UPDATE LEGAL/REGULATOR Y CELL THERAPY AND COMBINATION PRODUCTSVIC Congress – Cell Therapy Manufacturing Erik Vollebregt6 December 2012 www.axonadvocaten.nl
Introduction• Scope of ATMP regulation re cell therapy in CAT classification decisions• Developments in patent law
CAT Classification round-up• CAT publishes classification decisions since 1-7-2011• Two step approach assessment methodology cell therapies: 1. Definition of medicinal product under 2001/83 • Presentation criterion (claim) • Function criterion (function) 2. Definition of ATMP under 1394/2007 • contains or consists of engineered cells or tissues, and • substantially manipulated • not same essential function in recipient as in donor • presented with a view to regenerating, repairing or replacing a human tissue
ATMP definition seen otherwiseATMP Regulation‘s scope requires that cells making up the product1. 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 (2001/83 requirement); and5. are placed on the market (2001/83 requirement – as opposed to hospital exemption)
CAT Classification round-upUntil recently: CAT classification position on ATMP was always ―yes‖Recently CAT said ―no ATMP‖ to• cosmetic fillers (autologous cells of Stromal Vascular Fraction (SVF) of adipose tissue and cryopreserved purified autologous collagen in PBS.)• solution for intra-venous injection suspension of oncolytic adenovirus for treatment of colorectal cancer• suspension containing human islets of Langerhans, autologous or allogeneic
CAT Classification: cosmetic fillers• cosmetic fillers (autologous cells of Stromal Vascular Fraction (SVF) of adipose tissue and cryopreserved purified autologous collagen in PBS) • is medicinal product • but not engineered cells • cells are viable but not substantially manipulated • the essential function of cells is considered to be the same as in the donor‘s fat tissue
CAT Classification: treatment ofcolorectal cancer• Not cell therapy• chimeric adenovirus obtained by a process of bio-selection• mechanism of action is through the direct infection and replicating-lysing properties of the virus • not through the action of any recombinant nucleic acid sequence or to the product of genetic expression of this sequence• So: no ATMP – no exclusion of other categories?
CAT Classification: islets ofLangerhansNo ATMP because:No engineered cells• product is derived from pancreatic tissue by a number of steps that do not constitute substantial manipulation• manipulation of the tissue does not alter the biological characteristics and physiological functions relevant for the intended clinical use• no change in the biological characteristics of the islets: the cells of the islets do not divide and phenotype and function of the cells contained in the product are not changedSame essential function• same essential function in the recipient and the donor, i.e. pancreatic function• CAT explicitly excludes gene therapy product option
Combination ATMPs‗Combined advanced therapy medicinal product‘ means an advancedtherapy medicinal product that fulfils the following conditions:— it must incorporate, as an integral part of the product, one or moremedical devices within the meaning of Article 1(2)(a) of Directive93/42/EEC or one or more active implantable medical devices within themeaning of Article 1(2)(c) of Directive 90/385/EEC,and— its cellular or tissue part must contain viable cells or tissues,or— its cellular or tissue part containing non-viable cells or tissues must beliable to act upon the human body with action that can be considered asprimary to that of the devices referred to.
Combination ATMPsNo public classification summariesHowever, classified as ATMP:• Allogeneic human fibroblasts cultured onto a biodegradable matrix• Hollow fiber cartridges populated with the C3A cells to be used with ancillary support equipment• Autologous osteoprogenitor cells, isolated from bone marrow and expanded in vitro, incorporated, as an integral part, with 3D biodegradable scaffold• Autologous cultured chondrocytes integrated in a scaffold
New Medical Devices Regulation:scrutinyScrutiny procedure motivated by political decision to increase supervisionof conformity assessment of high risk devices• New MDCG will have the right to ‗call‘ up files from notified bodies• Procedure is not really well defined• It‘s the thing that the industry is most sceptical about in the proposed MDR
New Medical Devices Regulation:scrutinyScope• Class III devices; and• Other devices than class III, for a predefined periodOther devices if justified only by one or more of the following criteria:(a) the novelty of the device or of the technology on which it is based and the significant clinical or public health impact thereof;(b) an adverse change in the risk-benefit profile of a specific category or group of devices due to scientifically valid health concerns in respect of components or source material or in respect of the impact on health in case of failure;(c) an increased rate of serious incidents reported in respect of a specific category or group of devices;(d) significant discrepancies in the conformity assessments carried out by different notified bodies on substantially similar devices;(e) public health concerns regarding a specific category or group of devices or the technology on which they are based.
BrüstleECJ October 18, 2011Article 6 Biotech Directive:Inventions are unpatentable where their commercial exploitation would becontrary to ordre public or morality;Unpatentable (e.g.):(a) [process cloning humans];(b) [process for modifying germ line identity];(c) uses of human embryos for industrial or commercial purposes;(d) […]
Brüstle• Brüstle had applied for patent on isolated and purified precursor cells derived from human embryonic stem cells with the potential to develop into neuronal cells as treatment for Parkinson‘s disease• Brüstle used human blastocysts which had to be killed for deriving the embryonic stem cells• Questions asked by German court of appeal: • What is an embryo? • Does scientific research fall under ―industrial or commercial purposes? • what if the use of embryos is not in patent itself but a requisite for the applicability of the invention?
Brüstle ECJECJ:• An embyro includes all cells that are capable of developing into a human being and includes: • Fertilized cells from day one as long as they are totipotent; • Non fertilized cells where a nuclear of a human cell is implanted and stimulated to develop; • Parthenogenesis• Pluripotent cells are not an embryo (not capable of developing into a human being) but: if the invention requires prior destruction of a human embryo (even long time prior to invention), it is not patentable. • Brüstle method: the blastocyst needed to be destroyed by obtaining the embryonic stem cells so not patentable.
Brüstle ECJECJ:• Use of embryo‘s for scientific research purposes is also form of industrial and commercial application (already filing a patent is such form)• Interpretation of Biotech Directive is binding on all member statesAnd then?• Induced pluripotent cells derived from adult cells are allowed. But: techniques could advance to induce totipotent cells• Using embryonic pluripotent stem cells without killing embryo (but patent application should express that a technique is used that does not kill embryo)• Banking on other forms of protection (know how, data exclusivity)
Brüstle German Supreme CourtBrüstle at Karlsruhe German Supreme Court 27 November 2012(X ZR 58/07)• research methods that involve the use of stem cells gathered from human embryos destroyed in the process cannot be patentedHOWEVER• patents can be issued for stem cell research methods where the embryo from which the cells are collected is not destroyed orOR• where the stem cells are collected from embryos that are not capable of further development
Brüstle nationallyImplications?• Limitation of scope if ECJ Brüstle judgment but for Germany only• Today it is possible to produce replacement cells from the bone marrow cells of adults or from cord blood• Do we still need human embryos as a source of stem cells?
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