1. A Regulatory Overview Kesley D. Tyson, MS, CCRP
Project manager / operations support specialist
Emory university research administration services

2. Objectives
Provide a comprehensive overview of the following code of federal regulations:
21 CFR Part 11
21 CFR Part 50
45 CFR Part 46
21 CFR Part 56
21 CFR Part 312
21 CFR Part 812

3. 21 CFR Part 11
Electronic Records
Electronic Signatures

4. Electronic Records Subpart B
Any combination of text, graphics, data, audio, pictorial, or other information in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system
The rules apply to any records covered by FDA regulations that exist in an electronic form-including records that are required to be maintained whether they are submitted to the FDA or not.

5. Common Data Recorded Electronically
Clinical data initially recorded in electronic health records
Electronic laboratory reports
Digital medical images from devices
Electronic diaries completed by subjects

6. Electronic Source Data
Electronic source data are data initially recorded in electronic format
Capturing source data electronically and transmitting it to the eCRF should:
Eliminate unnecessary duplication of data
Reduce the possibility for transcription errors
Encourage entering source data during a subject’s visit
Eliminate transcription of source data prior to entry into an eCRF
Facilitate remote monitoring of data
Promote real-time access for data review
Facilitate the collection of accurate and complete data

7. Electronic Case Report Forms
eCRF: An auditable electronic record of information that generally is reported to the sponsor on each trail subject, according to a clinical investigation protocol.
The eCRF enable clinical investigation data to be systematically captured, reviewed, managed, stored, analyzed, and reported.

8. Electronic Signatures Subpart C
A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.
Signature Manifestations must indicate the following:
Printed name of the signer
Date and time when the signature was executed
The meaning (such as review, approval, responsibility, or authorship) associated with the signature.

9. eSignature Requirements
Shall be unique to one individual and shall not be reused by, or reassigned to, anyone else
Organization shall verify the identity of the individual before assigning an electronic signature
Person using signature shall certify the electronic signatures in their system are intended to be the legally binding equivalent of traditional handwritten signatures

10. Key Points
The use of electronic records and their submission to the FDA is voluntary.
If there is no FDA requirement that a document or record be created or maintained, then 21 CFR Part 11 does not apply.
Electronic copies of electronic records provided to FDA should be accurate and complete, but they do not necessarily have to be in the same file format and on the same media as the original electronic records.
The regulations represent the minimum requirements for implementation, but organizations can choose to make their systems more secure if they choose.
The determination of whether to use an electronic signature is up to an individual organization

11. 21 CFR Part 50 Protection of Human Subjects
Subpart B-Informed Consent of Human Subjects
Subpart D-Additional Safeguards for Children in Clinical Investigations
Primarily want to focus on informed consent for the sake of time

12. Informed Consent
Informed consent requirements apply to all clinical investigations regulated by FDA.
Informed consent must be obtained from the subject or legally authorized representative prior to initiating any research related events.
The CFR and ICH E6 both require that there is documentation of consent and that the subject receives a copy of the consent form; ICH specifies receipt of signed/dated copy
Required signatures
CFR only requires the subject to sign
ICH E6 requires the subject and the person conducting the consent process to sign

13. Informed Consent
Subjects should be kept informed of any changes or updates in the research
If the changes in the research affect the treatment of the subject or may affect the subjects willingness to continue in the study, the subject must be reconsented
Should be written in a nontechnical manner in understandable language
Must be signed before any study procedures are initiated, including screening procedures
Must be approved by the IRB
Should be amended when appropriate and subject reconsented
The IRB might determine:
Who performs the consent process
Who in addition to the subject must sign the consent form
Acceptability of “special circumstances” used to obtain written consent

14. 8 Required components of the ICF
A statement that:
The study involves research
An explanation of the purposes of the research
The expected duration of the subject’s participation
Description of the procedures to be followed
An identification of any procedures which are experimental
A description of any reasonably foreseeable risks or discomforts to the subject
A description of any benefits to the subject or to others which may reasonably be expected from the research
Disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject

15. 8 Required components of the ICF
A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained:
FDA regulations require notice that the Food and Drug Administration may inspect the records
ICH extends this notice to “regulatory authority(ies)”, the Sponsor an/or its representatives, and IRB representatives
An explanation as to whether any compensation and whether medical treatments are available if injury occurs
An explanation of who to contact for pertinent questions regarding:
The research project
Research subjects’ rights
Whom to contact in the event of a research-related injury
A statement that:
Participation is voluntary
Refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled
The subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled

16. Informed Consent: Additional Elements
A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable
Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subjects consent
Any additional costs to the subject that may result from participation in the research
The consequences of a subjects decision to withdraw from the research and procedures for orderly termination of participation by the subject
A statement that significant new findings developed during the course of the research which may relate to the subjects willingness to continue participation will be provided to the subject
The approximate number of subjects involved in the study

17. Informed Consent: Additional Elements
Notification that study results will be posted in the ClinicalTrials.gov website, when applicable
“A description of this clinical trial will be available on as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

18. Informed Consent: Other Considerations
Does not include language that waives or appears to waive the subjects legal rights
Does not include language that releases or appears to release investigator, institution, sponsor or their agents from liability for negligence
Subject has an opportunity to ask questions about the study

19. Short Form Written Consent
Can be used with IRB approval, most frequently for subjects who cannot read/English is not the first language
Impartial witness to entire consent process
A written summary (often the consent form) and all other written information read and explained to the subject
Oral consent from subject followed by signing and dating a short form if possible
Witness signs the written summary (consent form) and short form, attesting that information was accurately explained, apparently understood by the subject, and consent was freely given by subject
Person obtaining consent signs the written summary (consent form)
A copy of the written summary and the short form given to the subject or representative

20. Short Form Consent Process
Individual
Consent
Short Form Consent
Person obtaining consent
(i.e.-PI/Coordinator) X
Witness
Subject/LAR

21. Exemptions to Informed Consent
Human subject is confronted with a life-threatening situation necessitating the use of the test article.
Consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from the subject.
Time is not sufficient to obtain consent from the subject’s legal representative.
There is no available alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject.

22. Presidential waivers
The president may waive prior consent requirements for the administration of an investigational new drug to a member of the armed forces in connection with the member’s participation in a particular military operation.
The Secretary of Defense must first request such determination from the President for an IND sponsored by the DOD, and certify and document that the standards and criteria for waiver have been met.
The President determines in writing that consent:
Is not feasible
Is contrary to the best interests of the military member
Is not in the interests of national security

23. Informed Consent-Key points
Information given to the subject or legal representative must be in language understandable to the subject or representative.
Consent must be obtained “…only under circumstances that provide the prospective subject or representative sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.”
Informed consent documents must be approved by the IRB before use
Informed consent is an ongoing process that begins when the subject is first approached to participate in a study.
Informed consent must be obtained before a subject enters a study
Informed consent is documented by a written, signed and dated informed consent form
Consent forms should be written at approximately the 6th to 8th grade levels according to most IRBs
The informed consent process is only over when there is no additional relevant information to provide to the subject.

24. Trivia Question
The consent for your study was changed by the sponsor to reflect new information about adverse events. Nothing else changed—just the addition of two more possible adverse events to the list. Does the IRB need to approve the revised consent?
Yes. Any change in a consent that involves risk should be approved by an IRB before use.

25. Trivia Question
21 CFR 50.27(a) requires that a copy of the consent document be given to the person signing the form. Does this copy have to be a photocopy of the form with the subject's signature affixed?
No. The regulation does not require the copy of the form given to the subject to be a copy of the document with the subject's signature, although this is encouraged. It must, however, be a copy of the IRB approved document that was given to the subject to obtain consent [21 CFR 50.27(a) or 21 CFR 50.27(b)(2)]. One purpose of providing the person signing the form with a copy of the consent document is to allow the subject to review the information with others, both before and after making a decision to participate in the study, as well as providing a continuing reference for items such as scheduling of procedures and emergency contacts.

26. Trivia Question
Does FDA require the informed consent document to contain a space for assent by children?
No, however, many investigators and IRBs consider it standard practice to obtain the agreement of older children who can understand the circumstances before enrolling them in research. While the FDA regulations do not specifically address enrollment of children (other than to include them as a class of vulnerable subjects), the basic requirement of 21 CFR applies, i.e., the legally effective informed consent of the subject or the subject's legally authorized representative must be obtained before enrollment. Parents, legal guardians and/or others may have the ability to give permission to enroll children in research, depending on applicable state and local law of the jurisdiction in which the research is conducted. (Note: permission to enroll in research is not the same as permission to provide medical treatment.) IRBs generally require investigators to obtain the permission of one or both of the parents or guardian (as appropriate) and the assent of children who possess the intellectual and emotional ability to comprehend the concepts involved. Some IRBs require two documents, a fully detailed explanation for parents and older children to read and sign, and a shorter, simpler one for younger children. [For research supported by DHHS, the additional protections at 45 CFR 46 Subpart D are also required. The Subpart D regulations provide appropriate guidance for all other pediatric studies.]

27. Subpart D: Safeguards for Children
Children can participate in a clinical trial if:
The IRB determines that the clinical trial does not involve greater than minimal risk
Adequate provisions are made for soliciting assent of the child and permission of the parents or guardians

28. Safeguards for Children
If the IRB determines that the clinical trial involves greater than minimal risk:
The study intervention or procedure holds out the prospect of direct benefit to the child OR
The study involves a monitoring procedure that is likely to contribute to subjects well-being
Adequate provisions are made for soliciting assent of the child and permission of the parents or guardian
The IRB can approve a clinical trial that involves greater than minimal risk with no prospect for direct benefit of the subject IF:
The risk represents a minor increase over minimal risk
The experiences associated with the clinical trial are reasonably commensurate with those inherent in the actual or planned medical, dental, social or educational situations

29. Safeguards for Children
If the IRB determines that the clinical trial involves greater than minimal risk:
The risk is justified by the anticipated benefit to the subject
The relation of the anticipated benefit to risk is at least as favorable to the subject as that presented by available alternative approaches
Adequate provisions are made for soliciting assent of the child and permission of the parents or guardian
The IRB determines whether children are capable of providing assent taking into account the ages, maturity and psychological state of the children involved
The IRB can waive assent requirements if it determines:
The clinical trial involves no more than minimal risk
The waiver will not adversely affect the rights and welfare of the subjects
The clinical trial could not practically be carried out without the waiver
When appropriate, pertinent information is given to the subjects after participation

30. What’s the difference between 45 CFR 46 and 21 CFR Part 50?
45 CFR 46 is a Health and Human Services (HHS) regulation
21 CFR Part 50 is Food and Drug Administration (FDA) regulation
Example of differences between the regulations can be found here:
ucm htm

31. The Common Rule-45 CFR 46
The Common Rule is the baseline standard of ethics by which any government-funded research in the United States is held, and nearly all academic institutions hold their researchers to these statement of rights regardless of funding.
The current U.S. system of protection for human research subjects is heavily influenced by the Belmont Report. The Belmont Report outlines the basic ethical principles in research involving human subjects.

32. 21 CFR Part 56
Institutional Review Boards (IRB)

33. Purpose of the IRB
Assure appropriate steps are taken to protect the rights and welfare of human subjects participating in research.
The IRB utilizes a group of processes to review research protocols and related materials to ensure protection of the rights and welfare of human subjects of research.

34. Organization and Personnel Subpart B
IRB must register at a site maintained by the Department of Health and Human Services if it is located in the U.S. and:
Reviews clinical investigations regulated by FDA
Reviews clinical investigations that are intended to support applications for research or marketing permits for FDA-regulated products
All other IRBs may register voluntarily
The IRB must be registered prior to approving studies
An individual authorized to act on the IRB’s behalf must submit the registration information.
IRB registration information is entered into an Internet-based registration system maintained by the Department of Health and Human Services (HHS).

35. Membership Requirements
IRB Membership Requirements
Must have at least 5 members
Must have varying backgrounds
May not consist entirely of the same gender
May not consist entirely of members of one profession
Must include at least one member whose primary concerns are in the scientific area as well as one member whose primary concerns are in nonscientific areas
Must include at least one member who is not otherwise affiliated with the institution and who is not part of the immediate family of a person who is affiliated with the institution

36. Membership
No IRB may have a member participate in the IRB’s initial or continuing review of any project in which the member has a conflicting interest, except to provide information requested by the IRB
An IRB may invite individuals with competence in special areas to assist in the review of complex issues which require expertise beyond or in addition to that available on the IRB. These individuals may not vote with the IRB
A clinical investigator may be an IRB member, but may not participate in the review of their own study except to provide information requested from the IRB
A member of the IRB may satisfy more than one membership category

37. Institutional Review Boards
In reviewing research, the IRB is ensuring:
Risks to subjects are minimized
Risks to subjects are reasonable in relation to anticipated benefits
Selection of subjects is equitable
Informed consent is given in accordance to 21 CFR Part 50
Research plans make adequate provisions to monitor data, if appropriate
Privacy of subjects and confidentiality of data are maintained

38. Institutional Review Boards
The IRB also ensures that additional safeguards are taken to protect the rights and welfare of vulnerable subjects:
Prisoners
Pregnant women, children, fetuses
Handicapped
Mentally disabled
Economically or educationally disadvantaged

39. IRB-Key points
IRBs are one of the primary safeguards for the protection of human subjects of research
CFR Part 56 contains the FDA regulations that pertain to IRBs
An IRB must approve a study and the informed consent document before the study can start
There are special regulations concerning research in vulnerable subjects (children, pregnant women, prisoners, etc.)
IRBs must approve advertising prior to use
IRBs must approve any subject compensation
An investigator must report adverse events and study progress to the IRB at least annually
Continuing review of a study must be done at least annually

40. Trivia Questions
The IRB chair notified you in person that your study has been approved. Can you start enrolling subjects now?
No. You must wait for the official written notification. Most sponsor companies will not send you the investigational drug or device until they have a copy of the IRB approval letter, but even if they have you may not start until you have the written approval.

41. Trivia Question May a clinical investigator be an IRB member?
Yes, however, the IRB regulations [21 CFR (e)] prohibit any member from participating in the IRB's initial or continuing review of any study in which the member has a conflicting interest, except to provide information requested by the IRB

42. Clinical Trials
21 CFR Part 312
21 CFR Part 812

43. Drug Development
Before clinical trials can be initiated, an application containing the appropriate information must be submitted to regulatory authorities.
In the U.S., the document is an investigational New Drug (IND) Application, which must be submitted to the FDA.
An IND permits an unapproved drug to be shipped lawfully for the purpose of conducting investigations of the drug.
The IND is the official mechanism to provide information to the FDA.

44. Investigational New Drug 21 CFR Part 312
Subpart B-Requirements for an IND
Sponsor shall submit an IND to FDA if the sponsor intends to conduct a clinical investigation with an investigational new drug
A sponsor shall not begin a clinical investigation until the investigation is subject to an IND which is in effect
A sponsor shall submit a separate IND for any clinical investigation involving an exception from informed consent. Such a clinical investigation is not permitted to proceed without prior written authorization from FDA. FDA shall provide a written determination 30 days after FDA receives the IND or earlier

45. IND Format and Content A sponsor initiated IND must contain:
A Cover sheet (Form FDA 1571)
Table of contents
Introductory statement and general investigational plan
Investigators brochure
Protocol (s)
Chemistry, manufacturing, and control information (CMC)
Pharmacology and toxicology information
Previous human experience with the investigational drug
Additional information-e.g.-drug dependence and abuse potential, exposure to radiation, plans for pediatric studies

46. Labeling/Promotion/Marketing
Must bear the statement “Caution: New Drug-Limited by Federal (or United States) law to investigational use”
Shall not bear any statement that is false or misleading in any particular and shall not represent that the investigational new drug is safe or effective for the purposes for which it is being investigated
Promotion/Marketing
A sponsor or investigator, or anyone acting on their behalf shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug.
A sponsor or investigator shall not commercially distribute or test market an investigational new drug
A sponsor shall not unduly prolong an investigation after finding that the results of the investigation appear to establish sufficient data to support a marketing application

47. Phase I investigational studies
Initial introduction of an investigational new drug into humans
Small safety studies, usually done in healthy volunteers
Enrollment ranges from approximately participants
Designed to determine
Metabolism and pharmacologic actions of the drug in humans
Side effects associated with increasing doses
Gain early evidence on effectiveness

48. Phase II investigational studies
Usually the first studies in patients with the disease or condition of interest
Includes the controlled clinical studies conducted to evaluate:
Effectiveness of the drug for a particular indication
Indications in patients with the disease or condition under study
Determine the common short-term side effects and risks associated with the drug
Usually well controlled, closely monitored, and conducted in a relatively small number of patients
Usually involves no more than several hundred subjects

49. Phase III investigational studies
Large, comprehensive safety and efficacy studies
Expanded controlled and uncontrolled trials
Performed after preliminary evidence suggesting effectiveness of the drug has been obtained
Intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide adequate basis for physician labeling
Usually include from several hundred to several thousand subjects

50. Phase 3B and Phase 4 investigational studies
Phase 3B studies are those being done during the time the compound is in the FDA review cycle
Phase 4 studies are done after approval of the compound (post-marketing)
Address FDA requirements for additional information not in NDA (New Drug Application)
Continue assessing overall therapeutic value
Surveillance for less common adverse events (spontaneous reports, registries, etc.)
Design and number of subjects depends on study objective
May be similar to Phase 2 or Phase 3 study in design

51. IND Annual Report
The annual report should be submitted within 60 days of the anniversary date that the IND went into effect.
All IND maintenance documents sent to the FDA should be accompanied by a cover letter and a Form 1571 specifying what updated information is being sent to the FDA.

52. New Drug Application (NDA)
21 CFR Part 314-Applications for FDA Approval to market a New Drug or an Antibiotic Drug
The NDA is the sponsor’s formal application to market a new drug
The NDA is filed when the primary safety and efficacy studies are complete
The data gathered during the animal studies and human clinical trials of the IND become part of the NDA
The FDA must formally approve a drug before it can be marketed

53. IND Key Points
Clinical trials involve human subjects-(Pre-clinical trials DO NOT involve human subjects)
Before clinical trials begin, the sponsor must file an IND with the FDA
The IND is filed after significant pre-clinical testing has been done on a compound, and it appears to be reasonably safe for use in humans
A sponsor must wait 30 days after filing the IND before starting studies in humans
INDs must be updated annually

54. 21 CFR Part 812 What is an investigational device?
A device, including a transitional device, that is the object of an investigation. In vitro diagnostic products are medical devices.
Nonsignificant Risk Device
Devices that do not pose a significant risk to the human subjects. Examples include most daily-wear contact lenses and lens solutions, ultrasonic dental scalers, and Foley catheters.
Significant Risk Device
A device that presents a potential for serious risk to the health, safety, or welfare of a subject. Significant risk devices may include implants, devices that support or sustain human life, and devices that are substantially important in diagnosing, curing, mitigating or treating disease or in preventing impairment to human health. Examples include sutures, cardiac pacemakers, hydrocephalus shunts, and orthopedic implants.

55. Investigational Device Exemption (IDE)
An IDE allows investigational devices to be shipped for a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification [510(k)] submission to the FDA.
All clinical investigations of devices must have an approved IDE or be exempt from the regulations.
The sponsor of the clinical trial is responsible for submitting the IDE application to the FDA and obtaining IRB approval before the study can begin.
Sponsors are encouraged to contact the FDA to obtain further guidance prior to the submission of an IDE application. Early interaction with the Agency will help increase the sponsor's understanding of the FDA requirements, regulations, and guidance documents, and will allow FDA personnel to better understand the new technologies. Increased interaction between the FDA and sponsors will speed the regulatory process and minimize delays in the development of useful devices intended for human use.

56. Device Class I
General controls are sufficient to provide reasonable assurance of safety and effectiveness
General controls include:
Prohibition against adulterated or misbranded devices
Pre-market notification 510(k) requirements
GMPs
Registration of manufacturing facilities Listing of device types
Examples: elastic bandages, examination gloves, and hand-held surgical instruments

57. Device Class II
Devices for which general controls alone are insufficient to assure safety and effectiveness, and existing methods are available to provide such assurances.
In addition to complying with general controls, Class II devices are also subject to special controls.
Special controls may include:
Special labeling requirements
Mandatory performance standards
Post-market surveillance
Examples: powered wheelchairs, infusion pumps, and surgical drapes

58. Device Class III Most stringent regulatory category for devices
Requires full PMA
Insufficient information exists to assure safety and effectiveness solely through general or special controls
Class III devices usually support or sustain human life
Are of substantial importance in preventing impairment of human health
Present a potential, unreasonable risk of illness or injury
Examples: replacement heart valves, silicone gel-filled breast implants, implanted cerebella stimulators, and implantable pacemaker pulse generators

59. Pre-Market Approval (PMA)
Required process of scientific review to ensure the reasonable safety and effectiveness of medical devices
FDA approval required before the device can be legally marketed
510(k)
PMA
Substantial equivalence
Comparison to predicate device
Might contain clinical data
Shorter review time
Must be “Cleared” prior to marketing
Demonstration of safety and effectiveness
Valid scientific evidence
Includes clinical data
Detailed, lengthy application
Longer review time
Must be “Approved” prior to marketing

60. QUESTIONS

61. Just for Pun