nis considerations - germany - chcuk

© Dr Stuart McCully 2013CHCUK Ltd

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NIS Considerations - Germany An overview of the considerations when conducting Non-interventional Studies in Germany !!!Stuart McCully • CHCUK Ltd • NIS-C-DE-2013 Version 2 (Dec 2013) !


NIS Considerations - Germany Version 2 - Dec 2013 !!

Table of Contents !

!Disclaimer 3

Acknowledgement 4

Document History 5

SUMMARY OF CHANGES SINCE PREVIOUS VERSION 5

Study Classification 8

GENERAL CONSIDERATIONS WHEN PLANNING NIS 8

STEP 1 - DETERMINE WHAT TYPE OF STUDY YOU INTEND TO CONDUCT 9

STEP 2 - DETERMINE THE COUNTRY-SPECIFIC REQUIREMENTS 11

STUDY CLASSIFICATION - USEFUL LINKS 12

Regulatory Requirements 13

COUNTRY-SPECIFIC REGULATORY REQUIREMENTS 13

REGULATORY BODIES 13

DEFINITION 15

REGULATORY FRAMEWORK 16

SUMMARY OF THE NIS REQUIREMENTS IN Germany 18

APPROVAL & NOTIFICATION REQUIREMENTS 19

WHO IS RESPONSIBLE FOR WHAT? 21

BFARM GUIDANCE ON NIS 23

REGULATORY SUBMISSIONS ROADMAPS 31

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REGULATORY SUBMISSIONS DOCUMENTS 34

REGULATORY REQUIREMENTS - USEFUL LINKS 35

Study Conduct Considerations 37

APPROVALS AND NOTIFICATIONS 37

STUDY REGISTRATION 43

CONTRACTS 44

DATA PRIVACY & INFORMED CONSENT 47

STUDY COMPLETION ACTIVITIES 48

HUMAN TISSUE RESEARCH 49

STUDY CONDUCT CONSIDERATIONS - USEFUL LINKS 51

Best Practice Considerations 53

PHARMACEUTICAL SELF-REGULATION 53

REQUIREMENTS FOR NON-INTERVENTIONAL STUDIES 53

BEST PRACTICE CONSIDERATIONS - USEFUL LINKS 69

NIS Definitions 71

EUROPEAN NIS DEFINITIONS 71

NIS DEFINITIONS 71

Common NIS Terminology 73

COMMONLY USED NIS TERMS 73

COMMON NIS TERMINOLOGY 73

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NIS Considerations - Germany Version 2 - Dec 2013 !!!

Disclaimer !

Although this Compilation 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 Compilation is not an exhaustive source of all

current applicable laws, regulations, and guidelines relating to non-interventional studies.

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 research activities.

!!

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Acknowledgement !

My thanks go to Mark Heinemann for his support in researching the updates to the German

Drug Law.

!Acknowledgement: Mark Heinemann, Senior Submission Specialist, Late Stage Group,

inVentiv Health Clinical

!!!!!!!

! !"4



Document History !

SUMMARY OF CHANGES SINCE PREVIOUS VERSION

Summary of the changes since the previous of the NIS Considerations: Germany report (NIS-

C-DE-2013)

!NOTE: Look for the sections highlighted in the colour on the

left. This is a visual indication that a section has been updated or

is new

Area Impacted Details

Report Format The report has been reformatted to comply with Pages version 5

formatting

Competent Authority

Requirements

The BfArM website was updated/ relaunched on the 15th

November 2013. The impact being:

•All previous hyperlinks needed re-linked

•BfArM has released new FAQs related to the conduct of NIS

(in German only)

a. Refer to page 22

Regulatory Maps The following two new regulatory maps have been added:

1) Multi-Country Mandated Post-Authorisation Safety Studies

(PASS)

1) Germany-Only Mandated Post-Authorisation Safety

Studies (PASS)

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Legislation New NIS Notification Requirements

The 3rd law amending the German Medicinal Products Act came

into effect on August 13, 2013.

The new regulations are mandatory for all non-interventional

studies with start dates:

•later than 12 Aug. 2013,

•earlier than August 2013 and with an end date later than 31

Dec. 2013.

The new Art. 67 AMG requires the disclosure of "the actual"

compensation paid, paragraph 6 sentence 4 AMG.

The most important changes aim at the disclosure of the actually

paid fees for a physician’s participation in an observational study

and at the reporting requirements for the fees and any payment

updates after study start.

The sponsor must also explain the appropriateness of the

proposed fees in the contract template between sponsor and

physician/site.

!Refer to page 39 for more information


! !"6



!

NIS Guidance The Third Amendment of drug and other regulations of 7 August

2013 ( Federal Law Gazette . I S. 3108) entered into force on 13

August 2013. This amendment brought extensive changes for

the submission requirements for NIS (AWB) into effective. The

BfArM and PEI joint recommendations on the implementation,

planning and analysis of observational studies of 7 July 2010

therefore no longer reflect the current legal status again. The

recommendations will be revised in the near future according to

the new law. Until the publication of the updated

recommendations, the previous recommendations for

information remain available on this website (as per the BfArM

Guidance on NIS).

Pharmaceutical Self

Regulation

The following documents have been amended. The links within

the report have been updated accordingly:

• FSA Code of Conduct on the Collaboration with Healthcare

Professionals (FSA Code of Conduct Healthcare

Professionals) - Nov 2012

• Guidelines by the FSA Board of Management pursuant to

Section 6 Subsection 2 of the FSA Code of Conduct for

Interaction with Healthcare Professionals - August 2013

Extra content has been added in the ‘Best Practice

Considerations, covering:

•Hospitality

•Sweepstakes for Healthcare Professionals

Human Tissue

Research

Added a link to the new German Ethics Council, “Deutscher

Ethikrat” (DE): Opinion on The future of genetic diagnosis –

from research to clinical practice (April 2013)


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Study Classification GENERAL CONSIDERATIONS WHEN PLANNING NIS !

!!!!!!!!!!!!!!

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It Depends!

What are the regulatory

requirements for my NIS?


NIS Considerations - Germany Version 2 - Dec 2013 !!!STEP 1 - DETERMINE WHAT TYPE OF STUDY YOU INTEND TO CONDUCT

Before starting your study you first need to determine what type of study it is:

Is your Study Interventional?

Is your study an interventional clinical trial?

➡ Refer to the Decision tree

!Is your Study a Post-Authorisation Safety Study (PASS)?

Your study is a PASS if the objectives include at least one of the following conditions:

1. Characterization of the safety profile (e.g. identifying the most frequent adverse

reactions in a large population over time);

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Study !Classification!

Is#your#study#an#interven/onal#clinical#trial?#

Regulatory !Framework!

Interventional?!

PASS?!

Other NIS?!

Clinical Trials Directive !(2001/20/EC)!

Pharmacovigilance Directive !

(2010/84/EU)!

Country Specific!!

Is#your#study#a#post4authoriza/on#safety#study#(PASS)?#

Is#your#study#a#non4safety#related#non4interven/onal#study?#

��

��

��

��

��


NIS Considerations - Germany Version 2 - Dec 2013 !!2. Providing reassurance about the absence of a safety concern related to a specific

adverse reaction;

3. Investigating potential or identified risks, e.g. to characterize the incidence rate,

estimate the rate ratio or rate difference in comparison to a non-exposed population

and investigate risk factors and effect modifiers;

4. Evaluating risks of a product used in authorised indications by patients groups not

studied in the pre-authorisation phase (e.g. pregnant woman, elderly patient);

5. Assessing patterns of drug utilisation and use of the product that may have an impact on

its safety (e.g. co-medication, medication errors);

6. Evaluating the effectiveness of a risk mitigation activity (e.g. drug utilisation study,

patient or physician survey)

!Furthermore, if your study falls within the scope/definition of a PASS and it isn’t a study that

has been required by a Competent Authority as part of your Marketing Authorisation then it is

a ‘voluntary’ PASS. If you are the study sponsor you will need to determine, and document,

what your policy is with regards to the notification and reporting considerations for these

voluntary PASS. The EMA encourages Companies to notify and register these study in the

same way as Obligatory PASS. However, this is currently a business decision.

!Is your study a Non-Safety Related Non-Interventional Study?

If so, the requirements are not standardised and you will need to determine the country-

specific considerations.

!

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NIS Considerations - Germany Version 2 - Dec 2013 !!STEP 2 - DETERMINE THE COUNTRY-SPECIFIC REQUIREMENTS

The regulatory requirements for ‘Other’ NIS are very much dependent on a number of factors

(see below), which is why there isn’t generally a single answer to the question, “what are the

regulatory requirements for my non-interventional study?”

There are no short cuts. You will need to verify the country-specific regulations and

considerations for each of the countries where you intend to conduct your non-interventional

study.

!

!!

NIS Considerations�

Prospective study?!Retrospective study?!Which countries?!Which patient populations?!Tissue collection?!Tissue export?!Biobanking?!DNA analysis?!Secondary use of data?Secondary use of tissue?!

Notifications!Approvals!Submissions procedures!Registration!Classification!Insurance requirements!

�Other� NIS!Need to verify requirements

for each country!

! !"11


NIS Considerations - Germany Version 2 - Dec 2013 !!STUDY CLASSIFICATION - USEFUL LINKS !

!!

Useful Links Accessed From

Clinical Trials Directive (2001/20/EC) http://ec.europa.eu/health/files/

eudralex/vol-1/dir_2001_20/

dir_2001_20_en.pdf

Pharmacovigilance Directive (2010/84/

EU)

http://ec.europa.eu/health/files/

eudralex/vol-1/dir_2010_84/

dir_2010_84_en.pdf

EMA Good Pharmacovigilance Practices

(GVP)

http://www.ema.europa.eu/ema/

index.jsp?curl=pages/regulation/

document_listing/

document_listing_000345.jsp&mid=WC0

b01ac05804fcdb1

EMA Guidance on the 2010

Pharmacovigilance Legislation

http://www.ema.europa.eu/ema/

index.jsp?curl=pages/regulation/general/

general_content_000492.jsp&mid=WC0b

01ac058033e8ad

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Regulatory Requirements COUNTRY-SPECIFIC REGULATORY REQUIREMENTS !

REGULATORY BODIES

Competent Authority Paul-Ehrlich-Institute, the Federal

Institute for Vaccines and Biomedicines

(PEI)

or

The Federal Institute for Drugs and

Medical Devices (BfArM)

Research Ethics Committees Germany has a total of 53 research ethics committees (RECs)

Data Protection Agency Der Bundesbeauftragte für den

Datenschutz und die Informationsfreiheit

(BFDI)

(The Federal Commissioner for Data

Protection and Freedom of Information)

Pharmaceutical Self-Regulation Body The Association of Research-Based Pharmaceutical Companies (vfa)

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!

Pharmaceutical Code of Practice • FSA Code of Conduct on the

Collaboration with Healthcare

Professionals (FSA Code of Conduct

Healthcare Professionals) - Nov 2012

• Guidelines by the FSA Board of

Management pursuant to Section 6

Subsection 2 of the FSA Code of

Conduct for Interaction with

Healthcare Professionals - August 2013

! !"14


NIS Considerations - Germany Version 2 - Dec 2013 !!DEFINITION

Non-Interventional Trial

A non-interventional trial is a study, in the context of which findings resulting from persons'

treatment with medicinal products pursuant to the specifications for use contained in the

marketing authorisation are analysed using epidemiological methods; the treatment,

including the diagnosis and monitoring shall not follow a predetermined trial protocol but

shall result exclusively from current medical practice (as per Section 4(23) of the German

Drug Law (AMG)).

!Non-Interventional Study

Non-interventional studies, to which drug monitoring projects also belong, are prospective

studies with the purpose of gaining new insights from the treatment of patients on the

application of pharmaceuticals in accordance with the instructions laid down in the marketing

authorisation (e.g., harmlessness or efficacy of pharmaceuticals) (as per Section 19.1 of the

FSA Code of Practice).

The principle of non-intervention applies to all therapeutic and diagnostic measures. The

inclusion and treatment, including the diagnosis and supervision, do not therefore follow a

previously laid down study plan, but solely the physicians medical practise. The decision to

include a patient in a non-interventional study has to be clearly separated from the decision on

the prescription of a medicinal product. The data obtained has to be evaluated by means of

epidemiological methods (as per Section 19.1 of the FSA Code of Practice).

!!

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NIS Considerations - Germany Version 2 - Dec 2013 !!BFARM GUIDANCE ON NIS

What studies are considered observational studies ( AWB )?

Observational studies are studies that are intended to gather information on the application of

authorized or registered medicinal products. Observational studies are a sub-category of non-

interventional trials within the meaning of § 4, paragraph 23, sentence 3 German Drug Law

( AMG ), ie investigations, under which "findings from the treatment of people with drug

using epidemiological methods are analyzed here follows the treatment, including diagnosis

and monitoring is not a pre-defined test plan, but only the medical practice in so far as it is a

registrable or under § 21a paragraph 1 AMG is subject to approval medicines, this also takes

place under the conditions laid down in the authorization or approval of such information for

his application "The decision. to include the patient in an observational study, is separate

from the decision on the prescription of the medicine (as per the BfArM FAQs Relating to

NIS).

An observational study is not a clinical examination according to § 23 paragraph 4 sentence 1

AMG and is therefore not subject to approval. But it is according to § 67 paragraph 6 AMG

the physicians' federal associations, the Central Federal Association of Health Insurance, the

Association of Private Health Insurance Association show and the competent higher federal

authority immediately. No observational studies are studies in humans after the approval of

the drug, which are intended to explore clinical or pharmacological effects of drugs or to

detect or identify side effects or to study absorption, distribution, metabolism, or excretion

and carried out with the aim to be, to convince themselves of the safety or effectiveness of the

drug, and in which the treatment of patients, including diagnosis and monitoring goes beyond

the usual medical practice . Such are 23 sentence 1 as clinical examinations according to § 4

paragraph AMG perform. Characteristics of a clinical trial are eg a systematic allocation of

patients to treatment arms in terms of randomization and the use of medicines outside the

approved indication. These clinical trials are to be approved before the start of the competent

higher federal authority and to assess positively by the appropriate ethics committee. An

authorization by the competent higher federal authority and the favorable opinion of the

Ethics Committee are also clinical trials within the approved indication, so-called Phase IV

tests, required (as per the BfArM FAQs Relating to NIS).

! !"23



Study Conduct Considerations CONSIDERATIONS WHEN CONDUCTING NIS IN GERMANY

!

APPROVALS AND NOTIFICATIONS

Competent Authority (BfArM/PEI)

Authorisation by the Competent Authority (BfArM/PEI)

There is currently no requirement for NIS to be approved by BfArM/PEI.

!Notifying the Competent Authority (BfArM/PEI)

Before starting any NIS, the Sponsor of the study should notify BfArM/PEI (as per Section

67(6) of the German Drug Law (AMG).

At present there is no official notification; the notification of an NIS to the Competent

Authority should be submitted informally and should state (Refer to the BfArM FAQs and the

BfArM and PEI NIS Recommendation July 2010 – In German): 1

The time and location of the NIS

The purpose of the NIS

!

! !"37

! The Third Amendment of drug and other regulations of 7 August 2013 ( Federal Law Gazette . I S. 3108) entered into force on 13 August 1

2013. This amendment brought extensive changes for the submission requirements for NIS (AWB) into effective. The BfArM and PEI joint

recommendations on the implementation, planning and analysis of observational studies of 7 July 2010 therefore no longer reflect the

current legal status again. The recommendations will be revised in the near future according to the new law. Until the publication of the

updated recommendations, the previous recommendations for information remain available on this website (as per the BfArM Guidance on

NIS).



Best Practice Considerations BEST PRACTICE CONSIDERATIONS WHEN CONDUCTING NIS IN GERMANY

!

PHARMACEUTICAL SELF-REGULATION

Pharmaceutical Self-regulation Body (vfa)

The Association of Research-Based Pharmaceutical Companies (vfa) is the trade

organizations of research-based pharmaceutical companies in Germany that is affiliated with

EFPIA and represents more than two-thirds of the German pharmaceutical market.

For clarification (and to avoid confusion), the FSA or “Freiwillige Selbstkontrolle für die

Arzneimittelindustrie e.V.” is the Association of Voluntary Self-regulation for the

Pharmaceutical Industry and represents members of the Pharmaceutical Industry, Healthcare

Professionals and Patient Organisations. As such, the FSA is not a member of EFPIA.

The FSA can be considered as a control body supervising that ethical rules are respected in

Germany regarding interactions between the above mentioned stakeholders.

!REQUIREMENTS FOR NON-INTERVENTIONAL STUDIES

Non-interventional studies (NIS) describe all forms of pharmaceutical studies in which

physicians are not provided with treatment requirements: They can include any patients for

whom they prescribe the pharmaceutical in question. Apart from that, it is completely in their

discretion how they treat the patients. The administration of the pharmaceutical is the full

responsibility of the patient. This is different for clinical studies as required for the marketing

authorization of pharmaceuticals: There are strict selection criteria for patients eligible for

participation; for example, in most cases, patients who suffer from concomitant diseases will

not be able to participate. The study plan clearly declares which concomitant treatments are

! !"53


NIS Considerations - Germany Version 2 - Dec 2013 !!permissible and which are not. Furthermore, the pharmaceutical administration is monitored

by physicians and nursing staff (as per the vfa guidance - 2007).

During the post-marketing surveillance study as the most frequent NIS, many "treatment

cases" with a certain drug are documented by physicians, and these records are evaluated by

the manufacturer. This way, pharmaceutical companies can obtain information e.g. on very

rare side effects and the drugs' reliability even if therapy compliance is not optimal (as per the

vfa guidance - 2007).

"Post-marketing surveillance studies are an indispensable instrument in pharmaceutical

research," Yzer said. In this respect, the VFA also agrees with the German Federal Institute

for Drugs and Medical Devices (BfArM). Nevertheless, post-marketing surveillance studies

have become the target of criticism. To counter this situation, the VFA has developed the

following core recommendations:

Within the company, non-interventional studies are within the scope of responsibility

of the head of the medical department, both from an organizational and a budgetary

standpoint. Employees from other departments may participate but will be reporting to

the head of the medical department.

For each NIS, a consultation with one of the German ethics commissions must be

obtained.

After being educated, all patients included in an NIS must consent to participating in

the study in writing.

At the start of the study, information is entered into a publicly accessible online

register.

A summary of the study results must be published no later than 12 months after

completion of the NIS.

Other aspects are already clearly governed by the "Recommendations for the Planning,

Execution and Evaluation of Post-Marketing Surveillance Studies" by BfArM and the Code of

Conduct of the Voluntary Self-Regulation of the Pharmaceutical Industry (FSA). Both BfArM

and the Code suggest orienting the compensation on the fee scale for physicians. All post-

! !"54



NIS Definitions Considerations when providing access to unapproved drugs

EUROPEAN NIS DEFINITIONS !

NIS DEFINITIONS

Non-interventional Study (NIS)

A non-interventional study is a study fulfilling cumulatively the following requirements:

The medicinal product is prescribed in the us

ual manner in accordance with the terms of

the marketing authorisation;

The assignment of the patient to a particular

therapeutic strategy is not decided in

advance by a trial protocol but falls within

current practice and the prescription of the

medicine is clearly separated from the

decision to include the patient in the study; and

No additional diagnostic or monitoring procedures are applied to the patients and

epidemiological methods are used for the analysis of collected data.

Non-interventional studies are defined by the methodological approach used and not by the

scientific objectives. Non-interventional studies include database research or review of

records where all the events of interest have already happened (e.g. case-control, cross-

sectional and cohort studies). Non-interventional studies also include those involving primary

data collection (e.g. prospective observational studies and registries in which the data

collected derive from routine clinical care), provided that the conditions set out above are

met.

! !"71


NIS Considerations - Germany Version 2 - Dec 2013 !!In this context, interviews, questionnaires and blood samples may be performed as normal

clinical practice.

(as per Section A of EMA GVP Module VIII, Rev 1 - April 2013)

!Post-authorisation Safety Study (PASS)

Any study relating to an authorised medicinal product conducted with the aim of identifying,

characterising or quantifying a safety hazard, confirming the safety profile of the medicinal

product, or of measuring the effectiveness of risk management measures (Article 1(c)(15) as

2001/83/EC as amended by Directive 2010/84/EU)

!Post-authorisation Efficacy Studies (PAES)

Any study conducted where concerns relating to some aspects of the efficacy of the medicinal

product are identified and can only be resolved after the medicinal product has been marketed

(Article 21(a) as 2001/83/EC as amended by Directive 2010/84/EU)

!!!!

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Common NIS Terminology COMMONLY USED NIS TERMS !

COMMON NIS TERMINOLOGY

Acronym Term

AE Adverse Event

AR Adverse Reaction

CA Competent Authority (e.g., MHRA)

CI Chief Investigator

CRA Clinical Research Associate

CRF Case Report Form

CRO Contract Research Organisation

CSR Clinical Study Report

CTD Clinical Trials Directive (2001/20/EC)

CV Curriculum Vitae

DPA Data Protection Agency

EFPIA European Federation of Pharmaceutical Industries and Associations

GCP Good Clinical Practice

GPP Good Pharmacoepidemiology Practice

GVP Good Pharmacovigilance Practice

ICF Informed Consent Form

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ICH The International Conference on Harmonisation of Technical

Requirements for Registration of Pharmaceuticals for Human Use

ICH GCP ICH Good Clinical Practice Guidelines

IEC Independent Ethics Committee

IMP Investigational Medicinal Product

ISF Investigator Site File

ISPE International Society of Pharmacoepidemiology

MA Marketing Authorisation

MAH Marketing Authorisation Holder

NCA National Competent Authority

NIS Non-interventional Study

NTF Note to the File

PAS Post-authorisation Study

PAES Post-authorisation Efficacy Study

PASS Post-authorisation Safety Study

PI Principal Investigator

PIL Patient Information Leaflet

PV Pharmacovigilance

QA Quality Assurance

QC Quality Control

QMS Quality Management System

QoL Quality of Life

QP Qualified Person

Acronym Term

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!!

REC Research Ethics Committee

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SDV Source Data Verification

SIF Subject Information Form

SmPC Summary of Product Characteristics

SOP Standard Operating Procedure

SUSAR Suspected Unexpected Serious Adverse Reaction

TMF Trial Master File

WMA World Medical Association

Acronym Term

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