Regulatory news - July 2018

Keep up to date with regulatory news from around the world with the Cell and Gene Therapy Catapult regulatory newsletter.


European Commission (EC)

New guidance on the implementation of the regulatory requirements for medicines used under the GMO framework

Clinical trials conducted in European Union (EU) with Investigational Medicinal Products (IMP) that contain or consist of Genetically Modified Organisms (GMOs) must comply with applicable requirements under Directive 2001/18/EC ("deliberate release framework") and/or under Directive 2009/41/EC ("contained use framework") in addition to the legislation governing clinical trials. This GMO regulatory framework aims to ensure a high level of protection for human health and the environment.

Given the wide-range of gene therapies used in clinical trial over the last decade, a need has been identified for greater guidance on the implementation of the GMO regulatory framework. The document applies only to human cells genetically modified by retro/lentiviral vectors in cases where the applicant demonstrates that:

  1. there is no or negligible risk of formation of replication competent virus, and
  2. the finished product is free of residual infectious viral vector particles that are capable of being released in the environment

The document, jointly developed by the EC services and the Competent Authorities (CA) responsible for the implementation of the clinical trial legislation and those responsible for the implementation of the GMO legislation, has been endorsed by 17 European member states including Austria, Belgium, Cyprus, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Luxembourg, Malta, Norway, Portugal, Romania, Spain and Sweden..

The document, based on accumulated experience with the assessment of these products, includes

  • a section on “Environmental risk assessment (ERA) and data requirements” (in line with deliberate release legislation) including detail on:
    • Demonstration of absence of formation of replication competent virus,
    • Demonstration of absence of residual infectious viral vector particles in the transduced cells

This section is accompanied by an annex called “Specific ERA” designed for products intended to be used as investigational medicines. The annex demonstrates that these products have no hazards to animal health or the environment and negligible risks for human health for the relevant human hazards scenarios i.e. accidental transfer to immune incompetent individuals, erroneous administration to a different patient, donation of blood, cells, tissues or organs to immune-incompetent thirds provided that relevant control measures are implemented by the applicants.

  • a section on “Manufacturing requirements and containment levels” (in line with contained use legislation) recalling that the manufacturing of viral vectors and the ex vivo transduction of human cells with viral vectors should be performed under biosafety level (BSL) 2 but offering the possibility to downgrade to BSL 1 post transduction manufacturing activities under certain conditions.

The good practice should be read in conjunction with the common application form developed at the same time and endorsed by almost the same countries (except Czech Republic and Sweden). This common application form can be seen as a first step towards harmonization of the GMO regulatory framework between European countries and intends to standardise the type of information required.

Applicants preparing a GMO submission involving human cells genetically modified by retro/lentiviral vectors in European countries are advised to take into consideration the recommendations of this new GMO good practice guide.

Click here to view the good practice in full.

Click here to view the common application form.

Draft Guideline on “Good Clinical Practice for Advanced Therapy Medicinal Products

The new draft Guideline on Good Clinical Practice (GCP) specific to Advanced Therapy Medicinal Products (ATMP) - developed by the Commission services, the European Medicines Agency (EMA) and the expert group of the CA of the Member States – has been released for consultation. Stakeholders involved in clinical trials with ATMPs are invited to provide comment until 31 October 2018. ATMP are complex and innovative products which may pose specific challenges to the design and conduct of the clinical trials. The document – based on the current accumulated experience – address those specific issues related to ATMP. It includes for example the need of implementation of controls on logistical arrangements to administer product with short shelf-life, the need of specific arrangements for long-term follow up of the subjects, specific training on the mode af administration for some products. The document should be read in junction with the ICH Guideline on GCP applying as well to ATMP.

Click here to view the document in full.

European Medicines Agency (EMA)

One year report on the clinical data publication (Policy 0070)

Since October 2016, the European Medicines Agency (EMA) proactively publishes clinical data submitted by pharmaceutical companies to support their marketing authorisation applications (MAA) for human medicines under the centralised procedure. The clinical data, published on EMA’s clinical data website, include:

  • the clinical overview, providing a critical analysis of the clinical data in the submission package, including the conclusions and implications of the clinical data;
  • the clinical summary;
  • the study reports on the individual clinical studies;
  • three appendices to the clinical study reports, namely the study protocol, the sample case report form used to record information on an individual patient, and documentation of the statistical methods used to analyse the data.

The EMA is the first regulatory authority worldwide to provide open access to clinical data submitted by companies in support of their MAA but other regulators, such as the US Food and Drug Administration (FDA), are also implementing similar transparency measures.

The report published this month covers one year from the launch of EMA’s clinical data website and lists the 50 medicines for which clinical data were published, including orphan, paediatric, biosimilar and generic medicines. The report includes notably the results of a user survey of which the majoritystrongly agree that this initiative:

  • increases public trust in EMA’s decision-making and,
  • allows the reassessment of clinical data.

EMA states that due the current relocation to Amsterdam may impact the publication of clinical data as of the second half of 2018 and in 2019 due to prioritisation of critical activities at the agency

Click here to view EMA report on clinical data access.

Final guideline on the “Quality, non-clinical and clinical aspects of Gene Therapy (GT) medicinal products”

This guideline is a revision of the Note for Guidance on the “Quality, Preclinical and Clinical aspects of gene transfer medicinal products”, which was published in 2001. The revision process started in 2015 is now finalised. The guideline discusses the quality, safety and efficacy requirements for GT. Many of EMA’s modifications are minor changes compared to the initial draft, such as revisions to the wording and additions of references to other texts reflecting the nature of most of the feedback EMA received from the industry.

Click here to view the final guideline.

Click here to view the overview of comments received on the guideline.

Draft revision of guideline on the “Quality, non-clinical and clinical aspects of medicines containing genetically modified cells”

EMA released for public consultation a draft revision of the guideline on “Quality, non-clinical and clinical aspects of medicines containing genetically modified cells” last published in 2012. The guideline has been updated to consider recent developments in the field of genetically modified cell therapies.

  • The quality section has been updated to take account of the evolution of science and regulatory experience with an emphasis on starting materials (also considering implications for genome editing reagents/tools), comparability and validation.
  • The non-clinical section has been supplemented with current thinking on the requirements to conduct non-clinical studies and a specific section (6.3) on the scientific principles and guidance for CAR-T cell and TCR products, induced pluripotent stem cell derived cell-based products and cell-based products derived from genome editing.
  • The clinical section has been updated considering the experience of recent scientific advices and MAAs. An annex on clinical aspects specific to CAR-T cells has been prepared and included.

The guideline is in public consultation until July 2019.

Click here to view the draft revision of the guideline.

EMA identifies gaps in industry preparedness for Brexit

Back in January 2018, EMA launched a survey to gather information from pharmaceutical companies on their Brexit preparedness plans and to identify any particular concerns with regard to medicines supply that may impact. For marketing authorisation holders (MAH) of centrally authorised products (CAPs), Brexit may imply:

  • a transfer of the Marketing Authorization (MA) to a legal entity established in the European Economic Area (EEA), or
  • a change of the qualified person for pharmacovigilance (QPPV) or pharmacovigilance system master file (PSMF) to a location in the EEA including adaptations to their logistics, manufacturing sites, supply chains and contracts.

EMA received feedback from MAHs on over 90% of CAPs with an important step in their regulatory processes in the United Kingdom (UK). Overall, the survey results indicate that the MAHs of CAP are taking steps to make the necessary changes to their MA to prepare for Brexit. However, analysis of the survey responses shows that 88 products are at potential risk of supply. EMA is liaising directly with the marketing authorisation holders who either did not reply to the survey or have indicated in the survey that they do not plan to submit the changes required by 30 March 2019 and have manufacturing sites in the UK only, as this could potentially lead to supply disruptions.

Click here to view the report from EMA survey on Brexit preparedness.


International Pharmaceutical Regulators Programme (IPRP)

Reflection paper on Expectations for Biodistribution (BD) Assessments for Gene Therapy (GT) Products

This month, the IPRP working on regulatory convergence in the ATMP field released reflection paper laying out expectations for non-clinical biodistribution (BD) assessments for gene therapies (GT). BD assessments are conducted to determine the distribution, persistence and clearance of gene therapy vectors in the body, which are critical factors for understanding the effects and safety of a GT.

The general principles outlined in the document are applicable to many GT products, but do not apply to genetically modified cells. The document discussed several aspects of BD studies; considerations for First-in-Human (FIH) clinical trials, design, assay methods, circumstances that trigger additional BD studies.

Another refletion paper from the Cell Therapy WG is expected to be submitted to the management committee for approval in the coming months on “General principles to address the nature and duration of follow-up for subjects of clinical trials using cell therapy products

Click here to view the document.

Click here to view the document.


Food and Drug Administration (FDA)

FDA released six new gene therapy draft guidelines

FDA’s Center for Biologics Evaluation and Research (CBER) has released a series of much-anticipated draft guidance documents on gene therapy products.

The number of gene therapy medicinal products approved by FDA last year (Kymriah®, Yescarta®, Luxturna®) reflects the rapid advancements in this field. With the aim of foster developments of these innovative products the FDA has released six gene therapy-specific draft guidelines t to provide industry andacademia with with guidance for product development and greater regulatory clarity.

The documents, open for public comments until 10 October 2018, are presented in the table below.

Draft guidance name

Draft guidance type

Draft guidance summary

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

  • To supersede the document entitled “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs),” dated April 2008 (April 2008 guidance) (Ref. 1)
  • Provide sponsors with recommendations on how to provide sufficient CMC information to assure safety, identity, quality, purity and strength/potency of investigational gene therapy products.
  • Apply to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device.
  • Organised to follow the structure of the FDA guidance on the Common Technical Document.

Long Term Follow-Up After Administration of Human Gene Therapy Products

  • To supersede the document entitled “Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events” dated November 2006
  • To supplement the guidance entitled “Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus during Product Manufacture and Patient Follow-up; Draft Guidance for Industry” dated July 2018
  • Provide recommendations regarding the design of long-term follow-up (LTFU) observational studies for the collection of data on delayed adverse events following administration of a gene therapy product. Because of some of the additional uncertainty intrinsic to gene therapy i.e. questions related to the durability of the treatment effects as well as the theoretical potential for off-target effects if the genes do not insert correctly, there’s an increased need for robust long-term follow-up of patients in the post-market period.
  • Describe product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for LTFU observations
  • Describes the features related to effective post-market follow up.

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus during Product Manufacture and Patient Follow-up

  • To supersede the guidance entitled, “Guidance for Industry: Supplemental Guidance on Testing for Replication Competent Retrovirus in Retroviral Vector Based Gene Therapy Products and During Follow-up of Patients in Clinical Trials Using Retroviral Vectors” dated November 2006
  • Provide additional recommendations regarding the proper testing for RCR during the manufacture of retroviral vector-based gene therapy products, as well as during the follow-up monitoring of patients who’ve received retroviral vector-based gene therapy products.
  • Recommend the identification and amount of material to be tested.
  • Provide advice on general testing methods
  • New recommendations include:
  • FDA no longer recommend RCR testing on working cell banks for retroviral producer cells.
  • FDA recommends testing a sufficient amount of vector to demonstrate that your vector contains <1 RCR per patient dose.
  • FDA recommends that all retroviral vector transduced cell products be tested for RCR, including those cultured for 4 days or less.
  • FDA recommends providing data to support reduction or elimination of testing ex vivo genetically modified cells for RCR.
  • FDA recommends analysing of patient samples at the following time points: pre-treatment, followed by testing at three, six, and twelve months after treatment, and yearly for up to fifteen (15) years. However, if all post-treatment assays are negative during the first year, collection of the yearly follow-up samples may be discontinued.

Human Gene Therapy for Hemophilia

  • New disease-specific gene therapy guidance
  • Provide recommendations on the FDA’s current thinking on clinical trial design and preclinical considerations to support the development of these gene therapy products for the treatment of hemophilia A and B.
  • Provide recommendations regarding surrogate endpoints that could be used by sponsors pursuing accelerated approval

Human Gene Therapy for Rare Diseases

  • New disease-specific gene therapy guidance
  • Provide recommendations on preclinical, manufacturing and clinical trial design for all phases of the clinical development program for these types of gene therapies.
  • Assist sponsors in the design of clinical development programs, where there may be limited study population size, potential feasibility and safety issues, as well as issues relating to the interpretation of effectiveness.

Human Gene Therapy for Retinal Disorders

  • New disease-specific gene therapy guidance
  • Focus on issues such as administration specific to gene therapies for retinal disorders.
  • Provides recommendations related to product development, preclinical testing, and clinical trial design for such products

Public consultations




Consultation period



Study supporting the Evaluation of the European Medicines Agency Fee System

02 May to 02 Aug 2018

Draft questionnaire



Consultation period



Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

16 Nov 2017 to 18 Dec 2018

Draft guidance