Digitalisation – CDER’s NextGen Portal

The FDA is moving forward with digitalisation in all areas and the CDER NextGen Portal is a good example.

What is the CDER NextGen portal?

CDER’s NextGen Portal is a cloud based system for users to report information to the FDA. From Drug Development Tools (DDTs) to amendment submissions, stakeholders can utilise the NextGen Portal. This collaboration platform continues to reduce regulatory overheads for sponsors, research institutes and small businesses alike.

Submissions that can utilise the NextGen Portal include:

  • Letter of Intent (LOI) submissions: The LOI is the first DDT Stage submission for the FDA to review to determine whether the DDT will be accepted into the DDT Qualification Program.
  • Qualification Plan (QP) submissions: The QP is the second DDT Stage submission for the FDA to review. A QP submission can be submitted only after the DDT has received an “Accepted” LOI.
  • Full Qualification Package (FQP) submissions: The FQP is the third DDT Stage submission for the FDA to review. An FQP submission can be submitted only after the DDT has received an “Accepted” QP.

Additional submission types worth mentioning are non-eCTD submissions for applications that have been granted an eCTD waiver as well as research INDs.

How does it work?

The NextGen Portal offers real-time interactions between sponsor and regulator. Having submitted the initial research IND, the FDA sends an acknowledgement letter back to the sponsor directly via the portal. After the initial IND review, further information requests might be sent by the FDA, again via the portal. Sponsors can then use the portal to respond to any information request and submit amendments and/or clinical study data.

What are the benefits of submitting via the CDER NextGen Portal?

  • Efficiency: Eliminate the time and hassle of printing and mailing paper or physical media via online submission.
  • Timeliness: No more waiting for submission delivery, electronic delivery is instantaneous.
  • Ease of Use: Requesting via the Portal is easy, and all information regarding any request is stored in one place.
  • Automated confirmation: Receive automated confirmation of all transactions.

In summary

Another step into the right direction, simplifying the submission process and communication between regulator and sponsor. With technology around digitalisation in the pharmaceutical industry constantly evolving, the CDER NextGen Portal is certainly a step in the right direction.

eSTAR – FDA’s next move to go digital

On 10th January 2023 the FDA announced a joint eSTAR, the electronic Submission Template And Resource pilot together with Health Canada. This is another approach in digitalisation via harmonising submission formats, allowing originators to reuse data and documents in different regions. The pilot will test the use of a single eSTAR submitted to both the FDA and Health Canada.

What is eSTAR?

eSTAR is an interactive PDF form that guides applicants through the process of preparing a comprehensive medical device submission. This template contains:

  • Automation (for example, form construction and autofill)
  • Content and structure that is complementary to CDRH internal review templates
  • Integration of multiple resources (for example, guidances and databases)
  • Guided construction for each submission section
  • Automatic verification

Why eSTAR?

It is the intention of the eSTAR pilot to provide regulators with better quality submissions for a wide range of medical devices and help to ensure originators provide quality, comprehensive data, simplifying regulators’ reviews. With a standardised format, originators can make sure that submissions are complete, and hence premarket reviews can be performed more efficiently.

Technical restrictions

  • File size should be under 1GByte
  • Images and videos should be provided in compressed format
  • Ensure one attachment only for each attachment type question
  • Use bookmarks or table of contents for combined documents to ease navigation

In summary

I believe this is an excellent approach from the FDA and Health Canada to allow further harmonisation, thereby moving the entire submission process further to the digital world. A harmonised approach will simplify submissions for the originators and ease review burden for the regulators at the same time. A win-win for all concerned.

Article 57 xEVMPD to IDMP/SPOR – Automated Consistency Check

As stated in our previous blog, EMA’s webinar “DADI-PMS Webinar Agenda – ‘Variations Form for Human Medicinal Products – What will happen at Go-Live’” made it clear that data quality [in PMS] is dependent on xEVMPD.

PMS, the Product Management Service out of the EMA SPOR project builds on the data foundations of the Referential Management Service (RMS) and the Organisation Management Service (OMS) that are already implemented.

With EMA’s Agile approach, the first iteration of the PMS will cover a subset of the authorised medicinal product part of the ISO IDMP standards. As part of the first iteration, the new ISO IDMP compatible data submission format (HL7 FHIR) replaces the current data submission format, the eXtended EudraVigilance Product Report Message (XEVPRM). xEVMPD data will be migrated to PMS and hence the data quality in xEVMPD will have a direct impact on the data quality in PMS.

Why is data quality in xEVMPD so important?

Let’s face it, MAHs are responsible for their data, period. So it might be a good time for MAHs to check on xEVMPD data before it is actually migrated into PMS, thereby removing unnecessary corrections that might be required later on. Additionally, as PMS will serve as a base for other functions, inconsistent data could move rapidly around related system.

Here are just some of the data fields that might require another look to ensure consistency:

Marketing authorisation holder (MAH) of the AMP (Authorised Medicinal Product); has anything changed over the last year through e.g. merger or acquisition?
Qualified Person responsible for Pharmacovigilance (QPPV); have resources been replaced but not updated?
Master File Location; did the Master File move because of a change in infrastructure?
Authorisation/Renewal Date; has the renewal data been updated or has the product been withdrawn?
Product Indication(s) (using MedDRA coding); are there updates on the MeDRA coding that did not filter through?
Authorised Pharmaceutical Form; has the product moved to additional authorised forms?

All the above are just a few examples of data fields that are undergoing regular change.

How can this process be automated?

xEVMPD uses an EV Code (EudraVigilance code) as a unique code assigned to any entity (e.g. substance, product etc.). An EV Code is generated after the substance has been inserted successfully in the xEVMPD. This EV Code can be used to compare data exported from xEVMPD (via EVWeb) with data held locally. Differences can be identified as long as all data is in the defined format.

The process is simple:

  1. Locate the xEVMPD messages generated locally separated by EV Code.

2. Locate the xEVMPD messages exported from EVWeb.

3. Compare with further details on differences identified between data fields associated with the same EV Code.

In summary

MAHs are responsible for their data and hence it might be a good time to check on whether the data held by the MAH is consistent with the data held at the EMA before any data migration to PMS takes place. Data held in xEVMPD will be the base for PMS and hence the quality of xEVMPD data is paramount. Although later corrections are possible, being proactive rather than reactive will save MAHs and regulators a lot of time and money.

But time is running out…

Article 57 xEVMPD to IDMP/SPOR: PMS Data Migration

EMA’s webinar “DADI-PMS Webinar Agenda – ‘Variations Form for Human Medicinal Products – What will happen at Go-Live’” made it more than clear: data quality [in PMS] is dependent on xEVMPD.

Source: EMA

In our previous blog on PMS Data Migration we highlighted some of the challenges faced by Marketing Authorisation Holders (MAHs) already and these challenges remain. In fact, I believe these challenges became more obvious during the EMA (European Medicine Agency) webinar. xEVMPD (Extended EudraVigilance Medicinal Product Dictionary) data still needs to be submitted, allowing PMS (Product Management Service) updates to happen. In case of inconsistent or even incorrect xEVMPD data, PMS data would also be incorrect. As PMS feeds into other systems, the chain of data reuse highlights the importance of data quality.

What about the eAF and DADI?

The electronic Application Form (eAF) already makes use of SPOR, connecting data fields with the data held by the EMA. With the introduction of DADI (Digital Application Dataset Integration), in a step by step process more and more free text fields will be replaced with dropdown lists to increase data consistency and quality. However, some of these fields will also be fed from PMS and hence indirectly from xEVMPD. Although the output format from DADI will still be PDF, the file itself will already contain information in the new FHIR (Fast Healthcare Interoperability Resources) format. Another reason for keeping the xEVMPD data accurate, clean and consistent.

What are the challenges?

Considerable effort has been made to implement SPOR using an Agile approach by the EMA with all its benefits and drawbacks. A step by step release of SPOR allows all parties to align their processes and procedures early and make use of Organisations and Referentials already. With the PMS data migration ongoing, not all medicinal products are available from day one and hence not all MAHs will benefit. However, the Agile release approach allows a step by step introduction of PMS. There is also a question about products that currently are not on the xEVMPD database such as herbal medicines or homeopathic products. Clear guidance on the best way forward to handle these in PMS will be required.

In summary

The recent EMA webinar on DADI clearly highlighted the benefits of getting xEVMPD data up to date, clean, and consistent before any data migration to PMS takes place. Otherwise, any inconsistent or incorrect data will be migrated and will feed other systems and processes such as DADI or the eAF. Afterall, it is the responsibility of MAHs to keep their data correct and up to date.

Article 57 xEVMPD to IDMP/SPOR PMS Data Migration: are you ready?

The situation

All Marketing Authorisation Holders (MAHs) in the European Union (EU) and the European Economic Area are required to submit information on their authorised medicinal products to the Article 57 database of the European Medicine Agency (EMA) in accordance with Article 57(2) of Regulation (EC) No. 726/2004. It is a legally binding requirement from the EU pharmaceutical legislation.

Information on amendments to the terms of any Marketing Authorisation (MA) following variations, transfers, renewals, or withdrawals should be notified to the EMA no later than 30 days after authorisation.

As part of the IDMP SPOR (Substances, Products, Organisations and Referentials) project, the EMA will soon migrate the xEVMPD data to SPOR PMS (Product Management Service). But how can MAHs ensure data consistency between their own Regulatory Information Management (RIM) database and EMA’s xEVMPD database before the data will actually be migrated to SPOR PMS?

The problem

Let’s face it, although good progress has been made to implement SPOR, a lot still needs to be done. The iterative approach chosen by the EMA provided early access to Referentials and Organisations, allowing MAHs and other interested parties to benefit from these SPOR services. And that is not limited to MAH managing medicinal products for humans, it is also of benefit to the veterinary sector.

However, the EMA still needs to decide certain aspects of the implementation including whether replacing the Art 57 data submission format (XEVPRM) with the new ISO IDMP compatible format (HL7 FHIR (Fast Healthcare Interoperability Resources)) takes place only after all relevant application forms are released by the Digital Application Dataset Integration (DADI) project.

The implication

But now EMA’s data migration from xEVMPD to PMS is on the horizon and MAHs need to be certain that their data is consistent, avoiding costly corrections and resubmissions. It is time to start checking to avoid the implication of incorrect data to be migrated from xEVMPD to PMS. A lot of time and effort can be spared by ensuring data consistency between MAHs’ RIM and xEVMPD data before the migration will take place.

In summary

Time is of essence, no doubt. The longer MAHs wait to check on data consistency between RIM and xEVMPD, the higher the risk and cost of corrections will be. Corrections undertaken after the PMS data migration has been completed will be more complex and time consuming. Don’t delay as after all, MAHs are responsible for the data held at the EMA.

We will provide further details about options on how you can automate this process in a follow-up post, but please feel free to get in touch should you require any assistance.

A first glimpse of the UPD Public Portal

Although still under development, the UPD Public Portal offers a first glimpse of what will come: better access to medicinal product information for the public. Let’s have a look at what is on offer.

The homepage mainly gives access to the substance and medicine index as well as the search functionality. As expected, under the substance index, selecting a letter provides a list of substances starting with that letter. Selecting a substance from the list provides an overview in the search result screen which includes the:

  • active substance,
  • species,
  • date of last update, authorisation status,
  • legal status of supply,
  • package description,
  • route of administration,
  • availability per country.

Selecting the substance in the search result screen provides further product details including

  • product overview,
  • product identification,
  • product details,
  • availability,
  • authorisation details,
  • product assessment history,
  • additional information.

Using the medicinal index, which works in a similar way, the same product detail screen can be accessed.

Important for the public is that the UPD Public Portal also provides answers to questions such as:

  • How is the medicinal product used?
  • How does the medicinal product work?
  • What are the benefits and risk of the medicinal product?
  • Other information about the medicinal product

Users of the UPD Public Portal can also run a comparison of medicinal products with the product information displayed side by side. A handy feature, especially if one is not so familiar with particular medicinal products.

In summary

Although still under development, it is clear already that the public will benefit from the UPD Public Portal. Medicinal products can be searched and compared, any authorisation status checked on a country by country basis, and further details such as the SPC document can easily be accessed.

Medicinal Product Line Outsourcing

Change creates opportunity, they say. Here’s one change that might benefit – if handled right – the medicine originator, the service provider, and foremost the patient by just moving the responsibilities of an entire medicinal product line into different hands.

Part I – The Opportunity

What opportunity am I talking about, as outsourcing itself is neither new nor terribly exciting? I’m sure you have noticed a fair number of outsourcings of specific tasks such as eCTD submissions or QPPV activities by pharma. This might be for example to cover high peak demands, getting access to specialists or for exploring alternative markets. But what about outsourcing end of life or less profitable products or entire product lines? A single medicine or an entire product line will naturally reach a point in its life cycle, after all, when the original investment has been recouped, the vast proportion of profit extracted as a result, and market maturity has long been reached. Further business opportunities are limited and attention is drawn to products that make more (financial) sense. And should resources be scarce, this will certainly end the life of the product concerned. Never mind that Unexpected Adverse Drug Reactions for example have to be taken care of.

Should a decline in profit be the end of a medicinal product?

Reaching this stage in the medicinal product life cycle, a fair number of companies would rather retire or withdraw the product than continue offering a medicine low on profit and high on overheads. After all, this is a business and profits have to be made. There comes a tipping point when covering compliance with latest regulations, ‘housekeeping’ in terms of drug safety and other overheads to keep the product on the market, starts to eat away the last bits of revenue sought.

But just withdrawing the product might not be such a smart move, as there is still a definite value for all parties concerned, especially the patient. Wouldn’t it be kind of foolish to deny yourself and your patients such a benefit? Why not outsource the product?

And for others, why not take this opportunity off the originator’s hands? Doesn’t supporting mature products to extract all the remaining potential make better sense for all parties concerned? Wouldn’t it be more economical to support new and/or developing markets or find economies of scale that maybe weren’t possible before? The opportunities seem endless and rather appealing.

And that is where ‘Medicinal Information Management’ comes in. What do I mean by that? Medicinal Information Management is much more than Regulatory Information Management or RIM, as we are looking at the entire life cycle of the drug, with possible new undiscovered markets, maybe alternative product strength or form of administration, not only regulatory requirements and/or changes. This also extends into new areas of product marketing, whether in new regions or new target markets.

So how would ‘Medicinal Information Management’ work? Third parties would engage in dialogues with pharma companies, looking to take their mature less profitable products off their hands, paying a royalty and looking to extract all the remaining potential of the material. That third party can look, for example, to put this into new or developing markets or find economies of scale that maybe someone else wouldn’t. This is good economics; there is no need to let something ‘die’ that still has potential to give back to investors and patients at the same time.

Part II will look at how to overcome the challenge of doing all of the above effectively on limited budget.

Please feel free to contact us with any questions or if you require further information.

Are you listening to your animal patients?

We at Instem pride ourselves with mastering the technology to support the pharmaceutical, medical device and veterinary profession, bringing their life enhancing products to market faster. But that is not all. We also pride ourselves with being able to understand our clients’ patients, and this includes animals.

The need for getting a better understanding of animal patients.

When it comes to understanding our clients’ patients, animals are no exception. In the human world physicians can ask patients about the pain they experience, about a body ache or headache that requires treatment. Patients can usually explain how they feel, where they experience pain and what symptoms they have.

With animals, this is entirely different. Animals communicate using their own language – much more difficult for humans to read and understand. Different breeds communicate in different ways, but with time and experience, humans can begin to interpret signals. Let’s look at a few examples with horses.

Horses communicate largely via body language, a language they themselves understand very well of course.


The first thing most people will notice are the ears, always in motion, acting like two independent radars. With ears forward the horse generally signals relaxation. When the ears go back, the interpretation is more challenging: the horse might be listening to the rider, it might be listening to something else behind it. But if the ears are flat to the back, this could signal aggression.


The tail is another very visible part of the horse used for body language. Especially in the summer, horses are used to using their tail to get rid of flies. However, when tucked in it can signal nervousness or even fear. A fierce swishing can signal something more alarming, usually a sign of irritation or frustration.


Horses’ legs are somehow fragile, the same as the legs of many other species such as zebras or antelopes. But horses’ legs can also tell a story. Resting a hind leg is very common using a locking mechanism (the “stay apparatus” mechanism) and is how horses can sleep. Resting or even putting forward a front leg though is uncommon and would need investigating.

How to recognise the all important “I am really not well”?

There could of course be many symptoms a horse might display to let you know something is not quite right. Pawing the ground, lying down and getting straight up again might indicate colic. Defensive or even aggressive behaviour during brushing or saddling might indicate back pain. Frantic up and down head tossing might indicate discomfort, especially with a ridden horse. All of these are clear indications that something is not right. To be able to help, we humans have to read and understand the body language of animals.

In summary

At Instem we are proud of not only understanding our clients, but also our clients’ patients, enabling our clients to bring life enhancing products to market faster. Having the ability to better read and understand the body language of animals is key to enable our veterinary clients to provide better treatment for their patients.

Union Product Database – EMA’s Agile Approach?

With the pressure mounting to implement the New Veterinary Regulations (NVR) which came into force 28th January 2022, releases of the Union Product Database (UPD) to be implemented under the NVR are getting more frequent. In true software development fashion, is the EMA using the Agile approach to get solutions out more frequently and much quicker?

First things first: What is the Union Product Database?

The New Veterinary Regulations EU 2019/6 came into force 28th January 2022. Under the NVR, the European Medicines Agency (EMA) shall establish and maintain a Union Product Database as we highlighted in previous blogs here. But the UPD is still under development with the EMA releasing new versions of the software in a true Agile fashion. The latest iterative version v1.5.3-4 has just been released with a number of improvements and corrections.

What is Agile?

Agile is the ability to create and respond to change. It is a way of dealing with, and ultimately succeeding in, an uncertain and turbulent environment. Key Agile concepts include:

  • Incremental development: Agile teams usually favour an incremental development strategy where each release is usable and an expansion upon the previous version.
  • Iterative development: Agile projects are mostly iterative, allowing to repeat software development such as when prototyping.

Now to the changes in UPD v1.5.3-4, what is new?

With the latest release of the UPD there are new features implemented for MAHs that can be summarised as follows:

  • Search/view/export product (data and documents)
  • Notifications for Create and Update of products
  • Download, Submit and View Volume of Sales information
  • Submit VNRA (Variations Not Requiring Assessment) and View VNRA submissions
  • Submit updates for Marketing authorisation stat

There is also new functionality supporting the API:

  • Create MRP (data and documents)
  • Update Common Data for products under DCP/MRP (data and documents)
  • Update National Data for products under MRP (data and documents)

The (known) issues

Good progress has been made in getting the next version of the UPD ready for MAHs, NCAs, and every other member of the veterinary medicinal product community. There are however a fair number of issues still outstanding, with UPD 7992 and 7994 as mentioned in our previous blog being only two of them. Both were around the submission of sales data to be delivered by the MAH.

In summary

Again, good progress has been made with the UPD development in only a couple of weeks and new functionality has been made available to search and update data. Delivering the UPD via an Agile development process has certainly worked well, especially considering the tight deadlines. Nevertheless, there are still outstanding issues that need to be addressed and with the NVR now in force, urgent attention to these issues is required.

New Veterinary Regulations – Volume of Sales

Only days to go – The New Veterinary Regulation is coming into force on 28th January 2022.

Time is running out for Marketing Authorisation Holders (MAHs), regulators and solution providers. The New Veterinary Regulation (NVR) is coming into force on 28/January/2022. Part of the NVR is the requirement for MAHs to provide information about the “Volume of Sales”.

Why provide “Volume of Sales” data?

Chapter IV of the NVR, Section 1 Union Product Database states that alongside information such as name of veterinary medicinal product, active substance and strength, package leaflets or marketing dates, the Union Product Database (UPD) should contain “…the annual volume of sales…”. Member states shall collect the data on the volume of sales and on the use of antimicrobial medicinal products. The data will be used to enable the analysis of any incidents that might occur during product life cycle.

What shall be submitted?

MAHs have to provide the following:

i. Package Identifier (generated by the UPD)
ii. Country
iii. Country identifier
iv. Month/Year (time period of submitted volume of sales)
v. Volume of sales (per package, species, country and month)
vi. Species Identifier
vii. Species % (estimated split of use per species)
viii. Dose Factor (average number of animals that can be treated using one package)
ix. Comment (optional field)

What format is required?

MAHs can download a csv file with prefilled information for product identifier, product name, packaging and more. This csv file needs to be updated with the information as stated above.

It is also possible to access the UPD via an API using a Regulatory Information Management (RIM) solution to manage the relevant data.

What are the problems?

Using the csv file format has its disadvantages considering regional requirements or different versions of Windows® etc. Chapter 7 of the EU Implementation Guide of veterinary medicinal product data in the Union Product Database dated 13/December/2021 highlights some of the challenges and how best to overcome them.

But there is – at least for now – another catch: although great progress has been made with the UPD implementation with new releases coming out every few weeks, there are still a few issues that need to be addressed. As of 21/December/2021, two examples from the results of User Acceptance Testing for “Submit volume of sales” UC07 are

  • UPD-7985: zero/negative dose factor does not throw a validation error
  • UPD-7994: the system validates creation date of product from the downloaded file while submitting even if the field is not mandatory

With the deadline of the NVR coming into force on 28/January/2022, the resolution of these and other challenges is becoming time critical.

In summary

Time is running out for the UPD to be ready for MAHs, NCAs and solution providers. Rapid progress has been made to meet deadlines, but a few issues still need to be addressed. However, MAHs should be fully prepared ahead of time to allow provision of all required information for the UPD when released.

Please get in touch if we can be of assistance.