CELL BASED THERAPIESLEGAL & REGULATORYPresentatienaamdatum

Presentatorwww.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

• 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• ATMP vs NDA• 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 challengesProduct 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 (andpotentially 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

product.

As opposed to “practice of medicine”?

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?• 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 “Specials”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 jurisdiction

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 basis”

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 application

• 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 trialsInvestigational 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

THANK YOU