Sharon Longhurst Senior Pharmaceutical Assessor Biololgicals Unit MHRA UK implementation of the ATMP regulation – and how it impacts on hospital pharmacies Ask audience how many have been involved in clinical trials using ATMP’s or import/use of an ATMP on a patient specific basis. Apologise for amount of info on some slides – want them to be used as a reference source. Sharon Longhurst Senior Pharmaceutical Assessor Biololgicals Unit MHRA

Unlicensed Advanced Therapy Medicinal Products Specials Safeguarding public health Topics What is an Advance Therapy Medicinal Product and how are they regulated? Unlicensed Advanced Therapy Medicinal Products Specials Hospital Exemption Other considerations Pharmacy Specific issues

What is an Advanced Therapy Medicinal Product? How are they regulated?

What is an Advance Therapy Medicinal Product? The product must meet the definition of a Medicinal Product (MP) [Directive 2001/83/EC, amended by 2004/27/EC]: Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis. Where organisations need to classify whether what they have is a medicine or something else (e.g. a transplant or device). Might be worth adding that this advice can be obtained either from the national CA or EMEA. If is a medicine, the next stage (and next slide) is to decide what type of medicinal product it is.

What is an Advance Therapy Medicinal Product? An ATMP is a biological medicinal product [Directive 2001/83/EC, amended by 2003/63/EC annex 1, Part I] that can be classified as either [EC Regulation No 1934/2007]: Gene Therapy Medicinal Product (GTMP) Somatic Cell Therapy Medicinal Product (CTMP) Tissue Engineered Products (TEP) (or any combination of the 3) If combination of the 3; GTMP takes precedence

What is an Advance Therapy Medicinal Product? Gene Therapy Medicinal Products (GTMP) [Directive 2001/83/EC annex 1, Part IV; amended by 2009/120/EC] GTMP means an biological medicinal product which has the following characteristics: It contains an active substance which contains or consists of a recombinant nucleic acid used in, or administered to human beings, with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; Its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. GTMP shall not include vaccines against infectious diseases.

What is an Advance Therapy Medicinal Product? Examples of GTMPs Recombinant viruses: Adenovirus Adeno-associated virus Lentivirus Pox virus Measles virus Plasmid DNA Recombinant bacteria: Salmonella Used to deliver ‘therapeutic genes’: Immune modulatory genes (GM-CSF) Human cytokine receptor common gamma chain (X-SCID) β- globin gene (Thalassemia) Enzymes (pro-drug therapies)

What is an Advance Therapy Medicinal Product? Somatic Cell Therapy Medicinal Products (CTMP) [Directive 2001/83/EC annex 1, Part IV; amended by 2009/120/EC] Somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics: contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor; Is presented as having properties for, or is used in or administered to human beings, with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues. For the purposes of point (a), the manipulations listed in Annex I to regulation (EC) No 1394/2007, in particular, shall not be considered as substantial manipulations. Emphasis on ‘substantial manipulation’ and change in biological/physiological functions in order to separate from transplantation

What is an Advance Therapy Medicinal Product? Examples of CTMPs Limbal stem cells (repair of chemical burns to the eye) Endothelial progenitor cells / cardiac stem cells (heart failure) Mesenchymal stem cells (anal fistula) Genetically modified cells i.e. Haematopoetic stem cells (Host v’s graft disease; X-SCID)

What is an Advance Therapy Medicinal Product? Tissue Engineered Product (TEP) [EC Regulation No 1934/2007] Tissue engineered product means a product that: contains or consists of engineered cells or tissues, and is presented as having properties for, or is used in or administered to human beings with a view to regenerating, repairing or replacing a human tissue. A TEP may contain: cells or tissues of human or animal origin, or both the cells or tissues may be viable or non-viable additional substances i.e. scaffolds or matrices A definition of what is meant by ‘engineered’ is also given

What is an Advance Therapy Medicinal Product? Examples of TEPs Skin repair for burns or chronic wounds (in-vitro culture skin – multiple cell layers) Trachea repair Cartilage repair (autologous chondrocytes) Holy grail of cours – is to grow new organs We’ve all seen the picture of the mouse with a human ear growing on its back – but this coming into main stream treatment is a long way off. Autologous chondrocytes have been recently licensed as cell therapy – so descriptions of what are TEPs that you might find on the web may not actually be defined as TEPs by the EMEA.

How are ATMP’s regulated? Licensed Medicinal Products National each EU member state Mutual Recognition/Decentralised Procedure after national license this enables the companies to license the same product in other member states Centralised pan-EU license All ATMP’s manufactured on a routine basis require a Centralised authorisation [Notice to Applicants Vol 2A, Chapter 4 http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/] Explaine that a licensed product is one that has a Marketing Authorisation (Product Licence in older terminology) which also requires each site that make the product to hold a Manufacturer’s Authorisation Emphasising that where the product has to be licensed (because of routine manufacture etc) that the only option is the centralised route

How are ATMP’s regulated? The ‘licensed’ ATMP is regulated as other biological MP except: the follow-up of efficacy of ATMPs and of adverse reactions are required; traceability requirement for MAH; data is to be kept for 30 years minimum after expiry date; in the event of bankruptcy that data will be held by EMEA. traceability requirement for the hospital, institution or private practice where the product is used. new EMEA committee for assessment: Committee on Advanced Therapy (CAT)

How are ATMP’s regulated? ATMP Summary Must meet definition of a ‘Medicinal Product’ Are biological products that can be classified further as: Gene Therapy Medicinal Products Cell Therapy Medicinal Products Tissue Engineered Products Licensed via the ‘Centralised’ procedure Licensing requirements essentially the same as all biological medicines except: Market authorisation is reviewed by new committee (CAT) Pharmacovigilence requires efficacy follow-up Traceability onus on manufacturere and site where product is administered

Unlicensed Advanced Therapy Medicinal Products

Unlicensed Advanced Therapy Medicinal Products 2 mechanisms to enable the use of unlicensed ATMPs: Specials (Directive 2001/83/EC – article 5(1)) Hospital exemption (Regulation No. 1394/2007) Both are regulated at a National level (by MHRA in the UK) emphasise that an unlicensed product is one that does not have a Marketing Authorisation (PL) but each site of manufacture must hold a Manufacturer’s Authorisation – the types are discussed later HE was put into place by commission to encourage ‘innovation’ with appropriate safe guards for patients and to prevent organisations circumventing the licensing of products

Unlicensed Advanced Therapy Medicinal Products Specials Supplied to fulfil a special need test i.e. no equivalent licensed medicinal product available. Products are manufactured/prescribed by doctor, dentist or other supplementary prescriber. The administration and specification of the product is the prescribers responsibility. No stipulation on where i.e. hospital/private clinic, the products can be administered. Specials can be imported into, and manufactured in, the UK; they can also be imported out of the UK the quality of the product is in part contributed to by the site of manufacture being compliant with GMP MHRA can give advice on the type of license required – look at web site under ‘how we regulate’ and manufacturing licenses

Unlicensed Advanced Therapy Medicinal Products Hospital Exemption Can only be commissioned by a medical practitioner. Must be custom made to meet an individual prescription and preparation must be on a “non- routine basis”. Must be used in a hospital. Must be prepared and used in the same member state i.e. no import/export permitted.

Unlicensed Advanced Therapy Medicinal Products How are ‘Specials’ regulated? UK manufacturer most hold a ‘specials licence’ (an ‘MS’) Site will be GMP inspected Product released by ‘quality controller’, no QP requirement Pharmacies can be the holder of these licenses If the ‘special’ is imported into the UK from within EU, Norway, Iceland or Lichtenstein, the importer will need: A Wholesale Dealers License If imported from outside the EEA i.e. USA, the importer will need: A Specials License Specification of the product and its safety is the responsibility of the prescriber if imported into the UK ATMPs that are categorised as ‘specials’ have to meet the requirements described in the ATMP regulation in relation to GMP, PV and traceability. EEA includes Norway, Iceland and Lichenstein

Unlicenced Advanced Therapy Medicinal Products How are ‘specials’ regulated? The license holder i.e. the importer, must notify the MHRA of importation with at least 28 days notice. Information required: Name/trade name Active substance Amount to be imported (limited to ≤ 25 single administrations) Name and address of manufacturer Evidence of compliance with EU NfG on minimising the risk of transmitting animal spongiform encephalopathies Evidence of compliance with ‘Tissues and Cells Directive’ Supplier of the special is obligated to Report and record ADRs Maintain records relating to source of product, batches, sales Those administering the product are obligated to report ADRs using the yellow card scheme Compliance with Tissue and Cells Directive expected for all 3 ATMP types for the stages that it covers donation, procurement and testing – will be discussed further later on.

Unlicenced Advanced Therapy Medicinal Products How is the Hospital Exemptions regulated? MHRA will inspect manufacturer’s for GMP compliance Issue manufacturer’s licence Authorise the manufacture of categories of ATMPs rather than specific products Inspections will be risk based Manufacturer’s are obligated to: Record and report ADRs Risk Management Plan may be needed (case by case assessment) Implement traceability, quality, PV standards that are equivalent to that of a licensed product. Provide annual returns to MHRA re frequency of manufacture/units sold/description of product Inspections for both (specials and HE) are risk based – the GXPs started a risk-based inspection (RBI) scheme in April of this year and it is having its 6 month review now. there are 2 aspects to the RBI: 1. The interval between inspections – sites with more risk are inspected more frequently and/or more time is spent on site. 2. When on site, more time is spent on areas/activities perceived to carry more risk (e.g. don’t usually spend much time on pest control measures!)

Unlicenced Advanced Therapy Medicinal Products How is the Hospital Exemption regulated? Clinician responsible for administration must record and notify MHRA of ADRs. Hospital where it is used must implement traceability system i.e. tracing recipient of ATMP to donors of tissues using their manufacture if applicable) Arrangements must be made between hospital and manufacturer for provision of data traceability in case of bankruptcy ATMP can be distributed from site of manufacture to hospital under the manufacturing license; but if the hospital intends to distribute it to another hospital it will need a wholesale dealers license Import/export of ATMPs under HE is not permitted

Unlicenced Advanced Therapy Medicinal Products What is ‘non-routine use’? No definition given in the regulation (1394/2007) Clearly difficult to define, given: lack of experience of regulating unlicensed ATMPs unknown numbers and frequency of use of HE UK has drafted some guidance on the approach intended to be taken: each product manufactured at the same site will be assessed individually the overall numbers of the product prepared, the regularity/frequency of production, and the time period over which its manufacture has become established, will be considered Might be that one site manufactures a rAd expressing 2 different genes – so that they are essentially different products. In this case each product is reviewed independently from the other. Where new product results from modifications to an earlier product, consideration of whether the new product is produced routinely will e based on the consideration of the pattern of production of the new product not the old one. In determining what constitutes the same product the MHRA will consider the mode action and its intended use i.e. MoA, presentation), as well as the manufacturing process and product intermediates or product specific staring materials. The agency would not accept an argument that depended on the premise that all autologous products were by definition different products, where their intended use, manufacturing processes and final product presentations were the same. In a scenario where the scale/frequency of manufacture of a particular product starts off as very small/low, but the manufacturing rate progressively increases over a period of time, it should typically be possible to determine with a period of one-3 years where the scale and frequency of production means that preparation has become routine. Where preparation remains on very small scale and spasmodic, eg with some months elapsing between each preparation, it is possible that a significantly longer period would need to elapse before preparation could be reasonably regarded as routine.

Other considerations: Human Tissue Authority Health and Safety Executive DEFRA GTAC

Human Tissue Authority Responsibility for regulating human tissues and cells (other than gametes and embryos) for human application (EU Tissue & Cells Directive 2004/23/EC as amended): procurement testing processing storage distribution import / export The Human Fertilisation and Embryology Authority (HFEA) is responsible for the regulation of gametes and embryos for human application. MHRA works closely with HTA. Currently agreeing a memorandum of understanding to make information sharing easier and to work up proposals to conduct joint inspections.

Human Tissue Authority Relationship of EUTCD to 2001/83/EC Donation Procurement Testing Processing Preservation Storage Distribution HUMAN tissues and cells intended for human use Medicinal Products manufactured from HUMAN tissues and cells intended for human use Medicinal Products manufactured from ANIMAL tissues and cells intended for human use Tissues and cells not intended for human use Directive 2004/23/EC Directive 2001/83/EC Dir 2004/24/EC Other legislation

HSE / DEFRA ATMPs could consist of genetically modified organisms (GMO) recombinant viruses and bacterial expressing heterologous genes Administration could fall within: contained use directive – regulated by HSE deliberate release directive – regulated by DEFRA In the first instance, advice should be sought from HSE to determine which directive the product falls into, and appropriate notifications required

GTAC Gene Therapy Advisory Committee Ethical oversight of proposals to conduct clinical trials involving gene or stem cell therapies. To provide ethical advice on the use of unlicensed gene and stem cell derived therapies Advise ministers on the developments in this field

Pharmacy Specific Issues

Pharmacy Specific Issues GTMP Liquid formulations, stored frozen (<-80oC) Likely to be GMO If used under ‘contained use’ regulations reconstitution/dilution might be necessary using class II cabinet Specialised, non-Ph. Eur, product specific release tests therefore ‘in-house’ release testing by pharmacy impractical. Release for use likely to be on basis of certificate of analysis provided.

Pharmacy Specific Issues CTMP Liquid formulations Very short shelf life (<2 days) If long term storage is possible conditions might require liquid nitrogen In-house release impractical Expect to release for use on the basis of the provided certificate of analysis May also be GMO which might impact on preparation requirements If not a GMO, preparation for administration might require class I safety cabinet to maintain sterility

Hospital Exemption/FAQ Reference Sources Directives: Medicines http://ec.europa.eu/enterprise/pharmaceuitcals/eudralex/vol1_en.htm HTA www.hta.gov.uk Hospital Exemption/FAQ http://www.mhra.gov.uk/Howweregulate/Advancedtherapymedicinalproducts/index.htm GMP http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol4_en.htm

Back-up

Unlicenced Advanced Therapy Medicinal Products How is the Hospital Exemption Regulated? There are defined labelling and PIL requirements for the products (www.mhra.gov.uk/Publications/Consultations/Medicinesconsultations/Othermedinesconsultations/CON051874) The products can not be advertised, but the service can GTAC can be called upon to provide ethical advice to practitioners on the use of ATMPs Services i.e. transduction of haematopoetic stem cells

Pharmacy Specific Issues Assuming clinical benefit has been shown, how can the doctor continue to prescribe a product used in clinical trial? Additional administration of product used in a clinical trial has to be conducted as unlicensed use of a MP i.e. using the specials or hospital exemption, until the MA is granted. Any unused CT product is still considered an IMP, so can no legally be administered as an unlicensed medicine – new product has to be manufactured. All requirements previously described for unlicensed ATMPs are applicable.

Pharmacy Specific Issues Hospital running a clinical trial involving an ATMP If the product is manufactured within the hospital, the site will need a ‘Manufacturer Investigational Medicinal Products’ (MIA/IMP) license. If donor material is used, HTA compliance for donation, procurement and testing must be demonstrated. Containment issues may be needed – HSE/DEFRA. For GTMPs in particular, storage at -80oC is common. For CTMPs might need liquid nitrogen storage. Isolated storage, to ensure minimisation of cross contamination, is likely to be needed.

Hypothetical Case Example 1 Doctor wants to treat patient with an unlicensed cell therapy manufactured in USA HE not possible, must use ‘specials’ procedure Hospital/pharmacy must hold a ‘specials licence’ (issued by MHRA) before* importation Licence holder must notify MHRA of the intention to import not less than 28 days prior to importation ADR’s must be notified to the MHRA using yellow card scheme * If you need to apply for a license it could significantly delay the importation of the product as a GMP inspection will be needed prior to issue of the license If sites believe that they will need to import unlicensed products, they should apply for an MS in advance. This will require a GMP inspection of the facilities and Quality Systems. If they don’t hold an MS, they will have to use another site that already holds an MS to bring the products in to the UK for them. Once a site has been granted an MS, the timelines to get the product(s) into the UK can be quick – this is important since often these are emergency situations.

Hypothetical Case Example 2 2. Doctor wants to treat patient with an unlicensed gene therapy product manufactured in USA HE not possible, must use ‘specials’ procedure Hospital/pharmacy must hold a ‘specials licence’ (issued by MHRA) before importation Licence holder must notify MHRA of the intention to import not less than 28 days prior to importation ADR’s must be notified to the MHRA using yellow card scheme Advice from HSE/DEFRA needed as this product is likely to be a GMO might impact on product preparation prior to administration HSE/DEFRA notification requirements

Hypothetical Case Example 3 Doctor wants to treat patient with an unlicensed ATMP imported from a country within the EEA Same points as for cases 1 & 2 except hospital/pharmacy will need to hold a ‘Wholesale Dealers Licence’ (issued by MHRA)

Hypothetical Case Example 4 Doctor wants to treat patient with an unlicensed ATMP manufactured in the hospital or at a facility within UK Can use either ‘specials’ or ‘hospital exemption’ depending on ‘needs test’ specials: manufacturing facility will need ‘specials licence’ all other requirements as per previous examples HE: manufacturing facility will need ‘manufacturer’s licence’ Yearly reporting on manufacturing frequency of that product will be needed to ensure fulfilment of ‘non-routine’ Traceability/PV requirements need to implemented