What’s the deal with the FDA Feedback Letters?

This week I caught up with my colleague and fellow SEND obsessive, Mike Wasko. I asked him for his opinions on the FDA feedback letters that sponsors receive after IND submissions. Specifically, his thoughts on their importance and impact – Here’s what he had to say:

Whenever a sponsor receives a letter or feedback from the FDA, the initial knee jerk response of many is to panic.  I’d say approximately 95% of the time, there is no need to panic. A little context of what these letters/reports are, and why the FDA are providing them may be helpful.

When SEND first started being required, the industry desired feedback from the FDA, and to this date, it still does to aid with the moving target of best practices and new standards. In the first few years of the SEND requirements, only the inner circle of the SEND industry was able to get feedback on quality and preferences. Granted, extensive validation rules did not exist at this time, so the feedback was even more important. But this feedback only reached the participants (approximately 50 people) of the CDISC SEND Face to Face meetings with the FDA, which occur twice a year. To increase communication and feedback to the industry, the FDA introduced some new communication methodologies. First, they would start having SBIA (CDER Small Business and Industry Assistance) webinars to help give feedback to the community on submissions, areas of improvement, SEND at the FDA and more. The second was study specific feedback to sponsors. The assessment was provided by the edata team at the FDA, as part of the Kickstart services. The assessment included automated and manual review of the send package for compliance, rules, recommendations, consistency, and ensure the agency can reproduce the summarizations in the actual study report. 

So, the next logical question for sponsors is “what do I have to do” if you’ve received a letter of feedback from the FDA. Most of the time, nothing. The document itself states something along the lines of no action or response is needed unless specified. It also states the feedback is to aid in improving future submissions of SEND datasets. Great news, right?  Yes, if there are things that are very wrong, the report will indicate which findings must be fixed and a new package submitted. Industry would be well advised to implement the recommendations so that future studies don’t have similar issues. With that said, the question still exists, that if one receives such feedback from an IND submission, should you fix it for the NDA submission? The time between and IND and an NDA can be many years, and with the rate of change in SEND in terms of best practices, updating implementation and when to update is really a sponsor decision. My recommendation would be to implement the changes recommended at IND in order to ensure a smoother review at NDA. It is helpful to share the feedback with your SEND teams and your SEND partners/CRO/vendors to help the whole industry advance and improve. Especially since it is easy to apply small amounts of changes to your SEND practices as you go, rather than many all at once.

I thought that was a great update for Mike to share.

As usual, feel free to join the conversation and drop me a note at marc.ellison@instem.com

Till next time,

Marc

Countdown to the next SEND Requirements

So here we are again in March, probably the most significant month in the SEND calendar. At Instem we are busy gearing up for the Society of Toxicology meeting, which will finally be in person again after a two-year hiatus, what with you-know-what. March also means that we are due to have the latest FDA’s Study Data Technical Conformance Guide land (TCG). What surprises will the latest version hold for us? Further clarification on the scope of SEND, perhaps? Possibly an update to the list of ‘desired’ Trial Summary study parameters? I guess we’ll have to wait and see.

Most importantly though for SEND is the significance of March 15th when it comes to the FDA’s Data Standards Catalogue. This is the date when the clock starts ticking on new requirements. If you are not fully up to speed with what I’m referring to, I won’t bore you with the technicalities, but suffice to say that March 2022 signals the 12-month countdown to some new FDA requirements for SEND.

Of these, the latest addition to the Data Standards Catalogue is SEND 3.1.1 which includes minor improvements to the PC and PP domains to bring them in line with the FDA’s TCG. Any organization who has been following TCG regarding these domains, should have no issues adopting this new version. As for the Implementation Guide itself, it now includes much improved examples for PC and PP to show how these domains function together and how they relate to EX.

One very curious thing to note with this addition to the Data Standards Catalogue is the fact that SEND 3.1.1 has been added, but without an ‘End Requirement Date’ for SEND 3.1. This means that come next March, organizations have the choice of which version of SEND they choose to use for their submission. This is quite different to the hard change over we saw between SEND 3.0 and 3.1. However, if we consider SEND 3.1 following the TCG as just being the same as 3.1.1, then there’s no real difference.

More significantly for some will be the start of the requirement for SENDIG-DART 1.1. This brings Embryo Fetal Development studies into scope for the SEND requirement. Following the successful recent FDA Fit-For-Use pilot, tools and organizations should all be ready to create and consume these new SEND packages.

Although far more specialized, SENDIG-AR also becomes a requirement for Animal Rules studies. These are clinical efficacy studies where animals are used as surrogates for humans because human clinical trails would not be possible.

Also, we are now 12 months away from SEND being required for CBER. There are no special SEND considerations specifically for CBER in the SEND Implementation Guide or TCG, the only real additional requirement for CBER regards immune response data. When these data are collected, they should be submitted in either a custom IS domain or as part of the LB domain.

Finally, the requirement that will impact us all is the move to Define-XML 2.1. There’s probably a broader topic for us to discuss at some point, to consider the wider implications of the value of the define fine.

So, it’s March and the clock is ticking. The next 12 months are going to see a flurry of activity as we all gear up for these new requirements to take effect in March 2023.

Till next time

Marc

SEND Conformance Rules are NOT Boring!

Hey everyone – I’ve asked Christy Kubin over at Charles River Laboratories to share some of her thoughts here on Sensible SEND. As well as being a long term CDISC volunteer and co-author of the SEND IG, Christy now leads the SEND Conformance Rules Team and like me, she is a bit of a SEND nerd. Enjoy her post and until next time, Marc

By Christy Kubin:

When Marc first asked me to put together some thoughts about SEND Conformance Rules, I’ll admit I was a bit intimidated. Marc’s love of SEND is contagious, and his blog talks about the best and worst parts of working with SEND in a way that is approachable and fun; which are not words most people associate with either “conformance” or “rules”.  While some people might assume that working with conformance rules is boring, it has quickly grown to be one of my favorite projects. Conformance Rules are impacted by all aspects of SENDIG development, and working from the conformance rules perspective has allowed me to better see how all aspects of the SEND standard work together. 

Like Marc, I truly love donating my time to CDISC to help develop the SEND standard.  The SEND Conformance Rules team was my first opportunity to lead a team, and I am lucky to work with such an amazing team (all of which are “SEND Nerds”).  SEND Conformance Rules are the translation of the SEND Implementation Guide text into logical statements documenting the characteristics a SEND dataset must have in order to be in conformance with the SEND standard. Writing SEND Conformance Rules is the ultimate opportunity to “nerd-out” on SEND as we pour through the SENDIG line by line and analyze every word. One of the most interesting things I found about writing conformance rules is the opportunity it gives the team to really dig into implementation guide text and challenge our preconceptions.  This has certainly led to many fascinating and passionate conversations!  In the end, SEND Conformance Rules must be about fact, and rules must be attributable to definitive statements in the SENDIG.  No conformance rules are written for assumed best practices or unwritten rules; there is no room in conformance rules for reading between the lines. Only definitive SENDIG statements can be translated into rules. 

When the CDISC requirement for conformance rules began, our team was tasked with writing rules for the published SENDIGs (SENDIG v3.0, SENDIG v3.1, and SENDIG-DART v1.1). As you might imagine, that proved to be an interesting challenge as those implementation guides were not written with the idea of rules in mind.  The team is taking what we have learned from those initial rule sets to suggest best practices for future SENDIGs that would ensure that future published implementation guides (such as the upcoming SENDIG-GeneTox) clearly and definitively state what is necessary for conformance to the SEND standard. This should result in cleaner, unambiguous versions of SENDIGs and conformance rules moving forward.

Thank you for allowing me to share my thoughts on SEND Conformance Rules with you.

Best regards,

Christy

Are we there yet – Where’s the GeneTox IG?!

This week I caught up with my colleague and fellow SEND obsessive, Mike Wasko who leads the CDISC team developing the SEND standard for Genetic Toxicology. I asked him “What is the current scope and timeline of the SEND Genetox Implementation Guide?”, and here’s what he had to say:

“Some context is in order first.  The CDISC SEND GeneTox team, founded in 2015, has been working in an evolving state, as there have been many changes to scope, leadership and even CDISC practices.  The initial scope and intent was to model and create domains to support in vivo Micronucleus and Comet assays, as well as in vitro Micronucleus and in vitro Ames assays.  In addition to the representation of the raw data and trial design for in vivo data, the team planned to find a way to represent historical control data.  In vitro data and historical control data are two concepts which no CDISC team had ever ventured to undertake. 

As the team worked through the scope initiatives, it became apparent that in vitro and historical control data had not been attempted for a good reason.  It was extremely challenging to represent data without a subject attached to the data.  After many trials and tribulations, it was decided to reduce the scope to the smallest effective scope, which would provide investigators and agencies a way to standardize the genetox data at least for in vivo.  This could set a foundation for the future as well as lessons learned.  This would be similar to the process of SENDIG v3.0 being released: industry implementing and then lessons learned driving future releases.  Thus, the scope was reduced to in vivo Micronucleus and in vivo Comet assays.  Then with agency feedback, it was determined historical data did not need to be included.  The rationale was that either methodologies would be too complex to represent historical data, or it would severely increase the size/width of the GeneTox SEND domain representing the raw data.  Neither was ideal; thus it was agreed to remove historical data. 

Upon decision of the refined scope, work in the SEND GeneTox IG has been moving quickly.  Granted new CDISC practices have been introduced along the way.  Currently the draft IG is almost complete, including 3 detailed examples to represent the following:

  • in vivo Micronucleus slide based assay,
  • in vivo Micronucleus flow based assay and
  • in vivo Comet assay. 

The team has already worked with the Controlled Terminology team to develop controlled terminology and is working with the SEND Conformance Rules team.  As part of newer CDISC processes, not only must an IG contain examples, but for CDISC Internal and Public Review, it must be accompanied by the Conformance Rules as well as Proof of Concept datasets.  This will allow a more thorough review as well allow agencies and vendors to assess with their SEND tools.  The current roadmap puts the SENDIG-GeneTox out for public review in early Q3 2022, with approval and publication hopefully by end of Q1 2023.  It has been a road of challenges and changes, but the team came together and are getting it done.”

I thought that was a great update for Mike to share.

As usual, feel free to join the conversation and drop me a note at marc.ellison@instem.com

Till next time,

Marc

SEND: it’s not everyone’s cup of tea…

I make no secret of how much I love working with the SEND standard. I really enjoy both the time I donate to CDISC to help develop the standard; and the time I spend helping develop solutions that allow organizations to create and consume SEND datasets. This year marks my 10-year anniversary of working with SEND. Back in 2012, I attended my first CDISC conference, and I’ve discussed in this blog, how strange that experience was.

Prior to that meeting, I would have never believed that I’d devote the rest of my career to the world of data standards. “Data Standards”, even the phrase itself sounds dull and boring. Could there be anything less creative, less inspiring than “Data Standards”? Yet for some reason, I love nothing more than debating the best way to standardize the representation of nonclinical data.

Without seeing firsthand two individuals passionately argue opposing opinions on SEND, it’s hard to imagine that anyone could get so worked up about such things, but these debates happen all the time. And I love them.

And I’m not alone. Many organizations in our industry have individuals just like me, who care deeply for SEND. Who want to see their organization creating the best quality datasets possible, to provide the FDA with the cleanest, clearest data so the reviewer can focus on evaluating the safety, and not waste time grappling with poorly rendered data. We see SEND as vital to helping bring about faster and safer products, and that’s something that touches everyone.

I know many that read my blog, are equally SEND obsessed. It’s good to know we are amongst friends.

I also know that there are many who read this who are only on the fringes of SEND. Those who may be reluctantly engaging with the standard simply because they can escape it no longer. They do not share the passion or obsession. Understandably, their interests lay in other areas, and SEND is simply an additional burden.

Every organization needs a SEND obsessive. Either their own SEND nerd, or a partner who can just deal with all of this ‘SEND stuff’ for them. They need them, so that everyone else can take comfort in knowing that there’s at least one person that’s taking care of this. Worrying about the SEND datasets so others don’t have to. Ensuring that the next looming regulation date is going to be met. Pouring over every update to the FDA’s Technical Conformance Guide and making sure their organization remains compliant.

So, yes when it comes to SEND, there are obsessives, but it’s not everyone’s cup of tea. Fortunately, there are enough of us who love to nerd-out on this stuff, that everyone else can rest assured that someone, somewhere, is taking care of it.

‘Til next time,

Marc

SEND in 2022 – so what’s next?

Looking forward to the significant events and milestones that lay ahead over the next 12 months for SEND, barring any major issues, we should see the publication of the next version of the SENDIG-DART. That is the CDISC SEND standard for Reproductive and Developmental studies and this time around will focus on Juvenile Tox in direct response to the recent TCG update.

We should also see the publication of the SEND standard for Genetic Toxicology studies. In its first version, this standard is limited to Micronucleus and Comet Assays for In Vivo studies only, but even so, this is a significant publication, further widening the scope of studies now covered by SEND.

Also, we’d expect at least two updates to the FDA’s Technical Conformance Guide (TCG), based on their standard schedule, and I’m hoping to see the addition of SEND 3.1.1 to the Data Standards Catalogue before March to start the ball rolling on it’s adoption by the agency.

The reason that I’m so keen to see this added to the catalogue is that SEND 3.1.1 arose out of a significant issue seen during the original FDA pilot. Although seemingly small, it was a serious flaw in the definition of the Pharmacokinetic Concentration (PC) domain. A CDISC team was quickly assembled to resolve the issue, and the solution was released in the next TCG in the form of guidance of how best to represent the data in this PC domain. This was back in 2017. Finally, in 2021, SEND 3.1.1 was published which brings the Implementation Guide in line with the FDA’s TCG, and hopefully in 2022 we see it added to the catalogue.

2021 also saw the TCG add the much-debated “Scope of SEND” section. Juvenile studies that include multiple phases are still out of scope, while all other juvenile studies are in scope. Yet, the SEND Implementation Guides give no examples or assistance on how to represent such studies, and in particular, how to denote the Post-Natal Day number, which is a key piece of information for many of these studies. Resolving such issues is the focus of the next version of the SENDIG-DART, and so this is another example of the standard chasing something already published in TCG.

Personally, I’m a big fan of how quickly the TCG moves and sometimes that means that the SEND standard needs to play catch up. CDISC development and publication process is slow, yet the TCG would appear to be far more agile, and so we end up in these situations of the Standard needing to chase something already adopted by the agency.

I’ve made no secret of my opinion on the slow progress of CDISC and this is another example where that seems out of step with the pace of the agency. As last year saw the publication of SEND 3.1.1 to bring SEND inline with the TCG, I’m looking forward to SENDIG-DART being brought inline this year.

Drop me a note to share your opinion(s) at marc.ellison@instem.com.

‘Til next time,

Marc

The standard for the altruistic exchange of nonclinical data

This will be my final blog post of 2021, as I’ll be taking a break over the festive season. The season of goodwill is very apt for what’s on my mind this week.

Whether it’s media reports of how COVID-19 vaccines were collaboratively developed so rapidly; or the rise of consortia for exchanging pharmaceutical data for the purposes of accelerating drug development; it seems that data exchange is a hot topic and a potential game changer within our industry.

This week, I heard an impromptu address from Instem’s own CEO, Phil Reason, on this topic. Now I wouldn’t normally mention such things in my blog, as that’s all ‘a little bit too corporate’ but there was a real sense of altruism in the idea that we should be providing the technology to allow pharmaceutical organizations to easily exchange data and research to accelerate the development of new treatments. Our role, even our moral responsibility, is to ensure that that technology doesn’t become a barrier to such things and instead we should be striving to provide such capabilities.

As you can imagine, for someone who has dedicated the last 9 years of their career to developing and rolling out the Standard for the Exchange of Nonclinical Data, the topic really resonated with me, and my mind immediately went to thinking about the role of SEND.

I’m not claiming to have any answers here, but I do have lots of questions for the thought leaders within our industry and how they’d address this type of data sharing.

One thing that I’ve often heard thrown at SEND, is that its value is reduced as it only includes the individual raw data, and not the study conclusions. I’ve heard tales of individuals and organizations using SEND custom domains to list the study’s significant findings, but this is not the same as conclusions, and certainly the SEND custom domain structure wouldn’t seem a good mechanism for handling conclusions. So, would we need to supplement the SEND package in some way? What would that look like?

Which data are the most valuable for such altruistic exchanges? I don’t mean the idea that the Lab Results are more useful than Clinical Signs, I’m wondering about the value of nonclinical safety assessment studies, when compared to early discovery data, or later clinical trials. I mean, are these all equally valuable?

I’m also thinking about the time and effort it takes to convert data to SEND. Does that prohibit data from being exchanged, or at least makes it a little unpalatable? I mean, it’s one thing to go to the time and expense to convert a study to SEND for the purposes of a regulatory submission, but it’s another when it is simply to support someone else’s research and potential break through.

There are many other questions and topics buzzing around my head when thinking about the practicalities of such data exchange, but I’m inspired by the possibilities of finding new treatments and getting them to patients far more rapidly.

Festive greetings and I’ll see you again in the new year.

‘Till next time

Marc

The relative speed of SEND development

As we approach the holiday season and the eventual end of another year, I’m again thinking of how fast this year has passed. Also remembering childhood times when Christmas seemed to take forever to arrive. Now it seems I barely catch my breath and another year flies by. So yes, time is most definitely relative. As I look out of the window at the first dusting of snow, it seems truer than ever that the rate at which time passes, very much depends on your frame of reference.

The same is true of the world of SEND. I often hear the idea that SEND is moving too quickly. We barely get time to implement one change when another arrives. We are still adopting one standard when another is being forced on us. I mean, I know various organizations are still battling with the tighter control of the Microscopic Findings introduced in SEND 3.1, yet we already have SEND 3.1.1 published and now CDISC are talking about the SEND 3.2 with a whole raft of new domains and concepts to adopt.

I hear that point of view and while I have some sympathy for it, for me, SEND seems to move at an almost glacial pace. Take SEND 3.1.1 as an obvious example. This minor update addresses a crucial issue found with the Pharmacokinetics (PC) domain in SEND 3.0. Back in 2017 a small, expert team assembled to address this. Very quickly the solution was defined, yet it took until 2021 just to be published and still is not referenced on the Data Standards Catalogue.

In another example, as I’ve discussed here before, I joined CDISC back in 2012 to help work on the SEND standard for Reproductive Toxicology. It will be 11 years later before it finally becomes required in 2023.

Nervous System data is another area of disappointment. The domain was drafted back sometime around 2016 but it didn’t make the cut for SEND 3.1. Though it has examples, Controlled Terminology and Conformance Rules, it’s not making the cut for SEND 3.2 either. It’s currently scheduled for a tentative late 2025 publication, meaning we are looking at 2029 as the earliest that Functional Observational Battery and other CNS tests are going to be required in SEND. For an effort that began prior to 2016, this seems an unbelievably slow rate of progress.

The examples cited here are just some of many. My organization invests a huge amount of volunteer hours in CDISC because we honestly believe that the development of the SEND standard really does fit with our company vision to help our customers bring life enhancing products to market faster. We currently have more than 20 individuals giving time to CDISC, many of whom are actively leading teams. So, I personally feel the frustration of the snail-pace progress of SEND, but, like the changing of the seasons, the pace of progress is very much dependent on your frame of reference.

Till next time,

Marc

FDA provides more detail on the Scope of SEND

This past week was the CDISC SEND Virtual Face-to-Face meeting, and yes, I still snicker like a schoolboy at calling something a ‘virtual face-to-face’, but hopefully it’s the last one and by next Spring we can be face-to-face in person. Anyways, as is usual, the highlight of the week was the FDA public meeting. As you may imagine, this time it was dominated by discussions around the recent addition to the Technical Conformance Guide (TCG), momentously entitled the “Scope of SEND”.

I previously wrote about this when the FDA mentioned it at last year’s public meeting, and again when the recent TCG dropped. Then last week, the agency took the opportunity to take it apart, explaining their thinking and adding clarity.

The public meeting started with a reference back to the binding guidance. To serve as a reminder, that this is not optional, or subjective, and directly flows from that oh-so-important 2014 Guidance. Reinforcing the message that the recent TCG update is not adding anything new, it’s simply clarifying the position that harks back to that 2014 publication.

It was this time last year that the FDA clearly stated to industry that, although the Technical Rejection Criteria references the eCTD sections, the guidance doesn’t limit SEND requirements in the same way. A year later, we get a very detailed insight.

Without going into excessive detail, the guiding principle is this:

  • If the study starts after the requirement date, and;
  • The study needed to assess and support the safety of clinical investigations, and;
  • The study data can be represented in SEND;

Then the study requires SEND for submission.

Things like the age of the subjects, whether or not the study is GLP and the study report status were all discussed. It was clearly stated that these things do not affect whether or not the study requires SEND.

For some sponsors, this now causes a significant issue for certain studies. They may have studies already completed by their CRO, that at the time, incorrectly assumed that the study wouldn’t require SEND because it was in an eCTD section not covered by the Technical Rejection Criteria. So, they may have completed studies without SEND, which actually require SEND. However, fortunately for them, specialist SEND organisations like Instem can take completed studies and create SEND from the study report; allowing them to be compliant, even if they didn’t realise that SEND would be required when they initiated the study.

The FDA presentation also went to great lengths to talk about the value of SEND for regulatory purposes.  They described its value for primary reviews, and how it also assists in secondary and tertiary reviews. They described how SEND is “…used to conduct reviews that will impact regulatory decisions”.

Actually, it’s really inspiring hearing this, at a CDISC meeting focused on driving the SEND standard forward. The general feeling in the (virtual) room was really appreciative of the FDA’s openness in this way.

Till next time,

Marc