Application procedure for clinical trials in German-speaking countries to the ethics committee using the example of the federal authority

 
 

                   Clinical studies in German-speaking countries

 
According to Section 40 (1) of the German Medicinal Products Act, the sponsor may only commence a clinical trial of a medicinal product in humans if the responsible ethics committee has given its approval and the responsible higher federal authority has explicitly granted its authorization.
 
There are two higher federal authorities in Germany. The competent higher federal authority for the approval of clinical trials with medicinal products is the Federal Institute for Drugs and Medical Devices (BfArM). The Paul Ehrlich Institute (PEI) is responsible for tests with sera, vaccines, blood supplements, monoclonal antibodies, test allergens, test sera and test antigens.
 
The application for approval of the clinical trial is regulated by § 7 (1), (2), (3) of the GCP Regulation (GCP-V).
 
The sponsor must apply to the ethics committee responsible for the investigator for the required approval of the ethics committee (Section 42 (1) AMG).
 
In the case of multi-center clinical trials, the application for an approving assessment must be submitted by the sponsor to the ethics committee responsible for the head of the clinical trial (Section 42 (1) AMG; Section 7 (1) GCP-V). This ethics committee is the lead ethics committee for processing the application.
 
Each additional ethics committee involved for an investigator receives a copy of the application and the documents at the same time (§ 7 (1) GCP-V).
 
In collaboration with the ethics committees involved, the lead ethics committee issues a opinion. In doing so, the ethics committees involved examine in particular the information in the application that related to the local circumstances of the trial site. The participating ethics committees shall submit their proposals for the formulation of the opinion to the lead committee within a maximum of 30 days of receipt of the complete application.

 
Furthermore, approval must be obtained from the competent higher federal authority.
 
 
Appeal to an ethics committee
 
The approval of the ethics committee required in accordance with Section 40 para. 1 sentence 2 AMG must be obtained by the sponsor from the independent, interdisciplinary ethics committee responsible for the investigator in accordance with state law.
must be applied for. If the clinical trial is conducted by several investigators, the application must be submitted to the independent ethics committee responsible for the head of the clinical trial. The details of the formation, composition and financing of the ethics committee shall be determined by federal state law. The sponsor must provide the ethics committee with all information and documents required for its assessment. To assess the documents, the Ethics Committee may use its own scientific findings, consult experts or request expert opinions. It must consult experts or request expert opinions if the clinical trial involves minors and it does not have its own specialist knowledge in the field of pediatrics, including ethical and psychosocial issues in pediatrics, or if the clinical trial involves xenogenic cell therapeutics or gene transfer medicinal products.

The primary objective of the Ethics Committee is to protect the trial participants and patients  by the clinical trial. To ensure this, the committee members examine the submitted documents in detail before they are discussed in a meeting.
 
An ethics committee consists of the following members, for example:

• two doctors with several years of professional experience as a medical specialist

• a doctor/scientist with expertise in the field of drug effects or a corresponding doctor/scientist
• one in the field of medical biostatistics and

Biometrically competent physician/scientist or an appropriate physician/scientist

• a lawyer with the qualification for

Judgeship

• one pharmacist
• Laymen

 
Advice from the ethics committee includes an examination of the research approach (is it plausible?) and the risk for the trial participant and the information provided. Everyone takes part in a clinical trial must give their "informed consent". This means that they must be informed clearly and in detail about the nature of the clinical trial and possible risks before they can give their legally valid consent to participate in the trial. This means that written patient information is of paramount importance, so that this examined particularly critically. The lay member is primarily responsible for assessing the comprehensibility of the text. Unless there is an exception to the insurance obligation, insurance policies must  taken out for trial participants to provide compensation in the event of personal injury. The ethics committee is also responsible after the start of a clinical trial,

Official requirements
 
in view of changing circumstances, in particular those relating to the safety of the subjects, to examine whether the favorable assessment can be maintained. Approval may only be refused if

• the documents submitted even after the expiry of a sponsor within a reasonable period of time,

• the documents submitted, including the audit report plans, the investigator’s brochure and the modalities for the selection of trial participants do not correspond to the state of scientific knowledge, in particular the clinical trial is unsuitable prove the safety or efficacy of a medicinal product, including a different mode of action in women and men, or

• the provisions of § 40 para. 1 sentence 3 nos. 2 to 9, para. 4 and § 41.
• requirements are not met.

 
The principal investigator is usually invited to the ethics committee meeting and may be accompanied by another person (e.g. study coordinator or responsible employee of the pharmaceutical company of the substance under investigation).
 
The study leader or their representative should be very well prepared for the meeting and discussions. In most cases, special attention is paid to the question, the Methodology (statistics) and patient information, and
-education. The individual burden and risk for the patient are also frequently discussed. Here it is important to take the recommendations and criticism of the committee members seriously and, if possible, to include them in the study protocol.

 
A checklist of the required application documents can be found, for example, on the homepage of the Berlin State Office for Health and Social Affairs (www.lageso.berlin.de). The opinion of the ethics committee must generally be issued within 60 days for multi-center clinical trials and within 30 days for mono-center clinical trials 

Approval or rejection

Incoming application

10 days
Formal examination 

Letter of deficiency
14 days
Revision

Submission
Letter of deficiency
60 or 30 days content review 
Stop Clock unique opportunity for revision 

Submission
Examination 
 
Fig. 3: Ethics committee evaluation procedure

Official requirements
 
 

Submission of documents to the higher federal authority

A clinical trial may only be started if an ethics committee has approved it and the competent higher federal authority (BOB) has authorized it. The sponsor must submit all information and documents required for the assessment, in particular the dossier on the investigational medicinal product with the following content:

• Documents on quality and production
• Manufacturing authorization
• Results of analytical and pharmacological-toxicological testing 

In :

• Test plan
• clinical information on the investigational medicinal product, including the investigator’s brochure

 
By way of derogation, the summary of product characteristics (SmPC) may be submitted instead of the dossier if the investigational medicinal product is a medicinal product that is authorized within the EU and the SmPC is supplemented accordingly depending on the application. In addition, a special labeling of the investigational medicinal product can be waived for marketable (authorized) medicinal products, as far as the concept of the clinical trial allows.
 
While the ethics committee focuses  the risk-benefit ratio and the relevance of the study, the higher federal authority concentrates on the conduct of the study and the investigational medicinal products.
 
Once the application documents have been received, the higher federal authority checks them for formal completeness within 10 days. If the documents are incomplete, a letter of deficiency is generally sent and the applicant has 14 days to submit the missing documents. Upon receipt of the complete application documents

 
Approval is deemed to have been granted if the competent higher federal authority approves the clinical trial in writing or has not sent the sponsor any reasoned objections within 30 days of receipt of the application documents (implicit approval). If the higher federal authority notifies the applicant of any objections, the applicant has a one-off period of 90 days to revise the application. If no response has been received from the applicant after 90 days, the study is deemed to have been rejected. If the applicant comments, the higher federal authority must issue the decision within 15 days.

Official

Approval or rejection

Incoming application

Submission

15 days Examination

90 days one-time possibility for revision

Letter of deficiency

10 days Formal examination

Letter of deficiency

30 days content check

14 days Revision

Submission

 
 

Notification of the inspection to the supervisory authorities

 
According to Section 67 AMG, notification of the activity as an investigator or deputy must be submitted to the competent supervisory authority before the start of the trial. The form for the notification of a clinical trial in accordance with Section 67 para. 1 and
3 AMG and Section 12 (1-3) GCP-V with the competent federal state authority can be found on the homepage of the Central Office of the Federal States for Health Protection with regard to Medicinal Products and Medical Devices (www.zlg.de).

The monitoring authority responsible for the sponsor must be informed about the start, amendments and end of the clinical trial as well as about changes of address of the centers.
 
In clinical trials in which study goods are reconstituted (prepared), the name, job title and address of the person responsible for reconstitution must be stated when notifying the local supervisory authority.

Standard Operating Procedures
 
 
Standard Operating Procedures (SOPs) are standardized work instructions of a company or the contract research organization conducting the trial for all activities and work processes that must be adhered to in connection with clinical trials. The defined SOPs  intended to ensure and document that the clinical trial is conducted in accordance with the highest quality standards. They regulate the procedure during the clinical trial. The aim of SOPs is to standardize, simplify and make workflows transparent.
 
SOPs deal with the following topics, for example:

• Preparation of a clinical study (preparation of the study plan and study documentation)
• Subject and patient information
• Monitoring
• Dispensing and taking back medication and -administration
• Data management
• Safety aspects
• Degree
• Quality assurance and control

 
All persons involved in the study must be familiar with the SOPs relevant to them and act accordingly.
 

Study Protocol

The protocol is a basis for the proper conduct of a clinical trial in accordance with the legal requirements, the ICH guidelines (e.g. ICH-GCP E6, see Chapter 3) and the Declaration of Helsinki (WMA General Assembly in Somerset West 1996) (see Chapter 3.4).

The trial protocol describes the rationale, objectives, design, study participant population and procedure (planned treatments, data collection, documentation) and evaluation (data processing and biometric/scientific evaluation) of the clinical trial (see also definition in the GCP Regulation: GCP-V § 3 para. 2) for clinical trials conducted in accordance with the AMG. It also  the responsibilities of those involved in the conduct of the trial. The addressees of the trial protocol are the investigators, all other persons conducting the trial, committees (e.g. Data Monitoring Committee) and institutions (clinics, pharmacies, central laboratory, etc.). The protocol also forms the basis for the decision on the evaluation or approval of the trial by the ethics committee and the authorities.
 

 
When planning, conducting and evaluating clinical trials, various documents are required document and evaluate the clinical trial and to ensure the quality of the data collected. These documents can be used to demonstrate compliance with ICH-GCP and all applicable legal requirements.
 
These documents may also be reviewed by independent auditors and inspectors from the competent authorities.
 
The sponsor of the clinical trial is responsible for the completeness, availability and archiving of the study documents in the Trial Master File (TMF). In contrast to the Investigator Site File (ISF), the TMF does not contain any personal data or signed declarations of consent from study participants.

Before the TMF is created, it must be determined which documents (copy/original) are required in the TMF and which documents are to be filed elsewhere. This must agreed with the sponsor.
 

Maintenance of the TMF

 
The relevant study documents are  in the corresponding parts of the TMF. The storage of center-specific documents is usually sorted by center. At the second level, they should be sorted by person/center employee. Correspondence (e.g. e-mails, faxes, telephone notes, letters) is always filed chronologically.
 

Electronic documents

Electronically created documents are printed out and filed in the corresponding TMF section. Extensive electronic documents (such as database(s), programs, validations in the area of biometrics and data management) can only be saved/archived as electronic versions in consultation with the project manager. It is noted in the corresponding TMF section where the electronic document can be found.
 

Temporary withdrawal of study-related documents

In principle, the documents should remain in the TMF and not be removed. If it is necessary to remove individual documents for a limited period of time, a note is made in the appropriate place in the TMF section stating who removed the document, when it was removed and where it is located. Once the documents have been returned, the note is removed and destroyed.

Study documents

 
Alternatively, individual working copies can made. These are marked accordingly (e.g. "Copy"/"Working copy" stamp or corresponding handwritten note on the document). After use, these working copies are destroyed.
 
Storage of the TMF during the course of the study The individual TMF parts are stored in such a way that no third parties have access to the documents. Internal and external auditors and representatives of the authorities must always be granted access to the documents.
 

Return of study-related documentation

It is determined with the sponsor which documentation will be returned to the sponsor after the end of the study.
 

Investigator Site File 

When planning, conducting and evaluating clinical trials, various documents are required to document and assess the clinical trial and the quality of the data collected. These documents can be used to demonstrate compliance with ICH-GCP and all applicable legal requirements.
 
The availability of documents at the investigator’s site serves to ensure the proper conduct of the clinical trial. The Investigator Site File (ISF) contains all documents that are received, created and completed by the investigator in charge at the trial center during the course of the clinical trial.
 
These documents can also be audited by independent auditors and inspected by inspectors from the competent authorities.

The participating trial centers are each responsible for the availability and, where applicable, for the updating/completeness and archiving of the study documents on site.
 
 

 Creation of the ISF

 

• The ISF is prepared before the start of the clinical trial.
• An ISF is prepared for each test center. This can also  of several parts if required.
• Each ISF has a uniform structure and a uniform study-specific labeling:
• The table of contents of the ISF is compiled taking into account

The test plan is drawn up on the basis of local conditions and the test plan.

• If a section in the table of contents of the ISF is not required (e.g. emergency envelopes for an open study) and all subsections of this section are marked as "not required" in the checklist, this section can be deleted from the table of contents.

 

Delivery of the ISF

The ISF is usually handed over to the test center during the initiation visit - provided that all requirements for opening a center are met (i.e. ethics vote, approval of the higher federal authority [BOB], local authority notification and fully signed investigator contract are available for the center to be opened).
 
The ISF can also be handed out during an examiner meeting or sent by post.

Maintenance of the ISF

 

Study documents 

 
 
The maintenance, storage and - if applicable - updating of the ISF is the responsibility of the respective study team at the trial site, whereby the monitor checks the completeness/currency and storage of the ISF as specified in the monitoring plan.
 

Storage

The ISF must kept protected from access by third parties. Study personnel, auditors and inspectors must always be granted access.
 

Correspondence

• is always filed chronologically
• Filing by non-cash benefit if possible

 

Electronic documents

As a rule, electronically created documents (e.g. e-mails) are printed out and filed accordingly in the ISF.
 

Archiving

The ISF is usually archived at the test center, whereby the principal investigator must be informed of the length of the retention period during the final visit by the monitor.

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