Regulatory Education for Industry (REdI) Annual Conference 2023 Day 2 Session 3

code and the survey link moving on to our presentations we have three presenters in this block our first presentation is on padufa 7 post marketing requirements commitments pre-approval and post approval and our presenter is Miss Kathleen Weil she serves as senior science policy analysts program manager on the safety policy research and initiatives team or Spirit within Cedar's office of new drugs our next presenter from our

next presenter we will hear how Cedar is accelerating rare disease cures and the padufa 7 rare disease endpoint advancement pilot presenting will be Dr Carrie Jolie associate director for rare diseases for the rare diseases team within the division of rare diseases and medical genetics in the office of rare diseases Pediatrics Urology and Reproductive Medicine and our final presentation in this session is on padufa 7 chemistry

manufacturing levels assessment updates and will be presented by Dr perezma Patel division uh director of the division of new drug API in Cedars office of new drug products office of pharmaceutical quality please welcome our presenters hello my name is Kathleen Weil I'm the senior science policy analyst and pmrpmc program manager in the office of new drugs at Cedar I appreciate being invited to talk to you

about the new Paducah 7 PMR commitments today the focus of my talk will be on the following the two new PMR commitments under padufa 7 I'll also review the four authorities for pmrs we'll discuss how the agency will communicate anticipated pmrs during pre-approval and how the agency will review PMR release requests so let's get started in this slide I'm going to Define pmrs they are essentially

studies or trials that can be required under one of the four authorities listed here accelerated approval animal efficacy rule pediatric research Equity act which is Priya n50503 pmrs the definition of studies or trials for both of those definitions can be found in the October 2019 guidance titled 50503 of the federal Food Drug and cosmetic act and that's listed below with the website address in the footnote

on this slide 50503 PM hours are related to safety and reduced effectiveness as you may recall fda's authorities under 5050 were expanded in the Food and Drug administration's amendments Act fada of 2007 and the support Act of 2018. the support act stands for substance use disorder prevention that promotes opioid recovery and treatment for patients and communities the first PMR commitment I'll review is related to communicating

anticipated pmrs for the footnote below anticipated pmrs are those studies or trials Based on data received with the original application submission it's a very important definition this commitment addresses inconsistencies in the unpredictability in communicating anticipated pmrs and it recognized a need for a standardized process and in response to this observation we created new internal timelines and processes for communicating these anticipated pmrs please note that this

new commitment applies to only new molecular entity NDA applications and original bla applications to highlight the new timelines anticipated pmrs will be communicated no later than eight weeks before the padufa gold date for standard applications no later than six weeks before the padufa goal date for priority applications and please note that if major safety issues are identified in data that is received after the original application

submission then the timelines on this slide will not apply to communicating that safety PMR we may refer to this as an unanticipated PMR as far as padufa metrics we will try to meet this goal 60 percent of the time in 2023 70 of the time in 2024 and 80 percent of the time 2025 through 2027 after you receive the letter communicating anticipated pmrs we would like

you to encourage you to continue those discussions with the FDA about anticipated pmrs and pmcs as you recall post marketing pmcs are post-marketing commitments which are studies or trials agreed upon in writing between the FDA and the applicant we will We may include those in our anticipated communication letter to maintain consistency within our pmrpmc program and to communicate any of those anticipated pmcs we are aware

of aware of at the time for secondly we'd like you to consider study or trial design we prefer that you include only one study or one trial in each PMR or PMC this facilitates our ability to track and monitor the progress of these studies and trials using the schedule of Milestones which brings us to the third point please start to prepare a list of those Milestones

there should be at least one milestone in the schedule the schedule may include those Milestones listed here such as a draft protocol submission a final protocol submission a study trial completion date and a final report submission make sure your Milestone dates are reasonable and they include time for the FDA to review so for instance the protocol for longer studies and trials we may want you to

consider interim reporting submission milestones so that we can keep track of the progress of that study and throughout over the years as mentioned before for some pmrs only one Milestone may be needed in the schedule for instance with animal efficacy pmrs the study schedule may include only the final protocol submission milestone now let's discuss the second commitment which is for post approval or existing pmrs this

commitment is related to requests as I said over to release existing pmrs it was created to address the lack of a standardized process or timelines for reviewing the release requests related to existing pmrs in response the agency established several new standardized processes for reviewing these requests as you can see we created several processes and timelines related to the review of an applicant's release request going down

the pathway to the right from the purple box at the top when we receive a re a request to release a PMR if a request is received and the agency needs additional information to make a release decision we have 45 days to issue that request for additional information following the pathway down to the right once we receive the additional information we have 60 days to review

the original and additional information and issue a released not released decision letter starting at the top again and going down the pathway to the left if we receive a release request and we don't need additional information we have 60 days to review the request and issue a decision letter this slide is a continuation of the PMR post approval commitment regarding release requests it specifically addresses requests

for reconsideration if an applicant receives a letter that denies the release of a PMR what we call a not released letter the applicant can submit a request for reconsideration of that decision the request is reviewed by the division and Senior leadership and Senior leadership will be addressed in several different committees one of several different committees either the mpprc mpcc or perk it depends on which committee

it goes to based on the Ed the information provided in the request and the type of the PMR for example all pre-fpmrs will re be reviewed by perk the Pediatric Review Committee the agency has 45 days in this whole process to review the request take it to senior leadership and respond with a released or not released decision so what are the next steps for the applicant

to consider please ensure that a release request includes a complete justification and additional information or supporting information you think the agency will need for a request for reconsideration you should include the information submitted with the original request any other supporting information you think will be helpful for the agency to make its decision additionally applicants can help the FDA easily identify their submissions by clearly labeling the

release requests with the pmrpmc pmrpmc set number and including specific headings on the cover page related to the type of submission so for instance with the original release requests please clearly identify that with the pmrpmc set number if you're responding to additional information please clearly identify that as additional information for the PMR PMC release request again with the PMR PMC set number and for requests for

reconsideration to release the pmrpmc please make sure that you submit only one release request per submission this is our preference because it assists us with our internal processes and assigning a goal to that submission now for our first challenge question during the pre-approval process when should you review a facial communication about anticipated pmrs is that immediately after the mid-cycle meeting immediately after the late cycle meeting

receive it by eight weeks for a standard six weeks for a priority before the Paducah gold day for the application or in the approval letter the answer is at eight weeks or six weeks you should receive this communication at least by that time so now for our Second Challenge question FDA is now required to provide a response to a release request for a PMR within how

many days of receipt 30 days 60 days 90 days there's no requirement the answer is B 60 days some key takeaways from today's meeting include the following we discussed two new PMR commitments under padufa 7. we also discussed the new process for communicating anticipated pmrs during pre-approval and when the applicant can expect to receive a letter communicating anticipated pmrs those eight weeks before padufa gold date

for standard applications and six weeks before the padufa goal date for priority applications we also discuss new processes and timelines for reviewing release requests and when an applicant can expect the agency to respond for release requests we should respond within 60 days and regarding requests for reconsideration and including the review of the request and the additional information by the division and the senior leadership our response

should be within 45 days of receiving that request I also provided some next steps for applicants related to both new PMR commitments that we'd like you to remember thank you for listening to this presentation today I welcome any questions you may have hello my name is Dr Carrie Jolie I am the associate director for rare diseases and the lead for the rare diseases team our mission

is to facilitate support and accelerate development of drug and biologic products for the benefit of patients with rare disorders we are located in Cedar the center for drug evaluation and research I'm very happy to be speaking with you today on how Cedar is accelerating rare disease cures as well as updates on the padufa 7 rare disease endpoint advancement pilot program this is my disclosure slide I

have a number of learning objectives for you today the first is to discuss rare disease and organ product approval trends in the center for drug evaluation and research the second is to discuss challenges and considerations in rare disease drug development and the third is to share updates on Cedar's accelerating rare disease cures Arc program and on Cedar's prescription drug user fee act um seven rare disease

commitment the rare disease endpoint advancement pilot program and this ladder is a joint venture between Cedar and sieber the center for biologics evaluation and research when looking at the progress we've made in rare diseases between the years of 2015 and 2022 which you can see is that we really have made progress Cedar has approved 180 novel drugs for rare diseases in this time period and that

is exactly half of the drugs we have approved in total the FDA has approved over 550 unique drugs and biologics for over 1100 rare disease indications since the passage of the orphan Drug Act in 1983. however we are very very cognizant of the fact that 30 million Americans live with a rare disease and the vast majority of these do not have approved treatment and therefore we

understand and are committed to the fact that there is still significant work to be done despite the fact that we have made significant progress this next figure shows a proportion of Cedar novel drug approvals that are orphan over a time period starting in 2010 through 2022 specifically this figure shows the number of Novel drug approvals over this time in columns for each year that are divided

into the number of Orphan novel approvals in green and non-orphan Drug approvals in blue the purple line above indicates the percentage of Orphan drug approvals of all approvals in a specific year and so what you can see is that since 2010 the number of Orphan approvals has risen dramatically for Cedar and in addition the percentage of all approvals um that are orphan in each year has

increased this continued in 2022 where we approved uh 20 orphan drug approvals in comparison to 15 or 17 non-orphan approvals and this is 54 percent the next slide I wanted to show because it's a visual representation of Cedar's use of expedited development programs these are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of serious or

life-threatening conditions which includes many rare disorders you'll note that in dark blue we have the non-orphan percentages for each expedited program pathway or program and in red we have the orphan programs the percentage of Orphan programs that utilized these and I think overwhelmingly the takeaway here is that the orphan drug programs really make use of these programs that are intended to expedite development to a higher

degree even those that are non-orphan the expedited programs come with such benefits as increased engagement with the FDA the ability to utilize rolling review or in the case of the accelerated approval program pathway the potential approval of an application based on a reasonably likely surrogate so what have we learned from all of the programs that we review in Cedar and really what we've learned is that

we Face common challenges in rare disease drug development we know that our Natural History is poorly understood which is incredibly important when it comes to planning and designing a trial that can demonstrate benefit we know that diseases are progressive serious life limiting and often lack adequately adequate approved therapies so there's urgent need here we also know that many of these conditions have a pediatric onset and

so there's an additional layer of challenges and with direct developments and pediatric populations we know that there's very small population so this often restricts study design options we know that they're within very small populations can still be phenotypic and genotypic diversity within a disorder this makes it very challenging when you go to select the patient population specifically in which you need to study the potential effect

of a therapy we know that development programs often lack a solid translational background and this can be critical to several elements that are just critic uh really important array to use direct development such as the strength of confirmatory evidence when you're thinking of utilizing um a pathway towards demonstrating substantial evidence for Effectiveness that is one adequate and well-controlled trial plus confirmatory evidence translational background is also

critically important to the selection of a surrogate that you believe represents or is reasonably likely to represent a direct clinical benefit drug development tools can be lacking so outcome measures and biomarkers and also there can the lack of precedent including clinically meaningful endpoints these are often you know first um novel studies in inpatient populations that don't have a therapy so so the selection of an endpoint

is is novel and this can be very challenging in direct development for many rare diseases they're also common considerations for the environment of rare disease direct development so there's many smaller companies that have less regulatory experience there are active patient stakeholder groups who are looking to navigate and participate in rare disease drug development there is a dedicated academic community that may have limited knowledge of regulatory

requirements so that's not what they're thinking of when they are engaging or embarking on academic exploration or aspects of clinical trial development so from the cedar perspective where we receive drug applications to review for the establishment of substantial evidence of Effectiveness and safety it's our duty to engage with our stakeholders to enhance their understanding of the regulatory process and to gain their alignment and support so

how do we do this we do this through our accelerating rare disease cures program and so with this program we came together approximately a year ago with a vision of speeding and increasing the development of effective and safe treatment options to address the unmet needs of patients with rare diseases with a mission to really Drive scientific and Regulatory Innovation and engagement to accelerate the availability of

treatments for patients with rare diseases this is a schematic of what Cedar's accelerating rare disease cures program looks like our Arc program serves as an umbrella it is governed by the senior leadership from the office of new drugs the office of the center director and the office of translational science and the reason these three offices have come together is because they are really the center of

evaluating and dealing with rare disease drug applications on a day-by-day basis as part of their everyday work and therefore they are best poised to inform and align on policy development and share information about rare disease drug development to best address the challenges that I enumerated on previous slides the program is managed by the rare diseases team we serve as the program management office to execute Cedar's

Arc program and as I mentioned in my introduction we are padufa mandated to advance the development of drugs for rare diseases for the center and in serving this role for Cedar's Arc program this really enables us to fulfill our mission now although Cedar's Arc program is governed and managed by the offices and team that I just discussed we work very closely across Cedar with other offices

and divisions to rely on their expertise for various issues regarding rare disease drug development for example we work closely with the Office of Medical policy where rural data evaluation and real world evidence policy come out of we work very closely with the office of surveillance and epidemiology when needed for real world data as well as post-marketing issues related to rare disease drug development we might work

with the office of strategic programs when it comes to decision making and evaluation for benefit risk and then other Cedar offices and divisions are pulled in depending on the issues that we are addressing underseater's Arc program umbrella we also work very closely with other FDA offices and programs because tackling the challenges in rare diseases truly requires a collaborative approach and a community and so Cedar's Arc

program works very closely with the center for biologics evaluation and research on many of our issues as well as the center for devices and radiological help the oncology center of excellence is another partner when it comes to rare disease drug development and evaluation and within the office of commissioner who work very closely with certain offices specifically the office of urban product development the office of pediatric

Therapeutics where the patient Affairs staff as needed I encourage you all to visit RC website uh and email us at cedararkprogram fda.hhs.gov you're one for the arc program has been all about engagement so I'm going to highlight just a few of the conferences that we developed planned participated in because our goal in this engagement was not only to share our regulatory perspective on Innovation and how

to address challenges and rare diseases for topics that were very important to stakeholders both externally and internally but also to keep these incredible programs on a shared website for stakeholders in perpetuity so that when we come together and share Innovative learnings and discuss challenging problems anyone can come to our website and then view these conferences with topics that they addressed moving forward and in order that

it's really beneficial to as many people as possible so the first conference that happened around the time of our uh close to time of the inauguration of the arc program was an FDA NIH conference on regulatory Fitness and rare disease clinical trials and this was a really broad overview Conference of challenges that brought together all the different disciplines and how they approach these challenges and rare

disease direct development conference was done between the rare diseases team and the national Center for advancing translational Sciences at the NIH and the focus was really on academic investigators and those who were looking on how to bridge that gap between academic investigation and the regulatory aspects of a direct development program later that month there was an FDA Duke Margolis virtual public Workshop that centered around the

importance of translational science and direct development so surrogate endpoints biomarkers and more that was put on between the office of drug evaluation and science within the office of new drugs as well as the office of clinical pharmacology the focus there was on translational science and its use in the development of surrogate endpoints two more conferences that have just recently taken place one one was the FDA

Cedar Johns Hopkins center of excellence and Regulatory science and Innovation Cersei workshop on addressing challenges in the design and Analysis of rare disease clinical trials so considerations and tools the Cedar's rare diseases team worked very closely with our office of biostatistics as well as Johns Hopkins University to put on a wonderful two-half day conference on how to collect high quality and fit for purpose data for

rare disease clinical trials the use of real world data to inform rare disease drug development the design and Analysis of methodologies for use in rare disease clinical trials and that was a really wonderful conference that if you haven't seen we know that many of these topics are of the utmost important to our rare disease stakeholders which was the impetus for putting on the conference but again

it is available in perpetuity on the arc website also there was an FDA Cedar and University of Maryland center of excellence in regulatory science Cersei Workshop creating a road map to quantitative systems pharmacology informed rare disease direct development and as one can imagine this was primarily the office of clinical pharmacology within Cedar that led and planned this conference in conjunction with the University of Maryland and

so this is another important one that will live on in perpetuity on the arc website patient engagement is equally important as patients are the foundation and the reason for developing Therapies and their input is critical Cedar staff during our first year of Arc engaged in no less than 23 rare disease patient listening sessions with patient groups now patient listening sessions are held by the office of

Commissioners patient Affairs staff or Cedars professional Affairs and stakeholder engagement and you can go to that website to learn more about those Cedar staff also engaged in 19 patient-focused direct development meetings and the patient focused drug development meetings are held by the patient-focused drug development staff within the office of Center Director in Cedar and those are critically important as well we also wanted to increase our

communication and transparency about rare disease activities we've heard from people it's hard to know what's going on across Cedar when it comes to rare diseases so one of the things we did with Arc was launch a quarterly newsletter which you should really go and subscribe to to hear more about these conferences other conferences public-private Partnerships and other rare disease news that's highlighted going on across the

center we have also recently added a rare disease filter to FDA track so the FDA track has a center for drug evaluation and research drugs and biologics tracker and what we are now currently doing is adding a rare disease filter to the information that is provided on FDA tracks so that the public really has an understanding of how rare disease approvals are progressing and finally one

of the most important things that we've sort of engaged on in Cedar Arc during this year of Engagement is for Learning and education to advance and Empower rare disease drug developers the leader 3D project so what is leader 3D this is where Cedar really sought input from stakeholders who design or conduct rare disease drug development programs the purpose behind this is to identify knowledge gaps for

stakeholders without the regulatory process of rare disease drug development and then using the information that we receive for us to be able to create or expand educational resources for stakeholders through this engagement we're hoping to better understand exactly what the challenges are in green rare disease drug products to Market in identifying these knowledge gaps and producing educational materials what we were really focusing on was what

types of non-clinical and clinical pharmacology considerations our stakeholders struggling with what clinical trial design and interpretation issues are stakeholders struggling with and what regulatory considerations for rare disease drug development are stakeholders struggling with in parallel with this leader 3D effort Cedar is additionally working with the National Organization for rare disorders or Nord to develop an advanced Drug development education series for patients and patient groups and

you can read more about this at the link that's provided next I want to turn to some updates in a program that is not directly run by Arc but we expect to take a lot of the learnings under the umbrella of Arc and translate those to stakeholders internally and externally and it's the padufa 7 pilot program the rare disease endpoint advancement pilot program the impetus behind

this program is that it provides a mechanism for sponsors to collaborate with the FDA throughout the efficacy endpoint development process so as I mentioned before this is a challenge in rare disease these are often novel endpoints and a lot of time is spent on the challenges of trial design which are many in rare disease drug development and what we really felt was important and what stakeholders

felt was important in constructing Paducah 7 was spending time to focus on that development of a novel end point that can be that we're competent can demonstrate whether or not a therapy meets that bar of substantial evidence of effectiveness so in order for a proposal to be submitted to this idea program which as I said in Ford's increased interaction with the center for drug evaluation and

research as well as the center for biologics evaluation and research this is a joint program the associated development program should be active and address a rare disease with an active IND or pre-ind for the rare disease there are some caveats for that if there is a natural history study for example which is intended to look at an end point for a future study then that might

be able to be submitted as well the proposed endpoint is a novel efficacy endpoint intended to establish substantial evidence of Effectiveness for a rare disease treatment and what we mean by novel in this setting is that an endpoint could be considered novel if it's never been used before to support a drug approval or if it's been substantially modified from previous use to support a drug approval

and really whenever we're looking at selection for this program preference is going to be given the proposals that have the potential to Impact Drug development more Pro more broadly so one that utilizes a novel approach to develop an efficacy endpoint or an endpoint that could be potentially relevant to other diseases preference will also be given to accepting proposals that reflect as the program grows a range

of different types of endpoints this is a pilot program so there's a limited number of qualified approv uh proposals that are going to be selected in fiscal year 23 there's a maximum of one the program opens July 1st in fiscal year 24-27 FDA will accept up to one proposal per quarter with a maximum of three proposals per year for transparency because it's very important that we

translate learnings from these programs more broadly to rare disease stakeholders FDA will conduct up to three public workshops by the end of fiscal year 2027 to discuss various topics related to endpoint development also novel endpoints developed throughout our Dia may be presented by us in guidance document or on our public facing website or at the aforementioned public workshops and this may occur prior to the fda's

approval for the drugs studied in a trial sponsors will complete the RDA pilot program once they have completed the maximum of four RDA meetings and do not have additional endpoint focused questions or issues to discuss with us advice provided during these meetings does not constitute a regulatory decision and is considered non-binding completion of this meeting doesn't equal this meeting process doesn't guarantee approval it's to help

you develop an efficacy endpoint that is novel for a rare disease after completing these meetings however sponsor can certainly request additional input through any updates on our idea include the fact that we now have a website which I encourage everyone to visit there are frequently asked questions on this website so if you have questions about the program check there first they may already be answered you

should also be able to see proposal elements you should see meeting package elements you should see disclosure elements um and also links to endpoint development resources for the different various types of endpoints that you may be constructing I also wanted to take the moment to put in a plug for a virtual public Workshop that is taking place tomorrow and the eighth so it's a two-day workshop

it is jointly hosted by Center for drug evaluation and research the center for biologics evaluation and research and Duke Margolis Center for Health policy there's a link to register if you haven't heard of this Workshop already and if you have questions you can always email us at RDM meetings so the conclusions from this talk is that in recent years over 50 percent of Cedar's novel drug

approvals were for rare diseases Cedar's Arc program will help Cedar work more effectively with under our rare disease umbrella with all of our rare disease direct development partners and Cedar's Arc program really does look forward to sharing learnings from other rare disease programs such as the padufa 7 rare disease endpoint advancement pilot program I have a few Challenge questions for the group looking at Cedar novel

drug approvals from 2015 to 2022 approximately what percentage were for use in non-rear diseases versus rare orphan designation projects and the answers are here the correct answer I'm giving people just a moment to input input their answers is 50 percent in our challenge question two is that the RDA program will provide the opportunity for responses to engage with the FDA and what aspect of direct development

model informed drug development complex Innovative design rare disease endpoint advancement or all of the above it's a tricky question but the rare disease endpoint advancement is the correct answer we have additional Paducah programs for model informed drug development and complex Innovative design thank you so much I have really enjoyed speaking with you all today and I look forward to talking with you all in the question

and answer session afternoon my name is pareshma Patel and today I'll be presenting on chemistry manufacturing and controls assessment with a focus on expedited clinical programs and I'll provide some recent updates under Paducah 7. I'm currently a division director within the office of new drug products under the office of pharmaceutical quality by the end of today's presentation you should be able to describe some padufa 7

product quality enhancements name some common regulatory strategies to address CMC challenges under expedited programs and understand the CMC development and Readiness pilot generally the application process eligibility and selection criteria the outline of today's presentation is shown here I'll start with a brief overview of product quality under padufa 7 there are a few enhancements that are directly related to CMC assessment activities and today I'll be highlighting

the enhancements related to facilitating CMC Readiness for products with accelerated clinical development timelines well specifically focus on two areas one is a recently published map that published at the end of last year entitled quality assessment for products and expedited programs and the other is a CMC development and Readiness pilot that I'll briefly highlight from the cedar perspective I'll end with a brief summary and provide some

resources I'd like to give you a brief overview of the vision of the office of pharmaceutical quality which really describes the end goal when moving from Clinical development to commercialization we believe that a quality product of any kind consistently meets the expectations of the user and drugs are really no different patients expect safe and effective medicine with every dose that they take and pharmaceutical quality is

assuring that every dose is safe and effective free of contamination and defects and this is really what gives patients the confidence in their next dose of Medicine I'll start off by highlighting a recently published map titled quality assessment for products and expedited programs this map really outlines obq's current thinking on how to work with sponsors on CMC development for products with accelerated clinical timelines specifically products

that have been granted breakthrough or fast track designation or products that are part of the CNC Readiness pilot which I'll discuss toward the end of today's presentation this map may also be considered for products that are mission critical and examples of products that may address Public Health emergencies such as copen19 where there are no available treatments it may also include products meant to address drug shortages

or have orphan drug designation this map provides examples of regulatory flexibilities that may be considered to address CMC challenges or to expedite CMC development where it's warranted and the emphasis generally are two things one is early engagement between sponsors and FDA and when products have an expedite in clinical development timeline and the use of a science and risk-based approach in making regulatory decisions and applying flexibilities

as they are warranted and of course the end goal here is really the anticipated clinical benefit for earlier patient access to drugs the office of new drugs which is where our clinical divisions reside typically identifies products that qualify for an expedited program designation and this really based on the information that a product has demonstrated the potential to diagnose treat or prevent a serious disease or condition

for an unmet medical need once that designation has been granted the plays a significant role in communicating early with sponsors the team actively participates in Industry meetings including providing Forward Thinking and detailed advice for CMC related issues in a variety of meetings including type B type c and type D meetings typically focused on in CMC focused meetings the team Works to determine the status and progress

of CMC development and the proposed plans for commercial Manufacturing we also review the strategy to ensure that commercial facilities are ready for manufacturing and our cngmp compliant we work to identify opportunities to expedite CMC develop development using a risk a benefit risk framework as well and we identify potential regulatory flexibilities that may be warranted in the program the team also considers the data and information that

should be submitted to support a marketing application and the timing of that data so for example there may be data that that should be submitted at the time of NDA filing for example and other data that may be acceptable to be submitted during the NDA review cycle or even post-approval the assessment team generally aims to engage early with sponsors and establishes a communication plan for meetings

and other interactions to agree to regulatory approaches by the time a marketing application is actually submitted I won't spend too much time on this subject but I would like to briefly discuss the topic of facility readiness to facilitate a marketing application FDA really encourages early and enhanced communication for facility assessment at early CMC focused meetings this includes identifying any intended commercial facilities including those facilities that

may be used for uh commercial scale manufacturing testing or packaging as well as any facility that's part of referenced drug Master files that may be submitted as part of the marketing application any non-commercial facilities that maybe May generate data needed to support the marketing application cross-referenced applications such as drug Master files should have letters of authorization submitted to the applications as well information on the commercial

manufacturing process and comparison to the clinical manufacturing manufacturing processes [Music] the sponsors plan to ensure that commercial facilities are GMP compliant and ready for inspection the proposed strategy for commercial launch particularly if there are if there's anything atypical and I'll discuss some potential regulatory flexibilities in the next few slides related to commercial launch the strategy for submitting facility information and the timing for that information whether

that should be submitted in an D or or in the NDA and and that should be really discussed early with um FDA and something that's more specific to Blas is the submission of production schedules and Manufacturing schedules with this information opq's office of manufacture pharmaceutical manufacturing assessment works with the office of Regulatory Affairs to assess and make recommendations related to facilities one area that is emphasized

in this map is the air is examples of regulatory flexibilities and approaches and some general areas for consideration I'm gonna briefly uh discuss and list the the general areas here and then I'll kind of go into them in a little more detail over the next few slides the basic areas um and examples provided in the map of flexibility flexibilities uh related are related to control strategies

process validation analytical procedures marketing of batches manufactured with the clinical manufacturing route instead of the intended commercial process and finally stability data that's needed for a marketing application and the studies to support marketing [Music] one area of flexibility is related to control strategies the amount of flexibility that may be warranted is based on the sponsor's experience and overall understanding of the product and Manufacturing process and

all of the available data is considered when when it when related to control strategies of course the greater the understanding of these aspects including a thorough understanding of the product and Manufacturing process analytical methods and capabilities really helps the agency consider any alternative approaches that may be needed for controls the opq team typically will meet with sponsors and discuss strategies to establish commercial controls for or

specifications and acceptance criteria besides the overall manufacturing experience the team will also consider the proposed justifications um and assess the benefit risk considerations for the product taking in account the expedited clinical designation often sponsors May with expedited development programs may have limited manufacturing history clinical experience um and and in these cases the obq team may consider additional steps as part of the considerations for the overall

control strategy and this may include um asking for additional specification specification tests or in-process testing due to the limited data this may require some narrow narrow acceptance criteria or process parameters and there may be the option of setting wider limits until additional data are available the use of comparability protocols or CMC focused post-marketing commitments to revised specifications specification test or acceptance criteria once more knowledge and

experiences available is also an option and finally there may be times when analytical methods may need revisions and these could be considered as part of a post-marketing commitment there are a few alternate approaches when uh that may be considered for process validation particularly stage two validation which is the process qualification of the commercial process to demonstrate reproducibility and must be completed prior to commercial distribution there

are different requirements for process validation for ndas versus Blas and the focus here will um will be that any alternate approaches should really be discussed early with the opq team as part of the stage 2 validation based on the amount of data that is available there may be flexibilities in the submission strategy in certain studies may be submitted post-approval decoupling of the drug substance and Drug

product process validation is also a potential flexibility because both drug substance and Drug product processities need validation it may be possible to perform the PPQ activities in parallel to the drug product as long as the drug substance use in the drug product PPQ activities are considered comparable and representative representative of the commercial drug substance process another potential flexibility that may be discussed with the agency is

concurrent validation and release approaches opq may consider accepting a plan for commercial release of the stage 2 validation batches before all of the validation activities have actually been fully completed typically to accept a plan like this um the review team would need to see the data that the data supports that the processes in the state of control and that the uh that and the process is

capable of consistently delivering quality product meeting the specifications and quality attributes uh the equipment and testing methods should be qualified and validated and there should be a commitment from the sponsor to submit stability data for the concurrent validation post approval um and finally the overall submission strategy for data and the protocol to be submitted should be discussed with the opq review team I mostly covered the

flexibilities related to analytical for cities related to analytical methods and validation of those methods for a submission of ndas or Blas the regulatory requirement should be consistent with those outlined in 21 CFR 314 and 601 respectively in general the analytical methods used to support the control strategy should be suitable for their intended purpose there may be situations though during the review cycle where there may be

changes that are needed and to the analytical methods and these changes may be implemented as post-approval commitments as long as the control strategy is acceptable for approval it's important for a sponsors to know that these types of confirmatory changes may be considered as a PMC if if the assessment team finds that to be an acceptable approach another potential alternate approach uh is marketing or launching with

clinical batches sponsors may consider this in situations where they intend to scale up the clinical manufacturing process for commercial manufacturing and the scale-up activities May delay the commercial launch of their product in these situations commercial District Distributing information would need to be submitted to support the strategy identification of the manufacturing facilities that were used that are intended to be used for commercial distribution any material for

commercial manufacturing has to meet FDA standards including GMP regulations facility Readiness for inspection reminders that the stage 2 validation requirements um and those reminders are kind of communicated to the sponsor from the aopq review team and scale-up activities can be facilitated by either comparability protocols or pmcs related to those activities for scale up another area area that I would like to briefly touch on is commercial

launch with stockpiled clinical batches in these situations opq would need additional information on the facility that manufacture the clinical batches if the material was manufactured using a process that is representative of the commercial or a commercial process and intended commercial processes for future batches the quality of the batches should be reflective of the commercial control strategy and meet any updated specifications as part of the application

and of course the batches should be distributed with approved labeling flexibility is related to stability data and stability studies are often considered and evaluated by the opt review teams assessment team considers all available data and information including product and process understanding supportive stability data and any relevant prior knowledge if an alternate alternate approach is being proposed for submission of stability data the FDA encourages sponsors to

discuss the strategy with the opq team early specifically the aim would be to seek agreement on the stability data and overall strategy to establish a shelf life or retest period um prior to submission of a marketing application FDA would also recommend that sponsors also clarify the data and information that will be submitted and the timing of that data whether it should be submitted at filing or

can be submitted during the review cycle for example examples of regulatory flexibility or stability data or studies include submission of less than the recommended amount of data for primary stability batches additional stability data being submitted during the review cycle for an NDA or bla review stability data from batches that may differ in size from the recommendations outlined in ich q a so for example batches that

are less than the pilot scale and then submission of supportive data may be considered and may be helpful to establish a retest or shelf life that is longer than would be possible if relying only on the primary stability uh data in batches alone in these cases the opq team would assess comparability between the support of stability data to ensure that they are representative of the commercial

process this map also addresses the use of predictive stability models and focuses the use focuses on use of mathematical modeling of stability data to establish a retest date or stability or shelf life specifically for ndas predictive stability model modeling may be used to establish comparability between primary and supportive stability batches as well and may be used as part of the justification for using supportive stability data

the evaluation of any proposed ability model will really be evaluated based on the capability of the model to capture all relevant stability factors for example temperature light and humidity the validation of the um of the data demonstrating that the models kinetic assumptions are appropriate applicability of the model to The Container closure system and then information on whether a product stability indicating critical quality attributes were considered

when establishing the model and then information on on situations where that model would not really be appropriate I would like to summarize this portion of my talk map 5015.13 outlines the quality assessment considerations and Regulatory flexibilities for products and expedited clinical programs FDA really encourages early engagement to address any cmca challenges for these types of products and finally the goal here is really to provide patients

with earlier access to new drugs and biologics this brings us to challenge question number one the map quality assessment for products and expedited programs describes regulatory flexibilities for all of the following except a process validation approaches b control strategies C stability studies or D cgmp requirements the answer is d the map covers flexibilities for process validation approaches control strategies and stabilities data studies but does not

include any any flexibilities when when it comes to cgmp requirements next I would like to briefly introduce the CMC development and Readiness pilot and provide a very quick Cedar perspective for this pilot the background for this pilot is that often development of seed or regulated drugs with unmet medical needs have an accelerated clinical timeline and marketing applications for products in expedited programs still need to meet

fda's approval standards however products May face challenges Expediting certain CNC activities that are required for submission in a marketing application therefore the goals of this pilot are really to facilitate CMC development in a time in accordance with the timeline of clinical development this would include additional interactions with FDA during development use of Science and risk-based Regulatory approaches streamlining CMC development and again the goal here is

earlier patient access to products and I think one of the other goals overall for this pilot is to learn how to do this better and really understand how we could expedite CMC development when there is expedited clinical development this pilot is really part of the padufa 7 commitment letter and the associated Federal Register notice published last fall the pilot will accept between 8 to 10 proposals

every year for a four-year period six of those will be C burled products and three applications per year will be accepted for C duraled products the Federal Register notice outlines um that the sponsors who apply and are selected will have some additional interactions with FDA including product specific CMC advice during development two additional CMC focused type B meetings limited additional CMC focused discussions and the hope

is that there will be these interactions will lead to a mutual understanding of the approaches to CMC information that should be submitted for a marketing application I'll go over some of the basic eligibility criteria for this for this pilot sponsor should have an active commercial IND in electronic common technical document format the application should generally be submitted before the end of phase two with some exceptions

such as if the development is following an Innovative trial design or intended to treat a rare disease the thought here is that it would be most beneficial to participate in the pilot so that there's earlier so that there is sufficient time to discuss CMC development and address any CMC challenges the sponsor should demonstrate a commitment to pursued CMC development aligned with an expedited clinical development timeline

and for applications under considerations for Cedar the application should be intended for approval as an NBA or bla the program should be under an expedited clinical time frame with anticipated benefits for earlier patient access such as breakthrough or fast track designation sponsors who do not meet these egg criteria um uh may still apply even if they don't have expedited designation and the eligibility will be determined

by FDA typically in consultation with our office of new drugs the published FRN also describes the full request to participate process which includes providing a description of the CMC development program the projected timeline for product development and how that aligns with clinical development information on CMC activities that are anticipated to yield a complete CMC data package and information that would be needed for the marketing application

any identified CMC challenges um that would require FDA input and then proposed timing for the for the additional type B meetings if the applicant um does have that information and and is selected for the pilot of course the request to participate should really include a CMC development status and and plans um that that includes the available information on product characterization and critical quality attributes information on

the current status of drug substance and Drug product manufacturing processes and control strategies um particularly it'd be helpful to know if bioassays are used for your product and information on those bioassay development any plans for commercial manufacturing control strategies that those are known information on the proposed facilities and inspection history for any um any for commercial launch if available and then drug substance and Drug product

um assessment plans for stability and finally in information on process validation plans as well now of course FDA acknowledges that it's unlikely early in development that all of this information will be available but for the request to participate what we're really looking for is as much information as as possible as about the sponsor's current thinking um and and their uh thoughts for moving towards commercialization in

any specific challenges that may be seen the pilot applications will be reviewed in a quarterly manner um and FDA will aim to notify sponsors of their selection to the pilot within 180 days of receipt the pilot will generally accept an average of nine applications per year as I noted earlier and three of those will be within Cedar the overall criteria for selection um will be based

on whether or not facilitating earlier um patient access would be clinically beneficial the overall novelty of the product complexity of the product and the manufacturing process or technology this sponsors overall manufacturing experience and overall experience with the specific product type class or manufacturing process that will be used and finally I think it's important to note that the FDA is aiming to have a to achieve a

balance in diversity in the product types sponsors and therapeutic indications for this pilot I would like to summarize this portion of the talk at this stage the um the CMC development and writings pilot really aims to facilitate CMC development for products with expedited clinical timelines the emphasis is really to increase communication between FDA and sponsors for these types of programs the pilot started in April of

2023 and applications will be accepted throughout the years throughout the year and sponsors are really invited to apply for this pilot the overall goal is to provide patients with earlier access to new drugs and biologics and I would also like to draw your attention to um to a seabird perspective that will be uh presented uh at the latter latter end of this week June 8th through

9th on the same pilot on the cdrp pilot and there will be additional details presented on in that presentation so this brings me to challenge question number two how many Cedar cdrp applications will be selected per year under the pilot 10. 6. 3 or all of them the correct answer is three Cedar will take three applications per year and on average and C Burr will accept

six applications per year on average and with that I would like to provide you with some resources these are resources for the CMC development and Readiness pilot the website provides information on the on the Federal Register notice and additional information on how to apply and shown here are resources for the quality assessment for products and expedited programs including a link to the map as well as

some other guidance documents that are referenced as part of the map with that I'm happy to take any questions um and I would like to thank you thank you for those excellent presentations uh we are now ready to roll right into our panel session so if you have not had a chance to enter your questions into the Q a chat pod please do so now we

will again answer as many questions as time allows um it looks like there are some questions rolling in um let's see let's start with Miss Wild we have a question for you here for PMR release requests is it preferred to have a meeting to discuss the status and release of the PMR first or should the sponsor provide FDA the rationale for release of a PMR directly

to an application and labeled as described in the presentation hi um yes this is Kathy um that's a very good question and we're coming across that and I think it depends on the timeline um that you're looking for a response so sometimes a meeting may be preferable and you might get a written response before you would get a response related to the release request timeline so

it but if you submitted a release request it goes on a 60-day clock under the new process so it just really depends on what what your timing is what your preferred timing is for a response because those timelines are a bit different thank you I've got a few more questions for you um so could you talk a little bit about fda's expectations for CMC specific pmcs

and pmrs are these typically published on the FDA website or included in the approval letters so um I'm not the PM CMC PMC expert that would be um Prisma Dr Patel so what I can answer for you okay CMC first stands for chemistry manufacturing controls and there are actually some CMC pmrs post-migraine requirements if they're safety related they fall usually under the 50503 PMR Authority and

so if a CMC study happens to be required under 50503 it would be published on fda's pmrpmc website and the status would be displayed every quarter we update that website at the end on around the end of January April July and October and of course they would appear in the approval letters and you under our current process should see them in the as anticipated pmrs if

we have that information available by the time either eight weeks for standard or six weeks for priority before the padufa goal date I can tell you CMC pmcs are not published on fda's website um they are considered non-reportable reportable pmcs Under Fire what we call 506 bpmcs are considered those that fall under clinical safety study or tries chemical efficacy clinical pharmacology or non-clinical toxicology studies and

trials so that's what the difference is between a non-reportable PMC and a reportable PMC so I can address those two and from my experience and and Dr Patel please feel free to chime in I have seen the CMC pmcs as part of the approval letter and have had the privilege of working with the division and Cedar in ond and opq on some of those pmcs thank

you let's see we've got one more question for you here what information can we expect to see about anticipated pmrs in the communication so as far as I think I lost you a little bit there I think you asked what is expected to see in the anticipated PMR communication letter is it was that the question yes sorry about that what information can we expect what information

can we expect to see about anticipated pmrs in the communication letter so as per the padufa 7 commitment letter the agency agreed to add available information about the purpose of the study and trial the study trial Design Elements study trial type and population so those are things we think we will know by the time that letter goes out and is issued however you know please remember

this letter will not include a schedule of Milestones because it's too soon it won't include a pmrpmc set number those will all be discussed in what we call an engagement period between the time that anticipated PMR letter is issued in the time the padufa goal is met in the approval letter is issued thank you thanks we have a few questions coming in for Dr Carrie Jo

Lee Dr Lee is there a priority for a disease that has a severe phenotype or one that affects a larger number of cases yeah thank you for that question you know we talked a lot about expedited programs today and I think what what the person is asking is how one qualifies for that and really it's it's about whether or not it's a serious condition right so

it's a condition associated with morbidity um that really has the potential to interrupt day-to-day functioning which is why so many of our rare diseases irrespective of how rare they are on the Spectrum qualify for the expedited programs and those are again Fast Track breakthrough priority review and then there's a separate approval pathway um there's an additional approval pathway for the accelerated approvals and again this is

really about whether or not these are serious conditions often whether or not there's unmet need it could be rare or not rare thank you we 've overcome small populations for rare diseases do you allow more Global reach of patient population so that's another great question rare disease drug development is absolutely global and we work very hard at the FDA in partnership with our International regulatory partners

we have an international rare diseases cluster at which is between the FDA the European medical medicine Association um or agency and health Canada so we meet routinely to discuss shared indications and scientific considerations related to protocols and marketing applications in order to promote Global collaboration and rare diseases and it is not uncommon to have patients enrolled on multinational trials thanks one more question for you before

we move on to Dr Patel if a drugs mechanism of action is similar between a rare disease and a non-rare disease it may be possible for the drug developer to utilize animal efficacy data of this mechanism of action to support an odd application for the rare indication yep I lost you a little bit at the end but I actually yeah yeah I I think I think

uh what what the asker is getting towards or at least the way that I'm taking it is if you have a really good animal model um can you utilize that in support of a uh for efficacy in a rare disease marketing application now this would in general be in the setting of one adequate and well-controlled clinical trial uh plus confirmatory evidence in that confirmatory evidence can

be a number of things and whether or not an animal model could additionally be utilized to support confirmatory evidence for an application is really going to depend on the strength of that model and this is why translational science whether it's an animal model or in vitro work is so critical in rare disease drug applications so it's going to depend on the adequacy of that animal model

for the disease for the rare disease in question it's going to depend on whether or not you have defined pathophysiology for that rare disease so that you are confident that the therapeutic and the Target that it engages does in fact have a clinically meaningful benefit on the outcome for that disease so there's a number of factors that would go into play on the on the strength

of the use of an animal model for a rare disease indication and definitely in those cases I would say to come early to the FDA and describe your thinking so that we can advise on the strength of that model for the use in which you are intending thank you Dr Lee let's move on to Dr Patel first question what are the criteria to participate in the

pilot program um thanks for that question so the criteria for this ddrp pilot are really clearly outlined in the FRN and I think I provided the link to the website there um but I just want to kind of briefly go through it um a few of the the basic criteria include that the um the IND has to be a uh an ectd format um which is

electronic common technical document um typically we want to see something that's as early as feasible so before the end of phase two so that we actually have time to interact with sponsors and provide um helpful advice as development is proceeding um one of the other eligibility criteria is that there's a commitment to actually pursue CMC development in alignment with the expedited clinical development um and then

one of the other uh criteria to participate is that you either have an expedited critical time frame um so that there would be anticipated clinical benefit for earlier patient access or something like either breakthrough or fast track designation however there um you know FDA is encouraging sponsors that may meet this criteria but not have one of the designations to um that you know they can still

apply and the eligibility will be determined um by FDA once we actually see the whole application in hand um so those are just kind of the highlights of the of the of the requirements um and criteria to participate as part of the pilot but the FRN does clearly also provide some specific sieber versus Cedar eligibility criteria and I do encourage anybody that can to um to

attend the sieber uh talk later this week because there's a there's more time dedicated to the pilot discussion in that in that talk thank you thanks Dr Patel another question for you if this is an ultra orphan drug and the clinical batch is sufficient for at least a year of commercial Supply is this sufficient justification to perform process validation post-approval so thank you for that question

and I guess um I I would just want to clarify that the um for an marketing under 505 B so for an NDA um process validation is not a requirement at the time of marketing um so so an application can be submitted without having that process validation done and and and that would be uh conducted after uh approval of an application um and I think I

do want to point out though in a situation like this it is helpful to um discuss with the agency if there's any plans for flexibility especially in the situation of an ultra orphan drug where you may have limited batches or you're anticipating limited manufacturing of batches that you you discuss with the agency um any flexibilities on the requirements um at the time of marketing or any

uh flexibilities in how you're launching your commercial manufacturing um your your commercial launch uh plans essentially um so for example if you're planning to launch with clinical batches versus the perform um the the commercial process itself thank you thanks and I believe this question is for you um our PSB and PPQ batches needed for expedited programs bla and NDA thank you yes that is um that

does look like it is for me as well um so just to clarify again the PPQ uh batches um which is essentially what we call the stage two uh validation of the manufacturing process is not required for an NDA um for the submission of an NDA um however it is generally a requirement for Blas um so Blas uh it is it is a requirement for the

bla submission that those stage two PPQ uh batches and information be submitted um in the marketing application so that is the difference between Blas and ndas um and and again that is also outlined a little more clearly in the map thanks for that question thanks for those responses let's Circle back to Kathy Weil again so first question what if I don't receive a letter communicating anticipated

pmrs from the agency thank you for that question um if you don't receive a letter please keep in mind that per the com uh padufa seven commitments that these anticipated letters only apply to nme ndas and original Blas and they don't apply to resubmission resubmitted applications and also remember that the agency because this is our first year in this new process we have to meet uh

the goal 60 of the time so we may not be able to meet it all the time but we're working very diligently to meet it as much um and above 60 percent of the time for the first year if you you know want one and hey you haven't gotten one please feel free to reach out to your regulatory project manager your RPM in the division and

you can always ask ask about it at that time thank you thanks another question for you what if we require what if we request release of a PMR in our annual status report or with another submission yes thank you for that question I think that question came up a little bit earlier about putting it you know requesting a meeting versus um you know asking for it

as a specific release request we may if it comes in as part of the annual status report or that it's mentioned you know that you're going to request a release or as part of even an another submission other than say a meeting request the agency might reach out to you and request that you submit a release request in a separate submission so that we can accurately

track the progress of that request in our system using our notification goals and make sure that you know that request is handled appropriately as per our new padufa 7 commitments thank you um let's do one more question for you we have here if we receive a request for additional information about a release request what information should we provide yes thank you again um so the letter

that requests the additional information should explain exactly what the agency needs to better understand that request for release if it does not and and you need further clarification please reach out to your regulatory project manager for the division before you respond to the letter if you happen to respond to that letter before you know having a clear idea of what you want to provide we have

the opportunity to send into another additional request for information that will add to that and and explain further what we're looking for so thank you for that thanks let's move back to Dr Dr Lee Dr Lee would stimulated C peptide be a qualifying endpoint for the in the RDA pilot program for indications in preventing or stopping progression of autoimmune type 1 diabetes yeah so in terms

of our Dia proposal eligibility what you're going to want to remember is that the first sort of the the first gate is the sponsor has an active pre-ind or IND for a rare disease now there are some exceptions to that namely if you don't yet have an active development program but are initiating a natural history study where the proposed endpoint is intended to be studied which

would be applicable to a rare disease or if you have a common disease that you are studying that includes an Innovative or novel endpoint that you can then justify as applicable to a rare disease those that's sort of the first type of Eligibility criteria that one has to meet to submit a proposal for ardia and the second eligibility group of Eligibility criteria is around the proposed

endpoint so is the endpoint novel and what we mean by that is if it has never been used before to support a drug approval or if it's been substantially modified from previous use to support drug approval so those are the questions to sort of ask we have a web page up with this and a lot more information as well as the meeting that were two half

day meetings that we're having to coming up to both tomorrow and Thursday so I hope that people make use of those um and it'll be a lot of good information to share thank you let's take one more question for you what is the current status of the leader 3D program have leader 3D training events initiated or are trained currently available yep that's a great question and

I'm happy to share on this as well so leader 3D we are currently in the assessment phase so we've received a lot of feedback from external stakeholders and now we are reviewing that feedback and determining what are the priorities that our stakeholders really want in order to inform drug development for rare disease products we're also looking at you know what do we currently have available based

on their priorities that we could enhance versus what do we need to develop and so that's the phase that we are in and what I would really encourage people to do so that you are informed when we come when we start to come out with materials related to leader 3D is that you can sign up for the cedar Arc newsletter which was in my slides and

I believe my slides are going to be available shortly if they are not already um but I would really encourage people to sign up for that newsletter because we will always put information related to education and engagement for rare disease or rare disease stakeholders in there uh and there's also the cedar Arc webpage at which there is information on the leader 3D program thank you Dr

Lee latel could you comment on the applicability and use of predictive stability models for monoclonal antibodies or fusion protein products to set shelf life and The agency's View on them thanks uh for this question this is a really good question um So currently um FDA doesn't generally generally recommend productive stability modeling um for biologics um including monoclonal antibodies or fusion fusion proteins at this time um

the idea is really that the Declaration of these types of biologics is unlikely to be um amenable to mathematical modeling um with that being said I think that um if there's some sort of sufficient justification or data to support it that the FDA would certainly want to see that data as part of the justification if an applicant is interested in using um or is interested in

applying these sorts of models thanks thanks next question for you how many years is it anticipated that the pilot program will run yeah thank you for that question um so this is really outlined in the Paducah 7 commitment letter so um the pilot program at this stage is anticipated to run for four years from 2023 to 2027 and an FRN isn't is is planned to be

published annually in case they're already uh minor changes that need to be made to the pilot as as we you know learn um as they're a lesson learned annually from from the pilot itself um and to kind of get to someone else's question um the the idea is that sieber will take about um six applications a year and uh Stager will take about three there is

some flexibility in in that as well um again it'll probably just kind of depend on what we see um from year to year as as we run this pilot this pilot just initiated in April of this year so we'll kind of take those Lessons Learned and apply them to next year thank you thanks and one more for you is it still possible to submit the cedar

cdrp after three projects accepted are accepted and how do the sponsors know if there's yeah so uh good question um yes so we will be um reviewing the applications on about a quarterly basis so even if three applications have been um accepted into the pilot that doesn't mean that a fourth may not be right so it really just it's a case-by-case sort of basis at this

stage um but applicants will be notified um in about 180 days um once whether or not they've been selected into the pilot and if for some reason um uh an application was not selected um that doesn't mean that that same um applicant can't couldn't come back again uh for another cycle um so so just kind of there's a lot of flexibility here and I think um

we wanted to convey that as since the application process is currently open but the applications will be reviewed in enrolling in a rolling manner thank you for that thanks uh let's move on to we have a question that came in for Miss Kathy Weil can we submit more than one request for reconsideration if our release request is denied after requesting reconsideration yes great question we consider

the request for reconsideration decision sort of the end of that whole released request process so at this point that kind of ends the back and forth period about that PMR or and it could be a PMC but most the time it's usually going to be a PMR so thank you okay thanks we have some more questions for Dr Carrie Jo Lee uh Dr Lee let's see

here's a question difference between the RDA pilot program and the drug development tool or DDD DDT excuse me qualification programs right so the RDA pilot is really a series of focused meetings specifically on developing a novel endpoint for a rare disease so if you would like some very focused um you know promised up to four interactions with the FDA the relevant review Division and additional experts

across you know cedar or sieber depending on where the product is this that's sort of the meeting pathway that we would really encourage you to apply to the drug development tool qualification program is is different and the idea program if you complete that it doesn't result in qualification of an endpoint the drug development program really should be for sponsors who want to qualify their COA their

biomarker or their animal model for use under the animal rule thank you Dr Lee another question for you when would FDA recommend interacting with the FDA through the RDA pilot program instead of interacting with the FDA review division through the IND sure well the the RDA pilot program is in addition to whatever interactions are currently going on and the review divisions will be involved in the

RDA interactions so if if you as a sponsor you know rare disease drug development as I said in my presentation is very challenging there's a lot of of things to work out for a rare disease drug development program but if you're a sponsor who wants focused dedicated time spent solely on developing a novel endpoint which can often be very challenging that's really when you want to

accept one proposal for the phase that is going to be opening on July 1st so submitted between July 1st and September 30th there will be one proposal and it's on the fiscal year so each new year starts in October and then for the subsequent years so fiscal year is 24 to 27 we will be accepting one proposal per quarter with a maximum of three proposals per

fiscal year thank you we have some questions that came in for Dr Patel Dr Patel if scale up will delay commercial launch is it possible to commercially distribute clinical supplies with approved FDA commercial label Does the clinical Supply batch need to be prior to so thank you for this question um I think uh to kind of summarize um yes there is a possibility of launching so

your initial commercial batches being manufactured using clinical supplies um and the process validation can happen um after an application I'm thinking NDA right now after an NDA is actually um approved um but in order to launch with clinical batches again this would be in a situation where if if you know if you would delay commercial launch if you didn't launch with your clinical batches um if

the patient need is there then that is something that the FDA would consider um but in order to do that there would be a number of things that you would have to uh provide as part of your justification in addition your manufacturing facilities that manufacture the clinical batches will um will need to be assessed for acceptability as far as the facility statuses goes um and and

could be open to uh inspection if needed um to assure that those were manufactured under GMP inappropriate GMP regulations um and and so that would be like the the major thing that I think we would need to look at when it comes to the clinical Supply that's being used for the commercial patches um but but after but once the expectation is that the process validation State

shoe requirements would still be required after that NDA um has been approved I hope I answered that question thank you thanks another question sponsor apply cdrp again if the request was not accepted the first time yeah thank you for that question um yes I I think that the uh you know the idea of the pilot is um we will be accepting applications on a rolling basis

and as a program changes um it is encouraged that if an applicant feels like they may want to reapply um maybe something's changed in their program in their development program um though that is highly encouraged at this stage and we will be reviewing those on a quarterly basis um and kind of assessing assessing where the CMC development is and what challenges exist in the development program

as well um so so absolutely that is something that the FDA would consider thank you thanks this next question is addressed to both Kathy Weil and to you Dr Patel if a CMC PMC PMR is not on the approval letter or FDA website how does FDA track completion are these still considered optional and not a commitment or requirement um thank you I'll go ahead and take

the at least the first part of that question but I if I might take an opportunity to go back to the release reconsideration question I just would like to remind the audience that those requests for reconsideration go up through senior leadership for discussion and review so that I forgot to add to the prior response as for this question um if it's a a CMC related PMR

and a PMC both of those should be in the approval letter so I I just haven't had an experience where we've agreed upon post-marketing commitment in writing or required a PMR that's not in the approval letter as a reminder all pmrs and 506 bpmcs will be available on fda's website with the each quarterly update um and for both of these all CMC pmcs and pmrs are

tracked in our database of record so we monitor the their progress using that schedule of Milestones it's uh usually that's provided in the approval letter um I am where it says are these considered optional optional and not a commitment or a requirement they're usually anything that's in the approval letter is either agreed upon as a post-marketing commitment agreed upon in writing in the approval letter are

required in the approval letter if it's not in the approval letter it's um not an we don't consider that necessarily optional so that may be different in opq's office with pmcs but I'll I'll let um Dr Patel require or provide a response to that part thank you yeah thank you thanks Kathy I mean I think to just add a little bit to what you already said

um PM Pia there are CMC pmrs off um sometimes most often uh CMC pmcs are communicated uh to applicants um we usually work with applicants similar to a PMR in order to outline um the requirements and milestones for a PMC and uh and and that's how those pmcs are tracked according to those uh to the um you know the in like the interim reports and the

final reports and kind of when those deadlines are um those are also uh should be submitted uh should be provided as part of the approval letter that there is a PMC Associated a CMC PMC associated with um an approval thank you both for those responses uh Dr Carrie Jo Lee we have one question for you here what exactly is the difference between Cedar Arc and ardia

that's a good one so Cedar Arc the accelerating rare disease cures program is an umbrella program as I explained in my presentation and it's it's really sort of the the umbrella that sees all rare disease that initiatives and Drug development that is going on across the center in order to really provide strategic oversight on what we need to do in order to really engage with our

stakeholders internally as well as externally to strengthen rare disease drug development and the RDA program is a padufa 7 mandated pilot program so it is a rare disease initiative to which Cedar is taking part in and it will certainly be followed very closely by Cedar Arc it is a padufa commitment that the rare diseases team is implementing as part of our padufa requirements uh in terms

of being able to provide provide rare disease support to the Center and Cedar Arc would take learnings from ardia and ensure that they are being translated to our all parts of rare disease across across the center as well as Beyond external stakeholders that that we can thank you and I think we are out of time for questions so we are going to go into a short

break um I just wanted to thank again the presenters and panelists for responding to the questions and for your excellent presentations and to the audience for asking such great questions um so let's take a short break and we will reconvene at 2 50 eastern time thank you