Cell based therapies legal regulatory
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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

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Cell based therapies legal regulatory

Cellbasedtherapieslegal & regulatory





Begin with the end in mind
Begin with the end in mind

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

Regulatory arbitrage:

510(k) in US vs CE Mark in EU




Conditional MA

Texasapproach to autologousadult

Ask to verify and confirm
Ask to verify and confirm

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

Inherent challenges
Inherent challenges

Product qualification is challenge if (as if often the case):

  • the cells are heterogeneous in nature and have a heterogeneous mode of action (paracrine, stimulate innate and/or regenerative)

  • inability to identify a single mode of action (let alone a single API); and

  • the challenges identifying appropriate measures for pharmacodynamics and pharmacokinetics and pharmacological endpoints

    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:

  • challenges involved in establishing potency assays, dosage, and procedures that would enable a Qualified Person to sign off the cells before administration to the patient

Main selection criteria under atmp
Main selection criteria under ATMP

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.

  • Manipulations listed in Annex I to Regulation (EC) No 1394/2007, in particular, shall not be considered as substantial manipulations

Atmp definition seen otherwise
ATMP definition seen otherwise

ATMP Regulation’s scope requires that cells making up the product

are human;

are viable;

fall within one of three categories of ATMPs

  • Tissue Engineered Products (TEPs)

  • Gene Therapy Products; or

  • Somatic Cell-Based Therapies;

    are generated industrially manufactured or manufactured by a method involving an industrial process; and

    are placed on the market.

Substantial manipulation
Substantial manipulation

Does ATMP Regulation apply to cells that are used autologously?

  • use of the words “recipient” and “donor

  • No guidance in Part IV Directive 2001/83

    Annex I lists manipulations are not considered substantial manipulations

    Annex I list is not exhaustive (“in particular”)

  • isolated or concentrated cell population would not seem to constitute substantial manipulation

    Substantial manipulation criteria requires manipulation of properties for intended use of the cells in the ATMP (“relevant for the intended use”)

Same essential function
Same essential function

Examples from TravauxPréparatoires

  • Amniotic membrane used to heal a damaged corneal epithelium by growing new corneal epithelial cells, a function it does not normally perform in utero.

  • Non-substantially manipulated cartilage used to replace cartilage, even elsewhere in the body, is for homologous use and can reasonably be expected to function appropriately.

    • Not Regulated: This is not tissue engineering, but transplantation.

      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).

Placed on the market
Placed on the market?

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”.

Industrially produced
Industrially produced?

As opposed to hospital exemption?

  • The MHRA takes the view that there are two main areas for consideration in determining whether preparation of a product by an operator is routine or non-routine:

    • Whether it is the same product under consideration

    • The scale and frequency of the preparation of the specific product.

      As opposed to “practice of medicine”?

So how about hospital exemption
So, how about hospital exemption?

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).

So what about hospital exemption
So, what about hospital exemption?

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.

Hospital use vs specials
Hospital Use vs “Specials”

Are specials unregulated
Are specials unregulated?

EU Tissue & Cells directive (EUTCD) addresses quality and safety aspects – explicitly also for the purpose of cell based therapy

  • Medical product aspects regulated by Directive 2001/83 – provided that there is a medicinal product

  • If there is not a medicinal product, EUTCD and national rules concerning practice of medicine provide for quality, safety and application

    Autologous transplants of tissues and cells during same surgical procedure are even exempted from the EUCTD

Clinical trails
Clinical trails

Not always so evident what is being tested

Investigational medicinal product or something else?

  • Practice of medicine with a device?

  • Autologous graft?

    Clinical trial or established medical practice?

Clinical trials
Clinical trials

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

Clinical trials1
Clinical trials

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

Clinical trials2
Clinical trials

Investigational medicinal product or something else?

Atmp procedure be careful what you wish for
ATMP procedure – be careful what you wish for

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]