Regulatory Roadmap for the development of human medicinal Products
(Europe focus)
Welcome to the Regulatory Roadmap. This roadmap will help to identify the applicable Regulations and Guidance* for each phase of the development of Human Medicinal Products. It represents a time-based path through the entire lifecycle of a drug, from initial inception through to distribution and pharmacovigilance of the marketed product.
Just click on the various stages below to reveal the information.
Idea Expand
- 'Non GxP' Research
Description
Formulation of an idea or thesis to investigate a particular disease area. For pharmaceutical development purposes this should be linked to potential means of treating disease / curing disease / reducing symptoms / maintaining quality of life associated with producing a medicinal treatment.
Inputs
None
Processes
"Non GxP" Research
Guidance
Outputs
Target Drug / Hypothesis
RQA Courses / Seminars / eLearning
Discovery Research Expand
- 'Non GxP' Research
Description
Scientific investigation of a disease model and potential active candidates to establish possible marketable products.
No formal regulatory requirements exist for scientific research of this type and it must be understood that information gathered at this stage is inadmissible in regulatory filings.
Discovery Research covers the period from target identification to nomination and may be used when clinical studies yield results that require further investigation to:
- Identify potential candidate drugs (CDs)
- Perform preliminary safety & formulation tests
- Confirm pharmacological mode of action (potency & selectivity)
- Identify potential biomarkers
- Perform preliminary PK
- Demonstrate activity in in-vivo and/or in-vitro models
The aim is to select one or more CDs for each target for pre-clinical safety evaluation.
Inputs
Target drug / Hypothesis
Current medical knowledge
Processes
Regulations
Guidance
Outputs
Identification of Test Articles
Scientific Evidence to support hypothesis
Target identified
RQA Courses / Seminars / eLearning
Pre- Clinical Testing Expand
- 'Non GxP' Research
- GLP : Pre-Clinical Research
Pre-Clinical Testing
Description
Research designed to fulfill the requirements of the non-clinical safety section of the common technical document (ICH M4S). Safety evaluation of candidate Investigational Products (New chemical entities and Biologics), known as test articles, governed by Good Laboratory Practice (GLP).
Pre-clinical testing is performed to GLP and covers pivotal toxicology & safety pharmacology studies. This phase continues once clinical trials have commenced to establish the long term safety of new chemical entities.
Non-clinical evaluation of drug safety usually consists of standard animal toxicology studies. These studies usually include assessment of drug exposure, primarily parent drug plasma concentration. Generally, drug plasma concentration and systemic exposure in the non-clinical studies are compared with systemic exposure in humans to assess the potential risks suggested by non-clinical findings and guide monitoring in clinical trials.
Inputs
Processes
“Non GxP” Research
GLP : Pre-Clinical research
Regulations
Control of Substances Hazardous to Health (COSHH)
Animals (Scientific Procedures) Act 1986
GLP : UK Statutory Instrument 3106 (1999)
GLP : OECD Principles of GLP (1997)
GLP: (Codification Amendments Etc.) Regulations 2004
Home office Licensing of in-vivo investigations
Human Tissue Act requirements for in-vitro investigations
Guidance
ICH Safety Guidelines
OECD Series on Principles of Good Laboratory Practice (GLP) and Compliance Monitoring
Quality Assurance and GLP
The Roles and Responsibilities of the Study Director in GLP Studies
The Application of the Principles of GLP to Computerised Systems
Medicines Regulations
M3(R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
MHRA Use of non-GLP compliant facilities for the conduct of study phases
GLP studies can only be run in facilities that are Members of the UK GLP compliance monitoring programme
Human Tissue Authority
Outputs
RQA Courses / Seminars / eLearning
First in man/ clinical trials Expand
- GLP : Pre-Clinical Research
- GMP : Test Article
- GMP : IMP Manufacturing
- GMP & GCP : Trial Supplies
- GCP : Clinical Research (Phases I,II,IIa)
- GCP & GPVP : Pharmacovigilance
First in Man/Clinical Trials
Description
Phase I or First in Man/Clinical Trials - when an investigational medicinal product (IMP) developed and assessed through in-vitro or animal testing, is tested on human subjects for the first time.
Marketed products may fall under the same Regulations if the product is used as part of an interventional trial. (The product must meet the definition of an IMP).
Inputs
Test Article Safety Reports (GMP)
Pre- clinical Data (GLP)
Processes
GCP : Clinical Research (Phases 1)
GCP & GPVP: Pharmacovigilance
GMP : IMP Manufacturing
Regulations
GCP : Clinical Research (Phase 1)
- Clinical Trial UK Legislation
- Clinical Research EU Directives
GCP & GPVP : Pharmacovigilance
GMP : IMP Manufacturing
Guidance
GCP : Clinical Research (Phases 1)
- ICH E6 Good Clinical Practice
- ABPI phase 1 Guidance
- Medicines for human use Eudralex
- Clinical Trials Toolkit
- Serious Breaches Guidance
GCP & GPVP : Pharmacovigilance
- Volume 10 Entry CT3
- Volume 10 Entry CT4
- PV -Volume 10 Entry CT2
- MHRA Good Pharmacovigilance Practice Guide (Purple Guide) publication
GMP: IMP Manufacturing
GDP
Computer Systems Validation
Outputs
- Clinical Study Reports (CSR)
- Data to support the creation of the Common Technical Document for submission for marketing application
- Trial Master File (TMP)
RQA Courses / Seminars / eLearning
Pre- Licensing Activities Expand
- GLP : Pre-Clinical Research
- GMP : Test Article
- GMP : IMP Manufacturing
- GMP & GCP : Trial Supplies
- GCP : Clinical Research (Phases I,II,IIa)
- GCP & GPVP : Pharmacovigilance
Pre Licensing Activities
Description
- Phase II-IIIa research covers subsequent clinical trials conducted prior to a marketing licence application and is designed to gather further data in relation to safety and efficacy to be used as part of the submission. Marketed products may fall under the same Regulations if the product is used as part of an interventional trial. (The product must meet the definition of an investigational medicinal product -IMP.)
- Company Core Safety Information finalised and benefit-risk confirmed.
- Prepare marketing authorisation application (MAA)/new drug application(NDA) dossier.
- The process for gathering data contained in the clinical safety and efficacy section of the common technical document (ICH M4E) and establishing the Processes which formulate the Quality and Chemistry and Manufacturing Controls section of the common technical document (ICH M4Q).
Inputs
Clinical Study Reports
Trial Master File
Data to support the Dossier (Chemistry Manufacturing Control (CMC))
Test Article Safety Reports
Processes
GCP : Clinical Research (Phases II-IIIa)
GCP & GPVP : Pharmacovigilance
GMP : IMP Manufacturing
GMP : Test Article Manufacturing
Regulations
MAA Application
GCP : Clinical Research (Phases II-IIIa)
- Clinical Trial UK Legislation
- Clinical Research EU Directives
GCP & GPVP : Pharmacovigilance
Clinical Trials Directive 2001/20/EC
GMP : IMP Manufacturing
Guidance
MAA Application
- Volume 2A dealing with procedures for marketing authorisation
- Volume 2B dealing with the presentation and format of the application dossier
- Volume 2C dealing with regulatory guidelines
Common Technical Documents
Pre-submission Meeting Guidance
GCP : Clinical Research (Phases II-IIIa)
- ICH E6 Good Clinical Practice
- ABPI phase 1 Guidance
- Medicines for human use Eudralex
- Clinical Trials Toolkit
- Serious Breaches Guidance
GCP & GPVP : Pharmacovigilance
- Volume 10 Entry CT3
- Volume 10 Entry CT4
- PV -Volume 10 Entry CT2
- MHRA Good Pharmacovigilance Practice Guide (Purple Guide) publication
GMP: IMP Manufacturing
GDP
Computer Systems Validation
Outputs
Common Technical Document (CTD)
Prepare MAA/NDA dossier
Licensed/Compliant Manufacturing Facility
Finalise Company Core re Safety information, prepare regions prescribing information
Propose Clinical Phase IIIb and IV plans
Develop Life Cycle Management plans
Benefit-risk confirmed
Patient Risk Management Plan implemented
BARQA Courses / Seminars / eLearning
Licence Granted Expand
- GMP : IMP Manufacturing
- GMP & GCP : Trial Supplies
- GCP : Clinical Research (Phases I,II,IIa)
- GCP & GPVP : Pharmacovigilance
- GMP : Product Manufacturing
- GMP : Distribution
- GCP, GMP & GPVP : Post Marketing Studies
Licence Granted
Description
Manufacturing Authorisation(s) and product licence granted for the medicinal product.
Commencement of post marketing surveillance requirements for the product and commencement/continuation of clinical trials required for line extension or new indications.
Inputs
Common Technical Document (CTD) Dossier
Licensed/Compliant Manufacturing Facility
Processes
GMP : IMP Manufacturing
GMP & GCO : Trial Supplies
GCP : Clinical Research (Phases I-IIIa)
GCP & GPVP : Pharmacovigilance
Regulations
- Control of Substances Hazardous to Health (COSHH)
- Animals (Scientific Procedures) Act 1986
- Statutory Instrument 1031 - SI 2004/1031
- Statutory Instrument 3144 - SI 1994/3144
- ICH M4 - Common Technical Document for the Registration of Pharmaceuticals for Human use
- EudraLex - Volume 2 - Pharmaceutical Legislation Notice to applicants and regulatory guidelines medicinal products for human use
Pharmacovigilance
The reporting obligations under the provisions on pharmacovigilance for authorised medicinal products are set out in Directive 2001/83/EC and Regulation EC No. 726/2004
- Directive 2001/83/EC
- Regulation (EC) No 726/2004
- Regulation (EC) No 540/95 regarding reporting suspected unexpected adverse reactions which are not serious
Clinical Research
- Clinical Trials Directive 2001/20/EC
- Commission Directive 2005/28/EC laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products
Investigational medicinal product (IMP) Manufacturing
- Directive 2003/94/EC laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use
Guidance
Volume 9A of the Rules Governing Medicinal Products in the EU
MHRA: The Good Pharmacovigilance Practice Guide
Product Manufacturing
Computer Systems Validation
Outputs
Label and regulatory approval finalised
Sustain and maximise sales by introducing Life Cycle Management (LCM) line extensions
PRMP implemented, strategy for post launch surveillance defined
RQA Courses / Seminars / eLearning
Variations to a Licence Expand
- GCP & GPVP : Pharmacovigilance
- GMP : Product Manufacturing
- GMP : Distribution
- GCP, GMP & GPVP : Post Marketing Studies
Variations to Licence
Description
Maximised potential/contribution of compound
New indications
Patent extensions
Paediatric studies
Orphan drug status
Inputs
Product Licence
Submission of change request
Life cycle management
Ongoing surveillance
Signal detection
Updates to Company Core Safety Information
Processes
GMP : Product Manufacturing
GMP : Distribution
GCP, GMP & GPVP : Post Marketing Studies
GCP & GPVP : Pharmacovigilance
Regulations
Control of Substances Hazardous to Health (COSHH)
UK Medicines Act 1968
Commission Regulation EC/2141/96 regarding transfer of a marketing authorization
Commission Regulation EC/1084/2003 regarding variations
Commission Regulation EC/1085/2003 regarding variations
Commission Regulation EC/1234/2008 regarding variations
Commission Directive 2009/53/EC (amending Directive 2001/82/EC and 2001/83/EC) regarding variations to marketing authorisations
Product Manufacturing
Distribution
Pharmacovigilance
- Regulation EC/726/2004
- Commission Regulation EC No 540/95 regarding suspected adverse reactions which are not serious
- Commission Directive 2001/83/EC (as amended)
- Guideline on the definition of a potential serious risk to public health 2006/C 133/05
Good Clinical Practice
Guidance
Volume 9A of the Rules Governing Medicinal Products in the EU
MHRA The Good Pharmacovigilance Practice Guide(Purple Guide) publication
Eudralex Volume 2 Pharmaceutical Legislation Notice to Applicants and Regulatory Guidelines Medicinal Products for Human Use
Eudralex Volume 10 Clinical trial guidelines:
Computer Systems Validation
Outputs
Change process(es)
Maintain support to health authorities, routine compliance activities
Maximised potential/contribution of compund
RQA Courses / Seminars / eLearning
Licence Renewal Expand
- GCP & GPVP : Pharmacovigilance
- GMP : Product Manufacturing
- GMP : Distribution
- GCP, GMP & GPVP : Post Marketing Studies
Licence Renewal
Description
Inputs
Periodic Safety Update Reports (PSURs)
PSUR Assessment reports
Post-marketing studies
PRMP
Processes
GMP : Product Manufacturing
GMP : Distribution
GCP, GMP & GPVP : Post Marketing Studies
GCP & GPVP : Pharmacovigilance
Regulations
Guidance
Renewal of licences
Volume 9A of the Rules Governing Medicinal Products in the EU
MHRA The Good Pharmacovigilance Practice Guide (Purple Guide) publication
MHRA Orange Guide
TOPRA - The Organisation for Professionals in Regulatory Affairs
Computer Systems Validation
Outputs
RQA Courses / Seminars / eLearning
Terminate Licence Expand
- GCP & GPVP : Pharmacovigilance
- GMP : Product Manufacturing
- GMP : Distribution
- GCP, GMP & GPVP : Post Marketing Studies
Terminate Licence
Description
The voluntary, or otherwise, termination of the licence to manufacture and market a particular product;
At the end of the product life-cycle, i.e. when the product is off-patent and generic competition has eroded product revenue, the product may be removed from sale following withdrawal of the product from the supply chain and termination of all existing product licences.
Alternatively, the product may be divested and the product licences transferred to the new owner of the product.Inputs
Product Licence
Submission for Termination / Transfer Request
Product Divestment
Processes
GMP : Product Manufacturing
GMP : Distribution
GCP, GMP & GPVP : Post Marketing Studies
GCP & GPVP : Pharmacovigilance
Regulations
Control of Substances Hazardous to Health (COSHH)
Commission Regulation EC/2141/96 regarding transfer of a marketing authorisation
Commission Regulation EC/1084/2003 regarding variations
Commission Regulation EC/ 1085/2003/ regarding variations
Commission Regulation (EC) No 1234/2008 regarding variations
Commission Directive 2009/53/EC (amending Directive 2001/82/EC and 2001/83/EC) regarding variations to marketing authorisations
UK Medicines Act 1968
Product Manufacturing
Distribution
Pharmacovigilance
- Regulation EC/726/2004
- Commission Regulation EC/540/95 regarding suspected adverse reactions which are not serious
- Commission Directive 2001/83/EC
- Guideline on the definition of a potential serious risk to public health 2006/C 133/05
Good Clinical Practice
Guidance
Outputs
Or
Agreement of Licence Transfer
RQA Courses / Seminars / eLearning
*Covers Regulations, legislation and Guidance within the European Economic Area level, not including national legislation except for the UK.
The Roadmap is an overview generated by the RQA Regulatory Roadmap Working Party and is for Guidance only.
Users should ensure that its content is suitable for their particular use.
