Case Study: Early therapy classification considerations in developing skin equivalents

Practical insights for developers

How a therapy is developed and produced can affect its classification and determines the legal mechanisms that govern its regulation. 

In the case of developing skin equivalents for healing skin wounds, choices of preparation steps results in different therapy classification:

1.  If prepared by skin graft (autologous or allogeneic) with surgical procedures:

→ This therapy is Not an ATMP

• covered by European Tissues and Cells Directive (Directive 2004/23/EC)
• note: in USA, allogeneic skin is considered as medical device
• raises ethical issues in cases of donor skin (allogeneic)

2. If cells are mechanically separated and sprayed on wound bed to help heal the wound:

→ This therapy is Not an ATMP

• only minimally manipulating the cells. 
• covered by European Tissues and Cells Directive (Directive 2004/23/EC)

3. If growing epithelial cells (keratinocytes) from patient or donor's skin to stimulate healing:

1. if enzymes are used to separate between epithelium and epidermis:

   → This therapy IS an ATMP 

2. if individual cells are isolated, and cultured in medium: 

   → This therapy IS an ATMP (sCTMP)

3. if combined with sheets, mesh, support scaffold:

   → This therapy IS a combined ATMP (cATMP)

4. Alternatively, if the donor’s dermis structure is used as a scaffold to graft on patient's wound bed, and then spray patient's keratinocyte cells on to this scaffold

→ This therapy IS an ATMP (TEP)

The legal classification of the therapy being developed determines the applicable regulatory framework, the subsequent requirements that the product must meet, and the relevant procedures leading to commercialization. These include:

• The good laboratory practice (GLP) principles to be taken into account in relation to ATMPs
• specific good clinical practice (GCP) requirements for ATMPs 
• specific guidelines on good manufacturing practice (GMP) must be followed if the therapy being developed is classified as an ATMP.  A Question & Answer Guide from the European Medicines Agency is available here. (See also: EuroGCT's resource on Good Manufacturing Practice)
• all advanced therapy medicines are authorised centrally via the European Medicines Agency (EMA). (see also: EuroGCT's resource on Standard Marketing Authorisation Pathway: Centralised Procedure for ATMPs)
• guidelines on safety and efficacy follow up and risk management specifically for ATMPs

EMA guidelines relevant for ATMPs can be found here. Additional support from EMA for ATMP developers are summarised here.

As therapy classification is a non-trivial task, EMA has advised that the final classification should be considered on case-by-case basis, and taking into account the scientific recommendation on ATMP classification provided by the EMA's Committee for Advanced Therapies (CAT).

Therefore, it is recommended for developers to contact regulators at the national and/or European levels (including mainly the EMA, national medicines agencies and national reimbursement bodies) as early as possible in order to clarify the regulatory pathway applicable the gene and cell therapy in development and their associated regulatory requirements and incentives. (See also: EuroGCT's resources "Early interactions with regulators" and the sub-entries within.)