Regulatory news - September 2017

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


European Medicines Agency

Update on EMA relocation preparedness

At the end of September, the EMA published results of its recent internal staff survey on relocation across 19 potential cities following the UK’s exit from the EU. The survey is part of the agency’s Business Continuity Plan (BCP) aimed at prioritising activities in order to cope with potential significant staff loss due to the relocation.

The BCP has categorised it’s activities into three priority levels according to their impact on public health and the ability of the Agency to function. In case of a business continuity situation the Agency will first decrease the activities (and therefore the FTEs spent) on category 3 (lowest priority), followed by category 2 (medium priority) and lastly by category 1 (highest priority).

The figure below highlights the importance of the upcoming decision on the EMA’s future seat based on the relative retention of skilled and experienced staff which will be crucial to carrying out category 1, 2 and 3 activities.

Four clusters of candidate cities emerged. The first includes those cities where 65% or more of EMA staff indicated that they are likely to move (dark green). In the second cluster are cities where staff retention would range between 50 and 64% (light green). The third cluster includes those to which between 30 and 49% of staff are likely to relocate (light orange). In the last cluster are those cities where less than 30% of EMA staff said they would follow (dark orange).

With these results and in consideration of the priority activites, the EMA has announced that “for certain locations staff retention rates could be significantly less than 30%. This would mean that the Agency is no longer able to function and, as there is no backup, this would have important consequences for public health in the EU.”

Although the EMA did not go so far as to name the specific cities, in technical comments on potential facilities last month, EMA officials noted that Amsterdam, Barcelona, Copenhagen and Milan met agency requirements with those buildings only raising limited concerns. Vienna had more serious problems such as security, IT and conferencing technology.

Click here to view the press release from the EMA including results of the survey.


FDA finalises guidance on deviation reporting for human cells, tissues and cellular and tissue-based products (HCT/Ps)

Last month, the FDA finalised its guidance for complying with requirements to investigate and report HCT/P deviations, based on current good tissue practice (CGTP) requirements. An HCT/P is regulated solely under section 361 of the PHS Act and the regulations under 21 CFR Part 1271 if it meets all of the following criteria under 21 CFR 1271.10(a).

In the guidance document, the FDA provides detail on HCT/P reporting including who must investigate and when a report may or may not be required. The document provides some examples for reportable HCT/P deviations relating to core CGTP requirements.

Example of reportable deviations related to donor testing:

The following are examples of reportable HCT/P deviations which you discovered after you had already distributed an HCT/P that was obtained from a donor who was initially, but incorrectly, determined to be eligible. In each example, the donor information was overlooked and the donor was erroneously determined to be eligible.

a. Required donor testing was not performed for all RCDADs and other communicable disease agents (e.g., CMV).

b. Required donor testing for RCDADs was not performed in accordance with the manufacturer’s test kit instructions.

c. Required donor testing for RCDADs was performed with an unacceptable donor specimen, in that the specimen was collected 10 days before the recovery of musculoskeletal HCT/Ps.

d. A donor specimen was incorrectly filtered or collected in an expired sample collection tube (containing anticoagulant) and, as such, did not meet the requirements according to the manufacturer’s instructions.

e. A donor of viable, leukocyte-rich HCT/Ps was not tested for HTLV or CMV.

f. A donor specimen was tested using a diagnostic test kit instead of an FDA-licensed, approved, or cleared donor screening test.

g. A donor was either not evaluated for, incorrectly evaluated for, or the evaluation was not documented for plasma dilution.

FDA issues a clinical hold to two phase 1 INDs for Cellectis’ UCART123

The FDA has placed a clinical hold on both ongoing trials using Cellect’s UCART123 IMP, following the death of the first patient enrolled in Cellectis’ ABC study in blastic plasmacytoid dendritic cell neoplasm (BPDCN) using a CD123-targeting CAR-T therapy.

According to a press release from Cellectis on the 4th September 2017:

This was the first patient treated in the BPDCN study, a 78-year-old male treated with one prior therapy, who presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) at baseline prior to conditioning regimen. He received 30mg/m2/day fludarabine for 4 days and 1g/m2/day cyclophosphamide for 3 days, as a preconditioning regimen. On August 16, 2017 (Day 0), he received 6.25x105 UCART123 cells per kilogram, the first dose level explored in the protocol, without complication. At Day 5, the patient experienced a grade 2 Cytokine Release Syndrome (CRS), and a grade 3 lung infection, which quickly improved after a first dose of tocilizumab and institution of anti-infective therapy (broad spectrum intravenous antibiotics). He then experienced at Day 8 a grade 5 CRS, together with a grade 4 Capillary Leak Syndrome. Despite a treatment in keeping with CRS management including administration of corticosteroids and tociluzumab x 2 as well as intensive care unit support, the patient died on Day 9.

One other patient treated with UCART123 in the other phase 1 trial (in acute myeloid leukemia) experienced less severe (grade 3) CRS and equivalent (grade 4) Capillary Leak Syndrome. These adverse events put the patient in intensive care but had cleared by day 12.The root cause of these events is still unclear which may be related to more general safety issues for CAR-Ts or specific to its targeting of CD123.

According to an article by FierceBiotech; ‘it is conceivable Cellectis can prevent further patient deaths by lowering the dose of UCART123 and follow the example set by other CAR-T trials by intervening earlier and more aggressively to treat CRS’.

UCART123 is as an allogeneic (off-the-shelf) CAR-T product derived from donors rather than the patients themselves. Significantly, the first two patients treated have not experienced graft-versus-host disease (GvHD), a complication that arises when the immune system rejects an allogeneic transplant.

FDA publishes draft guidance regarding electronic submissions of REMS documents

A Risk Evaluation and Mitigation Strategy (REMS) is a program to manage known or potential serious risks associated with a drug product and is required by the Food and Drug Administration (FDA) to ensure that the benefits of the drug outweigh its risks.

As part of Kymriah’s recent US approval, a detailed REMS strategy was proposed by Novartis to mitigate the risks of cytokine release syndrome (CRS) and neurological toxicities. More specificially, the program aims to ensure that hospitals and their associated clinics have on-site, immediate access to tocilizumab as well as ensuring that those who prescribe, dispense, or administer Kymriah are aware of how to manage the risks of cytokine release syndrome and neurological toxicities. Moving forward, a well-described REMS strategy will likely be an important component for a number of cell and gene therapy submissions.

Over a three year time frame the FDA engaged stakeholders regarding REMS standardisation, the outcome of which was published online. As a follow up to concerns raised, the most recent draft guidance from the FDA outlines the Structured Product Labeling (SPL) format for submission as well as the implementation guide and requirements for the electronic submission of the content of REMS.

Click here to view the draft guidance.


Therapeutic Goods Administration (TGA)

New provisional approval pathway receives feedback following public consultation

Last year, Australia’s regulator for human medicines (TGA), announced it’s intention to set up a ‘Provisional Approval’ pathway allowing sponsors “to seek a time-limited provisional registration of certain prescription medicines that do not meet our full clinical data requirements, where the potential benefit of earlier availability of the medicine outweighs the risk that additional data are still required”.

This new mechanism, part of Australia’s broader Review of Medicines and Medical Devices Regulation (MMDR review) is similar in its vision to the EMA’s Conditional Marketing Authorisation (CMA) approval in Europe, designed to facilitate earlier access to certain promising medicines.

TGA’s public consultation published in March 2017, outlined the key objectives of the pathway, requesting feedback from various stakeholders on particular aspects of the registration process for medicinal products.

Based on publically available industry submissions, there was a generally held view that applying the same quality data requirements for provisional approval as for standard submissions may present a challenge during early clinical development, particular with respect to stability data to support the product’s shelf life and data on production-scale batches. A number of stakeholders also argued against a two year, time-limited provisional registration by the TGA, citing CMA in the EU which is not limited in time.

TGA now plans to use the consultation feedback to prepare a guidance document for publication before the implementation of the pathway.

Click here to view the full list of stakeholder comments published online.

Public consultations


International Council for Harmonisation