ICH vs FDA/CFR

Question 1

How did the US adopt ICG E6? What is the authority of ICH in US drug marketing registrations? What does the US/FDA suggest about the ICH?

Answer 1

ICH is NOT law in the US. They adopted it as a guidance document and it is voluntary to follow it. However, adopting the ICH makes you complaint per the FDA.

The ICH is does not have any authority on individuals, teams or the FDA in the US.

Question 2

What are the benefits for US clinical investigations to adopt ICH GCP? What are the draw backs?

Answer 2

It’s beneficial for sponsors to ask investigators to adopt ICH E6 guidelines as that will facilitate drug marketing registrations in other countries who have adopted ICH.

The drawback is that not all ICH E6 guidelines are the same as the CFR, thus, investigators need to be familiar with all of the regulations to adhere to both.

Question 3

What are the similarities between the CFR and ICH GCP in regards to IRB composition and voting?

Answer 3

• minimum number of members is 5
• Have to have least 1 member who has a non scientific focus
• at least 1 member who is not affiliated with the institution/trial
• Need to keep a record/list of all of its members and their qualifications
• Need to follow written procedures and record all activities and minutes
• IRB can invite experts to provide their insight
• Only those that have no association with the study should be involved in the review and vote

Question 4

What are the similarities between the ICH GCP and the CFR in relation to the procedures and operations of the IRB? (5)

Answer 4

• Both require that the IRB conduct an initial and continues review of investigational trials
• both require that the IRB determine the frequency of review based on risks (minimum 1 yr)
• both require that studies obtain approval on changes to protocol before proceeding, UNLESS it is to reduce immediate harm (ICH also states unless it is logistical/administrative changes)
• communicate their decision in writing to the investigators/sponsors + reasons for decisions (when necessary) and ability to respond/appeal
• both mention the ability to do an expedited review for minor changes

Question 5

For how long must an IRB/IEC maintain its records about a trial after its completion according to the ICH GCP and/or CFR?

Answer 5

3 years after study completion and they must be available to be reviewed if necessary

Question 6

What are the 5 criteria that differ between ICH GCP and CFR in regards to the elements that must be included in the ICF?

Answer 6

The ICH includes:
1. The probability of randomization
2. The pro-rated payment (if any) to the subject
3. That by signing the consent form, the participant is providing consent to the IRB/IEC, monitor, auditors and any applicable regulatory bodies.

FDA:
1. Only mentions that the FDA may access their data/records for monitoring/auditing purposes
2. The ICF must include a statement about clinical trials.gov

Question 7

How do both ICH E6 (4.8.14) and FDA regulations (§ 50.24) address the inclusion of subjects who cannot give informed consent personally?
A) Both strictly prohibit such inclusions.
B) Both require explicit IRB approval/favorable opinion.
C) ICH allows it only if IRB approval is impossible; FDA does not.
D) FDA allows it without IRB approval, unlike ICH.

Answer 7

B

Question 8

Considering the emergency situations outlined in both FDA regulations and ICH E6, what shared measure is emphasized to protect the rights, safety, and well-being of the subjects?

Answer 8

If consent from the subject or their legal representative/family could not be obtained before proceeding with the pharmaceutical product, both CFR and ICH E6 request that IRB approved protocol has steps in place to do their very best to contact their legal rep/family and informed them on the situation as also obtain their consent.

Question 9

In scenarios where obtaining informed consent is not feasible, how do the FDA regulations (§ 50.24) and ICH E6 (4.8.15) differ in their approach to family members’ involvement?

Answer 9

The FDA includes the option to obtain consent from family members in emergency situations, the ICH GCP does not.

Question 10

According to both ICH and CFR, how should consent be documented and should the subject receive anything post-consent?

Answer 10

They both require that the subject or their legal representative sign and date a consent form and that they receive a copy of the signed informed consent form.

Question 11

How does 21 CFR 50 differ from ICG GCP in regards to their informed consent requirements for children?

Answer 11

CFR: states that the IRB is responsible for determining if the proposed study population involving children have the capacity to provide assent (they will look at things like maturity, their mental state and age). It is emphasized that if possible, assent should be obtained.

ICH GCP: they only mentions that if a trial involves participants who can only be enrolled via their legal representative, that the investigators should do their best to explain the study to the extent that makes sense with the subject and if possible, obtain their written and dated consent.

Question 12

What is the legal status of ICG GCP (E6) in the US in comparison to other places in the world? What are the FDA’s recommendations regarding ICG GCP?

Answer 12

ICH GCP holds no legal power in the US, where as other counties have made it the law.

The FDA states that it is voluntary to adopt ICG GCP, however, adopting ICH is the gold standard for GCP

Question 13

How does ICH differ from FDA/CFR in terms of its IRB requirements?

Answer 13

ICH requires that the sponsor obtains a statement from the REB stating that they are ICH compliant.

Question 14

Consent: How does the FDA/CRF differ from ICH rin regards to consent? (3)

Answer 14

1. FDA only requires that the participant signs and dates their consent form. The person obtaining consent does not need to sign/date.
2. FDA states that a participant needs to be given a copy of the consent form, but it can be signed or unsigned. ICH requires that they receive a copy of the signed form.
3. FDA/CFR has to make subjects aware how their confidentiality information will be managed and that it may be accessed by the FDA. ICH has to include a written statement on the ICF that states their confidential information + health information may be accessing by the IRB, the sponsor, monitors, auditors and any applicable regulatory bodies. The sponsor MUST obtain written consent consent (as part of ICF) for this.

Question 15

Assent for minors + adults with cognitive impairments: How does the CRF/FDA differ from ICH regarding this? (2-3)

Answer 15

1. FDA/CFR pretty much requires studies do their very best to obtain consent from all participating minors, unless a waiver is put in place. Only focuses on children, does not mention anything about adults that cannot provide consent (e.g. dementia)
   -ICH states that children AND ADULTS WITH IMPAIRMENTS who are deemed not capable of providing assent, should have the study procedures explained to them to the level that they can handle AND provide assent when appropriate.
   - ICH: Children & adults with impairments that cannot provide assent should only participate in therapeutic trials UNLESS it meets the 4 exception criteria (study is legal, study could not occur without waiver, study has IRB approval for this, and study is low risk

Question 16

Subjects and LARs who cannot read/have a reading disability: how does the FDA/CFR differ from ICH in regards to how to proceed with these types of subjects?

Answer 16

FDA/CFR: offers to options: 1) short form consent form OR 2) someone else can act as witness
1) the person giving consent provides and oral presentation and a summary sheet. The witness signs both, the subject signs the short form consent form and receives a copy of the summary and form.
2) someone else (not specific) acts as a witness during these conversations

ICH: implement the use of an IMPARTIAL witness. This is someone who is independent of the study and that cannot be influenced by the studies success/recruitment. The witness should be present at all times when written information is given to the subject and their LAR. Consent form needs to be amended to include a section for the impartial witness to sign and date.

Question 17

Investigator responsibilities: how does the FDA/CFR differ and also relate to ICH in regards to this?

Answer 17

Both the FDA and ICH agree that all study operations are the responsibility of the PI.

1) FDA: requires investigator to sign an agreement (FDA 1572) with the FDA and submit it. ICH does not require the investigator to sign an agreement with the regulatory body.
2. ICH requires that all trial related medical decisions and guidance are done by a qualified physician/dentist investigator AND that investigator follows the good documentation practices + ALCOA + C.

Question 18

What are the differences between FDA and ICH regarding Essential Documents?
-Who’s responsibility is it to maintain these?

Answer 18

ICH GCP includes a section of Essential Documents, which are docs that essential to evaluate how the trial is operating.
- Investigator/Institution
- Sponsor should share access to CRFs (can’t be the only one allowed to access/control it)
- TMF should be created

The CRF does not have a section like this with a list of documents.

Question 19

What are the five similarities between the Sponsor and the ICH GCP regarding Sponsor Responsibilities?
Within those similarities, what are some differences?

Answer 19

1. The sponsor is ultimately responsible for overseeing and managing the clinical trial + data management + record keeping.
   - ICH also requires the the sponsor have a data management system AND control systems (SOPs, etc) for electronic data/systems/platforms
2. The sponsor is responsible for selecting the PI.
3. The sponsor can delegate all/some of their responsibilities to the CRO.
   -CRF/FDA accepts general statement for the cro to take on tasks.
   - ICH needs sponsor to continue providing oversight over cro.
4. The sponsor is responsible for monitoring the clinical trial.
5. Sponsor is responsible for ensuring compliance/non-compliance at site/investigator level.

Question 20

What does the CRF and ICH GCP have in coming regarding sponsor record keeping?

Answer 20

BOTH of them state that a Sponsor is responsible for keeping the records up to 2 years after the last drug marketing approval OR 2 years after the drug has been discontinued.

Question 21

What are the similarities and differences between the CFR and ICH GCP regarding emergency use of IP without consent?

Answer 21

BOTH require that the study has IRB approval (i.e. a special clause for a waiver of consent) in order to use the drug in an emergency situation.

CFR: has 7 criteria that a study must meet in order for the IRB to grant them this waiver (life-threatening situation + no better alternative treatment, potential for direct benefit, IRB approved all consent processes/forms, obtaining consent is not feasible, protection for pts rights and wellbeing are provided and are sufficient, the study could not operate without this waiver, investigators committed to doing everything they can to obtain consent from LAR)

ICH: allows it as long as the IRB has given approval. Urges investigators to first try to obtain consent from subject —> LAR —> if not successful and have waiver, go ahead, but continue to trying to get consent from either of them.

Question 22

How do the CFR and ICH GCP differ in terms of Investigator Notification to Subject’s Primary Physician?

Answer 22

The FDA does not specifically state this. In cases of emergency research, they do state that the subjects LAR should be made aware ASAP of the use of the IP.

ICH: requires that the subject is given the option to provide consent for the study team to notify their primary physician about their participation in the trial.