Guidelines for principles and rules for good clinical practices of advanced therapy medicinal...

GUIDELINES FOR PRINCIPLES AND RULES FOR GOOD

CLINICAL PRACTICES OF ADVANCED THERAPY MEDICINAL

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1. PURPOSE

This guideline is prepared to regulate the detailed rules for the good clinical practices of

advanced therapy medicinal products.

2. DEFINITIONS

2.1. Donation: Donation of human or animal tissue or cells designed for human

applications.

2.2. Human application: Use of tissues and cells in human recipients or extracorporeal

applications.

2.3. Tissue/cell center: A hospital or any other legal person, organization or entity which

undertakes processing, handling, storage or distribution of human tissues or cells.

2.4. Donor: Any alive or dead human or animal source from which human cells or tissues

are derived.

2.5. Efficiency follow-up: Systematic collection and compilation of data designed to

provide information about efficacy or efficiency of a medicinal product.

2.6. Safety follow-up: Systematic collection and compilation of data designed to provide

information about safety of a medicinal product.

2.7. Animal facility: A facility for activities relating to xenogeneic cell-based medicinal

products.

2.8. Advanced therapy medicinal product: Tissue- and cell-derived medicinal products for human use categorized as gene therapy medicinal products, somatic cell therapy medicinal products, tissue-engineering products and combined advanced therapy medicinal products.

2.9. Traceability process: Ability to localize and define each individual tissue/cell unit

during each stage from processing, testing and supplying through storage to distribution

to recipients or disposal units. This also means the ability to define the production site or

the tissue center, which receives, processes or stores tissues/cells as well as the donor

and to determine the recipients at the medical site(s), which administer the related

tissues/cells to the recipients; the traceability process also includes the competency to

localize and determine any data relating to the products and materials in contact with

these tissues/cells.

2.10. Blood center: A body or institution responsible for collecting and testing human blood

or blood components, irrespective of the purpose of use, and for processing, storage and

distribution procedures during the requested transfusion. Blood banks are excluded.



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2.11. Clinical follow-up: Follow-up of individual subjects by the investigator. This follow-up

includes prevention, screening, observation, diagnosis and treatment of diseases, as well

as injuries, complications, advers reactions and medical errors.

2.12. Supply: Process of procuring tissues and cells.

2.13. Supplier organization: A health services facility or a hospital or any other institution or

organization, not accredited, allocated, authorized or licensed as a tissue center,

responsible for supplying human tissues and cells.

3. DONATION, SUPPLY AND TESTING OF INVESTIGATIONAL ADVANCED

THERAPY MEDICINAL PRODUCTS

3.1. Except for the sponsor; investigators and manufacturers/importers and other parties,

including tissue centers, blood centers, supplier organizations, animal facilities and

donors, should be considered in relation to investigational advanced therapy medicinal

products (ATMPs). The responsibilities of these parties and applicable regulations

should be taken into consideration.

3.2. Donation, supply and testing of human cells and tissues used in the manufacture of

investigational advanced therapy medicinal products (ATMPs) should be performed

according to the "Regulation on Human Tissues and Cells and Safety of Related

Centers”.

3.3. Particularly if the investigational ATMP to be used in clinical trials contains human cells

and tissues, the legal requirements for donors should comply with the relevant

regulation.

3.4. If the tissues and cells used in the production of investigational ATMP are derived from

animal sources, the processes relating to donation should comply with the Good

Manufacturing Practices (GMP).

4. TISSUE CENTERS OR BLOOD CENTERS AND ANIMAL FACILITIES

4.1. The responsibilities of the tissue center or the blood center and the supplier organization

with regard to donation, supply, testing, traceability requirements and other technical

requirements (e.g., processing, handling, storage and distribution) of human tissues and

cells, including blood cells, to be used in the production of an investigational ATMP are

outlined in the “Regulation on Human Tissues and Cells and Safety of Related Centers”.

4.2. If tissues or cells of animal origin are used in production of investigational ATMPs, the

requirements for sourcing/donation, supply and testing are stated in the GMP guidelines

and the relevant regulation.



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5. PRODUCTION AND IMPORT OF INVESTIGATIONAL ADVANCED

THERAPY MEDICINAL PRODUCTS

5.1. The requirements for production and import of investigational ATMPs are stated in the

relevant regulation.

6. BASIC PRINCIPLES

6.1. Use of each investigational ATMP must be traceable. Individual products, use of sources,

manufacture, packaging, storage, shipping and delivery to hospital/organization/private

application should be traceable via subject management, reconciliation and disposal or

final procedures.

6.2. The connection number in the supervision chain (from donation to subject application)

should not be more than necessary. If a product or any part of a product is sourced from

a donor, records should contain sufficient details to enable tracing of the connections to

the donor and the individual subject receiving the product (or vice versa).

6.3. Subjects should be followed up during and after the clinical trial period to enable data

collection when required about their own treatment procedures. The content of the

follow-up and, if applicable, the long-term follow-up after the end of the trial should be

determined based on the content of the investigational ATMP and risk analysis and

current information obtained about the relevant investigational ATMP. The procedures

should be continued throughout the required follow-up period and contact with the

subjects should be maintained.

6.4. If tissues and cells of animal origin are used in production of an investigational ATMP,

special cells and tissues of animal origin (e.g., cell sequences used in the production of

viral vectors) should be derived according to the regulatory requirements.

6.5. The medical care of subjects and medical decisions made should be the responsibility of

a qualified physician or dentist. However, the sponsor’s representative must be present

during application of the investigational ATMP to the subject. This expert representative

may provide advice and information to principle investigator, but principle investigator

should remain responsible for the decision to stop or change the method of application.

7. TRACEABILITY

7.1. General Needs

7.1.1. If an investigational ATMP contains human cells or tissues, the sponsor,

manufacturer and investigator/institution at the center where the product is used

must ensure that a traceability system is already in place, in accordance with or

complementary to the requirements stated in the regulations regarding



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traceability requirements for tissue centers and blood centers. In case of tissues or cells

of animal origin, the same traceability requirements apply, as stated in the relevant

regulation.

7.1.2. There should be a connection between the donor/animal source and the donation

process at the tissue center/animal facility; a connection between the donation process

and the product at the manufacturing site; and a connection between the product and

the subject at the investigator’s site. Traceability should be possible in both ways, from

source to subject and from subject to source.

7.1.3. Good clinical practices include accountability/transparency requirements for

investigational products (IP). These requirements contribute significantly to

traceability starting from the manufacturer to the release of the IP. Traceability

requirements may be met by establishing sites that enable combination of traceability

and IP accountability in order to process each particular requirement.

7.1.4. Traceability requirements should be in line with the requirements outlined in the GMP

guidelines.

7.1.5. Should the clinical trial be suspended or discontinued prematurely or the product

development interrupted, the sponsor’s obligation to ensure that the traceability system

is continued must remain. If ownership of the investigational ATMP is assigned to

another legal institution, the new owner must assume the responsibility to maintain the

traceability. Should the sponsor go bankrupt or be liquidated, or if the ownership is not

assigned to another legal institution, the traceability records are submitted to the

national competent authority.

7.1.6. Traceability methods and documentation process must be explained in the clinical trial

protocol and modified if necessary.

7.1.7. Traceability requirements should be in accordance with the regulations for free

distribution and processing of personal information. Thus, the system must allow the

complete traceability criteria, from donor to recipient, by providing the following,

using anonymous encoding systems:

7.1.7.1. The identity of human donors should be protected and these donors should

only be identified by code numbers that can be traced back to the tissue centers/blood

centers and the full identification procedures.

7.1.7.2. The identity of subject should be protected and these subjects should only be

identified by code numbers that can be traced back to the full identification procedures

by the investigator’s site.



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7.2. Responsibilities

7.2.1. Regarding the investigational ATMP, the sponsor is responsible for ensuring that

the traceability system is established and maintained. The system must ensure

tracking of the individual products or starting materials and raw materials

including all materials that come into contact with cells or tissues contained in the

product, and use of sources, manufacturing, packaging, storage, shipment and

delivery at the investigator’s site using the individual product through voluntary

or other final compliance, disposal or destruction of the product.

7.2.2. If more than one party is included, the sponsor should ensure that the tasks of

each party are complete and determined and that traceability integrity is

maintained (e.g., the investigator who obtains tissues or cells from an autologous

donor prior to the production of the investigational ATMP should be the same

investigator at the site who is responsible for management of subjects).

7.2.3. The sponsor should ensure that a connection between the investigator’s site

where the product is used and the donor/donation supplier organization and the

investigational ATMP is established and should guarantee that the traceability

system is established and maintained with the help of agreements made between

the tissue center or the blood center or the animal facility, the manufacturer and

the investigator’s site.

7.2.4. The tissue center/blood center, supplier organizations or animal facility are

responsible for using a traceability system, for supply and donation of cells or

tissues required for production of investigational ATMPs, to trace the material

back until delivery to the manufacturer. These activities should be in accordance

with the relevant guidelines.

7.2.5. The manufacturer is responsible for using a traceability system for the

manufacturing period between reception of the finished investigational ATMP

from supplier organization, the tissue/cell center or blood center or animal facility

to delivery of the investigational ATMP to the sponsor for use in the clinical trials

and delivery to the clinical trial site. Supply or delivery of the investigational

ATMP to the sponsor is performed or controlled by the manufacturer. If the

sponsor monitors delivery of the investigational ATMP from the manufacturer to

the clinical trial site, the sponsor is responsible to ensure traceability of these

process stages.



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7.2.6. The investigator or pharmacist is responsible for implementing a subject and

product traceability system at the clinical trial site. This system should include

details that enable to connect each product with the investigator or the subject

receiving the product.

7.3. Archiving for Traceability Process by Sponsor, Manufacturer, Investigator and Trial Site

7.3.1. The sponsor of the site where the investigational ATMP is used should retain any

part of the traceability records of the tissue center/supplier organization, animal

facility, manufacturer and trial site for at least 30 years after the expiry date of the

product or for a longer period, if required by the clinical trial approval conditions

or based on the agreement with the sponsor. For tissue centers, if this period is

longer than the period mentioned in the relevant regulation, the sponsor should

ensure with agreements that traceability records are retained throughout the

specified period.

7.3.2. The minimum data set to be retained by each party is detailed in ANNEX-1.

8. SAFETY REPORT AND LONG-TERM FOLLOW-UP

8.1. Reporting of adverse events and reactions by the sponsor and principal investigator in

relation to clinical trials is stated in the relevant regulation. New events relating to the

conduct of the trial and development of the investigational ATMP and that may affect

the subject’s safety should be reported within the specified time frame using the

expedited reporting procedure. This procedure should include the following at a

minimum:

8.1.1. Serious adverse events which are related to the trial methods and may require an

amendment in the conduct of the trial;

8.1.2. Significant hazards for subject population.

8.2. The sponsor should provide the principal investigator with necessary information and

training relating to product-specific requirements or any other additional protocol for

adverse event reporting. The reporting process should be clearly explained and detailed

in the clinical trial protocol. The following safety issues should be addressed:

8.2.1. Adverse events relating to the product application procedure (surgical or other),

8.2.2. Suspected and confirmed infection conditions,

8.2.3. Unexpected reactions (e.g., hypersensitivity, immunological, toxic or other

reactions and re-emergence of the current virus, as a result of a modification in

production or function of the viral vector),



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8.2.4. Adverse events relating to a product error (including lack of efficiency),

8.2.5. Adverse events relating to medications required to be used concomitantly (e.g.

immunosuppression),

8.2.6. Adverse events relating to medical devices which are part of the product or used

for product application.

8.3. The differentiated cause-effect assessment of the safety issues mentioned above should

be explained in the clinical trial protocol and implemented in the adverse event

reporting system.

8.4. If a serious adverse reaction is observed with an investigational ATMP containing cells

or tissues or with combined investigational ATMPs, all relevant parties should be

notified.

8.5. The necessity, period and nature of the follow-up procedure should be determined by

the sponsor, based on a risk analysis including close contact, and current information

obtained about the investigational ATMP and the nature of the investigational ATMP.

The sponsor should also consider the relevant regulation concerning follow-up and risk

evaluation of subjects receiving the special forms of investigational ATMPs for more

detailed information about the required follow-up type and period.

8.6. The follow-up process should be adapted to the specific product requirements,

explained in the protocol and amended as necessary in line with the development

studies with the investigational ATMP; it should clearly define the follow-up activities

and should be performed before and after the end of the clinical trial.

8.7. The rationale for the selected follow-up, including the current sponsor information,

should be documented and retained as a required clinical trial document.

8.8. The follow-up procedure should consider the following aspects:

8.8.1. Follow-up for the protection of the subject (for example, clinical follow-up),

8.8.2. Follow-up with the aim to collect personal data (may not require all subjects), e.g.

safety follow-up and efficiency follow-up.

8.9. All subjects participating in a clinical trial conducted with an investigational ATMP

should receive an alarm card from the principle investigator, which should at least

contain the name of the subject, contact number of the principle investigator and

information about the medical treatment received and should be approved by the ethics

committee, permitted by the Turkish Medicine and Medical Device Agency and

previously agreed by the sponsor.



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8.10. The protocol should define the end of the trial and which follow-up procedure will be

used after termination of the trial. Safety and efficiency follow-up (like trial visits),

requiring an effective data collection procedure, should be part of the clinical trial,

whereas clinical follow-up and passive data collection procedures should be performed

after termination of the trial.

8.11. If follow-up is required after termination of the trial, particularly if follow-up involves

a long period of time, the sponsor should ensure that a procedure is in place for

follow-up of subjects undergoing procedures with the product, even if product

development is interrupted or the (former) sponsor ceases to exist as a legal

organization. This procedure should be stated in the protocol in a way that it can be

amended when necessary and archived as follows:

8.11.1. Appropriate information about follow-up of subjects after end of clinical trial,

provided to the healthcare authority which acts as a center for specific clinical

trials,

8.11.2. Telephone numbers providing data/consultancy in case of complications,

8.11.3. In case of serious adverse reactions, the Turkish Medicine and Medical Device

Agency, study site and sponsor should be notified and in case of safety/efficiency

issues, other sources of available data and independent records and the subject

alarm cards, informing the investigators about the product, should at least contain

the subject’s name, a 24-hour available contact number of the investigator and

information about the medical treatment. These should be previously agreed by

the sponsor, approved by the ethics committee and permitted by the Turkish

Medicine and Medical Device Agency. These items can be the same as those used

in the clinical trial, if they are not amended or provided as additional information

to conform to advanced follow-up procedures after termination of the trial.

8.12. If a subject withdraws from the trial voluntarily or at the discretion of the investigator,

follow-up should be continued depending on the consent obtained from the subject.

9. Turkish Medicine and Medical Device Agency

9.1. When assessing the approval for a clinical trial using an investigational ATMP,

Turkish Medicine and Medical Device Agency consider the adequacy of the follow-up

strategy and traceability arrangements, including definitions of completion of trial and

risk assessments.

10. ETHICS COMMITTEE



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10.1. To issue an ethical opinion about clinical trials requiring use of an investigational

ATMP, the ethics committee should carefully consider the relevant regulation and the

following aspects:

10.1.1. Traceability arrangements for protection and confidentiality of the subjects’

personal data,

10.1.2. In case of problems arising after end of the trial, information to be provided to the

subject for each product use (alarm card) and follow-up arrangements prior to and

after end of the trial, including the subsequent procedures for subjects

withdrawing from the trial,

10.1.3. Arrangements regarding close contact with recipients during follow-up,

10.1.4. for ethical issues relating to suitability of specific investigational ATMPs, written

informed consent forms and other documents,

10.1.5. For management of the investigational ATMP, situations where the sponsor’s

representative has to be present when the investigational ATMP is applied to the

subject,

10.1.6. Irreversible contents of specific investigational ATMPs and information provided

to subjects on this subject,

10.1.7. Special conditions where the donor is a relative of the subject, in order to protect

from “sibling/parent” pressure.

11. PRINCIPAL INVESTIGATOR AND OTHER INVESTIGATORS

Principal investigators and other investigators in clinical trials of investigational

ATMPs should:

11.1. establish and maintain a traceability system at clinical sites,

11.2. retain their parts of traceability records of a relevant person,

11.3. be aware of the reporting procedure of adverse events and reactions, including

reactions to application of the investigational ATMP,

11.4. have knowledge about the risk analysis of the investigational ATMP,

11.5. have knowledge about requirements of storage, handling, management, disposal and

elimination of the investigational ATMP, including environmental risks and dangers

resulting from close contact and product handling,



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11.6. have knowledge of requirements for use, application, implementation or management

of the investigational ATMP and its clinical, efficiency and safety follow-up,

11.7. ensure that special requirements for application of the investigational ATMP, such as

standardization of healthcare professionals’ surgical methods and training, are

forwarded to the study site by the investigator, including surgeons and other experts,

11.8. Inform trial subjects and, if applicable, their legal representatives about issues relating

to the investigational ATMP.

12. INFORMED CONSENT FORM

Apart from the provisions in the relevant regulation, an informed consent form or any

other written information provided to trial subjects should particularly contain

following issues:

12.1. Traceability arrangements, including provisions for protection and confidentiality of

the subjects’ personal data,

12.2. In case of problems arising after end of the trial, information to be provided to the

subject for each product use and follow-up arrangements prior to and after trial

termination, including the subsequent procedures for subjects withdrawing from the

trial,

12.3. Unsuitable conditions for long-term follow-up, if applicable,

12.4. Definition of relationship to the follow-up procedure following trial termination and

definition of trial termination,

12.5. The irreversible nature of the investigational ATMP, if applicable,

12.6. The need for the sponsor representative to be present for help and support during

management of the investigational ATMP, if applicable,

12.7. Risks and measures, including reduction procedures of investigational ATMPs

requiring gene therapy,

12.8. Any information obtained during the follow-up procedure and guiding information

about how possible risks resulting from close contact should be forwarded.

13. SPONSOR

13.1. The sponsor should establish and maintain a traceability system at clinical sites,



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13.2. The sponsor should retain parts of the traceability records for a specified period,

13.3. The sponsor should implement the appropriate adverse events and adverse reactions

reporting procedure required by the relevant regulation for investigational ATMPs,

13.4. The sponsor should provide information and documents, stating that the ongoing risk

analysis is performed and provided based on information about the product type and its

purpose of use, provided to the subject and the investigator assigned to the clinical trial

through the investigator’s brochure or its updates or through informed consent forms or

their updates,

13.5. The sponsor should share the risk analysis for combined products and the risk

management plan for the device part with the investigators,

13.6. The sponsor should define the need, period and nature of the necessary clinical, safety or

efficiency follow-up, including the procedures performed after withdrawal of subjects,

13.7. The sponsor should ensure that special requirements for application of the

investigational ATMP, such as standardization of surgical procedures and training

processes used by the principle investigator and other investigators, are implemented,

13.8. The sponsor should have knowledge about requirements of storage, handling,

management, disposal and elimination of the investigational ATMP, including

environmental risks and dangers resulting from close contact and product handling,

13.9. The sponsor should provide training to investigators about a specific treatment

requiring collaboration and about the use, application, implementation or management

procedures of investigational ATMPs that may require surgical procedures which may

affect safety and efficiency of the product. The sponsor should obtain information for

the standardization and optimization of these procedures during clinical development.

The sponsor should also determine whether his/her personnel should play a role in

these procedures and explain this in the agreements made with the clinical trial site and

in the protocol or related documents submitted to the ethics committee and the Turkish

Medicine and Medical Device Agency,

13.10. The sponsor should consult the national competent authorities about bio-safety, if

applicable.

14. PROTOCOL

Considering the contents of the protocol, the sponsor should at least take the following

issues into consideration:

14.1. When designing the protocol, the variables for the diseases and the nature of the used

investigational ATMPs should be considered; the protocol should estimate the important

flexibility that may be required for addressing this variability in the use of specific

investigational ATMPs. For example: the acceptable range for the cell numbers



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and cell applicability during administration to the subjects, acceptability windows for

inclusion and exclusion of criteria.

14.2. If the investigational ATMP contains human cells or tissues, the protocol should

contain a short description of the following:

14.2.1. Verification that donation, supply and testing procedures of human tissues and

cells are in accordance with the relevant regulation,

14.2.2. Whether the donor type and donation is part of the trial procedure,

14.2.3. Compatibility of the compliance criteria of the donated material with the

specified requirements.

14.3. If the investigational ATMP contains a medical device (e.g., a combined ATMP), the

protocol should include a short description of the following:

14.3.1. Device characteristics, performance and purpose,

14.3.2. A rationale for combining the investigational ATMP with the medical device,

which may provide information about the effects alone or in combination,

14.3.3. Compliance of the product with the essential requirements stated in the relevant

regulation.

14.4. When necessary, detailed instructions for trial blinding should be provided (e.g., when

the person responsible for subject randomization to the examination needs to remain

blinded or when the person responsible for application of the investigational ATMP

needs to be blinded, while the person at the clinical site cannot be blinded at the

preparation stage of the investigational ATMP).

14.5. The traceability procedures should be documented.

14.6. Information relating to the specific requirements for safety reporting, including the

procedures performed during the follow-up period after termination of the trial should

be included.

14.7. The termination of the trial should be described and its relation to the follow-up period

following termination of the study should be clarified.

14.8. Information about the required follow-up strategy (including the follow-up

procedures after study termination) for the investigational ATMP, together with the

rationale and goals based on an adequate risk evaluation, should be included.

14.9. Regarding the follow-up strategy, in particular the specific requirements for subjects

withdrawing from the trial voluntarily or at the discretion of the investigator should be

stated.



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14.10. If there is a specific application requiring special treatment with collaboration and this

application requires surgical procedures that may affect product efficiency or safety,

information about application of an investigational ATMP should be provided. If

applicable, this should contain information regarding the standardization and

optimization of the required procedures, including surgical procedures.

14.11. For application of an investigational ATMP, information and rationale should be

provided concerning the necessity of the sponsor representative to be present during

the administration of the investigational ATMP to the subject.

14.12. Instructions for whether a local preparation or a dilution is necessary should be

included.

14.13. For investigational ATMPs requiring gene therapy, information about viral reduction

and necessary measures should be provided, if applicable.

15. INVESTIGATOR’S BROCHURE

Considering the contents of the investigator’s brochure, the sponsor should at least

take the following issues into consideration:

15.1. Explanation of the scope and adequacy of the available information and their

limitations,

15.2. Information obtained from the ongoing risk analysis, based on the available data about

the purpose of use and product type, including the risk associated with the application

method (e.g., surgical operation, concomitant medication and related devices),

15.3. Information about the risk management plan (for launched products),

15.4. Information about the risks resulting from a product error,

15.5. Information about the safe use, storage, prevention and elimination of the product,

15.6. Information about short- and long-term safety issues relating to the investigational

ATMPs, such as issues relating to medical devices for combined ATMPs or infections,

immunogenicity/immunosuppression and malignant transformations.

16. REQUIRED DOCUMENTS

16.1. For maintaining records, the rules stated in the relevant regulation are applicable.

Traceability records should be stored for a minimum of 30 years after the expiry date of

the product or for a longer period if set forth in the agreement with the sponsor or

required by the conditions of clinical trial authorization.



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16.2. While protecting the data stipulated by law for both the donor and the clinical trial

subject, each party should make any required information available related to subject

information of the subjects taking part in the clinical trial conducted at the relevant

clinical trial site with the investigational ATMP and donor information at the supply

field of the investigational ATMP prior to completion or termination of the trial, during

the trial and subsequent processes with the aim to ensure two-way traceability.

16.3. Prior to the beginning of the clinical trial phase, during the planning stage, the

following documents should be prepared and filed before the formal start of the trial:

16.3.1. Tissue center/blood center, manufacturer, sponsor and investigator/trial site file:

Procedures, responsibilities and documentation details required to document the

relation to the subject receiving the donor product (or vice versa),

16.3.2. Sponsor file:

16.3.2.1. Documents used to determine the follow-up strategy,

16.3.2.2. Information about the required follow-up strategy (including the

follow-up procedures after study termination) for the investigational

ATMP, together with the rationale and goals based on an adequate risk

evaluation.

16.4. During the clinical trial, the following documents should be included in the file:

16.4.1. Tissue center/blood center or animal facility file:

16.4.1.1. Traceability records connecting the donor/animal source to the

donated material,

16.4.1.2. Updates of procedures, responsibilities and documentation

details required to document the relation to the subject receiving the

donor product (or vice versa).

16.4.2. Manufacturer file:

16.4.2.1. Traceability records for connection of the manufactured

investigational ATMP with the donated material,







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16.4.3.1. Traceability records for connecting the manufactured

investigational ATMP with the clinical trial site and the clinical trial

site with the patient code,



donor product (or vice versa),

16.4.3.3. Any updates on the documentation used to determine the

follow-up strategy,

16.4.3.4. Information about the required follow-up strategy (including the

follow-up procedures after study termination) for the investigational

ATMP, together with the rationale and goals based on an adequate risk

evaluation.

16.4.4. Principle investigator/trial site files:

16.4.4.1. Traceability records for connecting the manufactured

investigational ATMP with the clinical trial site and the clinical trial

site with the patient code, patient ID and the medical file,




16.5. After the trial is completed or terminated, all documents stated in this guideline and

stored by each relevant party should be filed together with the documents below:

16.5.1. Tissue center/blood center/animal facility file: Final traceability records

connecting the donated material with the donor/animal,

16.5.2. Manufacturer file: Final traceability records connecting the manufactured

investigational ATMP with the donated material,


16.5.3.1. Final traceability records connecting the investigational ATMP,

manufactured for the clinical trial site, with the clinical trial site and

the patient code,

16.5.3.2. Documentation of follow-up procedures, collected data and

contact information, clinical follow-up, safety follow-up and

efficiency follow-up.

16.5.4. Principle investigator/trial site file:



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16.5.4.1. Final traceability records connecting the manufactured

investigational ATMP delivered to the clinical trial site and the

clinical trial site to the patient code, patient ID and the medical file,

16.5.4.2. Documentation of follow-up procedures, collected data and

contact information, clinical follow-up, safety follow-up and

efficiency follow-up.

18. REPEALED REGULATIONS

The “Guidelines for Principles and Rules for the Good Clinical Practices of Advanced

Therapy Medicinal Products”, which entered into force pursuant to the Authority Approval

No. 7668, dated 05.09.2011, have been repealed.

19. ENFORCEMENT

These guidelines shall enter into force on their date of approval.

20. ANNEXES

ANNEX-1 TRACEABILITY RECORDS

1. Tissue Centers and Supplier Organizations

As stated in the relevant regulation.

2. Blood Centers

As stated in the relevant regulation.

3. Animal Facilities

As stated in the relevant regulation. In addition:

3.1. Source animal identification

3.2. Donor description including the following at a minimum:

3.2.1. Description of the animal facility

3.2.2. Animal ID number

3.2.3. Location of the facility

3.2.4. Type of donation (e.g., single & multiple tissue; alive & dead)

3.3. Product description including at least the following:

3.3.1. Description of the animal facility

3.3.2. Type of tissue and cell/product (basic terminology), anatomical class, if available

3.3.3. Pool number (if applicable)

3.3.4. Number of aliquots (if applicable)

3.3.5. Expiry date



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3.3.6. Tissue/Cell state (e.g., in quarantine, suitable for use)

3.3.7. Description of the product origin, materials used in the production stages, additives

coming into contact with tissues and cells and their effects on quality or safety.

3.3.8. Determination of the facility providing the final label

3.3.9. Description of the user facility and distribution dates:

3.3.10. Distribution date/Disposal

3.3.11. Description of the user facility

4. Manufacturers

4.1. Information on the material received from the supplier organization, depending on

whether it is a tissue center or an animal facility:

4.1.1. Description of the tissue center/animal facility/any agent (if applicable)

4.1.2. Type of tissue and cell/product (basic terminology)

4.1.3. Pool number (if applicable)

4.1.4. Number of aliquots (if applicable)


4.2. Description of the investigational ATMP, including at least the following:


4.2.2. Description of the product origin, materials used in the production stages, additives

coming into contact with tissues and cells and their effects on quality or safety

4.2.3. Description of the sponsor, contract research organization or principal

investigator/institution/site for the person to whom the product is supplied

4.2.4. Product name/code

4.2.5. Pharmaceutical form, route of administration, dosage unit amounts and strength

4.2.6. Group or code number

4.2.7. Trial reference code

4.2.8. Investigational identification number

4.2.9. Expiry date

4.2.10. Distribution date/Disposal

4.2.11. Launch of the finished product by a qualified person

5. Sponsor

5.1. According to the regulations for good clinical practices, the following documents

should be retained by the sponsor before, during and after the trial:

5.1.1. Shipping records of the IP

5.1.2. IP certificate of analysis

5.1.3. Assignment of treatment and decoding documentation

5.1.4. IP traceability at the site, covering the final usage of both used and unused products

5.2. These records and the necessary information for traceability purposes and the

minimum data set should be retained for 30 years after the expiry date of the product

or for a longer period, based on the conditions of the clinical trial authorization and the

agreements made. These should at least include the following:

5.2.1. Description of manufacturing site



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5.2.2. Description of the principle investigator/institution using the investigational

ATMP





5.2.7. Trial subjects' identity number

5.2.8. Expiry date

5.2.9. Date of application

5.3. In addition to those mentioned above, the investigator’s brochure and the latest

version of the protocol should be retained for the same time period to provide

information about the product and application.

6. Principal investigator and trial site for human application

6.1. According to the regulations for good clinical practices, the following documents

should be retained by the sponsor before, during and after the trial:

6.1.1. Shipment records of the IP

6.1.2. IP certificate of analysis

6.1.3. Assignment of treatment and decoding documentation

6.1.4. List of subject identification codes

6.1.5. IP traceability, covering the final usage of both used and unused products

6.2. These records and the necessary information for traceability purposes and the

minimum data set should be retained for 30 years after the expiry date of the product

or for a longer period, based on the conditions of the clinical trial authorization and the

agreements made. These should at least include the following:

6.2.1. Description of principle investigator and trial site

6.2.2. Whenever applicable, description of sponsor and contract research organization,

6.2.3. Description of manufacturing site





6.2.8. Trial identification code

6.2.9. List of subject identification codes (to connect trial subject code to subject name)

6.2.10. Expiry/retesting date

6.2.11. Date of application

6.3. Product name/code, trial reference code, trial subject code, date of application and

dosing information should also be included in the mentioned medical records, in order

to connect these to the retrospective product description and the prospective sponsor

and investigator traceability records.

6.4. Any records at the trial site, containing information about unused or disposed products

and their final state, should be retained.

Guidelines for principles and rules for good clinical practices of advanced therapy medicinal...

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