The Reflection Paper discusses methodological aspects of non-interventional studies (NIS) using real-world data (RWD) to generate real-world evidence (RWE) for regulatory purposes.

The draft document on the use of real-world data in NIS to generate RWE is open for comment until 31 August 2024.

While clinical trials are the main source of evidence for the assessment of benefits and risks of medicinal products in marketing authorization procedures (they generally use randomisation, blinding, and a controlled environment), NIS are so far more accepted in post-authorization safety assessments.

Their use to assess the efficacy of medicinal products is hampered by methodological restrictions, such as the absence of randomisation, uncontrolled conditions, non-standardised treatments and uncertainties about data quality and completeness.

The reflection paper provides some examples where NIS using RWD have supported regulatory decision-making processes.

  • To perform post marketing monitoring, investigate safety concerns and evaluate the effectiveness of risk minimisation measures.
  • To describe patterns of drug utilisation.
  • To characterise disease epidemiology.
  • To validate outcome measures.
  • To support the feasibility assessments and the planning of non-interventional post authorisation safety, efficacy and medicinal products utilisation studies.
  • To compare patient characteristics of the study population to those of the clinical practice population in the real-world.
  • To understand the clinical context, by describing standards of care, variability in clinical practices and unmet medical needs.



Non-interventional studies play an increasing role in the generation of evidence to define and complete the totality of the evidence required for novel vaccines and treatments as well as label extension for existing therapies.

The wide variety in research objectives, study designs, data and methods present a challenge for standardisation; on the other hand, the regulatory authorities evaluating the evidence generated from NIS and the different stakeholder groups have different expectations regarding their use and fitness for purpose.

It is important to continue the effort to achieve a shared approach.




  • The use of Real-World Data (RWD) is increasingly embedded in the scientific evaluation of human medicines.The newly published EMA document on the topic (Guidance on Real-world evidence provided by EMA), explains:
    • how RWE, derived from analysis of RWD, can be useful in the context of regulatory decision-making,
    • what types of studies can be conducted,
    • how the EMA can help identify the best resources to address a research question.


    An analysis of the RWD provided by the EMA could help

    • to fill knowledge gaps;
    • to provide independent and transparent RWE sources;
    • to carry out specific analyses tailored to the individual case, e.g. to support the work of EMA’s scientific committees;
    • generate evidence more quickly, shortening the process steps that an MAH would have to comply with to obtain the corresponding study approved;
    • avoid unnecessary duplication and inefficiency that might be typical of studies done by industry.

    An overview of the three main areas in which RWE can support regulatory decision-making is shown in the figure below (taken from the document).


    EMA’s Big data website.

The European Medicines Agency (EMA) has updated the Questions and Answers on the outsourced activities chapter to include “Chains of Contracts” in the pharmaceutical industry, a “setup” where one or more parties (sites/companies) are acting as signatory in a chain of contracts that links them together.

This new setup represents an innovative approach that allows greater flexibility in contractual relationships between different entities involved in the production of medicines, while maintaining high quality and safety standards.

Therefore, the setup introduces one or several separate legal entities between the contract giver such as MAH and MIA holder responsible for QP certification of the product and the contract manufacturer or any other entities included in the manufacturing/supply chain as a contract acceptor. In fact, the GMP activities concerned are sub-contracted over one or several levels”.



The Questions and Answers clarifies in which exceptional cases such a “chain of contract” setup would be acceptable instead of direct written contracts, the conditions to be met are as follows:

  • robust and timely communication – It should be ensured that robust and timely communication between the MAH, the MIA holder responsible for QP certification and the contract manufacturers is secured through the “chain of contracts”.
  • Access to contracts – The MIA holder and the QP should have access to all of the contracts in the “chain of contracts”. Contract manufacturers should have access to those contracts relevant to the activities they perform and the associated responsibilities. As per EU GMP Chapter 4 all these contracts are to be considered as part of the Pharmaceutical Quality System.
  • Written assessment – The MIA holder and the QP should perform a written assessment of the suitability and functionality of such a setup.
  • Notification of changes – Any changes in the “chain of contracts” must be notified to and approved by the MIA holder and the QP prior to the change of the respective contracts being implemented.
  • Audited and evaluated according to EU-GMP standards – All parties involved in the “chain of contracts” setup should be audited and evaluated in accordance with Chapter 7 and Annex 16 of the EU-GMP and should also be reflected in the supply chain diagram.
  • PQR – All contracts within the “chain of contracts” setup are reviewed as part of the product quality review (PQR) process.

Nonostante l’introduzione di questa nuova configurazione, l’EMA ha sottolineato che i “contratti scritti diretti” rimangono ancora la preferenza principale. I contratti scritti diretti sono quelli firmati tra le parti coinvolte direttamente nell’esecuzione delle attività specificate e offrono maggiore chiarezza e trasparenza nel processo.

Despite the introduction of this new setup, EMA underlined that “direct written contracts” are still prefererred. Direct written contracts are those “signed between the parties, that actually perform the activities stated in the contract”.


Guidance on good manufacturing practice and good distribution practice: Questions and answers

After the FDA had already published an initial discussion paper addressing Artificial Intelligence (AI) in the manufacturing of medicinal products, in early 2023, the EMA issued a draft reflection paper outlining the current thinking on the use of artificial intelligence (AI) to support the safe and effective development, regulation and use of human and veterinary medicines, on 19 July 2023.

This paper reflects on principles relevant to the application of AI and machine learning (ML) at any step of a medicines’ lifecycle, from drug discovery to the post-authorisation setting and reports the experience of the EMA in this context, in which scientific knowledge is rapidly evolving.

Recently the success of ChatGPT and related reporting have made the topic of Artificial Intelligence accessible to a wide audience.


General considerations

In general, it is mentioned that AI and ML, if used correctly, can effectively support the acquisition, transformation, analysis and interpretation of data within the medicinal products lifecycle.

A risk-based approach to the development, implementation and performance monitoring of AI and ML tools should enable developers to proactively define the risks to be managed during the life cycle of AI and ML tools.

AI and ML tools, when used properly, can effectively support the acquisition, transformation, analysis and interpretation of data within the medicinal product lifecycle. Section 5 of the document lists some guidelines and documents that may provide useful recommendations for implementing AI/ML applications.

It is essential to highlight that the marketing authorisation applicant or MAH is responsible for ensuring that the algorithms, models, datasets, etc. used are fit for purpose and meet ethical, technical, scientific and regulatory standards.


Content of the document

The document addresses the following topics:

  • AI in the lifecycle of medicinal products
    • Drug discovery
    • Non-clinical development
    • Clinical trials
    • Precision medicine
    • Product information
    • Manufacturing
    • Post-authorisation phase
  • Regulatory interactions
  • Technical aspects
    • Data acquisition and augmentation
    • Training, validation, and test data
    • Model development
    • Performance assessment
    • Interpretability and explainability
    • Model deployment
  • Governance
  • Data protection
  • Integrity aspects
  • Ethical aspects and trustworthy AI



The quickly developing field of AI and ML shows great promise for enhancing all phases of the medicinal product lifecycle.

Finally, the use of AI in the lifecycle of medicines should always comply with existing legal requirements, considering ethics and its underlying principles, and with due respect for fundamental rights. A human-centred approach should be adopted in the development and use of AI and ML.


The EMA has published an overview of the recommendations for the use of herbal substances and/or preparations in the paediatric population as set out in the European Union herbal monographs. The document summarises the indications and possible limitations of use in children, based on the assessment of the Committee on Herbal Medicinal Product (HMPC).

The age range and use of herbal medicinal products within this special patient population, are topics often addressed by healthcare professionals. The purpose of this overview is to provide a summary of the information included in the monographs for ease of reference.

The list is divided into two groups of herbal medicinal products:

  • well-established use -WEU: demonstrated sufficient safety and efficacy data (may only be placed on the market after obtaining a marketing authorisation);
  • traditional use -TU- accepted based on sufficient safety data and plausible efficacy (can be marketed after being registered through simplified registration).

The list is derived from the information contained in the EU herbal monographs, as adopted, and can be consulted either by alphabetical order or according to therapeutic areas, for example, constipation, cough and cold, wye discomfort, gastrointestinal disorders, sleep disorders and temporary insomnia, etc.

For each substance the indications in the therapeutic area, possible herbal preparations referred in the monograph, dosage form and method of administration, Target population and Justification for limited use, for example in children, are listed in a tabular list.


More detailed information is available in the EMA document European Union herbal monographs: Overview of recommendations for the uses of herbal medicinal products in the paediatric population.

To view all EU herbal monographs go to Herbal: European Union herbal monographs.

Last May, EMA opened a brief, one-month public consultation procedure (13 May 2022 – 13 June 2022), on a draft question and answer document on remote certification of batches by the Qualified Person (QP): “Public Consultation concerning the physical Attendance and the Location of Personal Residency of The Qualified Person“.

The COVID-19 pandemic has affected standard way of working, requiring the need to work remotely to ensure operations under business continuity mode.

To minimise risks of shortages while ensuring that the high standards of quality, safety and efficacy of medicines made available to patients in the EU were maintained, EMA has therefore developed, in cooperation between the European Commission and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human Medicine (“CMDh”), guidance on adapting “regulatory expectations” as a result of the new context created.

This guidance contemplates the possibility that the work of QPs needs to be adapted to allow remote batch certification when on-site presence is not possible. The GMDP inspectors’ working group is currently evaluating the possible flexibility for the physical presence of the QP at the authorised manufacturing site when batch certification or confirmation is carried out routinely and not only on an emergency basis.

The draft Q&A document, published on May 11, discusses the appropriate requirements and conditions for allowing QP work remotely.

The text clarifies that since the ultimate responsibility for the interpretation of EU legislation lies with the European Court of Justice, the content of this document is therefore subject to any other interpretation by the European Court of Justice.

Proceeding from the requirements in Annex 16 regarding validation and certification activities carried out by the QP, the text outlines four clarifications, expressed in question-and-answer form:

1.    Is remote batch certification/ batch confirmation by the QP allowed on a routine basis?

2.    Where remote QP certification / confirmation is allowed on a routine basis, what conditions should apply?

3.    Is the QP required to be a resident in the Member State where the authorised site is located?

4.    What are the technical requirements for the remote access and the signature used for batch certification / confirmation?

Commissione Europea, EMA ed HMAs – Q&A on regulatory expectations for medicinal products for human use during the COVID-19 pandemic

The European Medicines Agency (EMA) provides answers to frequently asked questions on Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) on its website. These have been discussed and agreed by the GMP/GDP Inspectors Working Group.

The guide, in the form of a question and answer (Q&A), provides further interpretation of the GMP and GDP guidelines published by the European Commission.

On January 28, 2022, Directive 2001/82/EC – EU Code for Veterinary Medicinal Products was repealed, as a result, the legal requirements for veterinary medicinal products have been updated and will be regulated according to Regulation (EU) 2019/6 of the European Parliament and of the Council on veterinary medicinal products. This regulation includes provisions on authorisation, post-authorisation measures, manufacture, import, export, supply and use of veterinary medicinal products, as well as restrictions and sanctions. Accordingly, the questions and answers have been supplemented and updated.

The new chapter deals with requirements for active substances that are used as starting materials for the manufacture of veterinary medicinal products.

The following are some questions that have been answered:


  1. Do active substances used as starting materials in veterinary medicinal products have to comply with Good Manufacturing Practices (“GMP”) for active substances for human medicinal products?
  2. Are there new obligations for active substances used as starting materials in veterinary medicinal products under the Veterinary Medicines Regulation?
  3. Is a GMP certificate mandatory for manufacturing sites?
  4. Can inspections conducted by third country competent authorities be considered when deciding whether a Union inspection should be triggered?


The complete list of questions and answers is available on the EMA website.