data should be dated, initialed, and explained. The chance should not obscure or cover up the original entry (no liquid correction, correction tape, or black markers).

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9
Q

When can an investigator deviate from a protocol?

A

When a deviation is necessary to eliminate an immediate hazard to one or more subjects, otherwise the investigator must obtain prior approval from the sponsor and IRB.

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10
Q

What kind of documentation is required for deviations for ICH E6?

A

Deviations must be explained in writing.

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11
Q

If an investigator deviates from the protocol w/o IRB approval to eliminate an immediate hazard to subjects, how soon should they report the deviation to the sponsor and IRB?

A

As soon as possible

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12
Q

If a study is terminated prematurely or suspended for any reason ICH E6 requires investigators do what?

A
  • Promptly inform subjects
  • Assure appropriate therapy and follow-up for subjects
  • inform the regulatory authority (if required)
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13
Q

What needs to occur during a consent process if a subject is unable to read?

A

ICH E6 requires an impartial witness be present and sign and date the consent form as an indication the the information was accurately explained, apparently understood, and informed consent freely given.

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14
Q

What are the subject related requirements for consent if the subject has an LAR?

A

Per ICH E6 subjects should be informed about the trial to the extent compatible with their understanding & if capable, the subject should assent by signing and dating the informed consent.

The FDA has similar recommendations.

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15
Q

Does ICH E6 allow “waiver of documentation of consent”?

A

No - This is only a provision of FDA 21 CFR 56

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16
Q

Per ICH E6 what are the requirements for administering a test article without consent in an emergency?

A

ICH E6 requires that a protocol describe the process for conducting the research in an emergency situation without first obtaining consent, and requires IRB approval of that process. The subject or their LAR should be informed about the trial as soon as possible and consent to continue should be requested.

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17
Q

Who originally came together to form the ICH?

A

European Union, Japan, and the US

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18
Q

What is the goal of ICH?

A

Standardize the technical guidelines and requirements for drug marketing registrations, so that applications for marketing around the world can occur w/o redundant testing.

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19
Q

ICH E6 is the international standard for what?

A

Design, conduct, monitoring and reporting of clinical research of investigational drugs.

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20
Q

Current ICH members

A

Canada, EU, Japan, Switzerland, US. Plus 3 industry members from the EU, Japan, and the US.

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21
Q

Number of members in the ICH expert working group

A

20 Total: 14 representatives from the founding members (4 US, 4 EU, 6 Japan), 2 from new members (1 Canadian, 1 Swiss), 4 observers (Brazil, China, South Korea, and the WHO)

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22
Q

What position does ICH E6 hold in the US?

A

Adopted by the FDA as guidance only. It is not mandated by law. (Adopted into law in some other countries)

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23
Q

What are the 4 main categories of ICH topics?

A

Quality, Safety, Efficacy (including E6), Multidisciplinary

24
Q

Two goals of E6

A

Protect the rights, wellbeing, and confidentiality of trials subjects. Ensure trial data is accurate.

25
Q

Where do the ethical principles of E6 originate?

A

The declaration of Helsinki

26
Q

Sections of E6

A

1) Glossary
2) Principles of ICH GCP
3) IRBs
4) Investigators
5) Sponsors
6) Protocols and amendments
7) IDBs
8) Essential documents for conduct of a clinical trial

27
Q

How does ICH E6 and the Code of Federal Regulations relate to each other?

A

ICH E6 does not contradict the CFR. They generally agree, but there are areas where ICH E6 goes beyond federal and HHS requirements.

28
Q

How does ICH E6 and the FDA differ on access to research records?

A

ICH E6 allows broader access to records and otherwise confidential medical records than the FDA. The consent must clearly outline this if a study is following ICH E6.

29
Q

How do sponsor requirements differ between ICH E6 and the FDA?

A

ICH E6 generally requires more from sponsors than the FDA does. For example:
- ICH E6 requires investigators to get a statement from the IRB confirming they follow GCP
- Require sponsors to verify each subject has consented in writing to direct access to their medical records for monitoring, auditing, IRB review, and regulatory inspection
These are not required by the FDA

30
Q

What are the ICH E6 requirements for signatures on consents? And how does this differ from FDA requirements?

A

21 CFR 50 only requires subject (or LAR) signature. ICH E6 requires subject (or LAR) signature AND signature of the staff conducting the consent.

31
Q

What does ICH E6 require regarding providing copies of consents to subjects?

A

ICH E6 requires the subject receive a copy of the consent they signed and dated. The FDA (21 CFR 50) only requires the subject receive a copy, either signed or unsigned.

When following ICH E6 the consent should include a statement that the subject will receive a signed and dated copy of the form.

32
Q

What are the ICH E6 consent requirements when a subject cannot read?

A

Unlike 21 CFR 50, ICH E6 does not allow the use of a short form. ICH E6 also requires an impartial witness when a consent is read to the subject. The consent would also need to include a signature block for the impartial witness (which can only be used if the subject cannot read). If the subject can read in a language other than English, the consent form must be provided in that language.

33
Q

How does ICH E6 differ from 21 CFR 50 on confidentiality information in consents?

A

ICH E6 requires consents include a statements about monitors, auditors, the IRB, and regulatory authorities having access to medical records. The FDA only requires there be a statement about the extent to which confidentiality of records will be maintained and that the FDA may review them.

34
Q

How does ICH E6 differ from the FDA on language about alternative options in consents?

A

ICH E6 requires that alternative treatments be listed as well as their potential risks and benefits. This is an area where many sponsors and IRBs decide to limit their compliance with ICH.

The FDA only requires the alternatives be listed.

35
Q

Which consent topics does ICH E6 require that the FDA does not?

A

ICH E6 requires the consent form to include a description of each arm of the study, the likelihood of being assigned to each of the study arms, and an explanation of “the subject’s responsibilities”. The FDA does not require any of these items.

36
Q

What information does ICH E6 require regarding potential benefits?

A

ICH E6 requires that if there is no intended clinical benefits that subjects be made aware. The FDA only requires an explanation of expected benefits but does not require the consent to explain that there is no expected benefit.

37
Q

How does ICH E6 and the FDA compare on information regarding payment in consent forms?

A

ICH E6 requires a description of anticipated prorated payments. FDA also recommends this.

ICH E6 does state that the IRB should review the amount and method of payment to assure no coercion or undue influence.

38
Q

How does ICH E6 and the FDA differ on their requirements for assent?

A

ICH E6 requires assent of adults capable of providing it. ICH E6 also requires, with a few exceptions, that for non-therapeutic research studies, that only subjects who can consent for themselves participate.

Exceptions:
- Objectives can’t be met without them
- Foreseeable risks are low as is the negative impact
- The study is not illegal
- The IRB has agreed to include them

39
Q

Required documents for IRB review?

A
  • Consent forms
  • Protocols
  • Recruitment materials
  • Written subject information
  • IBs
  • Available safety info
  • Info about payments and compensation
  • Investigator’s CV or other evidence of qualifications
  • Any other documents required for the IRB to fulfill it’s responsibilities

The FDA only specifically lists consent forms, “research proposals”, and “scientific evaluations”

40
Q

What are the ICH E6 requirements regarding CRFs?

A

The sponsor should not have exclusive control of the CRF data, and the sponsor should ensure the investigator has control of, and continuous access to, CRF data reported to the sponsor.

ICH E6 also requires that sponsors ensure that electronic data handling/collection systems are validated and follow the sponsor’s requirements for completeness/accuracy, and reliability. These systems must have maintained SOPs

41
Q

What does ICH E6 require regarding the medical care of trial subjects? And how does this compare to FDA requirements?

A

ICH E6 requires a qualified physician investigator (or dentist) be responsible for trial related medical (or dental) decisions. The FDA does not explicitly require this.

42
Q

How does ICH E6 and 21 CFR 312 differ on use of a CRO?

A

They both allow delegation (in writing) of sponsor responsibilities to a CRO. ICH specifies though that the sponsor must ensure oversight even if a CRO is used.

If all duties are delegated the FDA allows a general statement to this effect to be used. ICH does not.

43
Q

What does ICH E6 say is a sponsor’s responsibility if noncompliance occurs?

A

Take prompt action to ensure compliance. Perform a root cause analysis and implement corrective & preventative action. If the noncompliance is continuing and/or serious the sponsor should end the investigator’s/institution’s participation & notify regulatory authorities

44
Q

ICH E6’s requirements for sponsor monitoring of sites

A
  • Use a risk-based approach
  • Sponsor may choose on-site, on-site + remote, or just remote monitoring
  • Document the rationale for the chosen strategy
  • Monitors must submit written reports to sponsors after each visit or trial-related communication
  • Sponsor also required to document monitoring results

FDA regs in 21 CFR 312 only specify that the sponsor is responsible for ensuring proper monitoring of the investigation.

45
Q

How long does ICH E6 require sponsors retain essential documents?

A

At least 2 years after last approval of a marketing application in an ICH region and until there are no pending or contemplated marking applications. OR at least 2 years from the formal discontinuation of clinical development.

It also states that the IRB should keep the records for 3 years after completion of the trial.

46
Q

Per ICH E6, what is the purpose of trial monitoring?

A

To verify:
- The rights and well-being of human subjects are protected
- Reported trial data are accurate, complete, and verifiable
- The conduct of the trial is in compliance w/currently approved protocol, GCP, and applicable regulatory requirements

47
Q

How long does ICH E6 state that IRBs should keep copies of essential study documents?

A

3 years after completion of the trial

48
Q

What documents must a PI provide to the sponsor before they can begin enrollment of subjects?

A

A current CV, a completed/signed1572, financial disclosure forms for every member of the research team, and evidence of IRB approval.

49
Q

Per ICH E6 what are the elements of product accountability?

A
  • Shipping records (record of receipt of the product)
  • Managing the inventory and storage of the product
  • Dispensing logs (supplying of the product to subjects)
  • Explaining the correct usage to subjects
  • Pill counts - Monitoring usage by the subjects according to the protocol
  • Return or destruction at the end of the trial
50
Q

What must be in place before a sponsor can ship an investigational agent?

A
  • IRB approval
  • 1572 for drugs or Investigator Agreement for devices
51
Q

What is the purpose of audits, inspections, and monitoring?

A

Ensuring protection of human research subjects and data integrity.

52
Q

Who conducts audits, monitoring, and inspections?

A

Sponsors or CROs conduct audits and do monitoring. Regulatory authorities (such as the FDA) conduct inspections.

53
Q

What is the purpose of an inspection?

A

An inspection is “an official review of documents, facilities, records, and any other resources related to a clinical trial”.

They are for a regulatory authority to verify data, assure compliance with regulations, and assure protection of research subjects.

54
Q

What are the potential outcomes of an audit with negative findings?

A

Negative findings on an audit may affect the agency’s decision to accept data supporting a marketing application. It may also have implications for the investigator if misconduct is found (e.g. fraud, falsification, fabrication)

55
Q

What is the difference between an audit and monitoring?

A

Monitoring is an ongoing process to assess and assure compliance. Audits are generally conducted on a limited basis (only for certain sites/studies, not multiple times per site, not for every study, etc) and are a quality assurance measure to verify data integrity and clinical trial processes. An Audit may have recommendations for monitoring, and may result in SOP changes.

56
Q

Required regulatory documents for a clinical trial per ICH E6

A
  • IRB/IEC membership roster
  • IRB/IEC correspondence (submittal package, approval letters, etc)
  • Investigator Brochure
  • Investigator Curriculum Vitae (CV)
  • Protocol
  • Protocol Amendments
  • Form FDA 1572
  • ICFs (blank, all versions)
  • Signed ICFs
  • Correspondence
  • Investigational product records
  • Site Signature List (list and writing sample of all authorized personnel)
  • Monitoring Log
  • CRFs (blank and completed)
  • Source Documents
  • Laboratory Certification
  • Lab Normal Value Ranges
  • Delegation of Authority Log

SOCRA 2024 (11 decks)

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