Themes & Key Points The Problem Statement

Transcription

1 Themes & Key Points The Problem Statement Post-approval changes are inevitable and essential, however, it is difficult to manage evolving requirements and timelines in every country to ensure continuous product supply Different, customized dossiers describing the same product are difficult to maintain the differences are due to a number of factors, including: review timelines, stability requirements, post-approval changes regulations, customized details in the dossier, manufacturers, specifications, country-specific documents, specified supply chains Post-approval changes come in all shapes and sizes, can have a dramatic impact on supply chain agility and flexibility, and can cause instability in supply and in extreme cases, shortages Health Authorities are faced with a number of constraints (resources, processes, maturity of regulating manufacturers, political, legislative, etc.) Industry and Health Authorities have identified a number of mitigation strategies to address to challenges of managing post-approval changes however, these are not enough Will ICH Q12 solve these problems? How do we solve for the issues that exist beyond the ICH countries? 1

2 Themes & Key Points ICH Q12 Global Status and Impact Q12 will focus on technical and regulatory challenges by facilitating management of post-approval CMC changes to promote innovation and continuous improvement, but it will not solve ALL of the issues Harmonization and convergence for lifecycle management of CMC changes is ideal will reduce cost and burden on industry and regulators, and ensure patients have timely access to necessary therapies Streamlining and eventually harmonizing requirements and expectations across ALL agencies would be beneficial (but not likely) Q12 will change the focus from the original application (now only a milestone) to the entire product lifecycle (includes development, dossier/ecs, management of ECs, post-approval changes/comparability protocols, and commitments) need to address what the overall product lifecycle looks like Regarding container closure systems: Q12 does not only address DS or DP container closure is not excluded, but there is no specific example in Q12 using container closure syringes, delivery systems, etc. that are included as part of a drug filing and within Module 3 are within scope of Q12 Case study is being prepared in response to this suggestion 2

3 Themes & Key Points ICH Q12 Global Status and Impact (2) Established Conditions: The core concept of Q12 is ECs if Q12 gets this right, it will lead to true transformation of lifecycle management and transparency of submissions Transformation may only be possible if the output based established conditions pathway exists. One challenge for regulators is that existing guidance will need to defer to negotiated established conditions (ECs) as well as how to ensure consistency company to company, site to site, and product to product Whether a parameter is an established condition or not, the process (patient benefit/risk, link to product/process understanding) is the same the only thing that is different is the extent of review by a regulatory agency (EC s and non-ecs are managed under the PQS) The quality system expectations remain the same, regardless if the change were for an EC or a non-ec. 3

4 Themes & Key Points ICH Q12 Global Status and Impact (3) PQS ICH Q12 will build on ICH Q10 It is difficult to grade the Pharmaceutical Quality System (PQS) Provocative thought Could a company be ICH Q10 certified (similar to ISO certification)? Q12 focuses on two (2) enablers: (1) robust product process understanding and (2) effective PQS (which drives a company toward a positive quality culture) For Q12 to work, all elements of the lifecycle (CAPA, Management Review, etc.) must work together Use of active knowledge management to drive change over the lifecycle. Provides confidence that most changes can be managed solely under the company s PQS 4

5 Themes & Key Points ICH Q12 Global Status and Impact (4) Post-approval Change Management Protocols (PACMP) Post-Approval Change Management Protocols (PACMPs) are underused multi-element PACMPs may provide more bang for the buck Ideal state: marketing authorizations would describe change management system and include generic protocols for how changes will be evaluated change management system and protocols approved globally and changes implemented without submission Ideally, protocols would be submitted with the initial global marketing applications describing how changes will be evaluated so that improvements could be efficiently filed and implemented ICH countries have outlined an openness and willingness to accept the use of the PACMP (this will increase the use of this tool beyond the US). 5

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7 Themes & Key Points Changing LCM in Practice Mostly general consensus on output-based Ecs Not really driven by testing less, in some ways this means testing more. Where to put list of Ecs? Module 2? Don t just list them in a table? No requirement to start including Ecs in current applications, but if you re going to, give reviewers a heads up Some experience with submission of Ecs now.however, regulators aren t quite ready. How to increase communication between reviewers and inspectors? FDA using integrated inspection/review model and working to improve it further. Consensus that more discussions are needed around the micro controls required in P.3.3. Ecs for methods detailed technical knowledge needed to discuss further and not all method changes are the same Any method changes that impact specs would be Ecs General consensus that method performance characteristics should be Ecs Validation information is supportive and not Ecs 7

8 Themes & Key Points Changing LCM Clarity and consistency! in Practice (2) Industry consensus that desire for Ecs is not around increased flexibility as much as it is around ensuring clarity and consistency. A key to all this is transparency. Take the word flexibility out of the Q12 discussions altogether. Consensus that we are already operating this way, so we aren t introducing new layers of complexity and controls, rather we are putting clarity and consistency in place. This will also benefit regions that don t have clear guidelines around this already. Don t want to and in some cases (Japan) cannot change regulations.just provide more clear guidance. Training of reviewers will be a large effort coming out of this will be difficult and take time Possible to remove Ecs throughout lifecycle of product? Yes! Use CPV to enable increased product knowledge and link this to the LCM plan and comparability protocols. Removing Ecs does require a filing and sufficient justification. Q12 does need to address how Ecs will be managed over the lifecycle of a product 8

9 Themes & Key Points Changing LCM LCM Plan/Strategy in Practice (3) General consensus this is beneficial to capture all information in a central location. Lacking consensus on how information should be built into this document and what information would be binding in it What if reviewers disagree with this plan? What does it mean in terms of overall approval? Clear guidance that if a proposed reporting category is non-standard, a PACMP is needed to avoid confusion. This guidance should be included in Q12. 9

10 Themes & Key Points To Infinity and Beyond Drug shortages and links to ICH Q12 A deeper dive of the reasons for these shortages may be needed. Q12 will encourage a modernization to reduce risk. PQS is foundational and important to enable Q12 implementation and success. Improving post-approval change processes as a way to ensure technical innovation and drug product availability Current regulatory process complexity is not sustainable, it is causing drug shortages and it hampers technology innovation. Goal to reduce or eliminate reporting of low risk changes and have a united way of managing reportable changes. Combination products: while regulations vary across regions, there is a common challenge where the vast majority of delivery system products are filed with minimal guidance of what is an EC. A significant win is to have clarity regarding what aspects of the delivery systems requires a post approval change submission. One world, one regulatory standard. 10

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12 Change Happens: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management How do we close the gap between approval timelines (and data requirements) for post-licensure changes between ICH and non-ich countries? We know that global convergence will not happen, but there are small steps that could occur. For example, there are fundamental elements that could be addressed, such as common understanding of common capabilities (WHO is pushing for this). WHO is in the process of issuing their document on Good Review Practice. There are certain regional clusters that are attempting to address convergence of requirements (ex within EU member states). Also, Singapore procedures state that if approval has already been obtained in specific countries, only certain minimal information needs to be submitted for their approval. 12

13 The Problem Statement How does your organization manage post-approval changes to minimize the number of flavors that need to be manufactured and to minimize compliance issues? Provide a small amount of information to those Health Authorities that do not require all information. Maintain a redacted version of the core dossier that would have been submitted to the major markets to help with post-approval strategy. However, specific markets require different levels of detail. In some cases, the redacted dossier may result in more questions up-front from the Health Authority, but this has reduced the overall approval timeline in some cases. Work closely with the supply chain colleagues at your company need to ensure inventory is available for product launch within each particular country. In some cases multiple flavors of the processes/products may need to be managed based on specific country approvals, but changes can be bundled where possible. 13

14 The Problem Statement How does your organization manage post-approval changes to minimize the number of flavors that need to be manufactured and to minimize compliance issues? When questions are received from the Health Authority additional changes can be incorporated during this process. Additionally, other subsequent changes can be discussed with the Health Authority during the approval process. A company may need to have numerous supply chain bridging activities in place to manage product inventory. Collaborate with the local affiliate to help expedite product approval. The complexity of managing distributors, multiple dossiers in various languages, etc. is becoming a nightmare it is beneficial to maintain a document containing the critical elements/details of the products, which flavors are approved, which are pending, and when approval is expected. 14

15 The Problem Statement Based on what you have seen so far, is ICH Q12 going far enough to address the most critical issues associated with post-approval change management? If not, what is missing? Any proposed edits? One of the main potential benefits of Q12 is the possibility of downstream convergence and layering the framework required for future elements within lifecycle management to be addressed. Q12 will serve to incentivize innovation and how to enable supply to the patient in a more manageable manner (ex Japan and Canada will be introducing protocols). Hopeful that Q12 will open up new doors for both the regulators and industry. The topic of post-approval change management was not a hot topic two years ago. Q12, in combination with efforts in other areas such as WHO, will push this topic forward. One of the important elements Q12 addresses is ECs, and the ability to negotiate ECs at the time of filing. If there is acceptance of the existence of ECs then there is also acceptance of the existing of non-ecs these would not require regulator review and allow industry to manage these elements. On top of this, Q12 will layer the ability to downgrade the notification required. l 15

16 The Problem Statement Based on what you have seen so far, is ICH Q12 going far enough to address the most critical issues associated with post-approval change management? If not, what is missing? Any proposed edits? Q12 will not be the solution for everything! Based on a company s capability and maturity of their Pharmaceutical Quality System, some regulatory relief may been realized within ICH countries, but Q12 will likely not impact non-ich countries (these countries will not address global regulatory flexibility). Q12 will not do enough on harmonization of categories of change and requirements for each category this will mean significant regulatory change within each country. However, Q12 can lay out what is common in the regulatory framework with regard to post-approval changes and categories of change within the ICH countries (ex - there is always a pre-approval and a notification category). Industry will let the regulators know if Q12 is successful, but may need to develop good metrics going forward to show Q12 is successful. BPOG has some metrics, but metrics associated with ancillary documentation, stability requirements, approval timelines, dossier variations, flavors of dossiers, etc. need to be addressed. 16

17 The Problem Statement Based on what you have seen so far, is ICH Q12 going far enough to address the most critical issues associated with post-approval change management? If not, what is missing? Any proposed edits? Cautious optimism that Q12 will be beneficial where the effort is still lacking is in the ability to make changes without submitting a filing. Need to figure out a way to minimize filings/variations for changes such as multiple manufacturing sites/adding new site, supplier changes, etc. to create less work for industry and the regulators. The differences between the complexity of product/processes for biologics vs. small molecules needs to be addressed in Q12 Even after ICH Q12, we cannot harmonize 100%. Companies need to manage the EC document. Need a system within the company to maintain and manage ECs. The MAH has the primary responsibility to maintain the EC document this responsibility needs to be emphasized. 17

18 The Problem Statement Given that a single post-approval change of a relatively minor nature can take 3-5 years to implement globally, how can regulatory agencies within and beyond ICH countries work together to address significant challenges to supplying patients with products using the most up-to-date manufacturing processes and sites? A true global filing is likely not practical. Regulators want companies to deliver products globally to patients, but accountability needs to be addressed. Industry needs to help the MOHs understand the challenges, not just for those companies that have quality systems (QS s) that can be trusted, but also for those companies that are not as mature and their QS is not as robust. Fundamental elements could be addressed, such as common understanding of common capabilities (ex WHO is pushing for this). There are certain regional clusters that are attempting to address convergence of requirements (ex EU member states and Singapore, whose procedures state that minimal information is required to be submitted for product approval if the product has already been approved in certain countries). 18

19 The Problem Statement Given that a single post-approval change of a relatively minor nature can take 3-5 years to implement globally, how can regulatory agencies within and beyond ICH countries work together to address significant challenges to supplying patients with products using the most up-to-date manufacturing processes and sites? Work closely with Supply Chain colleagues. Need to make sure you have inventory that you can launch the product with. When questions are received from the agency, they incorporate other changes during this process. Also, they discuss these other subsequent changes with the agencies during approval. In some cases you may need to be running multiple flavors of the processes based on the country approvals. Can bundle a bunch of changes where possible. May have to have numerous supply chain bridging activities in place to manage the inventory. Also need to work with the affiliates to help expedite approval. Complexity of managing distributors, dossiers and the associated languages, etc. is becoming a nightmare need to maintain a document with the critical elements / details of the products, and which are approved, which are pending, and when approval is expected. 19

20 The Problem Statement Given that a single post-approval change of a relatively minor nature can take 3-5 years to implement globally, how can regulatory agencies within and beyond ICH countries work together to address significant challenges to supplying patients with products using the most up-to-date manufacturing processes and sites? Blue Sky Idea: Have one organization manage a central IT hub firms would submit post-approval changes to the hub, and regulatory agencies would have the ability to access the submission in the hub and address the change globally. However, there are issues with security and accessibility in this model. Countries within a region could work together to streamline the various versions of the dossier, but there is an accountability that needs to be addressed. If a decision were made outside one particular country, each country within the region would need to address accountability not sure how this would be managed. Regulators within a particular region could perform an initial review that is shared with each agency to help manage and expedite this process. Note that regulators would like to see a solution to address this problem as well. In some cases, the parent company may not be addressing the global filings (may be done via third parties) this adds another level of complexity. Need to improve communication one way to do this is via the change control process. 20

21 Changing How We Make Change: ICH Q12 Global Status and Impact How can we leverage ICH Q12 to focus global post-approval reporting on changes that really matter to patients? (a) How will the concept of established conditions have an impact on lifecycle management and post approval change? As a result of Q12, companies could be in a situation where a larger number of elements are negotiated on whether they are ECs or not, and the associated categorization is discussed (based on the relationship and trust between the regulator and the company) this may be different than what is in guidance/regulation. This could get very complicated to track across companies, sites, and products. If the ICH countries can manage the added complexity with ECs and change categories, it will be a big challenge for non-ich countries they may rely more on appropriate categorization (if they have it), or they may need to introduce categorization. 21

22 Changing How We Make Change: ICH Q12 Global Status and Impact Looking a few years ahead after the implementation of Q12, what does success look like? Success = harmonized definitions of EC, harmonized approach to post-approval changes, etc. the reduction in the number of filings that are submitted is also a measure of success Performance based/output-based parameters and explanation/justification are critical for Q12 success. This topic is currently under discussion within the EWG. It links back to the robustness of product knowledge this is where we want to be. Success = qualitative and quantitative. Examples include: reduction in the more severe /significant supplements, reduced ambiguity on what is to be reported, reduced ambiguity on ECs, reduced ambiguity on the appropriate reporting categories, and reduction in the barriers for sponsors to obtain output-based parameters Could potentially standardize and/or automate changes in a company s change management system this would make the review of CMC changes much quicker Would be ideal to capture the reduction in change categories in a protocol to facilitate ease of regulatory review. 22

23 Changing How We Make Change: ICH Q12 Global Status and Impact Looking a few years ahead after the implementation of Q12, what does success look like? When there are particular sections/elements that are not EC s which can be conveyed to a reviewer, this increases transparency and level of knowledge. It would be ideal to capture the reduction in change categories in a protocol to facilitate ease of regulatory review When particular sections of the submission and/or elements are not ECs and are conveyed to a reviewer, this increases transparency and level of knowledge 23

24 Changing How We Make Change: ICH Q12 Global Status and Impact Scientific risk and trust have come up as themes. This is an entire other level of transparency that has been discussed how will this be addressed in Q12? Cannot generate guidance that addresses trust each individual sponsor, their inspections, interactions with the regulators, etc. will establish this. If there is no trust, the entire ICH guidance model collapses. Also have to trust, but verify. The list of EC s will propagate what is happening with the product and the site (inspections, changes, etc.) and the PQS effectiveness. Q12 should include discussion or describe a situation indicating that a company is not locked into the original ECs forever should be able to provide justification as to why an EC is no longer an EC as more is learned about the product and gain knowledge The requirements for capturing EC s that is within guidance/regulation will not go away. However, if trust is lost there may no longer be the ability to use negotiated ECs may have to go back to what is inferred within the guidance/regulation 24

25 Changing How We Make Change: ICH Q12 Global Status and Impact How can we leverage ICH Q12 to focus global post-approval reporting on changes that really matter to patients? (b) What is the role of lifecycle management plans in the overall construct of ICH Q12? The EWG subgroup focused on LCMP is in the process of developing a template. How can we leverage ICH Q12 to focus global post-approval reporting on changes that really matter to patients? (c) What opportunities can industry pursue to expand the use of protocols to ensure more effective and meaningful change submissions? There are essential elements for harmonized global post approval change management: Consistent change classification and reporting, aligned data and content requirements, harmonized review and approval timelines and risk-based approach for how to manange change. ICH countries are one part of the overall challenge associated with lifecycle management. How can we ensure that ICH Q12 works globally to develop riskbased post-approval reporting and to drive acceptance of pathways such as protocols and established conditions? How will legacy products benefit from ICH Q12? What are the challenges for these products? It was noted that legacy products face the greatest challenges for ICH Q12 implementation. It was noted that the EWG recognized this and are working on strategies to ensure that approved products can also benefit from ICH Q12. 25

26 Changing Lifecycle Management in Practice: The Reality of ICH Q12 Concepts Established Conditions: How will ECs help reduce regulatory burden associated with post-approval changes? For example, setting ECs with limited process/product knowledge early in development could result in tight ranges that require loosening with more knowledge. How will these instances be facilitated? This question was not discussed in detail at the session Established Conditions: How can routine monitoring and verification be leveraged to maintain ECs over the product lifecycle? Continuous process verification can enable increased product knowledge, and this can be linked to the LCM plan and comparability protocols to allow removal of Ecs throughout the lifecycle of the product. Removing Ecs does require a filing and sufficient justification and Q12 should address how Ecs will be managed over the lifecycle of the product. It was discussed that one place to maintain the link between monitoring and verification to ECs is the LCM Plan/Strategy. There was a general consensus this is beneficial to capture all information in a central location. There was a lack of consensus on how information should be built into this document and what information would be binding in it, for example, what if reviewers disagree with this plan? What does it mean in terms of overall approval? Established Conditions: How does performance-based approach to ECs compare to QbD? Are ECs just re-designing design space? Isn t generating the product/product knowledge needed to define ECs the same as what is done for QbD? Use of Design Space claims are limited and may restrict movement because it may include too many parameters overall value is unclear (it is complicated to get a Design Space approved). The core of Q12 is the concept of ECs if Q12 gets ECs right, it will lead to true transformation of lifecycle management and transparency of submissions. One big win for ECs will be the output-based approach. 26

27 Changing Lifecycle Management in Practice: The Reality of ICH Q12 Concepts Established Conditions: Can established conditions be leveraged for currently marketed products? How do you enable ECs for products that are currently in the market? Will ECs be beneficial in these cases? There is no requirement to start including Ecs in current applications, but if you re going to, it is advisable to make sure your product reviewers know this is coming. One company has recent experience with submission of Ecs and FDA requested to remove them as regulators aren t quite ready to start reviewing these types of applications. Training of reviewers will be a large effort coming out of this it will be difficult and take time. Established Conditions: What should be considered in cases where advanced/enhanced process controls are proposed? There was a general consensus that output-based Ecs would be most beneficial and this could be gained more easily for programs with advanced/enhanced process controls. This doesn t always mean less testing, in some cases, it could mean more testing. Protocols: How can broad protocols be leveraged effectively to change specifications, for example. Can multiple changes be accounted for within a single protocol to facilitate global change? Is there an opportunity to standardize approaches across classes of molecules such that we can push towards more global efficiency? What elements of ICH Q12 do we already do globally? As an example, post-approval stability protocols are accepted globally even though there isn t an official protocol in the submission. The only discussion around protocols in this session was to clarify that for Ecs, if a non-standard proposed reporting category for changes is being considered, a PACMP is needed to avoid confusion. It was proposed that this guidance should be included in Q12 drafts. 27

28 To Infinity and Beyond Managing the Myriad of Post-Approval Changes in Non-ICH Regions One of the major tenants of ICH Q12 is the concept of Established Conditions. These established conditions would be legally binding information and any changes would require prior approval from health authorities. What is the right balance for registered established conditions that meet health authority expectations yet allow for reasonable life-cycle management activities? How will companies achieve this balance and how can ICH Q12 aid this activity? Will ICH Q12 provide additional clarity pertaining to the details expected in the regulatory filing in comparison to those presented during inspection? In theory, ICH Q12 has the potential to benefit regulators, industry, and patients by streamlining implementation of post-approval changes. How can ICH Q12 facilitate post-approval cycle times (3 to 5 years) and supply chain challenges for global implementation? How can Industry balance the regulatory requirements for life-cycle management changes between ICH and non-ich countries? ICH Q12 and life-cycle management strategies, including protocols and monitoring plans provide efficient ways of managing change. 28

29 To Infinity and Beyond Managing the Myriad of Post-Approval Changes in Non-ICH Regions ICH Q12 has the potential to stimulate and promote innovation with regard to continuous manufacturing improvement. Past initiatives to facilitate postapproval changes have met with limited success. How can stakeholders partner to ensure successful implementation of ICH Q12 principles this time around? ICH Q12 will provide what is needed to baseline reportable changes and to enable LCM, but more is needed. How can industry develop harmonized approaches for managing life cycle changes in order to create consistency, alignment and efficiency for implementation? It was suggested to consider if there were learnings from the combination products and device QMS that could be applied. ICH Q12 will help manage complexity of change, but more is needed for transformational change (J Mercer) Clarifying established conditions for manufacture and control based on risk, product type, development approaches, manufacturing experience, GMP status Development of product lifecycle strategy Provide harmonized tools to facilitate prospective changes over the product lifecycle, e.g. change management protocols Establish ICH expectations of assessment and implementation of frequent manufacturing changes 29

30 To Infinity and Beyond Managing the Myriad of Post-Approval Changes in Non-ICH Regions Combination Products: while regulations vary across regions, there is a common challenge where the vast majority of delivery system products are filed with minimal guidance of what is an EC. A significant win is to have clarity regarding what aspects of the delivery systems requires a post approval change submission. Non-ICH countries are working to meet the needs of an increased number of supplements, while also balancing resourcing challenges. Reviews can happen quickly, but the review may not start until the backlog of previous submissions is cleared. Biotechnology products are more challenging. More complex, mfg process contributes significantly to product quality profile. Being US and EU centric an blind industry to the complexities of a global expansion 30