Regulatory news: September 2016

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

Europe

European Medicines Agency (EMA)

MolMed’s Zalmoxis® granted conditional marketing authorisation

On 18th August 2016, Italy’s MolMed was granted conditional marketing authorisation by the European Commission for Zalmoxis - an adjunctive (add-on) treatment for haploidentical haematopoietic stem cell transplantation (HSCT) of adult patients with high-risk haematological malignancies.

Zalmoxis supports engraftment and restoration of the immune system after transplant. High-risk patients often undergo haploidentical transplants with a partial stem cell match usually from a family donor, carrying risk of graft versus host disease (GvHD). Zalmoxis involves genetic modification of the HSCT donor’s T lymphocytes with a γ-retoviral vector to express HSV-TK Mut2 (and ΔLNGFR) creating an inducible “suicide gene”, acting as a control mechanism for GvHD. If GvHD occurs following transplantation, the pro-drug ganciglovir or valganciclovir can be administered causing the activated, transduced T cells to undergo apoptosis. This strategy allows for direct targeting of those T cells responsible for intiating GvHD, preventing further development.

Zalmoxis was designated as an orphan medicine in 2003 due to the low number of patients undergoing haploidentical HSCT. Although more data are needed to determine the size of the benefit, EMA’s Committee for Medicinal Products for Human Use (CHMP) has concluded that Zalmoxis’ current benefits outweigh it’s risks. As part of the conditional approval, MolMed is required to provide results from a post-marketing confirmatory study (TK008) by March 2021 in high-risk acute leukaemia patients, comparing haploidentical HSCT followed by treatment with Zalmoxis with haploidentical HSCT containing T cells followed by treatment with cyclophosphamide (an established immunosuppressive administered during GvHD).

15-16 November EMA Workshop (London): Addressing challenges of innovative cancer immunotherapies

The EMA Committee for Advanced Therapies (CAT) will live-streaming a workshop dedicated to the scientific and regulatory challenges of genetically modified cell-based cancer immunotherapy products in November. This is a multi-stakeholder meeting between CAT and developers across industry and academia. Topics will focus on scientific developments in the field, regulatory requirements for product manufacture and testing as well as design of non-clinical studies and clinical development.

Please click here for a draft programme of the workshop.

Updated guideline for potency testing of cell based immunotherapy medicinal products for the treatment of cancer

In July 2016, the EMAs CHMP adopted a minor technical update to the guideline on potency testing of cell based immunotherapy medicinal products for the treatment of cancer (EMA/CHMP/BWP/271475/2006), agreed by the Biologics Working Party at the EMA.

The main purpose of the update was to reflect current best practice with regards to implementation of the 3Rs approach to preclinical research (replacement, reduction and refinement) and therefore a consultation phase was considered to be unnecessary.

Please click here to view the full guidance.

European Commission (EC)

New EC report - pharmacovigilance related activities of EU Member States and the European Medicines Agency concerning medicinal products for human use (2012 – 2014)

The European Commission has published a report on activities by EU Member States and the EMA to monitor the safety of medicines throughout their life cycle. The report gives an overview of the activities of the EU system since the new legislation came into effect in 2012 until July 2015.

Please click here to view the report.

EDQM

New Ph. Eur. general chapter on host-cell protein assays adopted

A new general chapter on Host Cell Protein (HCP) assays will be published in Supplement 9.1 of the European Pharmacopoeia including guidance on the selection, development and validation of an HCP assay. It describes specific considerations for in-house assays (process-specific or platform assays), the preparation of the assay reagents (HCP antigens and anti-HCP antibodies) including the development of a null cell line and a mock manufacturing process; the characterisation of the HCP antigens derived from the mock process; the immunisation of animals and the purification and characterisation of the resulting polyclonal antibodies.

The chapter will come into effect on 1st April 2017.

United Kingdom

MHRA

UK phase 1 trial approved with Cymerus™, a mesenchymal stem cell (MSC) product derived from allogeneic induced pluripotent stem cells (iPSCs)

On 19th September 2016, the Australian-based stem cell company Cynata received an approval from the UK medicines regulator to begin a study investigating the use of Cymerus, an MSC therapy derived from allogenic iPSCs, in pateints with steroid-resistant graft-versus-host disease (GvHD).

Cynata’s platform uses allogenic iPSCs (donor cells) as a starting material for generating mesenchymoangioblasts (MCA) precursor cells which are then differentiated to MSCs and used therapeutically. This process bypasses a reliance on continuous supply of MSC’s from new donors, potentially creating an ‘off-the-shelf’ universal MSC product and a route for more economic manufacturing of this type of therapy.

The immunomodulatory properties of MSCs have led these cells to being of interest in treating GvHD following transplantation, although approaches have generally focused on autologous (patient-specific) MSCs. This study will be conducted in a number of clinical centres in the UK and Australia, recruting patients who have undergone a bone marrow transplant (or similar procedure) and subsequently diagnosed with steroid-resistant Grade II-IV acute GvHD.

Health Research Authority (HRA)

HRA responds to EU Commission’s Clinical Trials Regulation consultations

The following clinical trial guidelines are currently open for public consultation at European Commission:

  • Ethical Considerations for Clinical Trials on Medicinal products conducted with Minors

  • Definition of Investigational Medicinal Products (IMPs) and use of Auxiliary Medicinal Products (AMPs)

  • Summary of Clinical Trial Results for Laypersons

  • Risk proportionate approaches in clinical trials

Please click here to view HRA’s feedback on each consultation.

USA

FDA Approves CLEVECORD™ from the Cleveland Cord Blood Center for stem cell transplant

On 12th September 2016, the FDA issued a biologics license to Cleveland Cord Blood Center for Clevecord, indicated for use in hematopoietic progenitor cell transplantation procedures from unrelated donors in patients with disorders affecting the hematopoietic system that are inherited, acquired, or result from myeloablative treatment. Clevecord is a minimally manipulated stem cell product derived from umbilical cord blood.

FDA Workshops, Meetings & Conferences

Online video available - Public Hearing; Request for Comments – Draft Guidances Relating to the Regulation of Human Cells, Tissues or Cellular or Tissue-Based Products (HCT/P)

The FDA has published videos from a two day public hearing held in September covering comments on draft guidances relating to the regulation of human cells, tissues or cellular or tissue-based products. The purpose of the public hearing was to obtain multistakeholder feedback on the following guidance documents: 

  1. “Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and FDA Staff” – draft guidance released Oct 2015

This new draft guidance provides HCT/P manufacturers, health-care providers and FDA staff with recommendations for interpreting the criterion of “homologous use” as it applies to HCT/Ps.

  1. “Guidance for Industry and Staff: Human Cells, Tissues, and Cellular and Tissue-Based Products From Adipose Tissue—Regulatory Considerations” - originally released Dec 2014

  2. “Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and Food and Drug Administration Staff” - originally released Dec 2014

  3. “Same Surgical Procedure Exception—Questions and Answers Regarding the Scope of the Exception” - originally released Dec 2014

Day 1 of public hearing

Day 2 of public hearing

Recently Issued Guidance Documents

Recommendations for Microbial Vectors used for Gene Therapy

On 15th September 2016, the FDA’s Center for Biologics Evaluation and Research (CBER) issued a new guidance document for investigational new drug application (IND) sponsors concerning microbial vectors used for gene therapy (MVGT) in early-phase clinical trials. This guidance follows a draft issued in October 2015 and covers CMC information as well as preclinical and clinical considerations for this type of vector.

It supplements the existing “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigation New Drug Applications (INDs)” from April 2008.

It is worth noting that this guidance recommends evaluating antibiotic sensitivity through in vivo biological activity, safety and biodistribution/persistence in addition to traditional in vitro testing which has been suffient in the past. The guidance mentions that antibiotic sensitivity tests “should contain at least two first line therapy and two second line therapy antibiotics normally used to treat infections with the microbial agent(s) for which the MVGT was derived.” It later notes that “data obtained from these studies can help guide the selection of effective antibiotics, as well as appropriate timing of antibiotic administration in the clinical trial.”

There is currently no official guidance for late stage development considerations with MVGTs.

To view the guidance please click here.

International

ICH

Draft ICH guidance entitled “E17, General Principles for Planning and Design of Multi-Regional Clinical Trials (MRCT).”

This draft guidance describes general principles for planning clinical trials conducted in more than one region under a single protocol. With the globalization of drug development, this guidance is intended to increase acceptability of data from MRCTs as the primary source of evidence supporting marketing auuthorisation in global regulatory submissions, to facilitate more efficient drug development and earlier access to medicines.

Whilst ICH has exisiting guidelines dealing with specific issues related to conducting clinical trials in more than one region, this broader guidance covers planning and design of MRCTs in order to increase the acceptability of MRCTs by multiple regulatory authorities. 

Some of the key requirements outlined in the guidance include:

  • A unified trial hypothesis with common comparators (comparators should in principle be the same in all participating regions)

  • A primary endpoint which is considered clinically meaningful in all regions (as described in ICH E9)

  • Participating sites should be able to enrol a well-described, well-characterised population of eligible subjects (clear and specific inclusion and exclusion criteria that are acceptable and can be applied across all regions should be included in the protocol)

  • All sites participating in the study should meet applicable quality and regulatory standards compliant with ICH E6-GCP standards

  • Timely and accurate flow of information should occur between the sponsor, trial management team and participating sites

Please click here to view the draft guidance and here for the associated concept paper.

Public consultations

European Commission (EC)

 

Title

Consultation Period

Category

URL

 

 

1.

Good Manufacturing Practice for Advanced Therapy Medicinal Products

28-Jun-16

to

26-Sep-16

Targeted stakeholder consultation

ec.europa.eu

 

2.

Concept of 'similar medicinal product' in the context of the orphan legislation

29-Jul-16

to

04-Nov-16

Public consultation

ec.europa.eu

 

 

 

 

 

 

 

 

European Medicines Agency (EMA)

 

Title

Consultation Period

Category

URL

 

 

 

1.

Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials

12-Apr-16

to

12-Oct-16

Draft guideline

www.ema.europa.eu

2.

Sterilisation of the medicinal product, active substance, excipient and primary container

13-Apr-16

to

13-Oct-16

Draft guideline

www.ema.europa.eu

3.

Requirements for quality documentation concerning biological investigational medicinal products in clinical trials

1-Jul-16

to

31-Dec-16

 

 

Draft guideline

www.ema.europa.eu

4.

Good pharmacovigilance practices (GVP) - Module VI – Management and reporting of adverse reactions to medicinal products (Rev. 2)

8-Aug-16

to

14-Oct-16

Draft guideline

www.ema.europa.eu

5.

Good pharmacovigilance practices (GVP) - Module IX Addendum I – Methodological aspects of signal detection from spontaneous reports of suspected adverse reactions

8-Aug-16

to

14-Oct-16

Draft guideline

www.ema.europa.eu

6.

Good pharmacovigilance practices (GVP) - Module IX – Signal management (Rev. 1)

8-Aug-16

to

14-Oct-16

Draft guideline

www.ema.europa.eu

 

UK MHRA

 

Title

Consultation Period

Category

URL

 

1.

MHRA GxP Data Integrity Definitions and Guidance for Industry

21-Jul-16

to

31-Oct-16

Public consultation

www.gov.uk

 

 

 

US FDA

 

Title

Consultation Period

Category

URL

 

 

1.

Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product

15-Jul-16

to

13-Oct-16

Draft Guidance for Industry and FDA Staff

www.fda.gov

2.

Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices

26-Jul-16

to

25-Oct-16

Draft Guidance for Industry and FDA Staff

www.regulations.gov

3.

Deciding When to Submit a 510(k) for a Change to an Existing Device

8-Aug-16

to

7-Nov-16

Draft Guidance for Industry and FDA Staff

www.regulations.gov

4.

Deciding When to Submit a 510(k) for a Software Change to an Existing Device

8-Aug-16

to

7-Nov-16

Draft Guidance for Industry FDA Staff

www.regulations.gov

5.

510(k) Third Party Review Program;

13-Aug-16

to

14-Nov-16

Draft Guidance for Industry, FDA & Third Party Review Organizations

www.regulations.gov

 

ICH

 

Title

Consultation Period

Category

URL

 

1.

ICH guideline E17 on general principles for planning and design of multi-regional clinical trials

June-16

to

31-Jan-17

Draft guidance for public consultation

www.ich.org

 

Australia TGA

 

Title

Consultation Period

Category

URL

 

1.

Regulation of autologous cell and tissue products and proposed consequential changes to the classification of biologicals

21-Jul-16

to

31-Oct-16

Public consultation

www.tga.gov.au

 

 

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