Pharmacist Rana Musa Al-ali (Malkawi) MSc (Pharmaceutical Quality Assurance) Registration Department/JFDA

Transcription

1 Pharmacist Rana Musa Al-ali (Malkawi) MSc (Pharmaceutical Quality Assurance) Registration Department/JFDA 1 2 ND MENA Regulatory Conference On Bioequivalence, Biowaivers, Bioanalysis, Dissolution & Biosimilars Amman (15 th -17 th September/2015)

2 1-Biologicals Vs small molecule drugs 2- Regulatory Pathway In Jordan 3-Biosimilars general considerations 4-Conclusions 2

3 1-Biologicals Vs small molecule drugs 2- Regulatory Pathway In Jordan 3-Biosimilars general considerations 4-Conclusions 3

4 Biologicals Vs Small Molecule Drugs Biological products: They include a wide range of products either synthezised or extracted from a biologic system, such as vaccines, blood & blood components, allergenics, somatic cells, gene therapy, tissues, & recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells & tissues. Biologics are isolated from a variety of natural sources - human, animal, or microorganism - & may be produced by biotechnology methods & other cutting-edge technologies. They often are at the forefront of biomedical research & may be used to treat a variety of medical conditions for which no other treatments are available 4

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7 Small molecule drugs 7 Made by chemical synthesis Low molecular weight Well defined structure Process independent Easily characterized Stable Mostly nonimmunogenic Biological drugs Made by living cells High molecular weight Complex & heterogeneous structure Strongly process dependent Difficult to characterize Unstable, sensitive to external conditions Immunogenic

8 Biologicals key points: There is a strong relationship between the manufacturing process & the characteristics of the final product. The safety & efficacy of the final product is very sensitive to small changes in the manufacturing process (the effect of these changes are difficult to predict) This could lead to a negative health consequences on patients 8

9 1-Biologicals Vs small molecule drugs 2- Regulatory Pathway In Jordan 3-Biosimilars general considerations 4-Conclusions 9

10 The only official body that is responsible for regulating all aspects related to medicines throughout their full lifecycle,starting from active ingredients until it s ready for patient s use as finished product. Works on providing & maintaining proper public health through allocating all possible means & tools to obtain medicines within a reasonable period of time after ensuring safety, quality & efficacy. 10

11 Drug Registration Unit Pharmacovigilance Unit Drug registration Division Herbal registration unit Files archiving Unit 11

12 History of Biopharmaceutical Regulatory system In 2004 : issuance of the criteria for Registration & Re-registration of all drugs. Since 2009, all drug applications submitted to JFDA followed the CTD format. In 7/5/2015 the guideline for Biosimilars registration in Jordan was released & published in the official gazette. 12

13 The guideline for Biosimilars registration in Jordan 13

14 The purpose of the Biosimilar registration guideline: Provide assistance to applicants (industry) on how to comply with the regulations. Introduce the concept of biosimilars. Require a baseline scientific comparison of the Biosimilar with the Reference drug (the comparability requirements) with regards to quality, safety & efficacy. Identify the level of clinical data needed to evaluate & approve the Biosimilar. Focus on the Quality assessment, with head-to-head comparison to the Reference drug with full characterization of quality parameters using state of the art techniques & analytical methods or procedures. Focus on-marketing safety studies to monitor any potential differences in safety including immunogenicity between the Biosimilar & Reference drug that become apparent once a Biosimilar enters the market. Specify details to ensure traceability with regards to Pharmacovigilance for biosimilars. 14

15 Major Articles in the guideline: Article (2), Definitions: RBP (Reference Biological Product): Innovator biological medicinal product either already approved/registered in the reference countries in the EU (via the centralized procedure), USA, Australia, Canada, Japan, &/or Jordan, this product should be registered on the basis of a complete dossier (full quality, safety & efficacy). The reference product is used in demonstrating the comparability of a biosimilar product through quality, nonclinical & clinical studies. 15

16 Biosimilar Product: a biological medicinal product that is similar to the reference product in terms of quality, safety & efficacy, contains a version of the active substance that is similar, in molecular & biological terms, to the active substance of the reference product. The posology & route of administration of the biosimilar must be the same as those of the reference medicinal product. Deviations from the reference product as regards strength, pharmaceutical form, formulation, excipients or presentation require justification. If needed, additional data should be provided. Any difference should not compromise safety. 16

17 17 Reference Biological Product VS Biosimilar Product

18 Manufacturing site: Site/s responsible for any step in the manufacturing of the active ingredient/s, starting from the storage & use of the Working Cell Bank. Site/s responsible for any step in the manufacture of the finished product. The batch release site. 18

19 Article (4): -This guideline is applicable to similar biological products that contain, as the active substances, well characterized proteins derived through modern biotechnological methods such as recombinant DNA, into microbial or eukaryotic cell culture. - It does not cover complex biologics such as bloodderived products, vaccines, immunologicals/allergens,and tissue, gene and cell therapy products. 19

20 Article (5): It is prohibited to register a biosimilar drug except after approving its manufacturing sites in accordance with the approved principles thereof. Article (6): It is prohibited to market a biosimilar drug except after its registration, pricing & the issuance of a registration number for it. 20

21 Article (7): JFDA reserves the right to request further information not specifically described in the guideline, to ensure safety, efficacy & quality of biosimilar products on justifiable scientific bases. Article (9): An application for registration for every pharmaceutical form & concentration must be submitted separately. Article (10): All Biosimilar drugs registered before the issuance of this guideline will be reviewed on a case by case bases upon the re-registration process. 21

22 Article (11): When conducting a post approval change on a registered biosimilar product, a variation application must be submitted with all the required documents to support this change. Article (12): This guideline follows the EMA guidelines on biosimilar drugs & all the relevant Guidelines on biological products containing biotechnology-derived proteins as active substance, & any further updates on the EMA guidelines are subsequently adopted by default. 22

23 23 Application submission

24 All biosimilars should be submitted as new DRUGS & should take NDA number. Biosimilars are evaluated by New drugs registration Committee. 24

25 Standing Committees Director General Higher Drug Committee Drug Directorate Generic Drug Registration Bio-equivalence Baby Formula Originator Drug Registration Vitamins and Minerals Pharmaceutical Manufacturing Site Accreditation PAC Cosmetics Clinical Research RE-Registration Pricing 25 Sera & Vaccines

26 General considerations for application submission It is required to submit a separate copy of the technical file for analysis purposes at the Drug Control Laboratory enclosing: Samples of the finished product (the number of which will be determined in accordance with the drug testing system). An adequate quantity for analysis of the reference primary active substance(s) & degradation products. 26

27 Major contents of Biosimilars file - Files should be on CTD format -CTD Format consists of 5 modules module 1: Regional requirements. module 2: Summaries of the other 3 modules module 3: Quality module 4: Non clinical data module 5: Clinical data For Biosimilars :Comparability studies with the Reference Product should be submitted. 27

28 CTD Module 1 Administrative Documents Country specific CTD Module 2 Summaries of other 3 modu. 28 Major contents of Biosimilars file (cont.) : Application forms Certificates :CPP(WHO format), prices, TSE/BSE Product Information: Labeling, outer & inner package, leaflet legalized SmPC, sample, registration status, list of registered similar products. Letter of accreditation of manufacturing site by JFDA. Specific requirements: Technical Contract, PMF approval certificate from the health authority. Pharmacovigilance system description: provide description of the system & presence of a qualified person for the notification of any adverse rxns Risk management plan (RMP) Quality Overall Summary Non clinical summary & overview. Clinical summary & overview. CDER Forum /Jordan FDA Oct.25-

29 Major contents of Biosimilars file (cont.) : Substance (API) Part : CTD Module 3 Comparability starting with the API to the finished product (Quality) Technical data : characteristics (impurities, purity, immunogenicity), manufacturers, manufacturing process, specifications, analytical methods, validation, containers, stability studies, batch analysis..) Drug Product part: composition, excipients, formulation development, manufacturers, manufacturing process & validation, specifications, analytical methods, validation, containers, stability studies, batch analysis. for intermediates + Final intermediates +finished product Batch record for 3 consecutive production batches (consistency). Batch numbering system. Plasma Master File (PMF) if needed. 29 CDER Forum /Jordan FDA Oct.25-

30 Major contents of Biosimilars file (cont.) : CTD Module 4 (Non clinical) -For biosimilars: comparability studies are required according to EMA guidelines CTD Module 5 (Clinical) -Clinical studies, -Published literature (peer reviewed Journals) -PSUR & Risk Management Plan -For biosimilars: comparability studies are required according to EMA guidelines 30

31 Comparability exercise considerations : Biosimilars can be approved based on an exercise to demonstrate proof of similarity in terms of quality, safety & efficacy of an already approved reference product. Comparability with the chosen reference product should be addressed for both the active substance & drug product. Applicants should note that the comparability exercise for a biosimilar versus the reference product is an additional element to the requirements of the quality dossier & should be dealt with separately when presenting the data. 31

32 Representative number of batches produced according to a manufacturing process with proven consistency intended for commercial use should be used to cover all comparability studies. Quality differences may impact the amount of non-clinical & clinical data needed, & will be dealt with on a case by case approach 32

33 Pharmacovigilance Plan/Risk Management Plan (RMP) Any post-market Risk Management Plan (RMP) should include detailed information of a systematic testing plan for monitoring immunogenicity of the biosimilar post-market. The RMP may be maintained & implemented throughout the lifecycle of the product. Risk minimization activities may differ from region to another so it s very important that the manufacturers should take the region specifications into consideration while setting the RMP. RMP should take into account identified & potential risks associated with the use of the reference product &, if applicable, additional potential risks identified during the development program of the biosimilar & should detail how these issues will be addressed in post-marketing follow-up 33

34 The Pharmacovigilance plan must be submitted in the registration file. The Pharmacovigilance plan should be designed to monitor & detect both known inherent safety concerns & potentially unknown safety problems that may have resulted from the impurity profiles of a biosimilar, or may have been undetected in premarket testing or otherwise not expected. 34

35 1-Biologicals Vs small molecule drugs 2- Regulatory Pathway In Jordan 3-Biosimilars general considerations 4-Conclusions 35

36 General development pathway difference RBP Discovery Development Pre- Clinical Phase I Phase II Phase III Biosimilar Development Pre- Clinical Phase I Phase III 36

37 Differences in the manufacturing process between RBP & Biosimilar arises from: Cloning the gene sequence on a different DNA Vector. Using a different host cell for expression. Using different fermentation process (different growth media for cell expansion). Using different purification protocol (different elution conditions) 37

38 Complex manufacturing process lead to: Heterogeneity of Biopharmaceuticals. Different cell lines producing the proteins could alter the 3D structure of the protein. Impact the receptor binding, stability, PK & safety. Immunogenic potential in patients. 38

39 POST-MARKET REQUIREMENTS Since limited clinical data are submitted at the time of approval, this requires a vigorous, comprehensive & well structured PV plan (to monitor immunogenicity & adverse drug reactions,..). Traceability. Periodic Safety Update Reports (PSURs). Reports should be continuously submitted to the authority (where appropriate ) and SmPC should be updated whenever new findings. 39

40 INTERCHANGEABILITY & SUBSTITUTION Biosimilars are not generic products & cannot be identical, but similar to their reference products, further biosimilar do not necessarily have the same indications or clinical use as the reference product; thus, the decision to treat a new patient with either a reference product or its biosimilar medicine, or switch in an already treated patient, between a reference product & its biosimilar should only be taken following the opinion of a qualified health professional Automatic substitution & active substance-based prescription cannot apply to biologicals, including biosimilars. 40

41 1-Biologicals Vs small molecule drugs 2- Regulatory Pathway In Jordan 3-Biosimilars general considerations 4-Conclusions 41

42 Summary & Conclusions Biologics are one of the fastest growing sectors of the pharmaceutical industry, that introduced many new treatments to life-threatening and rare illnesses. A biosimilar is not identical to the RB. Complexicity of biosimilar products in all aspects needs to be considered critically. Pharmacovigilance is a key pillar & very essential in tracking down any safety and efficacy problems that may arise from the use of biosimilars. There is a need for a regulatory framework to control the post approval changes of Biosimilars. 42

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