Generic Non-Interventional Study (NIS) Training slides with a UK focus

1. NON-INTERVENTIONAL STUDIES?
What are they?
How do they differ from Clinical Trials?
Stuart McCully, PhD
16th January 2011

2. DISCLAIMER
Although this material contains information of a legal nature, it
has been developed for informational purposes only and does
not constitute legal advice or opinions as to the current
operative laws, regulations, or guidelines of any jurisdiction. In
addition, because new standards are issued on a continuing
basis, this training material is not an exhaustive source of all
current applicable laws, regulations, and guidelines relating to
clinical research. While reasonable efforts have been made to
assure the accuracy and completeness of the information
provided, researchers and other individuals should check with
local authorities and/or research ethics committees before
starting clinical research activities

3. Topics Covered
1. Introduction: A Snapshot of Key Events a. The Nazi Medical Experiments
b. The Nuremberg Code and the Declaration of
Helsinki
c. The Tuskegee Syphilis (Observational) Study
d. Ethical Principles in Biomedical Research
2. Clinical Research: Clinical Trials vs NIS a. Research or Audit/Service Evaluation?
b. Research: Interventional or Non-Interventional?
c. What is a Clinical Trial?
d. The Regulatory Framework: Clinical Trials
e. The Regulatory Framework: NIS
f. What is a Non-Interventional Study?
g. Country-Specific Regulation of NIS: UK
h. How and Why are they Different?
i. “GCP-lite”
j. Ethical Principles in NIS
k. The Principle of Observation

4. Feel Free to Ask Questions...

5. Introduction: A Snapshot of Key Events
• Nazi Medical Experiments
• Nuremberg Code
• Declaration of Helsinki
• The Tuskegee Syphilis Study
• Ethical Principles

6. The Nazi Medical Experiments
• Experiments on twins
• Freezing experiments
• Malaria experiments
• Mustard gas experiments
• Sulfonamide experiments
• Sea water experiments
• Sterilization experiments
• Experiments with poison
• Incendiary bomb
experiments
• High altitude experiments

7. The Nuremberg Code (1947) & The Declaration
of Helsinki (1964)
• Voluntary consent is absolutely essential
• Studies should be based on good science
• The benefit should outweigh the risks
• Participants should be at liberty to withdraw
• The experiment should be conducted by scientifically
qualified persons
• Research protocols should be reviewed by an
independent committee

8. The Nuremberg Code (1947)
The voluntary consent of the human subject is absolutely essential.
This means that the person involved should have legal capacity to give consent; should
be so situated as to be able to exercise free power of choice, without the intervention
of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of
constraint or coercion; and should have sufficient knowledge and comprehension of
the elements of the subject matter involved, as to enable him to make an
understanding and enlightened decision. This latter element requires that, before the
acceptance of an affirmative decision by the experimental subject, there should be
made known to him the nature, duration, and purpose of the experiment; the method
and means by which it is to be conducted; all inconveniences and hazards reasonably
to be expected; and the effects upon his health or person, which may possibly come
from his participation in the experiment.
The duty and responsibility for ascertaining the quality of the consent rests upon each
individual who initiates, directs or engages in the experiment. It is a personal duty and
responsibility which may not be delegated to another with impunity.
Source: The Nuremberg Code

9. The Declaration of Helsinki (1964)
• Research with humans should be based on
laboratory and animal experimentation
• Research protocols should be reviewed by an
independent committee
• Informed Consent is necessary
• Research should be conducted by medically/
scientifically qualified individuals
• Risks should not exceed benefits
The Interests of the Patient should prevail over those of
science and society

10. The Tuskegee Syphilis (Observational) Study

11. The Tuskegee Syphilis (Observational) Study
• In 1932 the US Government misled 623 African-
Americans into participating into a study of untreated
syphilis
• The government induced these men to participate in a
study in which the government represented that the
participants were being treated for whatever their
ailments were
– They were never told what their ailment was
– They never gave their consent to be involved in a study
– Nor did they realise they were part of a study until the
story broke in July 1972
– Treatment was knowingly withheld for 40 years
Fred D Gray – Attorney, 8th April 1997

12. The Tuskegee Syphilis (Observational) Study
“Men who were poor and African American, without
resources and with few alternatives believed they had
found hope when they were offered free medical care by
the United States Public Health Service. They were
betrayed.
For 40 years, hundreds of men were betrayed, along with
their wives and children, along with a community in Macon
County, Alabama, the City of Tuskegee, the fine university
there, and the larger African American community. The
United States government did something that was wrong –
deeply, profoundly, morally wrong. It was an outrage to our
commitment to integrity and equality for all of our citizens.”
President Bill Clinton, 16th May 1997

13. The Tuskegee Syphilis (Observational) Study
“Medical professionals willingly and intentionally let
human beings suffer from a treatable, and then later a
curable illness. These researchers knew that mercury
and arsenic compounds could treat the disease, but the
Tuskegee men did not receive the medicine. Later the
researchers knew that penicillin could cure the disease,
but again, the Tuskegee men did not get the medicine.
They didn’t get treated until the 40 year study was
discovered and stopped amid public outcry in 1972. It
was a disgraceful episode for American Scientists.”
Vice President Al Gore, 16th May 1997

14. The Tuskegee Syphilis (Observational) Study
This case reaffirmed the principle that prior informed consent
should be obtained from individuals before they are allowed to
participate in human experimentation

15. Ethical Principles in Biomedical Research
• Protect the rights, safety and well-being of human
subjects
• Independent ethical review
• Informed consent
• Balance the benefits, harms and risks of study
participation
• Safeguard confidentiality
• Ensure scientific credibility

16. Clinical Research: Clinical Trial vs NIS

17. Research or Audit/Service Evaluation?
• NRES reviews research proposals to protect the rights and
safety of research participants and enables ethical research
which is of potential benefit to science and society
• Patients expect HCPs to undertake audit and service
evaluation as part of quality assurance. These involve
minimal additional risk, burden or intrusion for participants
and are regulated outside of NRES.
• Research may involve greater risk, burden or intrusion for
participants than standard clinical practice.
– Research requires review by a REC
– Research Governance Framework for Health and Social Care
Source: NRES Leaflet – Defining Research

18. Research or Audit/Service Evaluation?
Research or Audit? Audit • Outside scope of NRES
• Requires REC Review
Research
• Requires R&D Approval
Interventional or Interventional
• Requires MHRA Approval
Non-Interventional? (i.e., Clinical Trial)
Non-Interventional • Does Not Require MHRA
(e.g., Observational study) Approval

20. Research: Interventional or Non-Interventional?
Research or Audit? Audit • Outside scope of NRES
• Requires REC Review
Research
• Requires R&D Approval
Interventional or Interventional
• Requires MHRA Approval
Non-Interventional? (i.e., Clinical Trial)
Non-Interventional • Does Not Require MHRA
(e.g., Observational study) Approval

21. What is a Clinical Trial?
“Clinical trial” means any investigation in
human subjects, other than a non-
interventional trial, intended:
a) To discover or verify the clinical,
pharmacological or other
pharmacodynamic effects of one or
more medicinal products,
b) To identify any adverse reactions to
one or more such products, or
c) To study absorption, distribution,
metabolism and excretion of one or
more such products,
With the object of ascertaining the safety
or efficacy of these products
(As per Regulation 2(1) of SI 2004/1031 (as amended))

22. The Regulatory Framework: Clinical Trials

23. From Human Abuse to Regulated Use
Tuskegee
Syphilis Nuremberg Declaration
Study Code of Helsinki 1996
1932-1972 1947 1964 ICH E6
1938 - 1945 1957 -1961 Directive Clinical
WWII Thalidomide 65/65/EC Trials
1965 Directives
2001 &
2005
Cause Effect
(Abuse) (Regulations)

24. Good Clinical Practice: ICH E6
1. Glossary
2. The Principles of GCP
3. Ethics Committees
4. Investigator
5. Sponsor
6. Clinical Trial Protocol & Amendments
7. Investigator’s Brochure
8. Essential Documents for the Conduct of a Clinical Trial

25. Overview of Clinical Trial Regs (UK) – 31st August 2010
Regulation of Clinical Trials: UK
Ethics of Human Research
Declaration of Helsinki (1996)
GCP Guidelines
ICH Efficacy (E) Series
ICH E6
EU Implementing Directives
Clinical Trials & GCP
2001/20/EC
2005/28/EC EU Supporting Regulations &
EU Detailed Guidance
Directives
Interventional or Non-Interventional? UK Law
Document Retention
Decision Tree 2001/83/EC (as amended)
The Medicines Act 1968 [Annex 1, Part I, Section 5.2.c]
Competent Authority Submissions
GMP
ENTR/CT 1 The Medicines for Human Use 2003/94/EC
(Clinical Trials) Regulations [Annex 13]
2004 2001/83/EC (as amended)
IEC Submissions SI 2004/1031
ENTR/CT 2
Paediatric Studies
Amendments Ethical Considerations…
Safety Reporting
SI 2004/3224, SI 2005/2754, 1901/2006/EC
ENTR/CT 3
SI 2005/2759, SI 2006/1928, 1902/2006/EC
SI 2006/2984, SI 2008/941,
IMP vs Non-IMP SI 2009/1164, SI 2010/1882
Data Privacy
95/46/EC
TMF Content & Archiving
Data Protection Act 1998
Copyright © Dr Stuart McCully, 2009-2010
All Rights Reserved

26. Overview of Clinical Trial Regs (UK) – 7th September 2009
Clinical Research: How is it Regulated?
Ethics of Human Research
Bioethical Principles Declaration of Helsinki (1996)
ICH GCP Guidelines
Global GCP Guidelines ICH E6
EU Implementing Clinical Trials Directive GCP Directive
Directives 2001/20/EC 2005/28/EC
The Medicines for Human Use The Medicines for Human Use
(Clinical Trials) Regulations (Clinical Trials) Amendments
UK Law 2004 Regulations 2006
SI 2004/1031 SI 2006/1928
Copyright © Dr Stuart McCully, 2009
All Rights Reserved

27. Overview of Clinical Trial Regs (UK) – 7th September 2009
Clinical Research: How is it Regulated?
Ethics of Human Research
Bioethical Principles Declaration of Helsinki (1996)
ICH GCP Guidelines
Global GCP Guidelines ICH E6
Detailed Guidance Documents
Eudralex Volume 10
Clinical Trials & GCP
EU Implementing
2001/20/EC
Directives “The Investigator and
2005/28/EC
Sponsor shall consider all
relevant guidance with
respect to commencing and
The Medicines for Human Use conducting a clinical trial”
(Clinical Trials) Regulations
UK Law 2004 (as amended) [Schedule 1, Part 2.8 of SI 2004/1031 (as
amended by SI 2006/1928)]
SI 2004/1031
Copyright © Dr Stuart McCully, 2009
All Rights Reserved

28. Country-Specific Regulation of NIS: UK
Article 1.1 of the Clinical Trials Directive (2001/20/EC)
which is implemented into UK law by SI 2004/1031
states that “this Directive does not apply to non-
interventional trials”.

29. How and Why are they Different?
“The purpose for excluding these [NIS] trials from the scope of
the Directive 2001/20/EC is that these trials are typically of a
lower risk than interventional clinical trials.
Moreover, this restriction shall ensure that medical activities
which are normal clinical practice and as such part of the general
medical surveillance of a patient are excluded from the scope of
the Directive 2001/20/EC.”
(Source: Eudralex Volume 10 - Questions and Answers, Version 7.0, September 2010)

30. The Regulatory Framework: NIS

31. What is a Non-interventional Study?
“non-interventional trial” means a study
of one or more medicinal products which
have a marketing authorisation, where
the following conditions are met:
a) The products are prescribed in the
usual manner in accordance with
the terms of that authorisation
b) The assignment of any patient
involved in the study to a particular
therapeutic strategy is not decided
in advance by a protocol but falls
within current practice,
c) The decision to prescribe a
particular medicinal product is
clearly separated from the decision
to include the patient in the study
(As per Regulation 2(1) of SI 2004/1031 (as amended))

32. What is a Non-interventional Study?
“non-interventional trial” means a
study of one or more medicinal
products which have a marketing
authorisation, where the following
conditions are met:
d) No diagnostic or monitoring
procedures are applied to the
patients included in the study,
other than those which are
ordinarily applied in the course
of the particular therapeutic
strategy in question, and
e) Epidemiological methods are to
be used for the analysis of the
data arising from the study
(As per Regulation 2(1) of SI 2004/1031 (as amended))

33. What is a Non-interventional Study?
Source: ICH E2E – Pharmacovigilance Planning (2004)

34. The Regulatory Framework: NIS
The regulatory requirements for non-
interventional studies differ from clinical trials.
As a minimum:
• Highest standards of professional conduct
and confidentiality must be maintained
– Source: Eudralex Volume 9A, Part I, Section 7.7
With regards to conduct:
• In observational studies, the investigator
“observes and evaluates results of ongoing
medical care without 'controlling' the
therapy beyond normal medical practice.”
– Source: ICH E2E, Section 3.2.1

35. Country-Specific Regulation of NIS: UK
Applicable Legislation: Non-interventional studies (NIS) are controlled by a
combination of legislation and codes of practice in the UK.
• REC Approval
Fundamental Ethical Principles:
• Protocol
• Protect rights, safety and well-
• Informed Consent
Declaration of being of patients
NRES • Annual Progress Reports
Helsinki/ ICH E6 • Independent Ethical Review
• Substantial Amendments
• Informed Consent
• SAE Reporting
• Protocol
• End of Trial Notification
• Scientific Credibility
• Final Study Report
SI 2004/1031
• Legal definition of “NIS”
(as amended)
• MHRA Approval Not Required • Ethical Considerations
Eudralex Volume
9A • Data Confidentiality
(IPSE GPP/ ICH • Professional Conduct
E2E) • Safety Reporting in NIS
• Protocol
SI 1994/3144 • Final Report
(as amended) • Safety Reporting Requirements
ABPI COP
• Essential Criteria for Industry-
(Industry Code)
Sponsored NIS
Research
Governance
Framework for • REC Approval Required
Health and Social • R&D Approval Required
Care

36. Overview of NIS Regs (EU) – 8th Oct 2010
Regulation of Non-Interventional Studies: UK
Ethics of Human Research
Declaration of Helsinki (1996)
ICH Guidelines
ICH E2E
ICH E6
EU Supporting Regulations &
International Supporting Guidance European Directives
Directives
Non-Interventional Study or Clinical Trial? Medicinal Products
Eudralex Volume 10 - Decision Tree Document Retention
EC/726/2004 (as amended)
2001/83/EC (as amended)
2001/83/EC (as amended)
IPSE Guidelines [Annex 1, Part I, Section 5.2.c]
• Good Pharmacoepidemiology Practices
• Data Privacy Data Privacy
UK Law & Guidance
• GRACE Principles (Endorsed by IPSE)
95/46/EC
CIOMS International Ethical Guidelines Data Protection Act 1998
for Epidemiological Studies 2009
The Medicines for Human Use
The Medicines for Human Use
(Marketing Authorisations
General Considerations for Post- (Clinical Trials) Regulations
etc) Regulations 1994 (as
Authorisation Studies and Post- 2004 (as amended)
amended)
Authorisation safety Studies SI 2004/1031
SI 1994/3144
Eudralex Volume 9a [Chapter I.7]
• Safety Reporting
• Protocol and Report Guidance MHRA Website
• Competent Authority Notification
• Ethical Considerations
• Promotion of Medicinal Products NRES SOPs
• Participation of Healthcare
Professionals
• Procedures for Complaints NHS Research Governance
Framework(s)
EFPIA Code of Practice
October 2007 ABPI Code of Practice (2008)
Copyright © Dr Stuart McCully, 2009 - 2010
All Rights Reserved

37. Industry Guidance: ABPI Code of Practice
(2008)

38. Overview of NIS Regs (EU) – 29th June 2010
ABPI Code of Practice (2008): Non-Interventional Studies of
Marketed Products
According to Clause 13 of the ABPI Code of Practice (2008), non-interventional studies (NIS) that are
prospective in nature and involve the collection of patient data must comply with all of the following criteria:
1. The study is conducted for a scientific purpose
2. There is a written protocol
3. There are written contracts between the Study Sponsor and Healthcare Professionals and/or Institutions
4. Any remuneration provided must be reasonable and reflect fair market value
5. The study protocol should be submitted for review in those countries where the Ethics Committees are
prepared to review the document
6. Data protection legislation must be complied with
7. The Company’s Scientific Service must approve the protocol and must supervise the conduct of the study
8. The study results must be analysed and summaries be made available within a reasonable period of time
to the Company’s Scientific Service and the Healthcare Professionals who participated in the study
9. If the study shows results that are important for the assessment of benefit-risk profile of the medicinal
product, the summary report should be immediately forwarded to the relevant Competent Authority
10. Sales Representatives may only be involved in an administrative capacity and such involvement must be
under the supervision of the Company’s Scientific Service
Also:
• Companies are encouraged to publicly disclose the summary details and results of non-interventional
studies in a manner consistent with the parallel obligations for clinical trials
• Companies are encouraged to apply the same requirements (to the extent applicable) to all other types of
studies including epidemiological studies, registries and other studies that are retrospective in nature
Copyright © Dr Stuart McCully, 2009 - 2010
All Rights Reserved

39. How and Why are they Different?
Pre-Authorisation
Higher Risk
Clinical Trials
Post-Approval Marketing
Sponsor Driven
Commitment (PAC) Authorisation
Post-Authorisation
Post-Authorisation
Studies
Non-Interventional
Studies
Post-Approval
Sponsor Driven
Commitment (PAC)
Lower Risk
Risk Management Post-Approval Safety Post-Approval Study
Plan (RMP) Study (PASS) (PAS)

40. How and Why are they Different?
Clinical Trial Non-Interventional Study
• Ethical principles (DoH/GCP) • Ethical principles (DoH/GCP)
– Ethical review – Ethical review
• Novel/ “unknown” drug • Known/ Authorised drug
• Higher risk to subject • Lower risk
• Interventional • Non-interventional
• Clinical practice driven by • Routine clinical practice – not
protocol driven by protocol
• Harmonised GCP Framework and • No harmonised legal framework
regulations to ensure safety of (currently) due to lower risk to
subject and scientific credibility subject however greater focus on
• Strictly regulated due to higher data protection and scientific
risk credibility
– Routine monitoring, audits and • Less strictly regulated
inspections – Routine audits

41. Good Clinical Practice: ICH E6
1. Glossary
2. The Principles of GCP
3. Ethics Committees
4. Investigator
5. Sponsor
6. Clinical Trial Protocol & Amendments
7. Investigator’s Brochure
8. Essential Documents for the Conduct of a Clinical Trial

42. “GCP-lite”
• No IMP
• SmPC rather than IB
• Simplified Protocol
• Simplified Informed Consent
• Ethics Review
• No Competent Authority
Approval (e.g., MHRA or IMB)
• Simplified TMF/ISF
• Simplified CRF
• Reduced Monitoring

43. Ethical Principles in Non-Interventional Studies
For non-interventional post-authorisation safety studies, the Marketing Authorisation Holders and
Investigators should follow relevant national legislation in those Member States where this exists, in
addition to the guidance given here.
The highest possible standards of professional conduct and confidentiality must always be maintained
and legislation on data protection followed (see Directive 95/46/EC). The Patient’s right to
confidentiality is paramount. The Patient’s personal identifiers should be replaced by a code in the study
documents, and only authorised persons should have access to identifiable personal details if data
verification procedures demand inspection of such details. Responsibility for the retrieval of information
from personal medical records lies with the Healthcare Professional(s) responsible for the patient’s care.
Such information from medical records should be provided to the Marketing Holder, who is thereafter
responsible for the handling of such information.
It is recommended that non-interventional post-authorisation safety studies are referred to an Ethics
Committee. Studies conducted entirely using records not containing any personal identifiers e.g.
anonymised records) may not require an ethical review of individual study protocols. National
guidelines in this respect should be followed where they exist.
According to European data protection legislation, explicit consent is required when the study plans to
collect data containing personal identifiers, though some exceptions are envisaged.
(Source: Eudralex Volume 9A, Part I, Section 7.7)

44. The Principle of Observation
Observational Study:
• Non-experimental study*
• Epidemiological study
that does not involve
intervention*
• Observe ‘real-life’
scenarios
– E.g., a record of outcomes
in routine clinical practice
• Supplement existing data
on authorised drugs or
existing conditions
* CIOMS International Ethical Guidelines for Epidemiological Studies, 2009 (ISBN 92-9036-081-X)