Presentation on theme: "Sharon Longhurst Senior Pharmaceutical Assessor Biololgicals Unit MHRA"— Presentation transcript:
1Sharon Longhurst Senior Pharmaceutical Assessor Biololgicals Unit MHRA UK implementation of the ATMP regulation – and how it impacts on hospital pharmaciesAsk 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 LonghurstSenior Pharmaceutical AssessorBiololgicals UnitMHRA
2Unlicensed Advanced Therapy Medicinal Products Specials Safeguarding public healthTopicsWhat is an Advance Therapy Medicinal Product and how are they regulated?Unlicensed Advanced Therapy Medicinal ProductsSpecialsHospital ExemptionOther considerationsPharmacy Specific issues
3What is an Advanced Therapy Medicinal Product? How are they regulated?
4What 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.
5What 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
6What 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.
7What is an Advance Therapy Medicinal Product? Examples of GTMPsRecombinant viruses:AdenovirusAdeno-associated virusLentivirusPox virusMeasles virusPlasmid DNARecombinant bacteria:SalmonellaUsed 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)
8What 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
9What is an Advance Therapy Medicinal Product? Examples of CTMPsLimbal 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)
10What 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, andis 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 boththe cells or tissues may be viable or non-viableadditional substances i.e. scaffolds or matricesA definition of what is meant by ‘engineered’ is also given
11What is an Advance Therapy Medicinal Product? Examples of TEPsSkin repair for burns or chronic wounds (in-vitro culture skin – multiple cell layers)Trachea repairCartilage repair (autologous chondrocytes)Holy grail of cours – is to grow new organsWe’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.
12How are ATMP’s regulated? Licensed Medicinal ProductsNationaleach EU member stateMutual Recognition/Decentralised Procedureafter national license this enables the companies to license the same product in other member statesCentralisedpan-EU licenseAll ATMP’s manufactured on a routine basis require a Centralised authorisation[Notice to Applicants Vol 2A, Chapter 4Explaine 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 AuthorisationEmphasising that where the product has to be licensed (because of routine manufacture etc) that the only option is the centralised route
13How 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)
14How are ATMP’s regulated? ATMP SummaryMust meet definition of a ‘Medicinal Product’Are biological products that can be classified further as:Gene Therapy Medicinal ProductsCell Therapy Medicinal ProductsTissue Engineered ProductsLicensed via the ‘Centralised’ procedureLicensing requirements essentially the same as all biological medicines except:Market authorisation is reviewed by new committee (CAT)Pharmacovigilence requires efficacy follow-upTraceability onus on manufacturere and site where product is administered
16Unlicensed 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 laterHE was put into place by commission to encourage ‘innovation’ with appropriate safe guards for patients and to prevent organisations circumventing the licensing of products
17Unlicensed Advanced Therapy Medicinal Products SpecialsSupplied 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 UKthe quality of the product is in part contributed to by the site of manufacture being compliant with GMPMHRA can give advice on the type of license required – look at web site under ‘how we regulate’ and manufacturing licenses
18Unlicensed Advanced Therapy Medicinal Products Hospital ExemptionCan 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.
19Unlicensed Advanced Therapy Medicinal Products How are ‘Specials’ regulated?UK manufacturer most hold a ‘specials licence’ (an ‘MS’)Site will be GMP inspectedProduct released by ‘quality controller’, no QP requirementPharmacies can be the holder of these licensesIf the ‘special’ is imported into the UK from within EU, Norway, Iceland or Lichtenstein, the importer will need:A Wholesale Dealers LicenseIf imported from outside the EEA i.e. USA, the importer will need:A Specials LicenseSpecification of the product and its safety is the responsibility of the prescriber if imported into the UKATMPs 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
20Unlicenced 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 nameActive substanceAmount to be imported (limited to ≤ 25 single administrations)Name and address of manufacturerEvidence of compliance with EU NfG on minimising the risk of transmitting animal spongiform encephalopathiesEvidence of compliance with ‘Tissues and Cells Directive’Supplier of the special is obligated toReport and record ADRsMaintain records relating to source of product, batches, salesThose administering the product are obligated to report ADRs using the yellow card schemeCompliance 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.
21Unlicenced Advanced Therapy Medicinal Products How is the Hospital Exemptions regulated?MHRA will inspect manufacturer’s for GMP complianceIssue manufacturer’s licenceAuthorise the manufacture of categories of ATMPs rather than specific productsInspections will be risk basedManufacturer’s are obligated to:Record and report ADRsRisk 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 productInspections 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!)
22Unlicenced 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 bankruptcyATMP 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 licenseImport/export of ATMPs under HE is not permitted
23Unlicenced 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 ATMPsunknown numbers and frequency of use of HEUK has drafted some guidance on the approach intended to be taken:each product manufactured at the same site will be assessed individuallythe overall numbers of the product prepared, the regularity/frequency of production, and the time period over which its manufacture has become established, will be consideredMight 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.
24Other considerations: Human Tissue AuthorityHealth and Safety ExecutiveDEFRAGTAC
25Human 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):procurementtestingprocessingstoragedistributionimport / exportThe 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.
26Human Tissue Authority Relationship of EUTCD to 2001/83/ECDonationProcurementTestingProcessingPreservationStorageDistributionHUMAN tissues and cells intended for human useMedicinal Products manufactured from HUMAN tissues and cells intended for human useMedicinal Products manufactured from ANIMAL tissues and cells intended for human useTissues and cells not intended for human useDirective 2004/23/ECDirective 2001/83/ECDir 2004/24/ECOther legislation
27HSE / DEFRAATMPs could consist of genetically modified organisms (GMO)recombinant viruses and bacterial expressing heterologous genesAdministration could fall within:contained use directive – regulated by HSEdeliberate release directive – regulated by DEFRAIn the first instance, advice should be sought from HSE to determine which directive the product falls into, and appropriate notifications required
28GTAC 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 therapiesAdvise ministers on the developments in this field
30Pharmacy Specific Issues GTMPLiquid formulations, stored frozen (<-80oC)Likely to be GMOIf used under ‘contained use’ regulations reconstitution/dilution might be necessary using class II cabinetSpecialised, 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.
31Pharmacy Specific Issues CTMPLiquid formulationsVery short shelf life (<2 days)If long term storage is possible conditions might require liquid nitrogenIn-house release impracticalExpect to release for use on the basis of the provided certificate of analysisMay also be GMO which might impact on preparation requirementsIf not a GMO, preparation for administration might require class I safety cabinet to maintain sterility
34Unlicenced 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 canGTAC can be called upon to provide ethical advice to practitioners on the use of ATMPsServices i.e. transduction of haematopoetic stem cells
35Pharmacy 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.
36Pharmacy Specific Issues Hospital running a clinical trial involving an ATMPIf 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.
37Hypothetical Case Example 1 Doctor wants to treat patient with an unlicensed cell therapy manufactured in USAHE not possible, must use ‘specials’ procedureHospital/pharmacy must hold a ‘specials licence’ (issued by MHRA) before* importationLicence holder must notify MHRA of the intention to import not less than 28 days prior to importationADR’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 licenseIf 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.
38Hypothetical Case Example 2 2. Doctor wants to treat patient with an unlicensed gene therapy product manufactured in USAHE not possible, must use ‘specials’ procedureHospital/pharmacy must hold a ‘specials licence’ (issued by MHRA) before importationLicence holder must notify MHRA of the intention to import not less than 28 days prior to importationADR’s must be notified to the MHRA using yellow card schemeAdvice from HSE/DEFRA needed as this product is likely to be a GMOmight impact on product preparation prior to administrationHSE/DEFRA notification requirements
39Hypothetical Case Example 3 Doctor wants to treat patient with an unlicensed ATMP imported from a country within the EEASame points as for cases 1 & 2 excepthospital/pharmacy will need to hold a ‘Wholesale Dealers Licence’ (issued by MHRA)
40Hypothetical Case Example 4 Doctor wants to treat patient with an unlicensed ATMP manufactured in the hospital or at a facility within UKCan use either ‘specials’ or ‘hospital exemption’ depending on ‘needs test’specials: manufacturing facility will need ‘specials licence’all other requirements as per previous examplesHE: 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