Regulatory news - December 2017

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


European Commission (EC)

EC creates roadmap for a joint evaluation of Orphan Medicines and Pediatric legislation

Following on the publication of 10-year report on the Paediatric Regulation in October, the EC has identified the overlap and interplay between the orphan and pediatric regulations requires ‘further scrutiny’. The EC has established this month a roadmap for the review of these two pieces of legislation.

The purpose of this evaluation will be i) to look at the strengths and weakness of these two pieces of legislation, both separately and in combination, and ii) give insight on how the various incentives related to this legislation have been used, and their financial consequences, both in general and on a per-stakeholder basis e.g. patients, industry, payers.

A 12-week public consultation is due to start in Q3 2018 and a stakeholder meeting organised by the EC will follow in Q1 2019. Once the consultation is complete, a synopsis report summarizing the findings will be published.

Click here to read the EC roadmap

Public consultation on revision to GMP rules for sterile medicinal products (Annexe 1)

The EC launched from 20 December a three-month public consultation on Annex 1 of Eudralex Volume 4. The document has been developed in cooperation with the World Health Organization (WHO) and the Pharmaceutical Inspection Co-Operation Scheme (PIC/S). The document provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of quality risk management, to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented.

The overall length of the document has significantly increased. A clear revised structure has been adopted as shown the overview table displayed on the first page of the consultation document.

The main changes are considered to be the addition of new guidance on utilities such as water, air and vacuum systems; environmental and process monitoring and the introduction of quality risk management (QRM) principles.

Click here to access to the draft revised Annex 1

European Medicines Agency (EMA)

EMA recommended granting a marketing authorisation for Alofisel for the treatment of complex perianal fistulas in patients with crohn’s disease

Alofisel has received a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) becoming the tenth ATMP and the first allogeneic stem cell therapy recommended for marketing authorisation (MA). Alofisel has been licensed to Takeda for the exclusive development and commercialization outside of the U.S.

Tigenix’s product Alofisel is intended for the treatment of complex perianal fistulas in patients with Crohn’s disease. Complex perianal fistulas are considered one of the most disabling complications of Crohn’s disease and can cause intense pain and swelling, infection and incontinence. Alofisel consists of expanded adipose stem cells which, once activated, impair proliferation of lymphocytes and reduce the release of pro-inflammatory cytokines at inflammation sites. This immunoregulatory activity reduces inflammation and may allow the tissues around the fistula tract to heal.

The clinical program is based on a phase III ADMIRE-CD pivotal study involving 212 patients. After 24 weeks of treatment, half of the patients treated with Alofisel (49.5%) were in remission, compared to a third of the patients under placebo.

Due to the rarity of complex perianal fistulas, Alofisel received an orphan designation on 2009. The grant of the ten years of market exclusivity is currently being assessed by the Committee for Orphan Medicinal Products (COMP) based on available information.

Click here to read the EMA’s announcement

Click here for Tigenix press release

Brexit news from EMA

Following the EU decision to relocate EMA’s headquarters to Amsterdam on 20 November 2017, the agency began promptly working with the Dutch authorities to prepare for the move. It is already known that EMA's new permanent headquarters, the tailor-made Vivaldi building, will not be ready before November 2019 - eight months after Brexit. The Dutch government will offer temporary premises to EMA from 1 January 2019 until the building is ready. An agreement between EMA/Netherlands has been reached on a joint governance structure to steer and oversee the relocation project, with plans to progress activities within five work streams: temporary premises; permanent premises; staff relocation; financial and legal aspects; external communication.

Click here to read more information about EMA relocation

The UK’s withdrawal from the EU will impact on the activities of the Agency. The business continuity plan enters its second phase in January 2018 shifting resources from non-essential functions to work on Brexit-related issues. "This suggests that EMA will be able to maintain its core activities, but also signals that in other areas the agency will have to temporarily reduce or suspend activities" EMA said. A methodology for the redistribution of the work currently carried out by the UK’s national competent authorities has also been established. Details will be published on the full work program 2018 in the first quarter of next year.

Click here to read more information about the business continuity plan

EMA has updated the Q&A helping pharmaceutical industry to get ready for Brexit Some new topics have been inserted. For instance, orphan designation applications submitted after 29 March 2019, “patients in the UK should no longer be taken into account in the calculation of the prevalence of the disease in order to meet the requirements for orphan drug designation as set out in Regulation (EC) No 141/2000 i.e. a condition affecting no more than 5 in 10 thousand persons in the Union (EEA)

Click here to access to the updated Q&A related to the United Kingdom's withdrawal from the European Union

United Kingdom

Human Tissue Authority (HTA)

Government’s response to the public consultation on the coding and import regulations for human tissue and cells

The Department of Health (DH) published the Government’s response to the consultation on Human Tissue (Quality and Safety for Human Application) (Amendment) Regulations 2017. The objectives of the amendment Regulations are to transpose into UK law the two below EU directives:

  • The coding Directive (EU) 2015/565 affecting all HTA establishments licensed for human application and brings in measures to implement a Single European Code (SEC)
  • The import Directive (EU) 2015/566 affecting any establishment that currently is, or will in the future be, importing tissues and cells for human application

These Directives aim to facilitate traceability and to ensure that there are equivalent standards for imported tissues and cells in the UK. This amendment Regulations is expected to come into force in the UK on 1 April 2018.

Minor amendments have been made to the regulations after consultation and a guidance has been finalised providing clarification on coding/import requirements notably for establishments that procure starting material for the manufacture of Advanced Therapy (Investigational) Medicinal Products (AT(I)MPs).

Single European Code

“Will I need to allocate and apply the SEC-DI (Sequence Donor Identification) to material used as starting material for an AT(I)MP?

If tissues and cells are procured as starting material for the manufacture of an AT(I)MP, a SEC-DI has to be allocated after procurement and applied to the accompanying documentation prior to release to the manufacturing site. Establishments that procure starting material for the manufacture of AT(I)MPs may have ‘other’ listed as a tissue category on the TE Compendium, where no category of tissues and cells is available.

Will I need to apply the full SEC to a product classified as an AT(I)MP?

No, the full SEC should only be applied to tissues and cells products released for human application under the Quality & Safety Regulations”

Import licences

“Will I need an import licence to bring the starting material for an AT(I)MP into the UK from inside the EU? Outside the EU?

The EUTCD and Directive 2015/566 cover the donation, procurement, testing and import of human tissues and cells, that are to be used as starting material for AT(I)MP manufacture. An HTA licence for import will be required if tissues and cells are imported into the UK from a third country as starting material.

An import licence is not required for starting material brought to the UK from inside the EU, as long as material is brought in from organisations in the EU that are licensed or accredited under the EUTCD, as implemented by the country of origin.

If implementation of the EUTCD in the country of origin does not include licensing of procurement organisations, please contact the HTA for further advice.

Will I need an import licence to bring to the UK an AT(I)MP from inside the EU? Outside the EU?

If tissues/cells have been manufactured into an AT(I)MP in a third country and no further manufacturing steps take place before clinical use apart from reconstitution, then import will be regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). This is subject to the authorisation referred to in Article 13 (1) Directive 2001/20/EC, cf. Article 9(1) Directive 2005/28/EC.

Similarly, if partial manufacture of the AT(I)MP has already taken place in a third partycountry before import of the intermediate product, this will also be covered by the same legislation and its import will be regulated by the MHRA”

Click here to read the government’s response in full

Click here to read the HTA guidance on coding and import regulations for tissues and cells in the human application sector


Food and Drug Administration (FDA)

FDA approves Luxturna, a one-timeAAV gene therapy indicated for the treatment of patients with a rare form of inherited vision loss

FDA closes a successful year of approval in the field of cell and gene therapies (Novartis' Kymriah in August and Gilead’ Yescarta in October) by authorising this month a new adeno-associated virus gene therapy product from Spark Therapeutics. The product called Luxturna (voretigene neparvovec-rzyl) is indicated for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The targeted condition, a rare form of inherited vision loss that may result in blindness affecting about 6,000 worldwide, expands the use of gene therapy beyond the treatment of cancer.

The safety and efficacy of Luxturna were established in a clinical development program with a total of 41 patients between the ages of 4 and 44 years. The results show an improved vision in more than 90% of clinical trial participants based on their ability to navigate an obstacle course in low light, 72% a year after treatment.

Luxturna was approved by FDA under priority review and previously received orphan drug and breakthrough therapy designations from FDA. In addition, Spark Therapeutics received a rare paediatric Priority Review Voucher (PRV) of a subsequent marketing application for a different product.

Luxturna will be administered at selected treatment centers in the U.S. by leading retinal surgeons, who will receive specific training on the administration procedure. According to Spark Therapeutics, Luxturna is expected to be available for administration in these treatment centres late in the first quarter of 2018. To further evaluate the therapy's long-term safety, Spark Therapeutics plans also to conduct a post-marketing observational study involving patients treated with Luxturna

In his statement, the FDA Commissioner Scott Gottlieb also announces for next year the development of “disease-specific guidance documents on the development of specific gene therapy products to lay out modern and more efficient parameters — including new clinical measures — for the evaluation and review of gene therapy for different high-priority diseases where the platform is being targeted”.

Click here to read the FDA announcement

Click here to read Spark’s Therapeutics press release

FDA released a draft guidance on clarification of orphan designation of drugs and biologics for pediatric subpopulations of common diseases

As part of the FDA’s orphan drug modernization plan, FDA issued a draft guidance meant to close an unintended loophole that has allowed companies to avoid their obligation to conduct paediatric studies.

Prior to pediatric-specific legislation, FDA started to grant orphan drug designation to drugs for use in pediatric subpopulations of common diseases e.g. when pediatric subpopulation of an non-rare adult disease is below 200,000 in the U.S. to promote the development of drugs for these indications. More recently, several pediatric legislations have been created, notably the Pediatric Research Equity Act (PREA) in 2003. The PREA requires that certain marketing applications for new active ingredients, new indications, new dosage forms, new dosing regimens or new routes of administration contain an assessment of safety and effectiveness for the proposed indication in all relevant pediatric subpopulations. However, this requirement does not apply for these marketing applications for a drug for an indication for which orphan designation has been granted (“PREA orphan exemption”). The interplay of the pediatric-subpopulation designation and the PREA orphan exemption has led to the situation where a sponsor can submit a marketing application for use of its drug in the non-orphan adult population and be exempt from conducting the paediatric studies normally required under PREA if the drug holds at the same time an paediatric-subpopulation designation.

The orphan drug designation to drugs for paediatric subpopulations of common diseases will now not be granted unless

  1. The paediatric population constitutes “a valid orphan subset”, meaning "that use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug," or
  2. the sponsor "can adequately demonstrate that the disease in the paediatric subpopulation is a different disease from the disease in the adult population."

Click here to access to the draft guidance

FDA released a draft guidance on pediatric rare diseases

The draft guidance intends to facilitate drug development in pediatric rare diseases based on Gaucher disease model. The principles presented in this document is a proposal but may be extended to other rare diseases.

The novel approach consists of the use of a controlled, multi-arm, multi-company clinical trial. It aims at addressing the feasibility of developing multiple drug products for a rare disease in a time-efficient manner while minimising the number of patient treated with a placebo. A table at the end of the guidance presents the main inclusion criteria, relevant age groups, suggested efficacy endpoints, and study duration. The guidance address as well the long-term clinical follow-up and recommend an across patient registries, the use of extrapolation from adult studies to demonstrate efficacy.

Click here to access to the draft guidance

FDA released a draft guidance on Investigational In Vitro Diagnostics (IVDs) used in clinical investigations of therapeutic products

The draft guidance released by FDA aims to help sponsors and Institutional Review Boards (IRBs) in making determinations about the risks of investigational IVDs used in therapeutic product studies. It provides information on definitions and concepts for assessing investigational IVDs risks.

The document provides

i) basic information on definitions and concepts for assessing investigational IVD risks e.g. what is an investigational IVD? significant risk devices and non-significant risk devices

ii) a methodology for evaluating the level of risk associated with the investigational IVD. The document provides notably a list of key questions to be considered during risk assessment.

a. Will use of the results from an investigational IVD lead to some study subjects foregoing or delaying a treatment that is known to be effective?

b. Will use of the results from an investigational IVD expose study subjects to safety risks (e.g., adverse events from the investigational therapeutic product) that exceed the risks encountered with the control arm therapy or non-trial standard of care?

c. Is it likely, based on existing knowledge about the relationship between the biomarker and the investigational therapeutic product, that incorrect results from the investigational IVD would present a potential for serious risk to study subjects?

d. Does use of the investigational IVD require invasive sampling that is not part of standard of care?

The document describes as well how clinical trial designs can affect the risk of investigational IVD use.

iii) FDA’s recommendations in evaluating investigational IVDs in the context of clinical investigations for therapeutic products.

Click here to access to the draft guidance.

Draft guidance on CMC changes to certain approved BLA includingcellular, gene and cell-based gene therapy products

This guidance is intended to assist applicants and manufacturers in determining which reporting category is appropriate for a CMC change information to an approved biologics license application (BLA) including cellular, gene and cell-based gene therapy products.

The draft guidance, based on a tiered-reporting system, includes an Annex listing examples of post-approval manufacturing changes and recommended reporting categories by FDA between prior approval, changes being effected in 30 days, annual report. The document provides notably a specific section on changes to the cell banks/cell seeds. The document is currently in public consultation for 3 months

Click here to access to the full guidance


International Conference on Harmonisation (ICH)

Draft ICH Q12 - Technical and regulatory considerations for pharmaceutical product lifecycle management

This draft guideline is proposed to provide guidance on a framework to facilitate the management of post-approval chemistry, manufacturing and controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. This new guideline is intended to complement the existing ICH Q8 to Q11 Guidelines. This guideline applies to active pharmaceutical ingredients and pharmaceutical drug products, including marketed biological products. It is expected that ICH Q12 would not be implemented before the end of next year, as this document is opened to review and comment until December 2018 (see below “Public consultation” section)

The guideline is structured as follows, the main chapters of the core document are:

  • Categorization of post-approval CMC changes
  • Established Conditions (EC)
  • Post-Approval Change Management Protocol (PACMP)
  • Product Lifecycle Management (PLCM)
  • Pharmaceutical quality system and change management
  • Relationship between regulatory assessment and inspectors
  • Post-approval changes for marketed products

The core document is completed by three annexes that provides illustrative examples of ECs, PACMPs and PLCMs for both small and biological products.

This guideline aims to promote innovation and continual improvement, and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments.

Click here to access to the full document

Public consultations



Consultation period


Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development

01 Apr 2017 to 31 Mar 2018

Draft reflection paper