COMBINED ATMPS (cATMP)

Combined ATMPs contain one or more medical devices as an integral part of the medicine. An example of this is cells embedded in a biodegradable matrix or scaffold.

A combined ATMP must fulfil either (a and b) or (a and c):

1. it must incorporate, as an integral part of the product, one or more medical devices within the meaning of Article 1(2)(a) of Directive 93/42/EECor one or more active implantable medical devices within the meaning of Article 1(2)(c) of Directive 90/385/EEC
2. its cellular or tissue part must contain viable cells or tissues
3. its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to

For combined ATMPs, it is important to include the device in the validation process:

• Validation of the cell culture process with respect to the integrity of cells/scaffold
• Effect of the device on cell growth and activity
• Effect of cells on device function and integrity
• Characterisation and testing of the cell-device combination
• Impurities and degradation products from device component
• CE mark of device component, if possible

Selected documents and guidelines regarding combined ATMPs, focusing on quality:

• ISO 13485; a standard for quality management systems for medical devices (available for purchase sis.se)
• Environmental risk assessment of medicinal products for human use: Guideline CPMP/SWP/4447/00 (PDF)
• Community code relating to medicinal products for human use: Directive2001/83/EC
• Supplementary protection certificate for medicinal products: Regulation469/2009/EC
• The medical device/devices which is/are part of the product shall meet the essential requirements laid down in Annex 1 to Directive 93/42/EEC(for medical devices: Harmonised standards for medical devices) or Annex 1 to Directive 90/385/EEC(for active implantable medical devices: Harmonised standards for active implantable medical devices).
• Commission Regulation No 722/2012 concerning particular requirements as regards the requirements laid down in Directives 90/385/EEC and 93/42/EEC with respect to active implantable medical devices and medical devices manufactured utilising tissues of animal origin: Requirements for the medical device if utilising tissues of animal origin

Non-clinical studies are designed to support the use of a specific product to treat a specific clinical indication.The non-clinical studies conducted are an important element of the overall development pathway for an investigational product. They facilitate the establishment of feasibility and reasonable safety (case-by-case according to risk assessment) of the investigational product’s proposed clinical route of administration. The overall objectives for a sufficient pre-clinical programme for a combined ATMP may include:

• Establishing biological plausibility
• Identifying biologically active dose levels
• Selecting the potential starting dose level, dose-escalation schedule and dosing regimen for clinical trials
• Establishing feasibility and reasonable safety of the investigational product and its proposed clinical route of administration (ROA)
• Supporting patient eligibility criteria
• Identifying physiological parameters which can guide clinical monitoring
• Identifying potential public health risks (e.g. to the general public, caregivers, family members, close contacts (for example co-workers) and intimate contacts)

The resulting data from pre-clinical studies should address these objectives in order to guide the design of early-phase clinical trials, as well as to establish a platform for the conduct of future pre-clinical studies that may be needed to support later phases of product development.

Non-clinical studies should be performed in relevant species. Considering the nature of these products this is specifically challenging. It is always recommended to seek the advice of the relevant authorities when selecting the species for non-clinical studies, especially pivotal safety studies. Homologous products could be used, however in such cases bridging data to the human product is of the utmost importance.

ATMPs and cell-based ATMPs in particular present additional challenges that should be addressed, such as:

• Cell survival status following delivery
• Cell migration or trafficking to non-target sites
• Cell differentiation into undesired cell types
• Development of an immune response to the cells
• Uncontrolled proliferation or tumorigenicity

Combined ATMPs usually comprise both a delivery system and an ATMP. It is important to investigate both the delivery system and the ATMP, unless otherwise justified.

The EMA has a set of scientific guidelines on the non-clinical testing of a medicinal product; these guidelines are provided for:

• Environmental risk assessment
• Non-clinical development
• Pharmacology and safety pharmacology
• Toxicology

ATMPs differ from traditional medicinal products and some aspects of the guidelines may not be applicable. However, in such cases a rationale and risk assessment for not following the guidelines shall be available.

FIRST-IN-HUMAN

When the IMP is being tested for the first time in humans, it is useful to read the following guidelines from the EMA:

• Strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products(PDF)
• Guideline on requirements for first-in-human clinical trials for potential high-risk medicinal products

PHASE I/II TRIAL OBJECTIVES

The main purpose of a Phase I/II trial is safety evaluation; this includes assessment of the nature and frequency of potential adverse reactions and an estimation of the relationship to dose, but also other issues, such as feasibility of administration and pharmacological activity.

Clinical efficacy endpoints, as defined in specific guidance for the studied indication or disease, form the basis for the clinical evaluation of any ATMPs, including combined ATMPs. Additional cell- and tissue-specific endpoints may be required such as biochemical, morphological, structural and functional parameters, which are relevant for the targeted therapeutic claim. These endpoints can be used as co-primary or secondary variables and are expected to support the clinical primary efficacy variable.

FEASIBILITY ASSESSMENTS

Consideration should be given to designing early-phase trials to identify and characterise any technical or logistical issues in the manufacturing or administration of the product. Such issues may need to be addressed before proceeding with further product development.

DOSE EXPLORATION

To the extent possible, the dose selection (i.e. cell density or concentration of main constituents) should be based on findings from quality and non-clinical product development. Dose finding studies in the clinical setting should be conducted where feasible. However, the risks relating to high or suboptimal cell numbers should be considered and addressed. Limitations of the available amount of cells/tissue (e.g. due to autologous donation, manufacturing procedure) may lead to the use of variable doses on comparable sizes of defects. In these cases, the variable dosing should be justified and the correlation of the dose with the clinical efficacy should be carefully recorded and reported.

PHASE III TRIAL OBJECTIVES

Phase III usually is considered to begin with the initiation of studies in which the primary

objective is to demonstrate or confirm therapeutic benefit. Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. The investigational medical product must be in a final stage. These studies are intended to provide an adequate basis for marketing approval.