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«28 January 2016 EMA/CHMP/BPWP/144533/2009 rev. 1 Committee for medicinal products for human use (CHMP) Guideline on the clinical investigation of ...»

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Risk Management Plans should be compiled in compliance with the provisions of Volume 9A of The Rules Governing Medicinal Products in the European Union. The protocol of the post-marketing investigation should be included in the respective annex of the RMP.

Inhibitor formation The most serious complication of replacement therapy with factor VIII is the development of factor VIII inhibitors in PUPs and PTPs. A comprehensive analysis of reported de novo and recurrent inhibitors

should be provided as a cumulative report in RMP Annex VII, including:

Source of inhibitor reports (e.g. clinical trial/post-authorisation investigation/spontaneous reports) • Low and high titre, intermittent inhibitor.

• (Every positive laboratory test should be retested in a central laboratory with a second separately drawn sample from the same patient before a diagnosis of an inhibitor can be made. Samples should be stored for possible future testing.) Type 1 and 2 inhibitors •

Classification of risk to develop factor VIII inhibitor:

–  –  –

Inhibitor incidence should be expressed as point estimate and 95 % CI.

Special populations:

• Patients who underwent surgery and subsequently develop inhibitors − Any specific risk (e.g. inhibitor development, lack of effect) induced in switching to the product − from another factor VIII product should be discussed separately. This is in particular relevant for products with a significant change in the manufacturing process. The switch from prechange to post-change product should be investigated carefully.

Lack of drug effect Lack of drug effect and breakthrough bleeding may point to inhibitor development. A pre-defined case definition is essential. Careful follow-up including inhibitor evaluation (consumption, recovery, half-life, inhibitor testing) needs to be reported.

Hypersensitivity / anaphylactic reactions Hypersensitivity / anaphylactic reactions including against host cell proteins, excipients and residues used in the manufacturing process may occur. These reactions should be classified according to local and systemic hypersensitivity reactions. Patients developing anaphylaxis should be carefully investigated and followed-up for inhibitor development. An appropriate questionnaire/reporting form should be used with information collected on status of treatment (e.g. PUP/PTP). Data on relevant antibodies against factor VIII (using appropriate methods), e.g. IgE, IgG, should be submitted.

Measurement of plasma factor VIII levels significantly affected by the assay used for clinical monitoring Where there can be discrepant assay results depending on the assay used for clinical monitoring (see 6.1.1), some information will be included in the product information but other approaches may also be needed including educational material for training of clinical laboratories. The Risk Management Plan is an appropriate place to address the risk of discrepant monitoring of plasma levels and the measures to avoid this.

References Report of Expert Meeting on Factor VIII Products and Inhibitor Development, 28 February 2006 – 02 March 2006 (EMEA/CHMP/BPWP/123835/2006), http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500015512.pdf European Pharmacopoeia, 8th edition, Strasbourg, France, European Directorate for the Quality of Medicines & HealthCare (EDQM), Council of Europe, 2015.

Neugebauer B., Drai C., Haase M., Hilger A., Keller-Stanislawski B., Laitinen-Parkkonen P., Mentzer D.,

Rasmussen C., Ratignier C. and Seitz R. (2008), Factor VIII products and inhibitor development:

concepts for revision of European regulatory guidelines. Haemophilia, 14: 142–144.

doi: 10.1111/j.1365-2516.2007.01604.x

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Workshop report: Characterisation of new clotting factor concentrates (FVIII, FIX) with respect to potency assays used for labelling and testing of post infusion samples, 28-29 November 2013 (EMA/135928/2014) http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/07/WC500169760.pdf https://www.edqm.eu/en/Workshop-on-characterisation-of-new-clotting-factor-concentrates-newreport-available-1582.html?mbID=216 Dodt, J., Hubbard, A. R., Wicks, S. J., Gray, E., Neugebauer, B., Charton, E. and Silvester, G. (2015),

Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing:

challenges for caregivers and regulators. Haemophilia. doi: 10.1111/hae.12634 Applicants should also refer to other relevant European and ICH guidelines (in their current version)

including those on:

ICH E6 Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), ICH E8 Note for Guidance on General Considerations for Clinical Trials (CPMP/ICH/291/95), Guideline on strategies to identify and mitigate risks for first-in human clinical trials with investigational medicinal products (EMEA/CHMP/SWP/28367/07), Guideline on clinical trials in small populations (CHMP/EWP/83561/2005), ICH Q5E Note for Guidance on Biotechnological/Biological Products Subject to Changes in their Manufacturing Process (CPMP/ICH/5721/03), Guideline on comparability of biotechnology-derived medicinal products after a change in the manufacturing process - non-clinical and clinical issues (EMEA/CHMP/BMWP/101695/2006), Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins (CHMP/EWP/89249/2004), Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), and Volume 9A of The Rules Governing Medicinal Products in the European Union: RMP

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In order to allow for evaluation of a patient’s individual response, pharmacokinetic information e.g. existing PK data with the patient’s previous factor VIII product (at least historical or recent recovery and half-life) should be available prior to first administration of the new factor VIII product.

–  –  –

PUP study (novel products) (to be started after results of 50 ED in 20 children (0 - 12y, at least 10 of them 6y) are available and PK in children 0 - 12y completed)

–  –  –

Post-approval commitment of PUP indication 100 PUPs should be followed up to 100 EDs (50 PUPs from pre-approval PUP indication can be followed up to 100 EDs, 50 “new” PUPs for 100 EDs)

–  –  –

Diagnosis: haemophilia A • Severity: 1% factor VIII:C 5 • Number of exposure days before inclusion: 150 ED • PTPs of every age group could be included, provided that trial in children is finished (PK and • efficacy and safety) and report is submitted and evaluated by the relevant Competent Authority(ies). E.g. 60 PTPs 12y should be included in the study.

Immunocompetent with CD4 lymphocytes 200/µl, HIV negative or having a viral load 200 • particles/µl ~ 400000 copies/ml Documentation of patient’s characteristics Gene defect • Ethnicity • Family history of haemophilia • History of inhibitors • The viral status of patients should be documented. The patients should be HIV negative or have a • viral load 200 particles/µl ~ 400000 copies/ml) Co-morbidity or co-medication which would significantly impact blood coagulation or • immunoreaction (any information concerning this issue should be included) Patient enrolment At least 200 patients per post-marketing investigation • Follow-up of each patient must be at least 100ED • Progress on recruitment has to be reported on a regular basis (will be set out before approval of • procedure) A separate progress study report should be provided to the relevant Competent Authority(ies) 2 • years after marketing authorisation to allow for evaluation of recruitment status, progress and the adherence to timelines.

The post-marketing investigation should be completed within 4 years.

• Study procedures Before patient inclusion there should not be a clinical suspicion of inhibitors, and a recovery and • inhibitor test in a central laboratory should confirm that the patient is inhibitor negative at study entry. An inhibitor test which is not negative should be confirmed by testing a second separately drawn sample in a central laboratory.

Testing schedule (ED = Exposure Day) • At least 100 patients 1% should participate. In case patients with up to 2% baseline level are enrolled a separate statistical evaluation for 1% and 2% should be provided.

–  –  –

Testing should also be carried out if there is any suspicion of an inhibitor.

Patients’ diaries should be evaluated on total number of exposures per year and mean dose per kg • per patient/year (consumption).

Intended treatment regimen for every patient at study entry and reason for each ED should be • documented.

In case of bleeding: documentation of particulars; judgement of severity and treatment outcome • by clinician and patient (consumption).

In case of surgery different data are to be collected (surgical protocol) (e.g. type of surgery • (planned or emergency); documentation of complications; mode of administration, consumption).

Monitoring of all adverse events.

• Explanatory note Inhibitor tests should be performed when the plasma factor VIII level has reached a pre-substitution nadir (documentation for the last infusion should be provided). Inhibitor questionnaires/report forms should be used. In the case that patients are treated on demand, an inhibitor can be missed when the patients did not receive treatment for 2 weeks. According to the t1/2 of immunoglobulins, the inhibitor will drop gradually when treatment has been stopped. In case of a positive inhibitor test, also PK / recovery tests are necessary to confirm inhibitory activity.

Co-medication: At the present time, all patients are accepted in studies (provided they are immunocompetent CD4 lymphocytes 200/µl, HIV negative or having a viral load 200 particles/µl ~ 400000 copies/ml). Patients with HIV infection receive intensive co-medication, and it is unknown whether this, e.g. HAART therapy, can influence inhibitor formation or efficacy of treatment. Similar problems can be expected for HCV positive patients, some receive therapy and others have low platelets, decreased liver function and altered coagulation. These patients can be included in order to provide additional data on efficacy in this group but more parameters on co-morbidity should be collected.

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