# Presentation: 664919

## FDA Regulations Pertaining to Good Clinical Practice and Clinical Trials

- Steven Hirschfeld, MD PhD
- Office of Cellular, Tissue and Gene Therapy
- Center for Biologics Evaluation and Research
- FDA

## Fundamentals of Government

- Law (=Act, Statue)- developed and passed by Legislative Branch, signed by President. Published in the United States Code (USC)
- Regulation (=Rule)- developed and published by Executive Branch. Published in the Code of Federal Regulations (CFR)

## FDA Authority

- Derived from multiple laws and regulations
- Focus is on product and product use

## Some Applicable Regulations for Good Clinical Practice

- Human Subject Protection 21 CFR Part 50
- Financial Disclosures by Clinical Investigators 21 CFR Part 54
- Institutional Review Boards 21 CFR Part 56
- Investigational New Drugs 21 CFR Part 312

## 21 CFR Part 50 Human Subject Protection

- Part A- General Provisions
- Part B- Informed Consent of Human Subjects
- Part C- (Reserved)
- Part D- Additional Safeguards for Children in Clinical Investigations

## 21 CFR 50 Subpart D-Additional Safeguards for Children in Clinical Investigations

-        §_[50.50](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.50)_ - IRB duties.   §_[50.51](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.51)_ - Clinical investigations not involving greater than minimal risk.   §_[50.52](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.52)_ - Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.   §_[50.53](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.53)_ - Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects` disorder or condition.   §_[50.54](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.54)_ - Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.   §_[50.55](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.55)_ - Requirements for permission by parents or guardians and for assent by children.   §_[50.56](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=50.56)_ - Wards.

## Relationship of 21 CFR 50 Subpart D to 45 CFR 46 Subpart D

- The FDA regulations apply to all research utilizing FDA regulated products
- The HHS regulations apply to all research that is supported by HHS
- Research supported by HHS using FDA regulated products is subject to both sets of regulations
- The regulations are harmonized

## Subpart D Adaptation-Definitions

_**children**_ at Sec. 50.3(o) includes persons who have not attained the legal age for consent to treatments or procedures involved in clinical investigations as determined under the applicable law of the jurisdiction in which the research will be conducted. This provision means that the law of the site of the research will determine the legal age of consent of the participant.

## Subpart D Adaptation-Definitions

_**Parent **_is defined as a child's biological or adoptive parent.
- The term _**Ward**_ is used in HHS subpart D but is not defined. In Sec. 50.3(q), FDA has developed a definition for ward that is consistent with the use of the term in HHS subpart D. Under Sec. 50.3(q), a ward is a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law.

## Subpart D Adaptation-Definitions

**    **_**Guardian **_is an individual who is authorized under applicable State or  local law to consent on behalf of a child to general medical care. FDA  is adopting this definition and is adding text to clarify that  authorization to consent to general medical care must include  participation in research and, for purposes of this rule, a guardian is  also an individual authorized to consent to a child's participation in research.

## Subpart D Adaptation-Definitions

- The definition of ``_**permission**_'' at Sec. 50.3(r) is adopted from 45 CFR 46.402(c) of HHS subpart D with a minor change to clarify that  permission applies to participation in clinical investigations  involving FDA-regulated products. FDA's definition at Sec. 50.3(r) generally adopts the HHS definition and states that permission is the agreement of parent(s) or guardian to their child's or ward's participation in a clinical investigation.
- FDA's regulation at Sec. 50.3(r) adds a sentence clarifying that permission must be obtained in compliance with part 50, subpart B and must include the elements of informed consent described in FDA's regulations at Sec. 50.25.

##     FDA's regulation, like the HHS regulation, defines assent as a child's affirmative agreement to participate in research. FDA's definition also states that mere failure to object to participation in clinical investigations should not, absent affirmative agreement, be considered assent.

- Subpart D Adaptation-Definitions

## IND Regulations 21 CFR 50 Subpart DSection 50.50 IRB Duties

- In addition to other responsibilities assigned to IRBs under this part and part 56 of this chapter, each IRB must review clinical investigations involving children as subjects covered by this subpart D and approve only those clinical investigations that satisfy the criteria described in Sec. 50.51, Sec. 50.52, or Sec. 50.53 and the conditions of all other applicable sections of this subpart D.

## Subpart D Adaptation-Minimal Risk

-    FDA  anticipates that among the types of procedures that might be used in a clinical investigation that would present no more than _minimal risk_ to children would be clean-catch urinalysis, obtaining stool samples, administering electroencephalograms, requiring minimal changes in diet or daily routine, or the use of standard psychological tests. Examples of the types of clinical investigations that would present no more than minimal risk would include a taste test of an excipient or tests of devices involving temperature readings orally or in the ear.

## When May IRBs Approve a Clinical Investigation Not Involving Greater than Minimal Risk?

-     Under Sec. 50.51, an IRB may approve a clinical investigation in which no greater than minimal risk is presented only if an IRB finds and documents that adequate provisions are made for soliciting the assent of the children involved and the permission of their parents or guardians as set forth in Sec. 50.55.

## When May IRBs Approve Clinical Investigations Involving Greater Than Minimal Risk But Presenting the Prospect of Direct Benefit to the Individual Subjects?

-    Under Sec. 50.52, an IRB may approve a clinical investigation in which an IRB finds _more than minimal risk_ to children but that presents the prospect of direct benefit to individual subjects only if the IRB finds and documents that:
-     (1) The risk is justified by the anticipated benefit to the
-      subjects,
-     (2) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches, and
-     (3) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in Sec. 50.55. . These clinical investigations generally are performed in children with the disease or condition for which the product is intended.

## When May an IRB Approve a Clinical Investigation Involving Greater Than Minimal Risk and No Prospect of Direct Benefit to Individual Subjects, But Likely to Yield Generalizable Knowledge About the Subjects' Disorder or Condition?

-  Section 50.53 provides that in certain circumstances an IRB may approve a clinical investigation in which the IRB finds that _more than minimal risk_ to children is presented:
-  (1) By an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or
-  (2) by a monitoring procedure that is not likely to contribute to the well-being of the subject. The clinical investigation may be approved only if the IRB finds and documents that:
-     (1) The risk represents a minor increase over minimal risk;
-     (2) The intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;
-     (3) The intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition that is of vital importance for the understanding or amelioration of the subjects' disorder or condition; and
-     (4) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in Sec. 50.55.

## Subpart D Adaptation-IRB Approval Criteria

- FDA regulations set out criteria to be satisfied if an IRB is to
- approve research (Sec. 56.111). These criteria are the same for initial
- review and continuing review and include a determination by the IRB
- that:
-     (1) Risks to subjects are minimized,
-     (2) Risks to subjects are reasonable in relation to anticipated
- benefits,
-     (3) Selection of subjects is equitable,
-     (4) Informed consent is adequate and appropriately documented,
-     (5) Where appropriate, the research plan makes adequate provision
- for monitoring the data collected to ensure the safety of subjects,
-     (6) Where appropriate, there are adequate provisions to protect the
- privacy of subjects and to maintain the confidentiality of data, and
-     (7) Appropriate safeguards have been included to protect vulnerable
- subjects.

## Subpart D Adaptation-Monitoring

-    While the level of risk in a clinical investigation may change during the course of a study, appropriate strategies may be included in the study design that may mitigate risks. These might include exit strategies in the case of adverse events or a lack of efficacy, or establishing a data monitoring committee (DMC) to review ongoing data collection and recommend study changes, including stopping a trial on the basis of safety information.

## 21 CFR Part 56-Institutional Review Boards

**Subpart A--General Provisions**   §_[56.101](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.101)__ - Scope. __  §__[56.102](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.102)__ - Definitions. __  §__[56.103](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.103)__ - Circumstances in which IRB review is required. __  §__[56.104](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.104)__ - Exemptions from IRB requirement. __  §__[56.105](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.105)__ - Waiver of IRB requirement. _
**Subpart B--Organization and Personnel**   §_[56.107](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.107)__ - IRB membership. _

## 21 CFR Part 56-Institutional Review Boards

**Subpart C--IRB Functions and Operations**   §_[56.108](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.108)__ - IRB functions and operations. __  §__[56.109](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.109)__ - IRB review of research. __  §__[56.110](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.110)__ - Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research. __  §__[56.111](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.111)__ - Criteria for IRB approval of research. __  §__[56.112](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.112)__ - Review by institution. __  §__[56.113](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.113)__ - Suspension or termination of IRB approval of research. __  §__[56.114](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.114)__ - Cooperative research._

## 21 CFR Part 56-Institutional Review Boards

**Subpart D--Records and Reports**   §_[56.115](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.115)__ - IRB records. _
**Subpart E--Administrative Actions for Noncompliance**   §_[56.120](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.120)__ - Lesser administrative actions. __  §__[56.121](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.121)__ - Disqualification of an IRB or an institution. __  §__[56.122](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.122)__ - Public disclosure of information regarding revocation. __  §__[56.123](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.123)__ - Reinstatement of an IRB or an institution. __  §__[56.124](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=56.124)__ - Actions alternative or additional to disqualification_

## IND Regulations 21 CFR 312 Subpart AGeneral Provisions

-      §_[312.1](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.1)_ - Scope.   §_[312.2](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.2)_ - Applicability.   §_[312.3](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.3)_ - Definitions and interpretations.   §_[312.6](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.6)_ - Labeling of an investigational new drug.   §_[312.7](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.7)_ - Promotion and charging for investigational drugs.   §_[312.10](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.10)_ - Waivers.

## IND Regulations 21 CFR 312 Subpart BInvestigations New Drug Application (IND)

-       §_[312.20](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.20)_ - Requirement for an IND.   §_[312.21](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.21)_ - Phases of an investigation.   §_[312.22](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.22)_ - General principles of the IND submission.   §_[312.23](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.23)_ - IND content and format.   §_[312.30](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.30)_ - Protocol amendments.   §_[312.31](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.31)_ - Information amendments.   §_[312.32](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.32)_ - IND safety reports.   §312.33 - Annual reports.   §312.34 - Treatment use of an investigational new drug.   §312.35 - Submissions for treatment use.   §312.36 - Emergency use of an investigational new drug.   §312.38 - Withdrawal of an IND.

## IND Regulations 21 CFR 312 Subpart CAdministrative Actions

-     §312.40 - General requirements for use of an investigational new drug in a clinical investigation.   §312.41 - Comment and advice on an IND.   §312.42 - Clinical holds and requests for modification.   §312.44 - Termination.   §312.45 - Inactive status.   §312.47 - Meetings.   §312.48 - Dispute resolution.

## IND Regulations 21 CFR 312 Subpart DResponsibilities of Sponsors and Investigators 

-   	  §_[312.50](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.50)_ - General responsibilities of sponsors.   §_[312.52](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.52)_ - Transfer of obligations to a contract research organization.   §_[312.53](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.53)_ - Selecting investigators and monitors.   §_[312.54](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.54)_ - Emergency research under Sec. 50.24 of this chapter.   §_[312.55](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.55)_ - Informing investigators.   §_[312.56](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.56)_ - Review of ongoing investigations.   §_[312.57](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.57)_ - Recordkeeping and record retention.   §_[312.58](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.58)_ - Inspection of sponsor`s records and reports.   §_[312.59](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.59)_ - Disposition of unused supply of investigational drug.   §_[312.60](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.60)_ - General responsibilities of investigators.   §_[312.61](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.61)_ - Control of the investigational drug.   §_[312.62](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.62)_ - Investigator recordkeeping and record retention.   §_[312.64](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.64)_ - Investigator reports.   §_[312.66](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.66)_ - Assurance of IRB review.   §_[312.68](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.68)_ - Inspection of investigator`s records and reports.   §_[312.69](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.69)_ - Handling of controlled substances.   §_[312.70](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.70)_ - Disqualification of a clinical investigator.

## IND Regulations 21 CFR 312 Subpart EDrugs Intended to Treat Life Threatening and Severely Debilitating Illnesses

-       §_[312.80](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.80)_ - Purpose.   §_[312.81](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.81)_ - Scope.   §_[312.82](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.82)_ - Early consultation.   §_[312.83](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.83)_ - Treatment protocols.   §_[312.84](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.84)_ - Risk-benefit analysis in review of marketing applications for drugs to treat life-threatening and severely-debilitating illnesses.   §_[312.85](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.85)_ - Phase 4 studies.   §_[312.86](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.86)_ - Focused FDA regulatory research.   §_[312.87](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.87)_ - Active monitoring of conduct and evaluation of clinical trials.   §_[312.88](http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.88)_ - Safeguards for patient safety.

## For drugs covered under this section, the Commissioner and other agency officials will monitor the progress of the conduct and evaluation of clinical trials and be involved in facilitating their appropriate progress. 

- Section 312.87 Active Monitoring of Conduct and Evaluation of Clinical Trials

## Sec. 312.88 Safeguards for patient safety.

- All of the safeguards incorporated within parts 50, 56, 312, 314, and 600 of this chapter designed to ensure the safety of clinical testing and the safety of products following marketing approval apply to drugs covered by this section. This includes the requirements for informed consent (part 50 of this chapter) and institutional review boards (part 56 of this chapter). These safeguards further include the review of animal studies prior to initial human testing (Sec. 312.23), and the monitoring of adverse drug experiences through the requirements of IND safety reports (Sec. 312.32), safety update reports during agency review of a marketing application (Sec. 314.50 of this chapter), and postmarketing adverse reaction reporting (Sec. 314.80 of this chapter).

## Conclusions

- FDA has authority to regulate clinical studies using FDA regulated products
- FDA regulations incorporate IRB and FDA oversight of studies
- Regulations exist for studies using products intended to treat life threatening illnesses
- Regulations exist for providing additional safeguards for children enrolled in clinical investigations
- HHS and FDA regulations are intended to be harmonized