FDA Regulated Research

 

Content Authors

 

Susan Kornetsky MPH

Children's Hospital, Boston

 

David G. Forster JD, MA, CIP

Western IRB

 

Gary L. Chadwick PharmD, MPH, CIP

The University of Rochester

 

Introduction

The U.S. Food and Drug Administration (FDA) regulates drugs, biologics, and devices used in the diagnosis, mitigation, treatment, or prevention of diseases. This training module addresses FDA-regulated clinical research and the responsibilities of investigators, IRBs, and sponsors when they participate in a study of an FDA-regulated product.

 

FDA Review

The FDA conducts a thorough review of drugs, biologics, and medical devices for safety and effectiveness before granting approval for marketing. Before a product is marketed, the sponsor submits an application for approval by the FDA. This application contains a proposed "package insert" which may also be referred to as "labeling". This insert summarizes what the FDA has determined to be a safe and effective use of the product. The FDA bases its approval decision upon bioresearch data generated and reported to the FDA by the sponsor to support the marketing approval of a product. These data are collected by the sponsor during clinical research conducted under an IND (Investigational New Drug application) or an IDE (Investigational Device Exemption).

 

Drugs and Biologics

IND

Research involving a drug or biologic that has not yet reached the marketplace or that studies a new use of the marketed product requires an IND (21CFR 312). A sponsor develops a research protocol, which is then evaluated by the Food and Drug Administration. A sponsor can be a drug company, a cooperative group, or even an individual physician. After careful review, the FDA will allow human studies to proceed if it determines that the risk of exposure to the drug is reasonable. This determination is based upon:

 

•Data from prior animal or human testing.

•Methods of manufacturing.

•Plans for testing and reporting significant toxicities.

•A well-developed clinical research plan that minimizes risks to the subjects.

 

Investigational Use of a Marketed Drug

Investigators may want to use an approved product in the context of clinical studies. When the principal intent of the investigational use of the product is to develop information about safety or efficacy, an IND may be required. However the clinical investigation of a marketed drug does not require an IND if the following conditions are met:

 

•The data will not be used to support a new indication, new labeling, or change in advertising.

•The research does not involve a route of administration/dosage level or subject population that significantly increases the risks of the drug product.

•The research is conducted in compliance with IRB review and informed consent requirements.

•The research is conducted in compliance with requirements for promotion and sale.

 

(21CFR312.2(b))

 

Exemption from IND submission requirements does not mean exemption from IRB review and approval or from informed consent from subjects. The FDA should be consulted if there are any changes.

 

FDA Form 1572

•Investigators participating in drug and biologic studies subject to the IND regulations MUST sign Form 1572 [http://www.fda.gov/opacom/morechoices/fdaforms/cder.html].

•Form 1572 outlines the commitments that must be made by the investigator(s) regarding the conduct of the study.

•Form 1572 must list co-investigators who will be administering the drug or separate forms need to be submitted for these individuals.

•Form 1572 must list the IRB of record for that study site.

 

(21CFR312.53)

 

"Off Label" Use of Drugs, Devices, and Biologics

Good medical practice and the best interests of a patient require that physicians use legally available drugs, biologics, and devices according to their best knowledge and judgment. If physicians use products for an indication not listed in the approved labeling, they have the responsibility to be well informed and to base the proposed use on scientific rationale and medical evidence.

 

Use of a marketed product in this manner when the intent is practice of medicine does not require the submission of an IND or IDE. However, an individual institution may under its authority require oversight for this practice such as review by a Medical Practice or Pharmaceutics and Therapeutics Committee (21CFR312.2(d)).

 

Devices

The Definition of a Medical Device

A medical device is any health care product that does not achieve its primary intended purpose by a chemical interaction or by being metabolized. Medical devices include surgical lasers, sutures, pacemakers, and diagnostic aids such as reagents and test kits for in vitro diagnosis.

 

The Medical Device Amendments of 1976

The Medical Device Amendments of 1976 and the Safe Medical Devices Act of 1990 provide the regulatory framework for medical device development, testing, approval, and marketing. Manufacturers who wish to market a new medical device may need to submit a pre-market notification to the FDA. Some medical devices are exempt from the pre-market approval process. If the device is not exempt, FDA determines whether the device is substantially equivalent (21CFR807.81(a)(1)) to similar devices marketed before the 1976 amendment. These devices are often referred to as 510K devices (21CFR807.92). If the new device is not substantially equivalent, the company may need to demonstrate safety and efficacy in a pre-market approval application, which could include clinical trials.

 

Investigational Device Exemption (IDE)

An investigational device is a medical device that is undergoing clinical trials to evaluate safety and effectiveness. The IDE regulations specify how to conduct these clinical trials (21CFR812.2). The regulations require that devices be classified as "significant risk" or "non-significant risk" devices. The sponsor often first makes this classification, but the IRB must agree with the determination. The risk determination should be based on the proposed use of the device and not on the device alone.

 

Significant Risk (SR) Devices

A significant risk device presents a potential for serious risk to the health, safety, or welfare of the subject and it:

 

•Is intended to be implanted into a human;

•Is used in supporting or sustaining human life;

•Is of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise prevents impairment of human health;
or

•Otherwise presents serious risk to health, safety, and welfare of a subject.

 

(21CFR812.3(5)(m))

 

The sponsor must submit an IDE application to the FDA (21CFR812.20). There is no specific form for this purpose, but the regulations list elements required in the application. The trial cannot begin until FDA grants an IDE and the IRB grants approval for the study. By definition, a study with a significant risk device poses more than minimal risk to the human subjects and requires full IRB review.

 

Non-Significant Risk (NSR) Devices

A non-significant risk device, by default, does not meet the criteria of significant risk. It is considered to have an approved IDE application (i.e., no application is filed with the FDA), and is studied without FDA oversight if the sponsor complies with certain FDA requirements such as monitoring, record-keeping, and properly labeling the investigational device. The IRB must agree that the study meets the criteria for non-significant risk. The clinical trial of a non-significant risk device requires IRB approval, informed consent, and proper study monitoring and it must meet all other regulatory compliance requirements.

 

INFORMED CONSENT

Elements of informed consent are found in the FDA regulations at 21 CFR 50.25.

 

Informed Consent Waiver

Elements of informed consent are found in the regulations at 21 CFR 50.25

 

The FDA 21 CFR 50.23 and 21 CFR 50.24 provide exceptions to the requirement for informed consent under certain circumstances:

 

•In situations where requirements for exception from informed consent are met for emergency research (21 CFR 50.24).

•In life-threatening conditions involving an individual subject where requirements for an exception from informed consent are met. More specifically, FDA regulations (21 CFR 50.23) permit exception for informed consent in life-threatening situations where:

oThe investigator, with the concurrence of another physician, believes the situation for the human subject is life-threatening and necessitates the use of a test article (i.e., an investigational drug, device, or biologic).

oThe subject and/or legally authorized representative is unable to communicate consent. The FDA indicates that a Legally Authorized Representative is "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 procedure(s) involved in the research."

oThere is insufficient time to obtain consent.

oNo alternative exists that will provide an equal or better chance of saving the subject's life.

 

Is Oral Consent Appropriate?

The FDA allows waiver of written documentation of informed consent (i.e., consent of the subject is obtained, but the subject does not have to sign a consent document):

 

•When study participation presents minimal risk of harm to the subject

•And when the research involves no procedures requiring written documentation of consent outside the context of participation in a research study.

 

With a waiver of written documentation of consent, the consent of the subject or the subject's legally authorized representative is still required. The IRB may require the investigator to provide the subject with written materials about the research. (21CFR56.109)

 

Emergency Use of an Investigational Biologic, Drug, or Device

Investigators and IRBs may be confronted with the need to use an unapproved investigational drug or device in an emergency situation. In these circumstances, review by a full IRB may not be feasible because of the emergent nature of the problem. When this happens attention must be given to the IND/IDE requirements, informed consent, and IRB procedures. Please note that regulations exist-21 CFR 50.23-for unplanned emergency use (Regulations also exist for "planned" emergency research and can be found at 21 CFR 50.24).

 

The Definition of Emergency Use

Emergency use is the use of an investigational drug or device with a human subject in a life-threatening situation or in which no standard acceptable treatment is available and there is not sufficient time to obtain IRB approval. Life-threatening means that the likelihood of death is high unless an intervention interrupts the process. It also applies to a condition that is immediately and severely debilitating and that causes irreversible morbidity such as blindness or paralysis. (21CFR56.102(d))

 

IND/IDE Requirements for Emergency Use

If an individual patient does not meet the criteria for an existing protocol or an approved protocol does not exist, the usual procedure is for the physician to contact the manufacturer and determine if the drug can be made available for an "emergency use" under the company's IND. If there is no IND, the FDA may authorize the manufacturer to allow the drug to be used in advance of an IND submission or if the company agrees to provide the product, the physician can contact FDA, explain the situation, and obtain an emergency IND to permit shipment of the drug (21CFR312.36). If there is no IDE, the physician may use the device and notify FDA of its use after the fact. The physician should obtain an independent assessment from another physician and informed consent, however, before emergency use of the device occurs.

 

IRB Review Requirements for Emergency Use

In an emergency use situation the FDA permits an exemption from prior review and approval by an IRB (21CFR56.104c). For emergency use of devices, concurrence of the IRB chair is required before the use takes place. However, individual institutions may have a variety of policies to handle this situation. For example, the investigator may be required to notify the IRB office when an emergency use is being considered. Contact your local IRB office for further information. DHHS regulations do not prohibit an investigator from using any investigational or approved drug or device in an emergency situation for the clinical care of a patient. However, the information collected from the patient in whom the drug or device has been used should not be considered research data. IRB review and approval is required in all circumstances if the investigator wishes to use the data for research purposes.

 

Informed Consent Requirements for Emergency Use

In accordance with FDA regulations (21CFR50.23(a)), investigators are required to obtain informed consent from the subject or legally authorized representative unless both the investigator and uninvolved physician certify in writing that:

 

•The life threatening condition necessitates the use of the test article (i.e., an investigational drug, device, or biologic).

•There is an inability to communicate with or obtain informed consent.

•There is no time to obtain consent from a legal representative.

•There are no alternatives to provide equal or greater benefit.

 

After an Investigational Drug or Device has been used in an Emergency

Subsequent use of the investigational product at the institution should have prospective IRB review and approval. If the IRB was not notified before the investigational drug or device was used in an emergency situation, the IRB should be notified per institutional policy or within 5 working days (21CFR50.23(c)). The FDA and sponsor should be notified as necessary.

 

Further information on emergency use of investigational devices can be found at the FDA's Guidance on IDE Policies and Procedures page [http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm].

 

RESPONSIBILITIES

Sponsor Responsibilities

A "sponsor" may be an individual, a private company, an institution or other organization that is responsible for the initiation and conduct of a study involving a drug, device, or biologic. Investigators may assume this responsibility in addition to their role as investigator. Often these are called "investigator-initiated" studies. The sponsor's responsibilities include:

 

•Selecting clinical investigators qualified by training and experience.

•Informing and qualifying investigators by obtaining their commitment to supervise the study, follow the protocol, and obtain consent.

•Monitoring the conduct of the study by auditing documentation and conducting site visits.

•Completing regulatory filings related to the IND or IDE, adverse events, amendments or revisions, progress reports, withdrawal of IRB approval, and final reports.

•Controlling the distribution, tracking, and dispensation of the regulated products.

 

Investigator Responsibilities

Investigator responsibilities include:

 

•Ensuring IRB approval for the study is obtained before any subjects are enrolled.

•Ensuring that informed consent is obtained in accordance with FDA regulations.

•Ensuring that the investigation is conducted according to the investigational plan and applicable regulations.

•Administering the drug or using the device only in subjects under the investigator's supervision or under the supervision of a recognized sub-investigator.

•Maintaining adequate records of the dispensation of the drug or device.

•Returning unused materials at the end of trial.

•Preparing and maintaining adequate case histories and signed informed consent documents.

•Maintaining correspondence with the IRB and the sponsor to make sure that both have reviewed protocol amendments, recruitment materials, investigator brochures.

•Retaining records in accordance with regulations.

•Providing progress, safety, final and financial disclosure reports.

•Notifying the sponsor if IRB approval is withdrawn.

•Comply with International Conference on Harmonization (ICH) guidelines, if applicable. See Conference on Harmonization for ICH guidance [Submodule].

 

Inspections and Audits

The Bioresearch Monitoring Program of the FDA conducts routine, "not for cause," and "for cause" audits of IRBs, clinical investigators, and sponsors. The purpose of this monitoring is to ensure the quality and integrity of data submitted to FDA for regulatory decisions and to protect human subjects. The FDA may conduct on-site reviews of IRBs, research sites, pharmacies, manufacturing sites, etc. The FDA may also inspect, review, and copy records associated with the research.

 

 

21 CFR Part 11

21 CFR Part 11 Electronic Records; Electronic Signatures; Final Rule, often referred to as Part 11, was published May 20, 1997 and was intended to enable the use of electronic documents in the regulatory process for drugs and devices. Part 11 specifies processes that must be in place assuring that electronic documents and signatures are equivalent to paper documents and handwritten signatures.

 

For systems to comply with 21 CFR Part 11, a number of requirements must be met. For example:

 

•Computer systems utilizing electronic records and signatures must ensure accuracy, reliability, and consistent performance. Standard operating procedures (SOPs), audits, testing and training are required.

•Computer systems must use and maintain secure, computer-generated, time-stamped audit trails independently recording the date and time of entries and actions that create, modify, or delete electronic records.

•Computer systems must use system checks ensuring that only those individuals authorized to use the system are allowed access to the system (and access only those parts of the system they have authorization to use), alter records, and perform operations.

•Procedures must be established to ensure that records are retained for a duration of time, in an appropriate format, and to meet FDA requirements at a minimum [21CFR56.115(b), 312.57, 312.62 and 812.140].

 

In 2003, FDA clarified the application of Part 11 and limited the scope of its enforcement [www.fda.gov]. Under this narrower interpretation, FDA generally would not consider Part 11 to apply when computer systems are used to generate paper printouts of electronic records, and those paper records meet all the FDA requirements.

 

 

The FDA plans to publish a revised rule updating and clarifying the Part 11 requirements and the FDA's scope of enforcement. Until then, investigators and IRBs should check with their information technology (IT) support personnel (and as appropriate, sponsors) to ensure that either Part 11 compliance is maintained, or that Part 11 does not apply.

 

References:

•21 CFR Part 11 Electronic Records; Electronic Signatures; Final Rule

•Guidance for Industry: Part 11, Electronic Records; Electronic Signatures Scope and Application

 

Submodule: FDA Regulated Research: ICH for Investigators

 

Content Authors

 

David G. Forster JD, MA, CIP

Western IRB

 

Gary L. Chadwick PharmD, MPH, CIP

The University of Rochester

 

ICH for Investigators

1. INTRODUCTION: What is ICH?

The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use, commonly referred to as the International Conference on Harmonization (ICH) is an attempt to streamline the process for developing and marketing new drugs internationally. The ICH is comprised of representatives from the pharmaceutical industry and the regulatory bodies of the United States, Japan and the European Union. In addition, observers include Canada, the European Free Trade Area, and the World Health Organization.

 

 

The ICH has established several international standards of Good Clinical Practice (GCP) for the development of pharmaceutical products. The guideline that primarily affects investigators in the daily practice of clinical research is E6, "ICH Harmonized Tripartite Guideline: Guideline for Good Clinical Practice." The E6 guideline has 8 parts:

 

1.Glossary.

2.Principles.

3.IRBs.

4.Investigator.

5.Sponsor.

6.Protocol and amendments.

7.Investigator's brochure.

8.Essential documents.

 

The initial basis for drafting the E6 guidelines was the U.S. FDA regulations for the protection of human subjects (21 CFR 50 and 56).

 

II. LEGAL STATUS

After the guidelines were finalized, several countries adopted them as law. In the United States, however, the FDA adopted the ICH only as guidance (Federal Register, Vol. 62, No. 90, May 9, 1997, pages 25691-25709). Therefore, the ICH guidelines do not have the force of law in the United States and are not regulations. In the Federal Register Notice, FDA stated that the ICH 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."

 

Therefore, compliance is voluntary, but as with any published FDA guideline compliance is considered part of good clinical practice.

 

For sponsors, the advantage of complying with the ICH guidelines is that the FDA and equivalent government agencies in other countries will consider studies conducted in accordance with the ICH guidelines to meet the regulatory requirements of the drug approval processes for all of these countries. Increasingly, sponsors want investigators to meet the ICH requirements. However, certain requirements of ICH are not included in FDA or HHS regulations. Therefore, investigators need to be aware of the differences between ICH and FDA regulations so that they can fully comply with the ICH requirements when requested by sponsors.

 

III. DIFFERENCES BETWEEN ICH GUIDELINES AND U.S. REGULATIONS

The ICH E6 guidelines generally agree with the FDA regulations for IRBs, investigators and informed consent, but there are a few areas in which the ICH guidelines have requirements that go beyond either FDA or HHS (Common Rule) requirements. It is important for investigators to know what these differences are so that the investigator can comply with ICH when requested by a sponsor. References below are either to the ICH E6 guidelines or to the FDA regulations at 21 CFR parts 50 or 56.

 

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

One of the requirements of the ICH guideline is that "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." (ICH section 5.11). Oftentimes, sponsors will approach IRBs directly to obtain this statement, but some sponsors will request that the investigator obtain the statement from the IRB and then forward it to the sponsor.

 

2. Confidentiality of Medical Records

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

 

•ICH 4.8.10 states that the informed consent should indicate that 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 5.15.2 states that 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.

 

•FDA regulations (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.

 

Thus, ICH allows broader access to research records and to otherwise confidential medical records. Some subjects have complained about the extent of this access. Most consent forms currently permit access to research records by sponsors, and most investigators and subjects are not troubled by this. However, access by foreign regulatory agencies to research records and to subject's medical records is problematic for some investigators and subjects. Investigators must decide if they want to comply with ICH and agree to this access to subject medical records, and also must clearly disclose this information to subjects during the informed consent process.

 

3. Signature by Person Conducting the Consent Discussion

•ICH 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 only require the signature of the subject and the date the subject signed the consent form (50.27(a)).

 

To assure compliance with this requirement, the investigator 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.

 

4. Subject Receipt of a Signed and Dated Copy of the Consent Form

•ICH 4.8.11 requires that the subject or the legally authorized representative (LAR) receive a copy of the signed and dated written informed consent form.

•The FDA regulations allow subjects to receive either a signed or unsigned copy. (FDA Information Sheet "Frequently Asked Questions," September 1998, page 11). To be in compliance with ICH 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.

 

5. Assent of Children and Mentally Disabled Adults

•ICH 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, and FDA regulations, 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 getting 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 complete lack of capacity. In those situations, the consent of the legally acceptable representative is the only requirement.

 

6. Impartial Witness for Illiterate Subjects

•ICH 4.8.9 states that if a subject is unable to read or if a legally acceptable representative is unable to read, 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. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject's legally acceptable representative.

oThe ICH definition of "impartial witness", found at section 1.26, is, "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."

•The FDA addresses the documentation of informed consent for illiterate subjects by allowing the use of a short form consent document and a written summary for oral presentation (50.27(b)(2)).

Thus, the ICH guideline goes beyond the FDA regulations in requiring that the witness be impartial and specifying to what the witness should attest.

 

The investigator will need to consider how to document the signature of the impartial witness, as most consent forms for drug studies do not routinely include such a signature block. This can best be worked out with the investigator's IRB. If an investigator expects illiterate or blind subjects to enroll in studies on a regular basis, then there should probably 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."

 

7. Elements of Consent

A few of the ICH guideline requirements for elements of informed consent go beyond the FDA requirements, and would need to be included by the IRB for studies that are intended to meet ICH requirements.

 

Alternative Treatments

•ICH 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, as consent forms are already long and difficult to understand. 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 (50.25(a)(1)) 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 4.8.10(c) states in addition that 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.

•ICH 4.8.10(e) requires an explanation of "The subject's responsibilities." Some investigators include this information as part of the procedures section of the consent form.

 

Statement of no benefit

•ICH 4.8.10 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." Many investigators customarily include this information in the consent form.

Prorated payment in the consent form

•ICH 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.

•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 United States to include in consent forms.

 

8. Non-therapeutic Trials

The following two ICH sections address non-therapeutic research and the requirements for consent. These issues are not specifically addressed in the FDA regulations.

•ICH 4.8.13 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 be conducted in subjects who personally give consent and who sign and date the written informed consent form.

•ICH 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:

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

oThe foreseeable risks to the subjects are low.

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

oThe trial is not prohibited by law.

oThe 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.

 

Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed. The ICH requirements for inclusion of subjects in non-therapeutic trials are straightforward. To comply with ICH requirements, investigators should ensure that subjects without capacity are not used for non-therapeutic trials, except as described above.

 

9. Investigator Notification to Subject's Primary Physician

•ICH section 4.3.3. states that it is recommended 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.

 

10. IRB Responsibilities

There are several differences between the FDA and ICH regarding the responsibilities and duties of the IRB.

 

Documents the IRB must review.

The ICH provides a list of documents that the IRB should review, and IRBs routinely review most of the materials listed. Compliance with ICH requires reviewing all the listed materials.

 

•ICH 3.1.2 The IRB/IEC should obtain the following documents:

oTrial protocol(s)/ amendment(s).

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

oSubject recruitment procedures (e.g., advertisements).

oWritten information to be provided to subjects.

oInvestigator's Brochure (IB).

oAvailable safety information.

oInformation about payments and compensation available to subjects.

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

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

•The FDA regulations 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 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."

 

Review of Changes in Research

•ICH 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 4.5.3 adds that "Investigators should document and explain any deviations from the approved protocol."

•FDA regulations (56.108(a)(4)) requires review of changes in research. However, review of deviations is not required by FDA, and the ICH 4.5.3 requirement is quite burdensome when applied literally. Investigators should clarify with sponsors and their IRB whether and how this requirement will be satisfied.

 

IV. CONCLUSION

In the U.S., compliance with the ICH E6 guidelines is voluntary for investigators in that it is not federal regulation. For research institutions that conduct clinical trials of drugs, however, pharmaceutical sponsors often insist that the ICH requirements be met. Investigators should assess their level of compliance and decide if ICH requirements can be met without compromising subject protections or institutional values.