International Council for Harmonisation ICH E6

Goals of ICH

To standardize technical guidelines and requirements for drug marketing registrations, so that applications for marketing to various regulatory agencies around the world can occur without redundant testing

ICH E6 has become

The international standard for the design, conduct, monitoring, and reporting of clinical research of investigational drugs

Good Clinical Practice (GCP)

enhances protection of study subjects and the integrity of the data collected during a trial.

Legally Authorized Representative (LAR)

an individual, or judicial or other body, authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the research

Protocol Deviation (or Violation)

an unplanned excursion from the requirements of the protocol that is not implemented or intended as a systematic change.

CH membership includes which five (5) regulators?

Health Canada

European Commission EU

Ministry of Health Labor & Welfare

Pharmaceuticals &Medical device agency (PDMA from Japan)

Swissmedic

FDA

When does the ICH E6 guideline apply?

several countries adopted it as law. In the U.S., however, the FDA adopted the ICH E6 only as guidance

FDA adopted the ICH E6 only as guidance (HHS and FDA 1997) True or False

True: ICH guidelines do not have the force of law in the U.S. and are not regulations

Advantages of complying with ICH E6

Studies conducted in accordance with ICH E6 to meet the regulatory requirements of the drug approval processes for all of these countries.

(4) main categories of ICH guidelines

Quality, Safety, Efficacy, Multidisciplinary

"Efficacy" category

conduct of clinical research to support marketing applications for drugs.

ICH E6

provides a unified standard for designing, conducting, recording, and reporting research involving human subjects.

2 important goals of ICH E6 are to assure that:

1)The rights, well-being, and confidentiality of trial subjects are protected

2)Trial data are credible

principles of ICH GCP

Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

Next principles of ICH GCP

Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.

Investigator responsibilities include

qualifications, resources, medical care of research subjects, interactions with IRBs/IECs, compliance with protocols, management of investigational products, informed consent of subjects, recordkeeping, and reporting. Any investigator conducting clinical research under ICH guidelines must comply with these standards

Sponsor responsibilities include:

quality management, quality assurance and control, trial design, trial management, investigator selection, compensation to subjects and investigators, confirmation of review by IRB/IEC, supplying and handling the investigational product, adverse drug reaction reporting, monitoring, and auditing, among other responsibilities.

sponsor may transfer any or all of their responsibilities and functions to a Contract Research Organization (CRO)

the sponsor should ensure oversight of the CRO and specify in writing what responsibilities are transferred.

ICH E2A, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

describes the requirements for assessing safety in clinical research and focuses on the responsibilities of the sponsor for reporting adverse events (AEs)

ICH E8, Guidance on General Considerations for Clinical Trials

describes the drug development process and ICH expectations for establishing the safety and efficacy of investigational agents.

What are the differences between ICH E6 guideline, FDA regulations, and HHS regulations?

ICH E6 guideline generally agrees with the FDA regulations for IRBs/IECs, sponsors, and investigators

ICH guideline has requirements that go beyond either FDA (or HHS) requirements

ICH E6 is not codified in U.S. federal regulation and does not carry the same legally binding weight of the code of federal regulations.

In the U.S., compliance with the ICH E6 guideline is voluntary for investigators in that it is not a federal regulation.

research institutions that conduct clinical trials of drugs, however, pharmaceutical sponsors often insist that the ICH requirements be met.

A primary purpose of the ICH is to:

Require FDA registration of worldwide clinical trials.

Require publication of negative trial results.

Minimize the need for redundant research.

Develop mandatory worldwide regulations for drug development.

Minimize the need for redundant research

The ICH GCP guidelines:

Guarantee that a submission in any ICH region will be approved for marketing.

Require certification of clinical research sites and investigators

Replace FDA regulations for internationally conducted studies of drugs that will be marketed in the U.S.

Set standards for the design, conduct, monitoring and reporting of clinical research.

Set standards for the design, conduct, monitoring and reporting of clinical research.

ICH E6 describes standards that apply to:

Research sponsors only

Investigators, sponsors, and IRBs

IRBs only

Investigators only

Investigators, sponsors, and IRBs

In the United States, following the ICH E6 guideline is:

Voluntary for FDA-regulated drug studies.

Mandatory for studies conducted outside the United States.

Mandatory for investigational device studies.

Mandatory for drug studies.

Voluntary for FDA-regulated drug studies.

The initial model for drafting the ICH E6 guideline was the U.S. Food and Drug Administration (FDA) regulations for the protection of human subjects (21 CFR 50 and 56). True or False

True

The E6 guideline has eight (8) parts:

1) glossary; 2) principles; 3) IRBs/IECs; 4) investigator; 5) sponsor; 6) protocol and amendments; 7) investigator's brochure; and 8) essential documents.

Does the ICH E6 guideline "create or confer any rights for or on any person and or operate to bind FDA or the public.

NO; ICH E6 guideline "does not create or confer any rights for or on any person and does not operate to bind FDA or the public.

An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both" (FDA 1997, FDA 2018). TRUE OR FALSE

TRUE

Investigator to Obtain IRB Assurance that the IRB is in Compliance with ICH

"the sponsor obtain from the investigator/institution . . .[a] statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations."

Confidentiality of Medical Records

ICH E6 has broader different requirements than FDA or HHS concerning notice to subjects about potential access to identifiable research records by third parties.

ICH (2016) Section 4.8.10(n) states that the informed consent should indicate

"the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is authorizing such access."

ICH (2016) Section 5.15.2 states

"the sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection."

The FDA regulations at 21 CFR 50.25(a)(5) state only that in seeking informed consent, the following information shall be provided to each subject:. . .

(5) A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.

ICH E6 allows broader access to research records and to otherwise confidential medical records than is required by FDA regulations. TRUE OR FALSE

True

ICH E6 Section 8.1 also includes conditions about the essential documents (those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced) in the clinical trial master file, including that:

1)Sponsor and investigator should maintain a record of the location(s) of their respective essential documents, including source documents. The storage system should provide for document identification, search and retrieval.

2)Individual trials may require additional documents not mentioned in the essential document list. The sponsor and/or investigator should include these as part of Trial Master File (TMF).

The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during and after the trial

When a copy is used to replace an original document, it should fulfill the requirements for certified copies.

The sponsor should not have exclusive control of Case Report Form (CRF) data.

The sponsor should ensure that the investigator has control of and continuous access to CRF data reported to sponsor.

Investigator Responsibilities

FDA regulations at 21 CFR 312 (Investigational New Drug Application 2016) and ICH (2016) E6 agree that the investigator is responsible for conducting the clinical trial. There are very few differences, notably:

ICH and FDA PI Differences:

21 CFR 312.53 is more explicit in requiring the investigator to provide a signed statement (Form FDA 1572) to the FDA. ICH does not require a signed statement from the investigator to a regulatory authority.

ICH and FDA PI Differences: 2

ICH E6 Section 4.3 addresses the medical care of trial subjects and requires a qualified physician (or dentist when appropriate) investigator (or sub-investigator) to be responsible for trial-related medical (or dental) decisions. The FDA does not explicitly require this.

ICH and FDA PI Differences: 3

ICH E6 Section 4.9.0 requires that the investigator maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary.

Sponsor Responsibilities: ICH and FDA differences

The ICH (2016) E6 guideline is more detailed than FDA regulations at 21 CFR 312 (Investigational New Drug Application 2016) in addressing sponsor responsibilities, especially for monitoring and quality management of the trial.

Sponsor Responsibilities: ICH and FDA differences ICH E6 Section 5.0

ICH E6 Section 5.0 states that the sponsor should implement a system to manage quality throughout all stages of the trial process, and the quality management system should use a risk-based approach. This is a significant change for trial monitoring, which goes beyond routine periodic record auditing. For example, the new ICH E6 integrated addendum (R2) requires sponsors to implement systems to manage quality throughout all stages of the trial process. The system should use a risk-based approach including identification of study risks to determine which may safely be omitted from continual monitoring.

Sponsor Responsibilities: ICH and FDA differences ICH E6 Section 5.2.2 and 21 CFR 312.52 allow the sponsor to delegate (in writing) responsibilities to a contract research organization (CRO), but

ICH also requires that the sponsor ensure oversight even if duties are subcontracted to a CRO. FDA regulations state that if all obligations are transferred, a general statement that all obligations have been transferred is acceptable. ICH makes no such mention of a general statement being acceptable.

ICH E6 Section 5.5 and 21 CFR 312.53 both place the responsibility of selecting qualified investigators with the sponsor. True or False

true

ICH E6 Section 5.5 and FDA regulations agree that the sponsor is responsible for the trial management, data handling, and record keeping. ICH E6 Section 5.5.3 also requires?

The sponsor to ensure that the electronic trial data handling and/or remote electronic trial data systems conform to the sponsor's established requirements for completeness, accuracy, reliability, and are validated and that sponsors maintain SOPs for these systems.

ICH E6 Section 5.20.1 requires the sponsor to take prompt action to secure compliance when noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirements is discovered. ICH E6 further requires the sponsor to perform a root cause analysis and implement an appropriate corrective and preventative action depending on the significance of the noncompliance. Also, ICH E6 Section 5.20.2 states that if the sponsor identifies continuing and/or serious noncompliance, the sponsor should end the investigator's/institution's participation in the clinical trial and notify regulatory authorities.

True

Sponsor Monitoring

The sponsor is responsible for monitoring the study, per both ICH (2016) E6 and FDA regulations. ICH E6 has more detailed sponsor monitoring requirements.

FDA regulations at 21 CFR 312.50 (Investigational New Drug Application 2016) only state that the sponsor is responsible for ensuring proper monitoring of the investigation.

ICH E6 Section 5.18.3 states that the sponsor should:Develop a systematic, prioritized risk-based approach to monitoringThe sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, only centralized monitoring. Centralized monitoring, also referred to as remote monitoring, is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons.Document the rationale for the chosen monitoring strategy.

ICH E6 Section 5.18.6 requires monitors to submit written reports to the sponsor after each trial-site visit or trial-related communication. The sponsor is also required to document monitoring results.

ICH E6 Section 5.18.7 also requires sponsors to develop a monitoring plan tailored to the specific human subject protection and data integrity risks of the trial.

Sponsor Record Retention

ICH (2016) E6 requires that the sponsor retain essential documents until at least two (2) years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least two (2) years have elapsed since the formal discontinuation of clinical development. ICH E6 further states that the documents should be retained longer if required by applicable regulatory requirements or if needed by the sponsor.

Signature by Person Conducting the Consent Discussion

ICH (2016) E6 Section 4.8.8 states that "prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion."

The FDA regulations at 21 CFR 50.27(a) only require the signature of the subject and the date the subject signed the consent form.

To assure compliance with the ICH requirement, the consent form should include?

a signature line labeled "person conducting informed consent discussion." This line should not be labeled "Investigator's Signature," unless the investigator is always the person who obtains consent.

Subject Receipt of a Signed and Dated Copy of the Consent FormICH (2016) E6 Section 4.8.11 requires that the subject or the legally acceptable representative (LAR) receive a copy of the signed and dated written informed consent form.

The FDA?

The FDA regulations allow subjects to receive either a signed or unsigned copy (for example, a photocopy of the form without the subject's signature as long as it is the IRB-approved version of the consent form) (FDA 1998).

To be in compliance with ICH E6 guidelines, the investigator should include a statement in the consent form that the subject will receive a signed and dated copy of the consent form. Persons obtaining consent must then ensure that this procedure is followed. True or False

True

Assent of Children and Adults with Cognitive Impairments

ICH (2016) E6 Section 4.8.12 requires that "when a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject's legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject's understanding and, if capable, the subject should assent, sign and personally date the written informed consent."

HHS regulations at 45 CFR 46, Subpart D (Protection of Human Subjects 2017) and FDA regulations at 21 CFR 50, Subpart D (Protection of Human Subjects 2016) require?

that children assent to research unless there is an appropriate reason for waiving assent. However, neither FDA nor HHS regulations specifically require that incapacitated adults assent to research participation. To meet the ICH requirement, the investigator needs to have a policy for seeking assent, whenever possible, from decisionally-impaired adult subjects. This policy must account for the fact that often decisionally-impaired adults will not be able to assent, due to a lack of capacity. In those situations, the consent of the legally acceptable representative is the only requirement.

Impartial Witness for Illiterate Subjects

ICH (2016) E6 Section 4.8.9 states that "if a subject is unable to read or if a legally acceptable representative is unable to read then?

an impartial witness should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects is read and explained to the subject or the subject's legally acceptable representative, and after the subject or the subject's legally acceptable representative has orally consented to the subject's participation in the trial, and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form.

ICH (2016) E6 Section 1.26 defines "impartial witness" as,

"A person who is independent of the trial, who cannot be unfairly influenced by people involved in the trial, who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject."Therefore, the ICH (2016) E6 guideline goes beyond the FDA regulations in requiring that the witness be impartial and specifying to what the witness should attest.

The FDA regulations at 21 CFR 50 (Protection of Human Subjects 2016) address the documentation of informed consent for illiterate subjects

either by having the consent form read to the subject, or by allowing the use of a short form consent document and a written summary for oral presentation.

If an investigator expects illiterate or blind subjects to enroll in studies on a regular basis, then there should be

a signature block on the consent forms for an impartial witness, with the explanation that the signature block is only to be used "when necessary."

Emergency Situations:ICH (2016) E6 Section 4.8.15 states that "in emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested. When prior consent of the subject is not possible, and the subject's legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate . . . should be requested."

The FDA regulations at 21 CFR 50.23 and 50.24 (Protection of Human Subjects 2016) address emergency situations and consent. These regulations provide exceptions to the requirement for informed consent under the following circumstances:In research situations where requirements for exception from informed consent are met for emergency research (21 CFR 50.24);In treatment situations where an individual has a life-threatening condition and the following requirements are met and documented (21 CFR 50.23):The investigator, with the concurrence of another physician, believes the situation necessitates the use of a test article (in other words, an investigational drug, device, or biologic).The subject and/or LAR is unable to communicate consent.There is insufficient time to obtain consent.No alternative exists that will provide an equal or better chance of saving the subject's life.The IRB/IEC is informed of the use of the investigational product without informed consent within five (5) working days of the event.

ICH Additional Elements of Consent

Alternative Treatments, Probability of Assignment to Each Study Arm in a Study, Description of Subject's Responsibilities, Statement of No Benefit, Prorated Payment in the Consent Form

Alternative Treatments

ICH (2016) E6 Section 4.8.10(i) requires

an explanation of "the alternative procedure (s) or course (s) of treatment that may be available to the subject, and their important potential benefits and risks." Most sponsors, investigators and IRBs have not included the benefits and risks of alternative treatments in consent forms. This is an area where many sponsors and IRBs decide to limit their compliance with ICH. However, the investigator should explain the risks and benefits of alternative treatments to subjects when the information is necessary for the subject's full understanding and exercise of autonomy.

Probability of Assignment to Each Study Arm in a Study:

The FDA regulations at 21 CFR 50.25(a)(1) (Protection of Human Subjects 2016) state that the consent form must include: "A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental."

ICH (2016) E6 Section 4.8.10(c) states that in addition to the required FDA elements, the informed consent should include: "The trial treatment (s) and the probability for random assignment to each treatment."

This difference can be addressed by including a description of each arm of the study in the consent form, and including a statement about the likelihood of receiving each of the study arms.

Description of Subject's Responsibilities (2016)

ICH E6 Section 4.8.10(e) requires an explanation of "the subject's responsibilities." This information should be included in the consent form.

The FDA regulations do not specifically address subject responsibilities.

Statement of No Benefit ICH (2016) E6 Section 4.8.10(h) requires

an explanation of "the reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be made aware of this." This information should be included in the consent form.

Prorated Payment in the Consent Form

ICH (2016) E6 Section 4.8.10(k) states that "anticipated prorated payment, if any, to the subject for participating in the trial" must be included in the consent form. ICH E6 Section 3.1.8 states the IRB/IEC should review both the amount and method of payment to subjects to assure neither presents problems of coercion or undue influence.

While not an FDA requirement, prorated payment is addressed in the FDA Information Sheet entitled "Payment to Research Subjects," and it is common practice for IRBs and investigators in the U.S. to include payment information in consent forms.

Non-Therapeutic Trials

The following ICH E6 sections address non-therapeutic research and the requirements for consent.

These issues are not specifically addressed in the FDA regulations.

ICH (2016) E6 Section 4.8.13 states that "Except as described in ICH 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no anticipated direct clinical benefit to the subject) should?

should be conducted in subjects who personally give consent and who sign and date the written informed consent form."

ICH (2016) E6 Section 4.8.14 states that "Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:.

The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally.

The foreseeable risks to the subjects are low.

The negative impact on the subject's well-being is minimized and low.

The trial is not prohibited by law.

The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable opinion covers this aspect."

Investigator Notification to Subject's Primary Physician

ICH (2016) E6 Section 4.3.3. recommends that the investigator?

Inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed. There is no equivalent to this requirement under FDA regulations. Investigators should have a policy in place to address this notification requirement. It can be included in the consent form so that the subject's choice about the notification is documented in the consent form.

IRB Responsibilities

There are or are not several differences between the FDA and ICH regarding the responsibilities and duties of the IRB?

ARE

ICH (2016) E6 Section 3.1.2 states that the IRB/IEC should obtain the following documents:

Trial protocol(s)/amendment(s)

Written informed consent form(s) and consent form updates that the investigator proposes for use in the trial

Subject recruitment procedures (for example, advertisements or scripts for radio ads)

Written information to be provided to subjects (for example, questionnaires or subject diaries)

Investigator's Brochure (IB)

Available safety information

Information about payments and compensation available to subjects

The investigator's current curriculum vitae and/or other documentation evidencing qualifications

Any other documents that the IRB/IEC may require to fulfill its responsibilities

The FDA regulations at 21 CFR 56 (Institutional Review Boards 2016) do not specifically list in one place what documents an IRB should review. FDA requires the IRB to review

The consent form (56.109[b]), and further (56.115[a]) requires the IRB to keep "copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents."

IRB/IEC Record Retention

ICH (2016) E6 Section 3.4 and 21 CFR 56.115 (Institutional Review Boards 2016) both state?

The IRB/IEC should retain all relevant records for three (3) years after completion of the trial.

FDA CFR Title 21 section 312 - Sponsor shall retain the records?

A sponsor shall retain the records and reports required by this part for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified.

Review of Changes in Research

ICH (2016) E6 Section 3.3.7 states that "The IRB/IEC should [specify] that no deviations from, or changes of, the protocol should be initiated ... without prior IRB/IEC written approval." ICH E6 Section 4.5.3 adds that "Investigators should document and explain any deviations from the approved protocol."

ICH E6 Sections 8.2.7, 8.3.2 and 8.3.3 require documented approval/favorable opinion of the protocol and any amendments.

FDA regulations at 56.108(a)(4) (Institutional Review Boards 2016) require review of changes (amendments) in research. However, review of deviations is not explicitly required by FDA regulations.

Investigators should clarify with sponsors and their IRB how the review of deviations will be satisfied.

Waiver or Alteration of Informed Consent for No More than Minimal Risk Research

On 24 July 2017, the FDA issued guidance that they will not object if an IRB approves a waiver or alteration of consent for a no more than minimal risk clinical investigation if the IRB determines that:

The clinical investigation involves no more than minimal risk (as defined in 21 CFR 50.3[k] or 56.102[i]) to subjects;

The waiver or alteration will not adversely affect the rights and welfare of the subjects;

The research could not practicably be carried out without the waiver or alteration; and

Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

However, it is important to note that ICH E6 does not include provisions for waiving or altering consent for no more than minimal risk research.

Essential Documents are the documents that individually and collectively permit the evaluation of the conduct of the study and the quality of the data produced (ICH [2016] E6 Section 1.23).

They should be retained until at least two (2) years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least two (2) years have elapsed since the formal discontinuation of clinical development of the investigational product, unless required for a longer period by a regulatory requirement or an agreement with the sponsor (ICH E6 Section 8).

Centralized monitoring (also called "Remote monitoring")

is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (for example, data managers and biostatisticians) (ICH [2016] E6 Section 5.18.3).

IND application (21 CFR 312.56 and 312.53[d]

[Investigational New Drug Application 2014])

IDE

(21 CFR 812 Investigational Device Exemptions 2016)

ICH E6 states that the sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials.

ICH E6 states that if the noncompliance significantly affects the subject population or reliability of the trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventative actions.

Record-Retention Requirements: Both the FDA and ICH E6 require

that sites maintain study-related records for at least two (2) years after the drug has been granted marketing approval in the U.S. for the indication tested in the study or, if no application will be filed or if the application is not approved for the indication, for at least two (2) years after the investigation is terminated and the FDA is notified. In the case of a global marketing application, sites must maintain the study records for at least two (2) years after approval by the last regulatory agency consistent with ICH E6 requirements.

Record-Retention Requirements: For devices, according to FDA regulation at 21 CFR 812.140(d) (Investigational Device Exemptions 2016)

the investigator or sponsor shall maintain the records for a period of two (2) years from the date on which the investigation is terminated or completed, or the date that the records are no longer required for purposes of supporting a premarket approval (PMA) or a notice of completion of a product development protocol.

The site is required to allow monitors, auditors, the IRB/IEC, the FDA, and other regulatory authorities to access trial-related records upon request.

The sponsor is required to monitor the research to ensure that the trial is conducted in compliance with the protocol and regulations, the data are reliable, and human subjects are protected.

FDA and HHS regs do not require the assent of incompentent subjecst, but ICH does require they assent when possible

FDA and HHS do not require any stmts about subjects responsibilities , but ICH does