Regulatory news - July 2017

EUROPE

European Commission (EC)

EC publishes the applications from 19 cities offering to host the EMA after Brexit

As of 1^st August 2017, the European Commision has confirmed that there have been 19 bids to host the EMA following the UK’s departure from the European Union.

The EC’s decision on the EMA’s new home will be based on six criteria including operationality guarantees (the availability of appropriate offices), location accessibility, schools for EMA staffers' children (including the availability of multi-lingual schools), access to the labor market and health care for staffers' families, business continuity (to maintain and attract highly qualified staff) and geographical spread.

The cities proposed include:

• Amsterdam
• Athens
• Barcelona
• Bonn
• Bratislava
• Brussels
• Bucharest
• Copenhagen
• Dublin
• Helsinki
• Lille
• Malta
• Milan
• Porto
• Sofia
• Stockholm
• Vienna
• Warsaw
• Zagreb

EMA will temporarily suspend a number of ongoing activities as part of its business continuity plans during this relocation period including:

• Development of the European Medicines Web Portal, a new publicly-available online information source on all medicines marketed in the EU
• EMA’s contribution to the e-submission project that will allow applicants to electronically submit documents linked to authorisation requests for human and veterinary medicines in a secure and efficient way
• Development of a transparency roadmap for EMA that lays out future transparency measures of the Agency
• Participation in the benchmarking of medicines regulatory authorities in the EU as of 2018.

Click here to view the applications from each city.

European Medicines Agency (EMA)

EMA releases new legislation on Good Pharmacovigilance Practice (GVP)

GVP is drawn up to facilitate the performance of pharmacovigilance activities within the EU and applies to marketing authorisation holders, the EMA and competent authorities in Member States. New legislation for GVP was released in July 2012 and to support its implementation, a set of guidelines for the conduct of GVP has been developed by the EMA. These guidelines have been gradually adopted since 2012 and replaced specific modules within Volume 9A of the Rules Governing Medicinal Products in the EU.

On August 2^nd, the EMA published the following updates to the GVP guidelines which include:

• Revision 2 of Module VI on the collection, management and submission of reports of suspected adverse reactions is published as final with amendments in the light of the public consultation
• GVP Module VI Addendum I on the duplicate management of suspected adverse reaction reports
• A public consultation until 13 October 2017 is launched for new Product- or Population-Specific Considerations, namely on the paediatric population

Click here to view the introductory cover note from the EMA, discussing these updates.

Kite submits European Marketing Authorisation Application (MAA) for it’s CAR-T cell therapy, axicabtagene ciloleucel

US-based Kite Pharma has recently announced it’s submission to the EMA for approval of it’s CAR-T cell therapy, axicabtagene ciloleucel, as a treatment for patients with three lymphoma subtypes; relapsed/refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL), which are indicated in patients who cannot receive autologous stem cell transplants.

The submission to EMA’s Committee for Medicinal Products for Human Use (CHMP) and Committee for Advanced Therapies (CAT) is the first of it’s kind in Europe and comes after Novartis’ recent positive panel review at the FDA on its own data for its CAR-T product, CTL019 (see FDA, below).

Kite’s application includes primary data from the ZUMA-1 trial (NCT02348216), a Phase 1/2 trial in treatment-resistant or relapsed aggressive non-Hodgkin’s lymphoma patients which includes 101 patients across the three indications. Axicabtagene ciloleucel was one the first products to receive priority medicine designation (PRIME) from the EMA aimed at supporting the product’s development and accelerate its regulatory review.

The FDA is currently reviewing Kite’s biologics license application (BLA). A final decision is expected by 29^th November 2017.

Click here to view Kite Pharma’s press release.

EMA releases concept paper proposing revision of the Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells

The guidance on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (EMA/CAT/GTWP/671639/2008) came into effect in 2012. It covers all cases of genetically modified cells intended for use in humans, independent of whether the genetic modification has been carried out for clinical indication (i.e. gene therapy medicinal products), for manufacturing purposes or any other reason.

Regarding the update, EMA states:

“Since the current guidelineentered into force 5 years ago, scientific progress has been made in the field that needs to be reflected in the guideline. This affects primarily the availability of improved genome editing technologies which allow for simple approach to genetic modification of cells. The current guideline is focussed on genetic modifications by traditional methods, based on the use of vectors carrying recombinant nucleic acids. The newer technologies may use different starting materials and manufacturing processes. As these new tools potentially allow more precise gene modifications, different approaches to characterise and control modified cells are needed.”

The CAT has recommended a multidisciplinary revision of the current guideline to reflect the development and experience gained in the field, to provide where needed specific quality, non-clinical and clinical guidance for the development of CAR-T cells and related products as well as considerations on genome-editing tools when applied for ex vivo genetic modification of cells.

Click here to view the concept paper.

EMA releases concept paper in advance of new companion diagnostic guideline

The EMA has released a concept paper for public consultation outlining issues it plans to address in an upcoming guideline on the challenges in developing companion diagnostics for personalised medicines. This comes in response to the new in vitro diagnostic medical devices regulation (IVDR), which entered into force on 25^th May 2017 and will become applicable within five years. According to definitions in the new IVDR, assays used to measure predictive biomarkers will, in some cases, be considered companion diagnostics (CDx) and therefore according to the EMA ‘it is timely to consider developing guidance relating to the interface between medicinal products and predictive BM assays, including CDx’.

The agency goes on to say:

“Developments of medicinal products and IVDs are often independent, coming together only superficially towards the end. This may not be ideal as there remain gaps in evidence and validations. Therefore it would be helpful to provide guidance on using a close knit development programme linking the two, and use of clinical trials to generate evidence required to support validation of the diagnostic. The proposed guideline intends to highlight possible options to achieve this.”

It is anticipated that a draft guideline will be available 9-12 months after the end of the public consultation of the concept paper and will be released for 6 months external consultation.

Click here to view the EMA concept paper.

EMA adopts revised guidance on first-in-human clinical trials

EMA has adopted revised guidelines on conducting first-in-human clinical trials which enters into effect on 1^st February 2018. In the past 10 years trial protocols have become increasingly complex, often including different parts within a single clinical trial protocol and aimed at assessing for example single and multiple ascending doses, food interactions, or different age groups.

This revision is an update of the original guidance published in 2007 and is intended to further assist stakeholders in the transition from non-clinical to early clinical development and in identifying factors influencing risk for new investigational medicinal products (IMPs). The document includes considerations on quality aspects, non-clinical and clinical testing strategies, study design and conduct of FIH/early CTs. Strategies for mitigating and managing risks are given, including principles on the calculation of the starting dose to be used in humans, the subsequent dose escalations, the criteria for maximum dose and the conduct of the trial inclusive of multiple parts.

Click here to view the updated guidance.

USA

FDA

FDA advisory panel votes unanimously in favour of CTL019 as first CAR-T cell cancer therapy in the US

On 12th July 2017, an outside panel of experts to the FDA raised questions related to the safety and manufacturing of the Novartis treatment, known as CTL019 (tisagenlecleucel-T) for treatment of relapsed and refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). The Oncologic Drugs Advisory Committee (ODAC) voted 10 to 0 in favor of the benefit-risk profile for the first of a new kind of cancer therapy

The ODAC recommendation is based the Novartis-led ELIANA study (NCT02435849), the first pediatric global CAR-T cell therapy registration trial. Findings from a US multicenter trial and a single site trial examining the safety and efficacy of CTL019 among pediatric and young adult patients with r/r B-cell ALL also supported the recommendation and the Biologics License Application (BLA).

This advisory meeting forms part of the BLA review for CTL019 with the final decision from the agency still pending.

Bruno Strigini, CEO of Novartis Oncology said in a statement:

"The panel's unanimous recommendation in favor of CTL019 moves us closer to potentially delivering the first-ever commercially approved CAR-T cell therapy to patients in need. We're very proud to be expanding new frontiers in cancer treatment by advancing immunocellular therapy for children and young adults with r/r B-cell ALL and other critically ill patients who have limited options. We look forward to working with the FDA as they complete their review."

Click here to view the press release from Novartis.

Click here to view the briefing information for the ODAC meeting and here for the July 12th meeting materials.

International

ICH

New ICH concept paper for upcoming guideline on collecting safety data

The International Conference for Harmonisation (ICH) has released a concept paper and business plan for its upcoming guideline on targeted approaches to safety data collection, originally endorsed as a new ICH topic in November 2016. The internationally harmonised guidance will describe when it’s appropriate to use a targeted approach to safety data collection in some late-stage pre-marketing or post-marketing studies, and how such an approach would be implemented.

According to ICH:

“In the later stages of drug development, when the common side effects of a drug are well-understood and documented, a more targeted approach to safety data collection may be appropriate, as long as patient welfare is not compromised. Under such circumstances, some of the data routinely collected in clinical studies may provide only limited additional knowledge. These data may include: non-serious adverse events, routine laboratory assessments, physical examinations, vital signs, and concomitant medications. By tailoring safety data collection in some circumstances, the burden to patients would be reduced, a larger number of informative clinical studies could be carried out with greater efficiency, studies could be conducted with greater global participation, and the public health would be better served.”

In the business plan released together with concept paper, ICH states that it expects a draft version of the guideline (referred to as ICH E19) will be released by November 2018 and finalised by November 2019. It aims to have the guidance adopted by and sent out to its members in June 2020.

Click here to view the E19 concept paper and business plan.

Public consultations

EUROPEAN MEDICINES AGENCY (EMA)

FOOD AND DRUG ADMINISTRATION (FDA)

HEALTH CANADA