Regulatory news - October 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 and EMA publish joint action plan to further the development of cell and gene therapies

On the 20th October, the EC and EMA published it’s latest action plan to address some of the most pressing issues concerning the regulation of Advanced Therapy Medicinal Products (ATMPs) in the European Union. This comes after its publication on the application of the ATMP regulation in 2014 and contains follow-up on the status of the 19 proposed actions raised in a multi-stakholder workshop at the agency in 2016.

Some of the key action updates from this report include:

  1. The new EC guideline on GMP for ATMPs is expected by Q4 2017
  2. Engagment between the EC and national competent authorities to address the interplay between the GMO and medicines regulation is expected by Q3 2018
  3. A draft EMA guideline for investigational ATMPs, aimed at reducing discrepancies across the EU for ATMPs during clinical development is expected to enter public consultation in Q4 2018
  4. A new EMA scientific guideline on gene therapy and a review of the guideline for genetically modified cells, in light of scientific developments, is expected in Q4 2017 and Q1 2018 respectively. Development of a guidance on ATMP comparability is not expected until Q2 2019

Click here for further detail on the status of the proposed actions.

Commission adopts two acts on GMPs for human medicines

In September, the EC adopted two new acts into European legislation regarding the quality of medicines for investigational and human use. The first supplements Directive 2001/83/EC which originally combined nearly all aspects of European law on medicinal products. Commission Directive 2017/1572 includes 18 articles on varying topics, including conformity with GMPs, compliance with marketing authorisation, pharmaceutical quality systems, personnel, premises and equipment, production, quality control, outsourcing, complaints, recalls and self-inspections.

The second is a delegated regulation supplementing the latest Clinical Trial Regulation No 536/2014 which specifically covers investigational medicinal products and due to come into effect by 2019. Commission Delegated Regulation 2017/1569 sets GMPs for investigational medicines.

Regarding ATMPs, the regulation outlines in Article 16:

The good manufacturing principles shall be adapted to the specific characteristics of the advanced therapy medicinal products when used as investigational medicinal products. Investigational medicinal products, which are at the same time advanced therapy medicinal products, shall be manufactured in accordance with the guidelines referred to in Article 5 of [ATMP] Regulation (EC) No 1394/2007.

This particular article refers to drawing up guidelines in line with the principles of GMP and specific to ATMPs. The guideline went out for public consultation in the second half of 2016 and is currently with the EC, expected for release later this year.

New 10 year report published since implementation of the paediatric regulation

Ten years ago, the EC released a new regulation as part of an effort to encourage more paediatric research.

The paediatric regulation is structured around three main objectives:

  1. to encourage and enable high-quality research into the development of medicines for children;
  2. to ensure, over time, that most medicines used by children are specifically authorised for such use with age-appropriate forms and formulations; and
  3. to increase the availability of high-quality information about medicines used by children.

To meet these objectives, the regulation initially established the Paediatric Committee (PDCO) which is responsible for coordinating the EMA’s work on medicines for children aswell as setting up a system of obligations (i.e. conducting the additional paediatric research), rewards (an orphan reward and a supplementary protection certificate reward) and incentives (recuperating the additional upfront costs by effectively delaying the market entry of competitor products ).

The 18 page report report concludes that:

…the use of rewards was limited to 55 % of the completed PIPs [Paediatric Investgational Plans] and there are instances of over- or under compensation pointing to certain limitations of the current system. Additionally, the PUMA concept with its specific reward has failed to deliver.

In the years since implementation of the regulation, companies have been slow to increase their development of treatments for paediatric populations, particularly in oncology, which is often used as a case study for insufficient advances in an area of high unmet paediatric need.

The publication of this report also follows comments from European regulators and governments last summer, that the paediatric-use marketing authorisation (PUMA) has not lived up to expectations.

Moving forward, the Commision has identified that the overlap and interplay between the Orphan and paediatric regulations requires ‘further scruitiny’, particularly because the orphan reward has not been able to drive paediatric development in a similar way to how it has done for adult orphan development. A joint evaluation of those two legal instruments has been listed as a high priority.

Click here to view the report.

European Medicines Agency (EMA)

Plans for Brexit and business continuity at the agency published

As discussions for a post-Brexit future continue between the EU and UK, the EMA has released it’s 17 page Brexit Preparedness Business Continuity Plan (BCP).

Ensuring continuity of agency operations is the first major topic discussed:

…it is EMA’s aim to operate as long as possible under a “business as usual” scenario whilst in parallel preparing for the consequences of the outcome of the UK referendum, the latter both in terms of (1) the impact on its operations, as well as (2) the physical move to the new EMA premises in the new host Member State (MS). However, if such “business as usual” scenario can no longer apply, dedicated arrangements have to be put in place as laid down in this EMA Brexit preparedness BCP.

To strive for “business as usual” the agency has highlighted a need to maintain current staffing, either through potential entitlements for staff, under staff regulations, or other facilitating arrangements, recruiting additional resources to compensate for staff loss. Should these efforts be insufficient to maintain staff numbers, the BCP would need to be invoked, prioritising agency activities based on their criticality.

Details on the EMA’s approach can be found on the agency's website.

Latest updates ahead of new EudraVigilance launch

The release of the new EudraVigilance system is expected later this month and the EMA has published a few additional updates on what to expect during a transition to the new system. The EudraVigilance system was development in response to the updated European pharmacovigilance legislation adopted in 2012 and impacts medicines that are authorised OR being studied in clinical trials within the European Economic Area (EEA).

The aim of the new system is to allow developers/marketing authorisation holders to report suspected adverse events directly to EudraVigilance rather than to national authorities and promises greater transparency and access to suspected adverse event reports to the public. It will also allow for more efficient collaboration with the World Health Organization (WHO) by providing direct access to WHO's Uppsala Monitoring Centre (WHO-UMC).

The update includes a technical note from the EMA regarding a two week ‘downtime’ when some key EudraVigilance functionalities will be partially or completely unavailable to accommodate the transfer of around 11 million individual case safety reports (ICSRs) to the new system.

Click here for further details on the transition and impacted processes.

United Kingdom


NICE recommends NHS funding for GSK’s Strimvelis to treat children with ADA-SCID

In its first recommendation applying new, higher cost effectiveness limits for treatments of very rare conditions, the National Institute of Health and Care Excellence (NICE), responsible for evaluations of efficacy and cost–effectiveness of new treatments, has recommended the use of Strimvelis for the treatment of ADA-SCID (severe combined immunodeficiency due to adenosine deaminase deficiency) when no suitable matched related stem cell donor is available.

Strimvelis is the second gene therapy for an inherited disease to be licensed in the world, after Glybera which UniQure announced it would be withdrawing from the market. The treatment involves removing bone marrow cells and modifying them outside the body to produce working ADA enzyme. The modified cells are then returned to the patient via an infusion drip into a vein.

Professor Carole Longson, director of the centre for health technology assessment at NICE, said:

Strimvelis represents an important development in the treatment of ADA-SCID, offering the potential to cure the immune aspects of the condition and avoid some of the disadvantages of current treatments. This means that children born with ADA-SCID will now have a better chance of being able to lead as near normal a life as possible, going to school, mixing with friends, free from the constant threat of getting a potentially life-threatening infection.

Click here to view the draft recommendation from NICE.



FDA approves Kite’s Yescarta for treatment of adults with relapsed / refractory Diffuse Large B-cell Lymphoma

In its second gene therapy approval, the FDA recently gave Kite Pharma (recently acquired by Gilead Sciences for $11.9 billion) a green light for Yescarta, a chimeric antigen receptor (CAR) T cell therapy targeting CD19, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment.

The announcement from the FDA was combined with a statement from the Commissioner, Scott Gottlieb who said:

This approval demonstrates the continued momentum of this promising new area of medicine and we’re committed to supporting and helping expedite the development of these products. We will soon release a comprehensive policy to address how we plan to support the development of cell-based regenerative medicine. That policy will also clarify how we will apply our expedited programs to breakthrough products that use CAR-T cells and other gene therapies. We remain committed to supporting the efficient development of safe and effective treatments that leverage these new scientific platforms.

The safety and efficacy of Yescarta were established in a multicenter clinical trial of over 100 adults with refractory or relapsed large B-cell lymphoma. The complete remission rate after treatment with Yescarta was 51%. To further evaluate the long-term safety, the FDA is also requiring the manufacturer to conduct a post-marketing observational study involving treated patients.

Click here to view the full FDA announcment and here for Gilead’s press release.

Novartis submits an indication extension for Kymriah in adult patients with relapsed/refractory DLBCL

In a quick move from the first company to secure a CAR-T cell therapy approval worldwide at the end of August, Novartis recently announced that it has submitted a supplemental Biologics License Application (sBLA) to extend Kymriah’s use to patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL).

The latest submission and follow-up abstract published in advance of the 59th ASH annual meeting in December will put Novartis in head-to-head competition with Gilead and its newly approved CAR-T, Yescarta for the same patient population.

The Novartis submission is based on results from the global, multi-center Phase II JULIET study (NCT02445248) for Kymriah in adult patients with r/r DLBCL. JULIET was conducted in collaboration with the University of Pennslyvania, enrolling patients from 27 sites in 10 countries across the US, Canada, Europe, Australia and Japan.

Click here to view the Novartis press release.

FDA issues draft guidance for breakthrough devices

Based on legislation announced in last years 21st Century Cures Act, the FDA has announced its new breakthrough devices program which supersedes and combines several of the agency's existing programs to speed access to new devices.

The program applies to devices subject to FDA's premarket approval (PMA), de novo, and 510(k) pathways, and all devices accepted to the program are guaranteed priority review status. This status places devices at the top of the review queue and assigns additional review resources. It does not guarantee a faster review time unlike priority review for drugs.

The draft guidance describes some of the new program features which include:

  • Breakthrough Device Sprint Discussion

To support sponsors needing timely resolution of potentially novel issues, FDA offers “sprint” discussions with the goal of reaching mutual agreement on a specific topic within a set time period (e.g., 45 days).

  • Data Development Plan (DDP)

The DDP is a high-level document intended to help ensure predictable, efficient, transparent, and timely device assessment and review by outlining data collection expectations for the entire product lifecycle.

  • Clinical Protocol Agreement

A mechanism for obtaining agreement in writing for clinical protocols, which will be considered binding on both FDA and the sponsor.

  • Regular Status Updates

FDA and the sponsor of a Breakthrough Device may agree to have regular (e.g., bimonthly) status updates. Through these interactions, FDA and the sponsor may discuss general progress of the project and next steps or plans for future discussions.

Click here to view the full draft guidance, out for consultation until the 24th December 2017.

Luxturna gets a unanimous approval from FDA advisory panel

Following Spark Therapeutics’ recent BLA submission for its adeno-associated viral gene therapy, Luxturna, for the treatment of inherited retinal disease, the company met with the agency’s Cellular, Tissue and Gene Therapies Advisory Committee last month. Luxturna’s clinical trial program included 41 participants with vision loss aged 4 to 44 at the time of first administration.

In an effort to characterise the benefit/risk profile of the therapy, the key issues discussed at the meeting were concerning efficacy (treatment of younger versus adult patients and the use of a novel endpoint), safety (particularly with respect to a subretinal injection) and the duration of clinical response. Several of the younger patients also discussed their participation in the trial, noting the ways in which the treatment helped them to regain eyesight, in a similar format to the advisory meeting held for Kymriah last summer.

The panel voted 16 to 0 in favor of approving the subretinal injection.

Click here to view Spark’s briefing document to the FDA and the questions for the advisory committee.

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




Consultation period



Breakthrough Devices Program - Draft Guidance for Industry and Food and Drug Administration Staff*1

25 Oct to 24 Dec 2017

Draft guidance