Adventures in the Conduct of FDARegulated Drug and Device Clinical Investigations

1
Adventures in the Conduct of FDA-Regulated Drug
and Device Clinical Investigations
Presented by Karen Jeans, MSN, CCRN Program
Analyst, COACH
2
What This Presentation Will Cover

• Conducting research with investigational drugs
• Determining what is a drug
• Types of Investigational New Drug Applications
  (IND)
• Conducting research with investigational devices
• Significant Risk
• Non-Significant Risk
• Problem Areas for Investigators, IRBs, and
  Sponsors

3
Prologue

• FDA regulations are unlike the human research
  regulations known as the Common Rule regulations.
  This can create a lot of issues that are unique
  and yet similar to conduct of non-FDA regulated
  human research studies. Knowing what is and is
  not regulated by FDA can make your life a lot
  easier, regardless of your role.

4
What is FDA?

5
FDA Regulates Products

• Drugs, biologics, medical devices (diagnostic and
  therapeutic), foods nearly 25 of the U.S.
  economy
• FDA has responsibility for clinical
  investigations of FDA-regulated products
• Irrespective of study funding (unlike OHRP)
• Irrespective of study location within the U.S.
• Irrespective of whether for commercialization/mark
  eting or for scientific knowledge

6
It is Sometimes Hard to Figure out What FDA
Regulates
7
How Did it All Begin?

• 1937 Sulfanilamide the first wonder drug
  for strep throat and gonorrhea
• Made into Elixir of Sulfanilamide

8
Elixir of Sulfanilamide Incident

• 240 gallons shipped
• Resulted in 107 deaths
• No laws regarding safety
• Congress got involved

9
Levels of Authority at FDA

• Law Passed by Congress Governs the U.S. Public
  AND FDA
• Federal Food, Drug, and Cosmetic Act
• Regulation Promulgated by FDA to implement the
  law Carries the force of law
• Code of Federal Regulations
• Guidance FDAs best advice Alternate methods
  may be used to meet regulation
• Information Sheet Guidance for IRBs, Clinical
  Investigators, and Sponsors Significant Risk and
  NonSignificant Risk Medical Device Studies

10
Basic FDA Human Research Protections Governing
the Conduct of Clinical Investigations in Human
Subjects

• FDA regulations directed towards protection of
  human research subjects
• 21 CFR Part 50 Informed Consent
• 21 CFR Part 56 IRB Regulations
• These regulations are near-identical to the
  Common Rule which governs protection of
  subjects in federally funded research

11
Key Regulations Governing the Conduct of
Clinical Trials

• Regulations supporting FDAs unique product
  application review responsibilities and the
  Agencys broad public protection mission
• 21 CFR Part 312 IND Regulations (drug)
• 21 CFR Part 812 IDE Regulations (device)
• 21 CFR Part 314 NDA Regulations (drug)
• 21 CFR Part 814 PMA Regulations (device)
• 21 CFR Part 11 Electronic Records/Signatures
• 21 CFR Part 54 Financial Disclosure

12
What is FDA regulated research involving human
subjects?

• Definition of Clinical Investigation
• Clinical investigation means any experiment that
  involves a test article and one or more human
  participants and that is one of the following
  21 CFR 50.3(c) 21 CFR 56.102(c)
• Subject to requirements for prior submission
  to the Food and Drug Administration
• under 505(i) or 520(g) of the act.
• Not subject to requirements for prior
  submission to the Food and Drug Administration
  under these sections of the act, but the results
  of which are intended to be submitted later
  to, or held for inspection by, the Food and Drug
  Administration as part of an
• application for a research or
  marketing permit.
• Definition of Human Subject
• Individual who is or becomes a participant in
  research, either as a recipient of the test
  article or as a control (21 CFR 50.3(g)) or on
  whom or on whose specimen an investigational
  device is used or as a control. A subject may be
  in normal health or may have a medical condition
  or disease (21 CFR 812.3(p))

13
What is an investigational drug?

• A new drug or biological drug that is used in a
  clinical investigation. The term also includes a
  biological term that is used in vitro for
  diagnostic purposes. The terms investigational
  drug and investigational new drug are deemed
  to be synonymous for purposes of this part.
• 21 CFR 312.3(b)
• Overseen by
• Center for Drug Evaluation Research (CDER)
• Center for Biologics Evaluation Research (CBER)

14
Drug vs. Biological Drug

• Chemical synthesis
• Tylenol
• Ibuprofen
• Morphine
• Synthesis from living organisms
• Vaccines
• Epogen
• Insulin
• Humira

15
What Causes Trouble? Drug vs. Cosmetic

• Drug
• Articles intended for use in the diagnosis,
  cure, mitigation, treatment, or prevention of
  disease and
• Articles (other than Food) intended to affect
  the structure or function of the body of man or
  other animals
• FDC Act, Section 201(g)(1)
• Cosmetic
• Articles intended to be rubbed, poured,
  sprinkled, or sprayed on, introduced into, or
  otherwise applied to the human body . . . for
  cleaning, beautifying, promoting attractiveness,
  or altering the appearance
• FDC Act, Section 201(i)

16
Drug or Cosmetic?

• 1. Shampoo
• Skin Moisturizer
• Sunscreen lotion
• Deodorants
• Antiperspirants
• Toothpastes with fluoride
• Aromatherapy fragrances
• Collagen
• Soap

17
Why is this Important to Differentiate Drugs from
Cosmetics?

• Differences in intended uses
• Approval requirements are different
• FDA
• IRB

18
Now That Youve Figure Out it is a Drug

• Is it unapproved or approved?

19
New Unapproved Drugs

20
What is an Investigational New Drug (IND)
Application?

• Affirms a body of knowledge about the
  manufacturing, pharmacology, and toxicology of
  the drug to support its use in human testing
• Requires that the clinical investigation(s) be
  performed in accordance with Good Clinical
  Practice (GCP)
• Provides an additional level of protection
  through FDA oversight
• An IND is required when an unapproved drug or
  biologic is used in a clinical investigation

21
Common Types of INDs

• Commercial
• Noncommercial research
• Emergency
• Treatment

22
Phases of an Investigation Involving an IND

• INDs can be submitted for one or more phases
• Phase 1 Initial Introduction
• Phase 2 Dose escalation and effectiveness
• Phase 3 Safety and effectiveness to evaluate
  overall risk-benefit relationship of the drug
• Phase 4 Do not involve INDs

23

• Phase I Study of MT110 in Colorectal Cancer
  (CRC), Gastrointestinal (GI) and Lung Cancer
  (MT110-101)
• This phase I dose escalation study is intended
  to define the safety, tolerability and maximal
  tolerable dose (MTD) of MT110 in patients with
  advanced solid tumors.
• Phase II Phase II Trial of a 96-Hour Continuous
  Infusion of Paclitaxel Followed by Cisplatin for
  Patients With Stage III/IV and Relapsed NSCLC
• This is a Phase II study of paclitaxel (Taxol R)
  administered as a 96-hour (4 day) continuous
  infusion followed by a bolus of cisplatin for
  previously untreated patients with stage III/IV
  or relapsed non-small cell lung cancer (NSCLC).
  The goal of this phase II study is to determine
  the response rate of this infusional paclitaxel
  and bolus cisplatin regimen in patients with
  advanced NSCLC.
• Phase III Controlled Clinical Study of NPO-11 in
  Patients Undergoing Gastric Endoscopy
• Patients who require gastric endoscopy will
  receive an intragastric single dose of NPO-11 20
  mL. The superiority of NPO-11 to placebo as a
  premedication for endoscopy will be verified in a
  randomized, double-blind, parallel-assignment
  design based on the percentage of patients having
  no gastric peristalsis at both 2 minutes
  post-dose and the end of endoscopy (primary
  outcome measure).The safety of NPO-11 will be
  evaluated based on adverse events and adverse
  drug reactions (ADRs) observed between
  administration and seven days after
  administration in comparison with the placebo
  group.

24
New Unapproved Drugs

25
Approved Drugs The Problem

26
Marketed Drugs in Off-Label Use vs. Clinical
Investigation

• Dr. Sue Yason calls you wanting to use Botox for
  a patient in her clinic. She wants to inject
  Botox into the muscles around the right eye of a
  81-year old male patient who has severe
  migraines.
• Botox is only approved for use of treatment of
  wrinkles between the eyebrows in people ages
  18-65 years old. It has not been tested on
  people under 18 or over 65.
• She wants to know whether she needs to submit
  this to the IRB Committee or call FDA for
  permission.

27
But What If . . .

28
Is an IND always required?

• No IND is needed when an approved product is used
  in the course of medical practice (even for an
  indication different from the approved
  indication)
• But an IND may be required when an approved
  product is used in a clinical investigation

29
IND Needed?

• Five conditions for no IND needed in clinical
  investigations involving human subjects with an
  approved drug
• Not intended to support labeling change
• Not intended to support advertising change
• No significant increase in risk (administration,
  dosage, subject population)
• In compliance with FDA regulations regarding
  informed consent and Institutional Review Boards
• In compliance with FDA regulations regarding
  advertising

30
How Does One Get an IND?

• Submit an Application to FDA with 9 components
• Cover Sheet and Form FDA 1571
• Table of Contents
• Introductory Statement and General
  Investigational Plan
• Investigators Brochure
• Clinical Protocol
• Chemistry, Manufacturing and Control Information
• Pharmacology and Toxicology Information
• Previous Human Experience
• Additional Information
• 21 CFR 312.23

31
When Does the IND Go Into Effect?

• FDA notifies sponsors in writing the date it
  receives the IND application
• Receives an IND number
• 30-day rule
• Earlier notification
• Clinical hold
• 21 CFR 312.40(b)

32
What We Have Covered

• Drugs vs. Biologics
• Drugs vs. Cosmetics
• Off-Label vs. Clinical Investigations of Marketed
  Drugs
• Investigational New Drug Applications

33
The Special INDs Emergency and Treatment

• Emergency INDs are used for emergency use of a
  test article regulations
• 21 CFR 50.23,
  56.102(d), 56.104(c), 312.36
• Treatment INDs are used for treatment protocols
  or treatment IND
• 21 CFR 312.34
• Neither of these are INDs used to support
  marketing

34
Emergency IND

• Intended subject does not meet the criteria of an
  existing study protocol but meets the criteria
  for emergency use
• Manufacturer cannot make the unapproved
  investigational drug or biologic available under
  the companys IND
• FDA request by telephone or other rapid
  communication means

35
Emergency Use of an Unapproved Drug Criteria

• Emergency use of a Test Article Regulations
• Use of a test article on a human subject
• in a life-threatening situation
• no standard treatment is available
• there is not sufficient time to obtain IRB
  approval
• 21 CFR 56.102(d)

36
Emergency Use Authorization is not Emergency Use
of a Test Article
37
Human Subject Severely debilitated or
life-threatening condition Standard acceptable
treatment unavailable, and Sufficient time not
available to obtain IRB approval
IND obtained by investigator from sponsor or
authorized by FDA

Informed Consent obtained from participant
No Informed Consent can Be obtained from
participant
Written certification by investigator and
non-study participating physician or
independent determination of investigator
Test Article administered
IRB Report within 5 working days
38
FDA Regulations Usually Involved with Emergency
IND

• Emergency IND regulations
• Emergency Exemption from Prospective IRB Approval
• Exception from Informed Consent Requirements
• Targeted to Investigators
• Not to be confused with Planned Emergency
  Research (21 CFR 50.24)
• Planned Emergency Research Not Allowed by VA

39
Why Does One Need a Treatment IND?

• The investigational drug
• intended to treat a serious or immediately
  life-threatening disease
• no comparable or satisfactory alternative drug or
  other therapy available to treat that stage of
  the disease in the intended patient population
• under investigation in a controlled clinical
  trial under an IND or the clinical trials have
  been completed
• sponsor is actively pursuing marketing approval
  of the investigational drug with due diligence.
• Confusion about terminology humanitarian use
• (21 CFR 312.34(b))

40
Treatment INDs

• Require IRB approval
• Sponsor may apply for a waiver of local IRB
  review
• Protocols for one or thousands of potential
  subjects

41
Whats the Major Difference Between

• A Phase III IRB-approved protocol with a
  commercial IND
• vs.
• An IRB-approved protocol with a treatment IND?

42
Review of Three INDs

• Commercial IND
• Noncommercial Research IND
• Most Common
• Treatment IND
• Requires IRB approval
• Emergency IND
• Does not require prospective IRB approval, but
  must be reported to IRB within 5 working days
  after use

43
IRB Issues

• Does the IRB need to review the IND application?
• What is the IRBs role in validating the IND?
• What is the IRB s role in emergency use of a
  test article?

44
IRB Issues

• Does the IRB need to review the IND application?
• NO

45
IRB Issues

• What is the IRBs role in validating the IND?
• Applies to portion of AAHRPP element 1.5.A
• Policies and procedures describe how the
  organization decides whether an IND or IDE is
  required.
• When an IND or IDE is required, policies and
  procedures describe how the organization
  determines that a valid IND or IDE is present
  before approval of the research.

46
IRB Issues

• Validation of the IND
• More than making sure a number is on an IRB
  application
• Source document
• Industry-sponsored clinical trials
• Clinical Protocol
• Sponsor correspondence or e-mail
• FDA correspondence
• Investigator-initiated
• FDA correspondence
• AAHRPP does not define who or what entity must
  conduct the validation (Element 1.5.C.)

47
IRB Issues

• What is the IRB s role in emergency use of a
  test article?
• FDA regulations only require retrospective IRB
  notification
• Did the use meet the criteria for an emergency
  exemption from prospective IRB approval?
• If informed consent was not obtained, did the
  investigator meet the requirements for exception
  from informed consent requirements?

48
Summary of Drug Issues

• Drugs vs. Biologics
• Drugs vs. Cosmetics
• Off-Label vs. Clinical Investigations of Marketed
  Drugs
• IND Determinations
• Types of INDs
• Commercial
• Noncommercial
• Emergency
• Treatment
• IRB Issues related to INDs

49
Devices

• What is a medical device?A medical device is
  defined, in part, as any health care product that
  does not achieve its primary intended purposes by
  chemical action or by being metabolized. 
• What is an investigational medical device?An
  investigational medical device is one that is the
  subject of a clinical study designed to evaluate
  the effectiveness and/or safety of the device.

50
What Makes Device Studies Difficult to Conduct?

• Emergency Use
• Treatment IDE (Investigational Device Exemption)
• Significant Risk Devices
• FDA approved IDE
• Non-Significant Risk Device
• Abbreviated IDE
• Humanitarian Use Devices
• Compassionate Use
• Single patient or small group use of an
  unapproved device
• Custom Devices
• 510K

51
Types of Medical Devices

• Contact Lenses
• Tissue Adhesives
• Hemodialyzers
• Urology Catheters
• Stents
• Surgical Lasers

52
FDA Regulations for Devices

• Issues addressed by the Center for Devices and
  Radiological Health (CDRH)

53
Investigational Device Exemption (IDE
Regulations(21 CFR Part 812)

• Allows an unapproved device to be shipped for
  clinical evaluation
• Similar to IND regulations
• Identifies sections of the Act from which IDEs
  are exempt
• Identifies exempted investigations (e.g. cleared
  devices, IVDs)
• Defines Significant Risk (SR) and Non-Significant
  Risk (NSR) investigations

54
IDE Regulations(21 CFR Part 812)

• Clinical investigations undertaken to develop
  safety and effectiveness data for medical devices
  must be conducted according to the requirements
  of the IDE regulations.
• Unless exempt from the IDE regulations, an
  investigational device studies must be
  categorized as
• Significant Risk (SR) or
• Nonsignificant Risk (NSR)

55
Significant Risk (SR) Study

• Presents a potential serious risk to the health,
  safety, and welfare of a subject and is
• an implant or
• life supporting or sustaining or
• of substantial importance in diagnosing, curing,
  mitigating, or treating disease or preventing
  impairment of human health
• FDA approval required
• Examples
• Extended wear contact lenses
• Cardiac stents

56
Nonsignificant Risk Studies

• FDA approval not needed
• Not to be confused with the concept of minimal
  risk
• Examples
• Urologic catheters
• Low level biostimulation lasers
• Conventional implantable vascular access devices

57
Deciding whether a Device Investigation is SR or
NSR

• IRB written policies and procedures regarding
  device review
• Best abilities
• Information in regulations and guidelines
• Risk evaluation provided by applicant
• Reports of prior investigations
• Proposed investigational plan
• Subject selection criteria
• Monitoring procedures
• Outside assistance

58
Significant Risk or Non-Significant Risk
Investigations

• Case Example

59
Major Differences Between SR and NSR
Investigations

• SR Investigations
• Submission of an IDE application to FDA required.
  
• Study may not commence until FDA has approved the
  IDE application and the IRB has approved the
  study.
• NSR Investigations
• No submission of an IDE application to FDA
• Sponsor required to conduct the study in
  accordance with the abbreviated requirements of
  the IDE regulations
• Study may not commence until the IRB has approved
  the study.

60
IRBs Role in SR and NSR Decisions

• IRB decision
• If IRB agrees that a study is NSR, no submission
  to or review by FDA is necessary before starting
  studies in humans.
• If IRB considers the study to be SR, the sponsor
  must obtain an IDE from FDA before proceeding
  with clinical studies.
• NOT AN OPTION An IRB considers a study to be
  NSR when FDA approves an IDE for a SR device.

61
Required IRB Policies and Procedures

• When the IRB determines that an investigation
  presented for approval as involving an NSR device
  actually involves an SR device, the IRB is
  required to notify the investigator and, where
  appropriate, the sponsor.
• Written procedures for conducting its initial
  review of research.
• Written procedures for reporting its findings and
  actions to the investigator.
• Procedures for determining whether a study is SR
  or NSR should be included among the written
  procedures.

62
Key Points to Remember

• IRBs may agree or disagree with a sponsors
  initial NSR assessment.
• Risk determination should be based on the
  proposed use of the device in an investigation,
  and not on the device alone.
• Criteria for deciding if SR and NSR studies
  should be approved by the IRB are the same as for
  any other human research study.
• FDA has the ultimate decision in determining
  whether a device study is SR or NSR.

63
Summary of Device Issues

• Device Definitions
• IDE Regulations
• SR and NSR Determinations
• IRB Role in Medical Device Investigations

64
What Causes Problems for Investigators,
Institutional Review Boards, and Sponsors?

65
What Causes Problems for Investigators?

• Conducting the clinical investigation according
  to signed investigator statement and applicable
  regulations
• Obtaining informed consent
• Control of devices under investigation

66
Commonality

• Protecting the rights, safety, and welfare of
  subjects under the investigators care
• 21 CFR 312.60
• 21 CFR 812.100

67
Sponsor-Investigator Issues

• Unique to investigators holding an IND or IDE and
  assuming the sponsor function in a clinical
  investigation
• Sometimes confused with sponsor-investigators of
  studies not involving an IND or IDE

68
Key Sponsor-Investigator Issues - IND

• Some key FDA requirements in conducting
  Sponsor-Investigator research include
• Selection of research staff qualified by training
  and experience
• Commitment to personally conduct or supervise the
  investigation according to the research plan
• Selection of study monitor(s) qualified to
  monitor the progress of the project
• Maintenance of adequate records showing the
  receipt, shipment, or other disposition of the
  investigational drugs and records of
  participants case histories
• Completion of regulatory filings, including
  submission of amendments, annual and final
  reports

69
Key Sponsor-Investigator Issues IND (cont.)

• Some key FDA requirements in conducting
  Sponsor-Investigator research include
• Timely submission of reports (adverse events and
  other)
• - Written (Notify the FDA and PIs no later than
  15 days from observation)
• Serious, unexpected adverse experience
  associated with the use of the drug
• Any findings from tests in laboratory animals
  that suggest significant risk for
• human subjects
• - Telephone or facsimile reports (Notify the FDA
  no later than 7 days from observation if fatal or
  life-threatening event)
• - Other reports
• Safety information should be summarized in
  annual reports

70
Sponsor-Investigator Issues - IDE

• Some key FDA requirements in conducting
  Sponsor-Investigator research include
• Selection of research staff qualified by training
  and experience
• Commitment to personally conduct or supervise the
  investigation according to the research plan
• Selection of study monitor(s) qualified to
  monitor the progress of the project

71
Sponsor-Investigator Issues IDE (cont.)

• Some key FDA requirements in conducting
  Sponsor-Investigator research include
• Maintenance of accurate, complete and current
  records, including correspondence with the FDA,
  monitor and IRB, records on shipment and
  disposition of devices and records of
  participants case histories and exposure to the
  device
• Completion of regulatory filings, including
  amendments (supplemental applications)
• Timely submission of reports
• - Unanticipated adverse device effects (10
  working days of learning of event)
• - Progress (regular intervals, but no less than
  annually)
• - Current investigator list (6-month intervals)
• - Recall and device disposition (30 working days
  after request is made)
• - Final Report (within 30 days of completion or
  termination of investigation)

72
Key Regulatory RequirementSponsor-Investigator
Monitoring

• Two major issues
• Who can be a monitor?
• What constitutes adequate monitoring?

73
Who Can Be A Monitor?

• Applicable FDA Regulations
• A sponsor shall select a monitor qualified by
  training and experience to monitor the progress
  of the investigation.
• 21 CFR 312.53(d)
• A sponsor shall select monitors qualified by
  training and experience to monitor the
  investigational study in accordance with this
  part and other applicable FDA regulations.
• 21 CFR 812.43(d)

74
Who Can Be A Monitor?

• There is nothing in FDA regulations that states a
  sponsor-investigator cannot serve as a monitor.
• AND
• There is nothing in FDA regulations that states a
  sponsor-investigator can serve as a monitor.

75
What Constitutes Adequate Monitoring?

• No universal tool or master template policy
• Following the written procedures for monitoring
  included in the investigational plan 21 CFR
  812.25(e)
• Obtaining a signed investigator agreement from
  each participating investigator 21 CFR
  812.43(c)
• Providing investigators with the information they
  need to conduct the investigation properly (21
  CFR 812.40)
• Ensuring subjects signed an IRB-approved informed
  consent form prior to instituting study
  activities
• Device or drug accountability
• Maintaining accurate, complete, and current
  records of disposition that describe the batch
  number or code marks of any devices returned to
  the sponsor, repaired, or disposed of in other
  ways by the investigator or another person, and
  the reasons for and method of disposal 21 CFR
  812.140(b)(2)

76
Summary

• Drug Issues
• Drugs vs. Biologics
• Drugs vs. Cosmetics
• Off-Label vs. Clinical Investigations of Marketed
  Drugs
• IND Determinations
• Types of INDs
• Commercial
• Emergency
• Treatment
• IRB Issues Related to INDs

77
Summary (cont.)

• Device Issues
• Device Definitions
• IDE Regulations
• SR and NSR Determinations
• IRB Role in Medical Device Investigations
• Problem Areas for Investigators, IRBs, and
  Sponsors

78
Multiple Issues with Conducting FDA-Regulated
Research with Drugs and Devices

• Issues created by the regulations
• Issues of non-regulatory origins
• Doing whats right
• Over-interpretation of the regulations
• Treating recommendations/guidance as regulations
• Fear of litigation
• Gaps in the recommendations/regulations/guidance

79
How to Contact FDA For Questions

• 1-888-INFO-FDA (1-888-463-6332)

80
How to Contact FDA For Questions Medical Devices

• Questions about medical devices (other than GCP
  questions)
• www.fda.gov/cdrh/dsma/dsmastaf.html
• Manufacturer's assistance 800-638-2041
• Consumer assistance 888-INFO-FDA
• Questions about whether a product is subject to
  IDE regulations call 240-276-4040

81
How to Contact FDA For Questions - Drugs

• Questions about drug products (other than GCP
  questions)
• 301-827-4570
• Druginfo_at_fda.hhs.gov
• Questions about whether a product is subject to
  IND regulations call 301-827-4570

82
How to Contact FDA For Questions - Biologics

• Questions about biologics (other than GCP
  questions)
• 301-827-2000
• Octma_at_cber.fda.gov (consumer oriented)
• Matt_at_cber.fda.gov (manufacturers' assistance)
• Questions about whether a product is subject to
  IND regulations call 301-827-2000

83
How to Contact FDA For Questions Good Clinical
Practice

• E-mail gcp.questions_at_fda.hhs.gov
• Telephone [phone]
• Facsimile 301-827-1169
• Mail Food and Drug Administration Good
  Clinical Practice Program (HF-34) Parklawn
  Building, Room 14B-17 5600 Fishers Lane,
  Rockville, MD 20857

84
QUESTIONS