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US Medical Device Regulations > Clinical Trials (Ch. 3) > Flashcards

Clinical Trials (Ch. 3) Flashcards

1
Q

What is the purpose of clinical trials?

A

To assess whether a new drug, biologic, or medical device provides a safe and effective way to treat, prevent, or diagnose a disease in a particular patient population

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2
Q

What does GCP stand for?

A

GCP: Good Clinical Practice

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3
Q

What is the definition of GCP?

A

GCP: Good Clinical Practice
An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.

(Also: Regulations and requirements with which clinical studies must comply; these apply to manufacturers, sponsors, clinical investigators, and IRB’s)

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4
Q

What is 21 CFR Part 11?

A

21 CFR Part 11: Electronic Records, Electronic Signatures

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5
Q

What is 21 CFR Part 50?

A

21 CFR Part 50: Protection of Human Subjects (Informed Consent)

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6
Q

What is 21 CFR Part 54?

A

21 CFR Part 54: Financial Disclosure by Clinical Investigators

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7
Q

What is 21 CFR Part 56?

A

21 CFR Part 56: Institutional Review Boards

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8
Q

What GCP standard is applicable to drugs and biologics?

A

ICH E6(R2) Good Clinical Practice Guideline

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9
Q

What is the purpose of following GCPs?

A

Ensures human subjects’ rights, safety, confidentiality, and well-being are protected during clinical research; defines the roles and responsibilities of the different groups involved in clinical research

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10
Q

What GCP standard is applicable to medical devices?

A

ISO 14155:2020 - Clinical investigation of medical devices for human subjects - Good clinical practices

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11
Q

What is ISO 14155?

A

ISO 14155:2020 - Clinical investigation of medical devices for human subjects - Good clinical practices

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12
Q

What is ICH E6(R2)?

A

ICH E6(R2) Good Clinical Practice Guideline

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13
Q

What is the significance of the Pure Food and Drug Act (1906)?

A

Pure Food and Drug Act (1906):

  • Prohibited the manufacturing and interstate shipment of adulterated drugs or foods in the US
  • All products must have proper labeling and list all ingredients (cannot be misbranded)
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14
Q

What is the significance of the Food, Drug, and Cosmetic Act (FD&C Act) (1938)?

A

Food, Drug, and Cosmetic Act (FD&C Act) (1938):

  • Revised the misbranding standard for therapeutic claims
  • Changed the definition of misleading from “false and fraudulent” to “false or misleading in any particular”
  • Required drug labels with adequate directions for safe use
  • Introduced the NDA premarket review process
  • The drug must be safe before it can be marketed
  • Provided an initial definition of medical devices, with some problematic overlap with drugs
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15
Q

What is the significance of the National Research Act (1974)?

A

National Research Act (1974):

  • Authorized federal agencies to develop human research regulations for government-funded research involving human subjects
  • Required the development of IRBs for the protection of human research subjects
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16
Q

What is the significance of the Medical Device Amendments (1976)?

A

Medical Device Amendments (1976):

  • Established premarket requirements for Class III devices
  • Established the 510(k) process
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17
Q

What is the significance of the Belmont Report (1979)?

A 
Belmont Report (1979):
- Report released by the National Commission establishing ethical principles for research in human subjects
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18
Q

What is the significance of the Common Rule (1981-1991)?

A

Common Rule (1981-1991):

  • Department of Health and Human Services (HHS) issued regulations based on the Belmont Report and Code of Federal Regulations (CFR), 45 CFR (public welfare) Part 46 (protection of human subjects) to protect human subjects
  • In 1991: core DHHS regulations (45 CFR 46 Subpart A) were adopted formally by more than 17 departments and agencies
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19
Q

What is the significance of the Safe Medical Devices Act (1990)?

A

Safe Medical Devices Act (SMDA) (1990):

  • Established quality system and postmarket surveillance requirements
  • Provided discretion on PMA panel review
  • Clarified Humanitarian Use Devices (HUD) for HDE applications - not required to contain the results of clinical effectiveness investigations
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20
Q

What is the significance of the Food and Drug Administration Modernization Act (FDAMA) (1997)?

A

Food and Drug Administration Modernization Ac (FDAMA) (1997):

  • Established the Biologics License Application and harmonized it with the New Drug Application
  • Exempted most Class I and some Class II devices from the 510(k) process, reducing clinical trial requirements
  • Established the “least burdensome” approach provision
  • Improved dispute resolution and mandated interested parties’ free and open participation
  • Enabled evaluation of automatic Class III designation, allowing sponsors to request lower classification in cases of minimal risk (de novo review)
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21
Q

What is the significance of the Medical Device User Fee and Modernization Act (MDUFMA) (2002)?

A

Medical Device User Fee and Modernization Act (MDUFMA) (2002):

  • Established a fee schedule for most device submission types to achieve shorter review times
  • Requires the FDA to include pediatric experts on the panel for a product intended for pediatric use
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22
Q

What is the significance of the Medical Device User Fee and Stabilization Act (2005)?

A

Medical Device User Fee and Stabilization Act (2005):

- Amended MDUFMA to limit the provision to reprocess single-use devices (SUDs) and the manufacturers who reprocess them

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23
Q

What is the significance of the Food and Drug Administration Amendments Act (FDAAA) (2007)?

A

Food and Drug Administration Amendments Act (FDAAA) (2007):

  • Required all clinical trials (except Phase 1) to be registered in the clinical trial registry databank (clinicaltrials.gov)
  • Required results from clinical trials that serve as the basis for efficacy claims and postmarketing studies to be posted on clinicaltrials.gov
  • Reauthorized PDUFA
  • Reauthorized and expanded MDUFMA
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24
Q

What is the Hippocratic Oath?

A

An oath taken traditionally by physicians, the primary tenet is to cause no harm to the patient

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25
Q

What is the significance of Sulfanilamide elixir?

A

Sulfanilamide Elixir Public Health Emergency (1937):

  • S.E. Massengill Company
  • Treatment for strep was dissolved in sulfanilamide, a toxic chemical
  • Not tested for safety or toxicity
  • Led to 105 deaths
  • Led to the FD&C Act in 1938 (to show a drug was safe)
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26
Q

What is the Nuremberg Code?

A
  • A result of WWII and Holocaust atrocities

- Lists 10 basic moral, ethical, and legal principles for human medical research

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27
Q

What are the 10 points of the Nuremberg Code?

A
  1. Voluntary consent
  2. Beneficial to society
  3. Based on preclinical animal study
  4. Avoid all unnecessary suffering/injury
  5. Research should not be conducted when there is reason to believe death or a disabling injury will occur.
  6. Risk must be minimized
  7. Proper preparations and adequate facilities
  8. Conducted only by scientifically qualified persons
  9. Subjects can end their participation
  10. Research should be terminated if, at any time, continuation is likely to result in subject injury, disability, or death
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28
Q

What is the Declaration of Helsinki?

A
  • Created in 1964 by the World Medical Association (WMA)
  • Ethical principles for medical research involving human subjects
  • Not a legally binding document itself, but has been incorporated into regulations throughout the world
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29
Q

What are the sections of the Declaration of Helsinki?

A
  1. Preamble
  2. General Principles
  3. Risks, Burdens, and Benefits
  4. Vulnerable Groups and Individuals
  5. Scientific Requirements and Research Protocols
  6. Research Ethics Committees
  7. Privacy and Confidentiality
  8. Informed Consent
  9. Use of Placebo
  10. Post-Trial Provisions
  11. Research Registration and Publication and Dissemination of Results
  12. Unproven Interventions in Clinical Practices
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30
Q

The National Research Act (1974) developed what offices/departments?

A
  1. US Office for Human Research Protection (OHRP)

2. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

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31
Q

What was the significance of the Dalkon Shield IUD incident?

A

Dalkon Shield IUD Public Health Incident (1970-1976):

  • Caused 11 deaths / 209 miscarriages
  • Led to Medical Device Amendments (MDA) of 1976
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32
Q

What was the significance of the Cooper Report?

A

Cooper Report:

  • By the Cooper Commission
  • Analysis of medical devices on the market
  • Called for improvements in the definition of medical device and premarket requirements
  • Led to Medical Device Amendments (MDA) of 1976
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33
Q

What is the Belmont Report?

A
  • Released in 1979 by National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (result of National Research Act)
  • Establishes principles for human subjects’ research
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34
Q

What are the three basic ethical principles outlined in the Belmont Report?

A
  1. Respect for Persons
  2. Beneficence (the moral obligation to act for the benefit of others)
  3. Justice
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35
Q

What is the Common Rule?

A

A federal policy regarding Human Subjects Protection that applies to 17 Federal agencies and offices

36
Q

What is the Common Rule regulation?

A

45 CFR 46,

45 (public welfare) CFR 46 (protection of human subjects)

37
Q

What are the Common Rule subparts?

A

Subpart A: core requirements
(additional subparts for vulnerable populations)
Subpart B: pregnant women, human fetuses, and neonates
Subpart C: prisoners
Subpart D: children

38
Q

What are the International ethical guidelines for health-related research involving humans?

A
  • Created in 1993 by CIOMS and WHO
  • Revised in 2002, 2016
  • An international ethics guideline for biomedical research, with special attention on protecting subjects’ rights in developing countries
39
Q

What does CIOMS stand for?

A

CIOMS: Council for International Organizations of Medical Science

40
Q

What does WHO stand for?

A

WHO: World Health Organization

41
Q

What does ICH stand for?

A

ICH: International Council for Harmonization

42
Q

What are the four phases of (drug and biologic) clinical trials?

A 
(Preclinical)
Phase 1: "First-in-human" 
Phase 2: 
Phase 3: Pivotal
Phase 4: Postmarketing
43
Q

What does IND stand for?

A

IND: Investigational New Drug

44
Q

What does FIH stand for?

A

FIH: first-in-humans

45
Q

What information is collected during the Preclinical Phase?

A

Data from animal research to collect efficacy, toxicology, and pharmacokinetic info

46
Q

How many people typically participate in a Phase 1 clinical trial?

A

Phase 1
Study Participants:
20-100 healthy volunteers
(unless the treatment would make healthy people sick, then the patient population will be used, e.g. cancer patients)

47
Q

How long do Phase 1 clinical trials typically last?

A

Phase 1

Length of Study: Several months

48
Q

What is the purpose of Phase 1 clinical trials?

A

Phase 1
Purpose: Safety and dosage; to evaluate the product’s action, determine a safe dosage range, identify side effects, and gain early effectiveness evidence

49
Q

How many people typically participate in a Phase 2 clinical trial?

A

Phase 2
Study Participants:
Up to several hundred people with the disease/condition (the patient population)

50
Q

How long do Phase 2 clinical trials typically last?

A

Phase 2
Length of Study:
Several months to 2 years

51
Q

What is the purpose of Phase 2 clinical trials?

A

Phase 2

Purpose: Efficacy and side effects, further evaluate safety

52
Q

How many people typically participate in a Phase 3 clinical trial?

A

Phase 3
Study Participants:
300 - 3,000 people who have the disease/condition (the patient population)

53
Q

How long do Phase 3 clinical trials typically last?

A

Phase 3

Length of Study: 1 to 4 years

54
Q

What is the purpose of Phase 3 clinical trials?

A

Phase 3
Purpose: Efficacy and monitoring of adverse reactions; confirm effectiveness of the treatment, monitor side effects, compare it to commonly used treatments, and safety info

55
Q

How many people typically participate in a Phase 4 clinical trial?

A

Phase 4

Study Participants: Several thousand people with the disease/condition (the approved patient population)

56
Q

What is the purpose of Phase 4 clinical trials?

A

Phase 4
Purpose:
Safety and efficacy; gather information on the drug’s effect in various populations and any side effects of long-term use
(after the drug has been approved by FDA during Post-Market Safety Monitoring)

57
Q

What is the definition of a protocol?

A

A document that describes the background, rationale, objectives, design, methodology, statistical considerations, and organization of a clinical research project

58
Q

What information must be included in a protocol (for drug/biologic studies)?

A
  1. STUDY OBJECTIVES: Statement of the study’s objectives and purpose
  2. INVESTIGATOR, FACILITY, AND IRB INFO: a. The name and address and a statement of qualification for each investigator, b. name of each sub-investigator, c. name and address of the research facilities to be used, and d. the name and address of each IRB reviewing the study
  3. SELECTION CRITERIA: a. The subject selection criteria (inclusion and exclusion criteria) and b. the estimated number of subjects to be enrolled in the study
  4. STUDY DESIGN: The study design, including the control group type to be used (if any) and a description of the methods to be used to minimize bias (e.g. blinding)
  5. DRUG DOSAGE: a. The method for determining the dose to be administered, b. the planned maximum dosage, and c. the duration of each subject’s exposure to the drug/biologic
  6. TRIAL MEASUREMENTS: A description of the observations and measurements to be made during the study
  7. METHOD OF TRIAL MEASUREMENTS: A description of clinical procedures, laboratory tests, or other measures taken to monitor the drug’s effects on the subjects and to minimize risk
59
Q

When does a protocol for a drug/biologic trial need to be submitted to the FDA?

A

Prior to starting the clinical trial

60
Q

When does a protocol amendment need to be submitted?

A

Any changes that affect subject safety significantly (Phase 1), or any changes that significantly affect subject safety, scope of the investigation, or the study’s scientific quality (Phase 2 or 3)

61
Q

When can a protocol amendment be implemented?

A

After (1) the amendment has been submitted to the FDA for review and (2) the IRB has approved the change

62
Q

What are examples of study changes that would require a protocol amendment to be submitted?

A
  1. Increase in dosage or duration of exposure of individual subjects to the drug or biologic, or a significant increase in the number of subjects to be enrolled in the study
  2. Significant study design change (adding or dropping a control group)
  3. Adding a new test or procedure to improve monitoring for, or reduce the risk of, a side effect or adverse event, or dropping a test intended to monitor subject safety
  4. A new investigator added to a previously submitted protocol
63
Q

Is informed consent for a study required?

A

Yes - except in limited circumstances like life-threatening situations, military operations, or public health emergencies

64
Q

What does ICF stand for?

A

ICF: informed consent form

65
Q

True/False: The consent process occurs throughout the trial.

A

True - Additional information may need to be given to the subject, and the subject may need additional opportunities to ask questions and receive answers.

66
Q

What is the purpose of the ICF (Informed Consent Form)?

A
  • Ensures the subject is presented with the required information about the drug/biologic or trial
  • Allows the subject to make an informed decision about participating
  • Provides the subject with a reminder of the trial’s elements, as well as contact info
  • Documents the subject’s voluntary agreement to participate
67
Q

Who is responsible for ensuring that the informed consent process is adequate?

A

All parties involved in the clinical research - sponsors or CROs, IRB’s, and clinical investigators

68
Q

What are the 8 required elements of an ICF?

A
  1. Description of the clinical investigation
  2. Risks and discomforts
  3. Benefits
  4. Alternate procedures or treatments
  5. Confidentiality
  6. Compensation and medical treatment in the event of injury
  7. Contacts
  8. Voluntary participation
69
Q

Who is responsible for protecting subjects’ rights, safety and welfare during a clinical investigation, and for ensuring an ICF is obtained from each subject prior to participation?

A

Clinical investigator

70
Q

What does IRB stand for?

A

IRB: Institutional Review Board, or Independent Review Board

71
Q

What is the definition of an IRB under FDA regulations?

A

An appropriately constituted group formally designated to review and monitor biomedical research involving human subjects to ensure subjects’ rights and welfare are protected

72
Q

What are the three types of IRB review?

A
  1. Exempt from IRB Review
  2. Expedited review
  3. Full board (convened) review
73
Q

What is expedited IRB review?

A

A procedure through which certain types of research may be reviewed and approved without convening an IRB meeting (permitted if the research involves no more than minimal risk)

74
Q

What are examples of an expedited IRB review process?

A
  • Research where an IND is not required
  • Collecting blood samples in normal means
  • To review minor changes to previously approved research
75
Q

What is an exemption from the IRB review?

A

An exemption from the IRB review requirement is permitted for one emergency use of a test article in an institution, if the product’s emergency use is reported to the IRB within 5 working days

76
Q

What is a waiver provision?

A

The FDA may waive any of the IRB requirements for specific research activities, used when alternative mechanisms are available to ensure human subjects’ rights and welfare protection

77
Q

What is an example of a waiver provision?

A

When a sponsor wishes to conduct a foreign clinical study under an IND, when an IEC following GCP would be used instead

78
Q

What does IEC stand for?

A

IEC: Independent Ethics Committee

79
Q

What are the two types of FDA inspections of IRBs?

A
  1. Surveillance Inspections

2. Directed Inspections

80
Q

What is a surveillance inspection (of an IRB)?

A

Periodic, scheduled inspections to review the IRB’s overall operations and procedures

81
Q

What is a directed inspection (of an IRB)?

A

Unscheduled inspections focused on the IRB’s review of a specific clinical trial
(Generally resulting from a complaint, clinical investigator misconduct, or safety issue)

82
Q

What type of information does the FDA review during an IRB inspection?

A
  • IRB membership records
  • IRB procedures and guidelines
  • IRB meeting minutes (for the past year)
  • Clinical investigator study documents sent to the IRB
  • IRB study documents sent to the clinical investigator
  • Other study materials
83
Q

What type of form will be issued to the IRB if findings are found during the inspection?

A

Form FDA 483 - inspectional observations

84
Q

What does EIR stand for?

A

EIR: Establishment Inspection Report

85
Q

What are the three types of letters that can be sent to the IRB from the FDA following an inspection/review?

A
  1. Letter stating there are no significant deviations
  2. Informational or Untitled Letter - identifies deviations where voluntary corrective action is sufficient
  3. Warning letter - identifies serious deviations and requests prompt corrective action
86
Q

What are examples of administrative actions that the FDA can take against IRBs?

A
  • Withholding approval of new studies conducted at the institution or reviewed by the IRB
  • Directing that no new subjects be added to ongoing studies
  • Terminating ongoing studies (when doing so would no endanger the subjects)
  • Notifying relevant state/federal regulatory agencies, in instances when the non-compliance creates a significant threat to human subjects’ rights and welfare
87
Q

What was the Coast IRB letter incident in 2009?

A

The GAO created a fake clinical trial for a fake product, and sent it to 3 IRBs. The Coast IRB approved the study, and the FDA gave a warning letter for failing to ensure basic elements of the trial, minimize safety risks, etc. The IRB closed a few weeks later.

US Medical Device Regulations (11 decks)

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