Cell based therapies legal & regulatory. Presentatienaam datum. Presentator www.axonadvocaten.nl. Begin with the end in mind. Determine regulatory qualification of the product (or products ) as early as possible and keep validating your assumptions along the way
Determineregulatoryqualification of the product (or products) as early as possible and keep validatingyourassumptionsalong the way
Notonly as a matter of compliance
But also as a matter of strategyandexecution of business model
Different regulatoryendpointsnecessitateradically different business models and financingneeds
510(k) in US vs CE Mark in EU
ATMP vs NDA
Texasapproach to autologousadult
Be critical about the answers you get along the way and keep in mind who is answering the question
Every government agency will exhibit a degree of regulatory bias and a tendency to want to regulate
In case of doubt about safety / efficacy they will choose the regime they consider the strictest
Product qualification is challenge if (as if often the case):
As a result, significant effort will be directed towards developing new (and
potentially valuable) biomarkers, diagnostics and delivery systems
Other practical difficulties, e.g. in GMP:
Cells or tissues are in scope of ATMP if they fulfil one of the following:
— the cells or tissues have been subject to substantial manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended [(clinical use – if somatic cell therapy) or (regeneration, repair or replacement – if TEP)] are achieved.
— the cells are not intended to be used for the same essential function or functions in the recipient as in the donor.
ATMP Regulation’s scope requires that cells making up the product
fall within one of three categories of ATMPs
are generated industrially manufactured or manufactured by a method involving an industrial process; and
are placed on the market.
Does ATMP Regulation apply to cells that are used autologously?
Annex I lists manipulations are not considered substantial manipulations
Annex I list is not exhaustive (“in particular”)
Substantial manipulation criteria requires manipulation of properties for intended use of the cells in the ATMP (“relevant for the intended use”)
Examples from TravauxPréparatoires
Recent CAT decision re concentrate of autologous bone marrow-derived mononuclear cells to be injected into ischemic heart tissue to regenerate through stem cell-induced angiogenesis by non-haematological differentiation of BM-MNC into vascular cells or by paracrine effects of the stem cells.
The product is not intended to be used for the same essential function (haematological restoration).
The ATMP Regulation does not alter the basic requirements in the Medicinal Products Directive (2001/83) that a product needs to be
“industrially produced” and
“placed on the market”.
As opposed to hospital exemption?
As opposed to “practice of medicine”?
ATMP Hospital Use Exemption effectively immunises a wide range of cell-based therapies that would otherwise be considered ATMPs
prepared on a non-routine basis according to specific quality standards;
used within the same Member State in a hospital;
under the exclusive professional responsibility of a medical practitioner;
in order to comply with an individual medical prescription; and
for a custom-made product for an individual patient.
Unlike the “specials” exemption, the Hospital Use exemption is still available after a competing product is approved (see TiGenix).
Member States shall ensure that national traceability and pharmacovigilance requirements as well as the specific quality standards referred to in this paragraph are equivalent to those provided for at Community level
Honoured in the breach: virtually no applications
The travauxpréparatoires in respect of the Regulation shows that at one stage, the proposed description of the exemption was “a non-patented, non-profit, one-off and non-standardized process”. While this was not finally adopted, ]this was intended to be a very narrow exception. The CAT consistently assets that this is intended to be a narrow exemption.
EU Tissue & Cells directive (EUTCD) addresses quality and safety aspects – explicitly also for the purpose of cell based therapy
Autologous transplants of tissues and cells during same surgical procedure are even exempted from the EUCTD
Not always so evident what is being tested
Investigational medicinal product or something else?
Clinical trial or established medical practice?
Authorities tend to impose strictest rule available and consider everything cell-based an investigational medicinal product by default, even if it is clearly not by definition of the ATMP regulation.
e.g. Dutch CCMO definition of cell therapy research
Also European guidance is not helpful and does not take into account specific characteristics of cell therapy
GCP note for ATMP announced by EMA but so far not published
So companies have to rely on obsolete EU guidance
Investigational medicinal product or something else?
So far only one product approved (Filed before ATMP Regulation)
EMA has been encouraging use of the procedure without much success
Applying for SME benefits is a science in itself
Clinical Development of Advanced Therapy Medicinal Products in Europe: Evidence That Regulators Must Be Proactive
[RomaldasMaciulaitis, Lucia D’Apote, Andrew Buchanan, Laura Pioppo, and Christian K Schneider]