ETHICAL

CONSIDERATIONS &
ISSUES

Dr. N. SRINIVAS
ICRI

1
 ETHICAL
CONSIDERATIONS &
ISSUES
 Individuals involved in ethical issues

 Ethical considerations related to CT design

 Ethical considerations in protocol development

 Ethical considerations in conducting a clinical

trial

2
 Individuals involved in ethical
issues
 Investigators
Notify any relevant findings- revised ICF

 IRB/IEC (21CFR 56)

 Investigator’s staff – protocol violations

 Staff of the institution who will participate in the

clinical trial – Diagnosis & Bioanalysis
 Cont…
 Staff at the sponsoring institution – site selection,
monitoring visits PISV, SIV, SCV, data analysis,
publications, interaction among players

 The regulatory agency

 Patient / guardian- Inform alternate treatment

 Press & other media

 Clinical Research Contractors

 Ethical considerations related to
CT design
 Is there a need for the clinical trial – sponsor has
right & obligation to terminate CT.

 Is it ethical to include a placebo treatment group –

use of alternate medicine if available.

 Choice of an marketed active control

 Has the clinical trial eliminated obvious bias and

deception – Types of deception – approval by IRB-
ICF- stress reduction by oxprenolol
 Cont…
 Has sufficient attention been given to
sample size – False +\- results

 Is the statistical power of a trial

adequate to show an effect if it is
present

 Are the patient’s chances of receiving

an active medicine acceptable
 Cont…

 What is the safety of patients

entered in to clinical trials?

Normal volunteers versus patients

 Cont…
 What types of patients are to be entered
in to a clinical trial?
 Volunteers
versus patients – antiepileptics/
enzyme induction/ expected toxicity

 Inpatients versus out patients

 Types or groups of pts who require special

consideration – who are unable to protect
their own rights.
 Ethical considerations in protocol
development
1. Inclusion/ exclusion criteria

 Sex of the patient

 Age of the patient

 Pregnancy & lactation

 Sensitivity to a trial medicine

 Cont…
 Concomitant / Add-on medicines : Monotherapy
as favorable CT data becomes available

 Previous medicine & non medicine treatment

 Wash out period of non trial medicines – while

shifting treatments don’t consider data till WoP.

 History of other diseases – include after initial

safety & DI profile is obtained – Risk/ Benefit.
 Cont…
 Present clinical status – unrelated stable or
unstable disease- severity of trial related illness

 Participation in another medicine trial

 Institutional or environmental status (coerced for

ICF)

 Occupation

 Litigation – secondary gain if no improvement with

IP
 Cont…
2. Choice of efficacy parameters-
Resources
3. Individuals conducting the tests –
competency in patient care, collection,
analysis, data interpretation

4. Choice of safety parameters- assess risk

& exclude patients at high risk
5. Modifying dosing schedules as per
protocol - Feasibility
 Cont…
6. compliance

7. Patients lost to follow up

8. Pts discontinued from clinical trial –

rechallenged with medicine-- ICF

9. Early trial discontinuation

 Cont…

10.Medical emergencies – overdose/ SAE

11.Amount of data to collect

12.Instructions for pts, investigators & trial

personnel
 Cont…

13.Continuation protocols

14.Large multicenter trials

15.Confidentiality of the data

 Ethical considerations in
conducting a clinical trial
1. Recruiting & screening pts for a
clinical trial- phase of trial- monetary
inducement Vs charging in
Treatment IND

1. Providing information to referring

physicians

2. Protocol violations
 Cont…

4. Conducting a clinical trial in

developed countries

5. Conducting clinical trial in developing

countries- exploitation, marketing of
IP in country or patients / IP not used
in area like oral contros.
19
20
21
22
 Regulatory
Inspections of
Clinical Trials

23
 Inspections…

 How does the FDA inspector prepare to inspect?

 How can you be prepared?
 How should you act during the inspection?
 How should you respond post-inspection?
 Local Strange but True!

24
 Inspection

 The inspection is defined as an Act by

Regulatory Agency of conducting an official
review of documents, facilities, records and any
other resources.
 Verification of compliance with GCP and need to
subject data, information and documents to
inspection in order to confirm that they have
been properly generated, recorded and reported
is essential.

25
 What are the results of inspection?

 To provide evidence of official supervision.

 To raise international confidence in the standards.
 To assure that the methods employed in the
generation of data are scientifically valid and
ethically appropriate and that they yield accurate
and reproducible data.
 Mutual recognition of CR data generated in different
areas of the world reducing risk and unnecessary
duplication of research.
 To accelerate global drug development.
26
 Contd..

 Identifies a need for corrective and preventive

follow-up action.
 Quality improvements should be seen as a long-
term and valued by-product of inspection.
 Educative process that aids harmonisation.

27
 How FDA Trains Inspectors

 Get Technical - Read x-rays, ECGs, lab results

 Fill in the Blanks - Question missing dates, times,
information, offer to retrieve records yourself
 Be suspicious of blame shifting - tell CI he/she is
totally responsible for the conduct of the study
 Expect Fraud - Start from the assumption the records
are bogus and the study is a fraud, and work back
 Cultivate Whistleblowers - establish rapport with
study staff, be approachable and available, listen to
grievances, observe working conditions

28
 FDA Inspections of Investigators

Purpose:
 Determine that the rights, safety and welfare of
subjects have properly been protected
 Assess adherence to FDA regulations and statutory
requirements
 Determine quality and integrity of data submitted in
support of products pending FDA approval
The inspectors are employed by the Bioresearch
Monitoring Division as opposed to the persons who
give approval to do the study and who approve the
PMA for market release
29
 Permitting FDA Inspections:
Investigators and Sponsors
 Regulations require that sponsors and investigators
grant access to authorized FDA employees
 Any location where devices are manufactured, processed, packed,
installed, used or implanted or where records of use/results are kept )

 Records Inspection -
Sponsor, IRB, Investigator (or anyone acting on their behalf)
will permit authorized FDA employees to inspect & copy all
records relating to an investigation.

30
 FDA Inspections of Investigators

Two types of inspections:

 Routine Surveillance
 Occur after Premarket Approval (PMA) / New
Drug Application (NDA) submitted
 “For Cause”
 Suspicion of wrong doing, complaints,
termination of a site, etc.

31
 Reasons for Inspecting an Investigator
Could Include:

 The investigator is doing a large volume of work

 Gaps in IRB approvals and/or IRB suspension
 The investigator has done work outside of his/her field
of specialty
 The investigator reports substantially superior efficacy
for a device when compared to data generated by other
investigators studying the same device
 The investigator reports no severe or few adverse
effects when other investigators report numerous
adverse effects of a given type

32
 Reasons for Inspecting an Investigator
Could Include Cont..:
 The investigator seems to have too many patients with a
given disease for the locale or setting in which he/she
practices
 The investigator reports results showing a lack of visit-to-visit
variability or which are inconsistent with results submitted by
other investigators
 Suspicion of fraud or scientific misconduct
 Serious quality systems break down noticed by RA.
 Major public health implications result in legal action.
 Collection of legal admissible evidence.

33
Investigator Deficiencies: FY 2000-2004

Reference: “Building Quality into Device Clinical Trials”,

34
Medical Alley, April 20, 2005
IRB Deficiencies: FY 2000-2004

Reference: “Building Quality into Device Clinical Trials”,

35
Medical Alley, April 20, 2005
 Complaints:
“Allegations of Research Misconduct”

41 41

15
9

Reference: “Building Quality into Device Clinical Trials”,

36
Medical Alley, April 20, 2005
 Preparing for Inspection

 Ensure all site personnel are trained prior to study

start
 Discuss potential for inspection and what to expect
 Notify appropriate interested parties immediately if
contacted
 Assess the site
 Discuss potential issues
 Identify work space for inspector

37
 When the FDA calls for Inspection:

• Schedule the inspection as soon as possible after

being called by the FDA investigator. Generally
the inspection is requested/scheduled within a few
business days to a week of the call

• When confirming the appointment, request

information on the reason for the inspection and
any special areas to be emphasized during the
inspection

38
 Conduct of Inspection

 Identify the primary contact person for inspection

 Upon arrival, the FDA investigator MUST present credentials
and issue a Notice of Inspection, Form FDA-482
 The inspector’s name and credentials numbers should be
obtained and documented.
 The Investigator and/or primary contact person should
arrange for and attend all interviews conducted by the FDA
investigator
 Escort the FDA Inspector to a designated work area and
escort throughout inspection
 Establish a schedule for the visit

39
 Conduct of Inspection cont.

Interview Guidelines:
 Do not engage in conversation unless asked a direct
question
 Restrict statements to answering those questions
asked by the FDA Investigator
 Do not provide excuses or shift blame (either on previous
employees, staff members, IRB)
 Do not guess at answers – If uncertain of correct answer,
obtain the correct information and provide to the FDA
Investigator
 Do not answer questions which lie outside the authority
of the Inspector (sales data, personnel information
relating to salaries, performance reviews, etc.)
40
 Conduct of Inspection: Interview
Guidelines cont.

 Be responsive and cooperative, but do not volunteer

information
 Should a question be unclear—clarify!!
 Should a question or request seem unreasonable,
state your objection
 The FDA keeps notes on everything you state, make
sure it is the truth
 FDA will ask you and/or others similar questions
multiple times to ensure similar response

41
 Conduct of Inspection cont.

 Generally, inspections follow the format

established in FDA’s Compliance Program
Guidance Manual 7348.811.
 Make certain that all documents are current and
immediately accessible. Since the inspector(s)
will want to review source documentation, notify
your medical record departments of the
scheduled inspection so medical records will be
easily accessible.

42
 Conduct of Inspection cont.

 Provide requested copies of documents and stamp

confidential (keep extra copy as a reference)
 Maintain notes of requests/questions of the
Investigator during the inspection
 FDA will request a list of other study/research
projects that the investigator is involved
 Clarify any misunderstandings or confusion as
soon as possible

43
 Conduct of Inspection cont.

 Areas to be addressed will include:

 Identify who is responsible for various tasks, examples:
 Who verified eligibility criteria
 Who obtained informed consent
 Who collected adverse event data
 Determine degree authority is delegated to other staff
members-how the investigator supervised the conduct of
the trial

44
Finding from a 2003 Warning Letter to an investigator:

“…Delegating work to research staff does not

relieve you of the responsibility to supervise
the clinical investigation. You are responsible
for the accuracy and completeness of the
study records and for any discrepancies found
in the records.”

45
 Conduct of Inspection cont.

 What the IRB reporting/communication requirements

are (e.g.: specific adverse event and protocol
deviation reporting)?
 What is your process for informed consent?

46
Findings from a 2002 Warning Letter an Investigator:

“You failed to ensure that legally effective informed

consent was obtained. For example, study subjects
with randomization numbers X through Y signed a
wrong version of the consent form.”

47
 Conduct of Inspection cont.

 How, when, and where study data/activities is

collected/performed
 How investigational product is accounted for and
controlled (whether or not devices are “on the shelf”
or not)
 Monitor’s communications with the clinical
investigator
 The monitor’s evaluations of the progress of the
investigation

48
 Study Documents Required for the
Inspection Will Include:

1) Reports of unanticipated adverse events/serious

adverse events reported to IRB and sponsor
2) Your IRB’s SOPs for AE/Protocol Deviations
3) All IRB approvals, including all approved versions of
informed consent
4) Progress reports to the IRB
5) Clinical Investigation Plan/protocol (all versions) and
Case Report Forms
6) Investigator Agreement/1572 and CVs

49
 Study Documents Required for the
Inspection Will include cont.
7) Training records of all site personnel involved in
trial
8) Source documents for CRF entries, prior medical
history, condition of the subject at the time of
entry into study, meds, if required by study,
laboratory reports, and any special testing per
protocol.
9) Documentation for any correction to CRFs
10) All correspondence, records, & reports
11) Investigational device/drug accountability

50
Finding from a 2003 Warning Letter to an investigator:

“In addition to the failure to use the device control

documents required by the investigational plan, you
failed to prepare and maintain accurate, complete,
and current device accountability records, as
required by 21 CFR 812.140(a)(2). Specifically,
records of investigational devices returned to the
sponsor contained inaccurate information regarding lot
numbers and quantities.”

51
Finding from a 2003 Warning Letter to an investigator:

“You failed to fulfill your device control responsibilities under the

investigational plan. You did not ensure that the
investigational devices were maintained under
controlled access storage. The devices were received by
hospital staff not part of the clinical investigation…personnel
who were not clinical study staff …had keys to the storage
area where devices were kept…”

52
 What Happens After an Inspection?

 FDA Investigator will conduct exit interview

 Will discuss findings => issue a written Form FDA 483
(Inspectional Observations)
 Clarify any questions/confusion
 Investigator may respond verbally during exit interview
and/or respond in writing (strongly recommended to
respond in writing)
 Be accountable to issues; have a corrective action plan!
 Direct responses to FDA District Office in upper left corner
of 483

53
 What Happens After an Inspection cont:

 Inspector prepares detailed report called Established Inspection

Report (EIR)
 EIR, 483 (if applicable), copies of all materials collected during
inspection, any responses from Investigator are forwarded to
the FDA Center
 FDA Center evaluates information

54
 Evaluation to Classify and Mail
Prompt Letter to Investigator

 NAI – No Action Indicated

 A letter that generally states that the FDA observed no
significant deviations from regulations. Letter may not
actually be sent all the time
 VAI – Voluntary Action Indicated (483)
– An informational or untitled letter identifies deviations from
statutes and regulations for which voluntary corrective action
is sufficient (unless otherwise specified)

55
 Evaluation to Classify and May
Prompt Letter to Investigator cont.

 OAI – Official Action Indicated (Warning letter)

 A Warning Letter identifies serious deviations from statutes and
regulations. A Warning Letter generally requests prompt
corrective action by the clinical investigator and formal written
response to the agency (FDA).

56
 Investigator Non-Compliance

 FDA may disclose to Sponsors and IRBs records indicating

violation or potential violation by investigator that is
conducting or has conducted studies
 Besides issuing letters, FDA may take other administrative
action against investigator
 May initiate process of disqualifying an investigator from
receiving investigational product or research if he/she has:
 Repeatedly or deliberately violated FDA regulations
 Submitted false information to the Sponsor or FDA

57
 In Conclusion….

 The best preparation for an FDA inspection is close adherence

to the Clinical Investigational Plan/protocol and FDA regulations
 Particular attention should be paid to documentation of:
 medical histories
 adverse events/deviations
 receipt and disposition of investigational product
 documentation of informed consent process
 training
 The importance of orderly, accurate records can not be
underestimated!!

58
483 Finding from a 1999 Investigator Inspection:

“Consent form contained unapproved whiteout where

subject’s signature appears.”

483 Finding from a 1995 Investigator Inspection:

“Several instances of data being scratched out

(obliterated) rather than lined out were noted. One
instance of liquid paper being used to correct data
was noted”

59
 Spectrum of QA Metrics

Human
Short cuts
Errors
Deliberate invention
Exaggeration
Carelessness

NEGLIGENCE FRAUD

60
 Strange but True!
 Site evaluation report prepared after the site has started
enrolment
 Basic study requirements not assessed during site
evaluation
 Site staff CVs never updated during the course of study
 Non validated labs used for study purposes
 Back dated signature and data filling on FDA forms
 Ethics committee approval was taken from first site for
the other site without prior documentation and
willingness of the second site for the same
61
 Strange but True!
 Ethics Committee chairman signature forged by study
personnel
 Wrong version of ICD and protocols approved by the
Ethics Committee
 Wrong version of ICD translations was signed by study
patients
 ICD signed by site personnel in back dates
 Source documents re written and original thrown away
 Lab reports made to avoid late A/E reporting or cover
protocol violations in back dates
 Site transfused blood to enroll a patient on study
62
 Strange but True!
 Monitoring and contact reports prepared in one sitting for last 4-6
months
 Monitoring report not reviewed
 Country and site files prepared near the end of the study
 Destruction of CTM before audit to avoid accountability of
discrepancies
 Filling of patient’s diary by site staff
 Preparation of Temperature logs of last 4 months in one day
 Attachment of fake service and maintenance contracts by site staff

63
"The bitterness of poor quality
remains long after the
sweetness of meeting the
deadline has been forgotten”

64