Legal and regulatory issues

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
• Not only as a matter of compliance
• But also as a matter of strategy and execution of business model
Different regulatory endpoints necessitate radically different business
models and financing needs
Regulatory arbitrage:
• 510(k) in US vs CE Mark in EU
• Hospital Use exemption
• Compasionate Use
• Conditional MA
• Texas approach to autologous adult
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
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
• 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 Regulation’s scope requires that cells making up the product
1. are human;
2. are viable;
3. fall within one of three categories of ATMPs
• Tissue Engineered Products (TEPs)
• Gene Therapy Products; or
• Somatic Cell-Based Therapies;
4. are generated industrially manufactured or manufactured by a method
involving an industrial process; and
5. are placed on the market.
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
Examples from Travaux Préparatoires
1. Amniotic membrane used to heal a damaged corneal epithelium by
growing new corneal epithelial cells, a function it does not normally
perform in utero.
2. 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?
The ATMP Regulation does not alter the basic requirements in the
Medicinal Products Directive (2001/83) that a product needs to be
(i) “industrially produced” and
(ii) “placed on the market”.
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
As opposed to “practice of medicine”?
So, how about hospital
ATMP Hospital Use Exemption effectively immunises a wide range of cellbased 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
• 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 travaux préparatoires 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
The ATMP must be prepared and used
in the same EU Member State
Products meeting the requirements of
the scheme can be manufactured in the
UK or imported from a compliant
The ATMP must be commissioned by a
medical practitioner
Products can be prescribed by doctors,
dentists and supplementary prescribers
The ATMP must be custom made to
meet an individual prescription and
preparation must be on a “non-routine
There is a special needs test
(interpreted to mean the absence of a
pharmaceutically equivalent and
available licensed product)
The ATMP must be used in a hospital
There is no stipulation as to location
Unrelated to status of other products
Must cease once an MA is granted for
an equivalent pharmaceutical
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
• Autologous transplants of tissues and cells during same surgical
procedure are even exempted from the EUCTD
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
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 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 trials
Investigational medicinal product or something else?
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
[Romaldas Maciulaitis, Lucia D’Apote, Andrew Buchanan, Laura Pioppo, and Christian K Schneider]
ATMP procedure

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