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How to get from.....

How to get from. what we have. to what we want. CURRENT STATUS. Name change ADAPIVE PATHWAYS. Roma, 17.02.2015 Roma 15.07. 2015. New publication by “Guru”. Eichler G., et al.

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How to get from.....

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  1. How to get from..... what we have to what we want

  2. CURRENT STATUS Name change ADAPIVE PATHWAYS Roma, 17.02.2015 Roma 15.07. 2015

  3. New publication by “Guru” • Eichler G., et al. • From Adaptive Licensing to Adaptive Pathways: Delivering a Flexible Life-Span Approach to Bring New Drugs to Patients • CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2015 • 15.feb.2015 0n line

  4. Wrap-up picture

  5. EMA: Six medicines selected to go forward in the pilot24.12.2014 EMA received 34 requests 6an advanced-therapy medicinal product (ATMP), • orphan medicines • from small- or medium-sized companies (SMEs). • cancer indications. six medicines selected to go forward into more in-depth discussions with the company with the participation of all stakeholders, including health-technology-assessment (HTA) bodies and patients’ representatives.

  6. Update:Adaptive pathways The first of the in-depth discussions, on the quality aspects of an ATMP, took place in December 2014, with others already planned during 2015 A full review of the outcome and impact of the adaptive pathways pilot project will be conducted once at least six medicines selected for the pilot have completed a procedure of parallel scientific advice with HTA bodies The Agency continues to receive the Application Forms

  7. What do we have??? Very good CMC IMP ( covers only CMC) to be updated Guideline on the Requirements for QualityDocumentation Concerning Biological Investigational Medicinal Products in Clinical Trials(2011) Clinical trials published (critical apraisal with consideration of EU guidelines for the treatment of DFU, GCP and GPhV compliance needed) List of non-clincial studies performed (critical apraisal, GLP of all studies needed) Safety from the published paprers (critical apraisal of the data an PhV system needed)

  8. Issues to be adressed in paprallel to the efficacy and safety Tumorigenicity Immunogenicity PK/PD profiles Dose /posology adjustments Pharmacovigilance System Master file • IMPD Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials

  9. To do list Create a team of experts to address all critical issues and make the assessement of the needs and timelines Create links and seek support from the learned societies involved in the therapy of the disease Create links and seek support from the patients associations

  10. To do list Create link and seek support from the HTA institutions Create a team of medical experts to assist the registry foundation and real time data colection One can realize the tasks when the product documentation is consolidated

  11. The team • Regulatory (1) • Toxicology (1) • Quality (3) • Medical expert(s) (3) • Statistician and medical writer (1-2) • Registry design and management (2) • Data management (2) • PhV systems (2) • Public relations (1) • CRO

  12. The team • 1 1/2

  13. Timelines Brainstorming round table meeting to discuss issues listed in the Adaptive (Licensing) Pathways(Pilot project) Submission Form Can be called upon when the team is defined and constituted Conditions for performaces must be clearly set up

  14. Timelines

  15. Team set up timelines

  16. How to start? • Presenting AP procedure • Presenting current status of the EGF • Presenting the Sponsor • Presenting the project design • Presenting the project aims • Informing about the conditions

  17. INTRODUCTION 1.1 Legal Basesand Framework ofpharmacovigilance II RESPONSIBILITIES IN PHARMACOVIGILANCE 2.1 Responsibilitiesof Drug andManufacturersRegistrationHolders 2.2 ResponsibilitiesoftheResponsible for Pharmacovigilance (RPV) andthePharmacovigilance Group 2.2.1 ResponsibilitiesoftheResponsible for Pharmacovigilance (RPV) 2.2.2 ResponsibleofthePharmacovigilance Group

  18. III ORGANIZATION OF THE CIGB PHARMACOVIGILANCE SYSTEM 3.1 Objective 3.2 Limits, time intervalsanduniverse 3.4 Procedures

  19. IV OPERATION OF THE PHARMACOVIGILANCE SYSTEM OF THE CIGB 4.1 Spontaneousreports 4.2 Assessmentofthenotifications 4.3 Analysisof ARD or ESAVI 4.4 Generationofsignals 4.5 Expeditiousnotificationofadversereactions

  20. V DATABASES 5.1 Analysisofpharmacovigilancedata VI GROUPS OF EXPERTS ON PHARMACOVIGILANCE VII RISK MANAGEMENT PLAN AND STRATEGY TO MINIMIZE RISKS

  21. VIII INVESTIGATION OF NOTIFICATION ALERTS OF APPEARANCE OF SUSPICIONS OF MORTAL, SERIOUS AND LOW FREQUENCY ARD IX SYSTEM FEEDBACK X GENERAL PRINCIPLES FOR WRITING DOCUMENTS ON PHARMACOVIGILANCE

  22. XI PERIODIC SAFETY UPDATE REPORTS (PSUR) XII POST-MARKETING SAFETY STUDIES (PMS) XIII FILING XV GLOSSARY OF TERMS XVI REFERENCES

  23. Responsibilities of the Responsible for Pharmacovigilance (RPV) and the Pharmacovigilance Group The monitoring of the safety of drugs must comply with the Good Pharmacovigilance Practices issued by the World Health Organization (WHO) and the Pan American Health Organization (PAHO) and it should be carried out in agreement with the Uppsala Monitoring Center (UMC), WHO collaborating center.

  24. Organization of the CIGB pharmacovigilance system Establish a system that allows knowing the extent and significance of Adverse Reaction to Drugs (ARDs) and Adverse Events Supposedly Attributable to Immunization (ESAVI), by drugs or vaccines produced by the CIGB, and used by the Cuban population or abroad.

  25. Generation of signals It is the responsibility of specialists to evaluate on a quarterly basis the information contained in the database in order to identify signals. Whenever it is considered that the signal generated is an imminent health problem, it must be expeditreportingto the Direction of Clinical Researches and the Directorate General of the CIGB, CECMED and/or MINSAP in a period not less than 72 hours after reaching that conclusion.

  26. Risk management plan and strategy to minimize risks The risk management process of a product at CIGB is defined by activities planned to identify, assess the risks associated with their use, identify strategies to minimize or eliminate them and maintain a systematic monitoring and communication thereof, according to the SOP 4.10. 146.07.

  27. Conclusion Collection, processing, management and assessment of the safety data are close to the EU requirements.

  28. An overview of available studies • Advantages: • Available studies share the same methodology with two doses (some use placebo control), • They use the same posology with 25/75 μg three times a week, • They use the same method of administration, • Total number of subjects included is relatively significant (N=396). • Drawbacks: • Total number of studies is only 5, • Primary endpoint is granulation, as opposed to epithelization which is required in EU.

  29. A shortoverviewoftheresults • Study No. 1: • DFU 21 to 78 cm2, • 75% of ulcer surface was under granulation tissue in 7 patients in mean of 33 days, • Complete closing in these subjects was seen after average period of 57 days. • Study No. 2: • Lesions >20cm2, Wagner 3 or 4, more than half lesions ischemic, • Complete granulation was seen in: • 83% subjects in average time of 3,8 weeks (75 μg), • 61% subjects in average time of 4,9 weeks (25 μg).

  30. A shortoverviewoftheresults (contd.) • Studies No. 3 and 4: • Observational, prospective, longitudinal studies, • Included were subjects with DFUs > 20 cm2 (median), Wagner 3 or 4, • Study using 25 μgdosage regimen showed: • 84% subjects achieved full granulation within 8 weeks, • 73% had complete lesion closure after average of 75 days. • Study using 75 μg dosage regimen showed: • All subjects achieved full granulation after average time of 23 days, • 80% had complete lesion closure after average of 35 days.

  31. A shortoverviewoftheresults (contd.) • Study No. 5: • Confirmatory, multicenter, randomized, double-blind, placebo-controlled, • Included were subjects with DFUs over 20 cm2 in area, Wagner 3 and 4, more than 50% ischemic, • Best response was seen in 75 μg group with 87% of patients with complete granulation, • Complete glanulation in placebo group was 58%, • Effect in neurotic ulcers was more significant compared to ischemic ones.

  32. National extension use inCuba • 1850 subjects with all grades and severities of DFUs were followed, • In Wagner grade 1 and 2 80,4% subjects had total granulation, • In Wagner grade 3 and 4 75,8% subjects had total granulation, • In Wagner grade 1 and 2 mean time to granulation was 3,4 weeks, • In Wagner grade 3 and 4 mean time to granulation was 4,3 weeks.

  33. Adverseeventsfrom all mentionedstudies

  34. An overview of available studies- Conclusion • Significant number of subjects was included in clinical studies and extension use, • Greater dose (75 μg) had more favourable results achieved in shorter average time when compared to the 25 μg dose, • Effect seen in placebo groups is probably due to extensive wound cleaning which is not part of the standard care, • Effect was more pronounced in neuropathic compared to ischemic ulcers, • Safety profile is favourable, with the most common AEs related to application procedure, • Design of the studies allows for meta-analysis of the results.

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