Structured Authoring – Streamlining Regulatory Submissions

It still surprises me that in an industry such as life sciences where quality, compliance and accuracy is of utmost importance, data that can be automatically handled is managed manually. Manual data management is prone to errors, is time consuming and is sometimes even a risky approach of dealing with information across different business functions. Companies that already use Regulatory Information Management (RIM), manage most of the data such as marketing application, excipient and indication in electronic format. So why manually transfer – and thereby copy – data that is already managed in RIM systems in electronic format to an SPC (Summary of Product Characteristics), medicinal product packaging or the Package Information Leaflet (PIL)? This just increases the risk of data inconsistencies, leading to marketing applications updates or even medicinal product recalls.

So how might structured authoring eliminate this issue?

Let’s face it, if the data is already manged in RIM, why not reuse it elsewhere? Let’s look at some examples: medicinal product name, indication, and excipient are already in use when compiling marketing applications in eCTD format. Some of the data is even used to build the eCTD backbone.

Now checking on the EMA QRD template (version 10.2, Rev.1 09/February/2021 ), it contains the same information: the name of medicinal product (section 1), the therapeutic indications (section 4.1) and a list of excipients (section 6.1). If we already manage the same data in RIM for the eCTD, why not reuse the same data to generate the SPC or PIL?

When we think about authoring, we think about medical writers, scientific documents or tools such as an editor. And how do we create structure in a document? We might refer to templates that define the look and feel of a document but also define how paragraphs, fonts or headings are laid out. The most important part though, the content, is still authored manually. This process creates unstructured data inside documents, one of the major challenges recently identified during the implementation of IDMP. Using structured authoring, documents can be automatically created by reuse of data.

The benefit of structured authoring.

Most companies are still copying the data from RIM systems or spreadsheets to SPC or PIL. A manual error prone process that can be avoided using the method of structured authoring. Using this method, data is inserted into documents automatically, even keeping a record for future life cycle. This process not only ensures data consistency across business functions but also provides the opportunity to share data from a ‘single place of truth’. Documents can be partly filled in automatically, thereby reducing manual more error prone tasks, and at the same time creating uniform content. In a regulated environment such as life sciences this is one of the key areas, supporting production and management of quality medicinal products. Quality is what gives patients and consumers confidence in their next dose of medicine. CDER’s KASA approach would be a prime target for structured data but more on that in a future post.

If you need further information, please do not hesitate to get in touch.

Veterinary Medicinal Products – VNeeS changes are coming

The EMA recently released a draft version 3.0 of the VNeesS specification for the provision of electronic submissions for veterinary medicinal products in the EU. Although more updates are expected, the EMA states that the basic folder structures of the draft specification are not subject to further changes. But what have Marketing Authorisation Holders (MAHs) to look out for?

Why has the VNeeS specification been updated?

The main reason for adapting the VNeeS guidance document is to align with Regulation (EU) 2019/6. One example being the change for “Variations / Extension” as shortly the marketing application will be valid for an unlimited period.

What is the impact of changes undertaken to the file/folder structure?

For a start, suppliers have to update their software to incorporate the new file/folder structure. This will lead to a new software release for MAHs in some form, with the supplier either providing a new software package or updating the database tables holding the relevant information. In any case, updates are required.

Marketing Authorisation Holders have to adapt the changes in file/folder structure too. In case of a more manual submission process, the naming conventions need to be incorporated into the current process. In case Marketing Application Holders are utilising publishing software or RIM solutions, software upgrades are required. This could be time consuming and requires additional resources.

In addition, there is another obstacle to look out for: references to section “4a3-tas” that use the section name might not be valid anymore. Further details are outlined below.

Last but not least the VNeeS checker has to be updated, providing support for the new file/folder structure and change in folder names.

What needs to change?

There are subtle changes that nevertheless need to be taken care of. Comparing for example file/folder structures for VNeeS 2.7 against VNeeS 3.0 (draft) for “Folder structure and Standard files for an electronic application for a pharmaceutical product”, we can pick up the following:

Current format VNeeS 2.7

The proposed new file/folder structure is as follows:

New format VNeeS 3.0 (draft)

Checking the same Table under “Folder structure and Standard files for an electronic application for a pharmaceutical product”, we can also identify a new sub section in Part 4a (Part 4a3-dose-determ). Incidentally, this moves the current sub-section Part 4a3 to become the new Part 4a4.

New format VNeeS 3.0 (draft)

In summary

From the outside, the changes in the new VNeeS file/folder structure are subtle. However, considering that software suppliers have to update the VNeeS file/folder structures and their validation engines and MAHs have to update their system, whether RIM or publishing tools, work has to be undertaken on both sides. As of today, no mandatory date for the VNeeS 3.0 implementation has been published but software suppliers as well as MAHs need to prepare accordingly.

New eCTD rejection criteria in force at the FDA

Marketing Authorisation Holders beware!

The FDA has just announced that the Center for Drug Evaluation and Research (CDER) will begin rejecting submissions that fail eCTD validation checks 1551 and 1553. Both validation errors are of high severity as described in the eCTD Validation Criteria specification. The different severity levels can be summarised as follows:

  • High: The error is a serious technical error which prevents the processing of the submission and will require resubmission. The submission is considered not received by FDA.
  • Medium: The error may impact the reviewability of the submission but cannot be determined without further inspection by the review staff. The submission might be considered received by FDA.
  • Low: The error is a technical error which may or may not impact the reviewability or the integrity of the submission. The submission will likely be considered received by FDA.

And time is up!

As announced in the Federal Register Vol. 86, No. 165, CDER will begin to reject marketing authorisation applications in eCTD format that fail to pass either eCTD validation 1551 or 1553 from 18/October/2021.

What are validation errors 1551 and 1553?

eCTD validation error 1551 is about missing Product Labelling information that sponsors have to provide in Module 1.14.6 for 2253 submissions. Sponsors are required to submit the most up to date labelling information under 21CFR314.81(b)(3)(i). Please note this is valid for US DTD version 3.3.

eCTD validation error 1551

eCTD validation error 1553 is about FDA Form 2253. MAHs are required to submit Form 2253 for Submission Type of “Promotional Labelling”. Other Forms are not permitted under this Submission Type. Please note this is valid for US DTD version 3.3.

eCTD validation error 1553

In summary

Marketing Authorisation Holders have to take this FDA notice seriously as CDER will start to reject applications in eCTD format that do not conform with validation criteria 1551 and 1553.

FDA eCTD file formats updated

New opportunities for Pharma companies!

Now Pharma companies can use audio and video files to support their promotional material during marketing authorisation applications, making the entire process more engaging.

Over the last few months, the FDA has updated the file formats that are permitted within the eCTD. New formats have been added to the file format specification “Specifications for File Format Types Using eCTD Specifications”, now in its version 7.0.

  • In March 2021, the following file types for modelling and simulation were added: .cmpx, cmpz, .wksx, .wksz, ,lbrx, .lbrz, .mdb, .pbk, .opd, .psd, .spd .c, .cpp, .m, .mat, .rmd, .phxproj, .py, .jl, .cas, .dat.
  • In May 2021, the chemical file type .sdf was added.
  • And in October 2021 the file type .zip was added to allow grouping of large sets of aECG xml files.

The “Specifications for File Format Types Using eCTD Specifications” specifies that in general, documents should be provided in searchable PDF format. Other document types as well as images should be rendered into PDF, maintaining searchability were possible. However, other types of file formats are acceptable in the eCTD and many new file types have been added this year.

Besides the more common document file types such as .doc and .docx or image formats such as .gif, .bmp, the FDA now also permits audio and video file formats in Module 1.15 Promotional Material.

New this year are file formats for modelling and simulation with the additional file types as outlined above. These file types are permitted by the FDA in Module 5 Clinical Study Reports (CDER only). No additional archiving format has been provided.

In May this year, the structured data file format or .sdf was added, which will be accepted in Module 3.2.P.5.5 (Characterization of Impurities) as well as Module 3.2.S.3.2 (Impurities).

One further addition has just been added in October 2021, which is the .zip file format for grouping of large sets of aECG (annotated Electrocardiogram) xml files.

In summary

With the addition of new file types such as audio and video, further opportunities are opening up for marketing authorisation holders to complement their promotional material and make use of new technologies.

FDA’s novel excipient pilot program is open for candidates

CDER (Center for Drug Evaluation and Research) recently launched a new voluntary Novel Excipient Review Pilot Program, intended to allow excipient manufacturers to obtain FDA review of certain ‘novel excipients’ prior to their use in medicinal products. This pilot is geared at fostering development of excipients that may be useful in scenarios in which manufacturers and originators have difficulties in using existing excipients.

This pilot will initially be available for novel excipients that

(1) have not been previously used in FDA-approved drug products, and
(2) do not have an established use in food.

For excipient manufacturers, the pilot consists of two stages: The first stage is to provide a high-level overview of the ‘novel excipient’, with stage two providing a full data set including toxicology and quality data.

What is a ‘novel excipient’?

Excipients are inactive ingredients that agencies review as a component of a finished drug. This could be in a new drug application but also in a generic drug application. These inactive ingredients can work to stabilise medications and help the body absorb the active ingredients. Other areas of use are for flavouring, colouring or coating of the medicinal product. ‘Novel excipients’ are any excipients that are not fully supported by existing safety data yet.

Why this pilot then?

Excipients can certainly help with delivering drugs to where they are needed in the body. They can also play a part in helping patients to tolerate medication, but sometimes this is associated with risks. Triggering allergies for example is one area of concern. Hence regulators evaluate excipients for safety and stability as early as possible, so as not to negatively impact any medicinal product delivery to the patients. With this pilot, the FDA opens a pathway to evaluate ‘novel excipients’ that could provide important public health benefits. Submissions are voluntary, allowing excipient manufacturers to obtain early review of certain ‘novel excipients’ prior to their use.

How are ‘novel excipients’ selected?

The FDA will accept a limited number of ‘novel excipients’ for this pilot. Selection preference will be given to proposals demonstrating

• a potential public health benefit – one example being excipients promoting development of new therapies for serious diseases.
• potential to improve characteristics that may lead to new drug development
• likelihood of timely delivery of complete package ready for assessment.

In summary

The ‘novel excipient’ pilot will work to promote development and use of new excipients, where using existing excipients is challenging or not possible. Its success will be measured with the review and identification of ‘novel excipients’ that improve drug development including new medicinal products, to be introduced to the patients for an unmet medical need.

Subsequent Recognition Procedure: A new kid on the block?

In Europe, Marketing Authorisation Applications (MAAs) can be submitted following different procedures. If Marketing Authorisation Holders (MAHs) desire access to all member of the European Economic Area (EEA) using a single procedure, the Centralised Procedure (CP) is the way to go. The EEA includes the members of the European Union plus Norway, Iceland and Lichtenstein. For applications on a country by country basis the National Procedure (NP) would be appropriate, the most common procedure also used worldwide. In Europe though there are two additional procedures in place to accommodate specific EEA requirements: the Mutual Recognition Procedure (MRP) and the Decentralised Procedure (DCP). Both procedures try to eliminate costly approval for medicinal products that are already approved in another member state.

The MRP procedure should be used where a medicinal product has already received a Marketing Application (MA) in a Member State (MS) at the time of application.

The DCP procedure should be used where a medicinal product has not yet received a MA in a MS at the time of application.

Both MRP and DCP are procedures to obtain MAs in more than one MS. It is open for all applications not falling under mandatory scope of the Centralised Procedure. One of the most important aspects for both MRP and DCP is that for both procedures, MS’s rely on each other’s scientific assessment.

But now there seems to be a new kid on the block, the Subsequent Recognition Procedure (SRP) supporting veterinary marketing applications.

When can it be used?

The Subsequent Recognition Procedure may be used after completion of a first Mutual Recognition Procedure or a Decentralised Procedure for the recognition of a Marketing Authorisation by additional Member States for the same veterinary medicinal product. The SRP can be used in MS’s, which were not included in the original MA or in Concerned Member States (CMS) where the MA was withdrawn.

At the end of a successful SRP, the “new” CMS will either recognise the MA of the product with the same SPC, labelling and package leaflet that were approved in the earlier MRP or DCP, or a new variation will be introduced in the “old” CMS to implement any requested changes linked to Potential Serious Risk (PSR) concerns. Minor editorial changes can be submitted with the first variation after the closing of the procedure.

Is the SRP really new?

In short: No. The SRP could also be referred to as the Repeat-Use Procedure (RUP), which was the common term previously used before implementation of Regulation 2019/06/EC.

What is required?

According to the Council of the European Union, Proposal for a Regulation of the European Parliament and of the Council on veterinary medicinal products, dated 08/June/2018, the following administrative information referred to in Article 7(1)(a) should be submitted

  • Applicant such as name and address of manufacturing sites;
  • Identification of the veterinary medicinal product such as product name and substance;
  • Product information such as summary of product characteristics (SmPC) and proposed text for packaging;
  • Other information such as list of countries the MA has been authorised in.

For the SRP, additional information is required:

a) A list of all decisions granted, suspending or revoking MAs concerning this veterinary medicinal product;
b) Information on the variations introduced since the MA by DCP (Article 46(5)) or MRP(Article 48(5a)) was granted;
c) A summary report on pharmacovigilance data.

In summary

With SRP, are we introducing another submission type for veterinary medicinal products? Not quite as the Repeat Use Procedure was covering most of the aspects of SRP. There are however a few areas to notice such as outlined in Article 48a of the “Proposal for a Regulation of the European Parliament and of the Council on veterinary medicinal products”. One aspect of interest is the handling of the MA in case of disagreement between respective member states. More another time.

Digital Transformation for the benefit of the equine world

Digital transformation (DX) is the adaptation of digital technology, the transformation of services and business processes to replace manual or outdated non-digital processes. However, DX is much more than the integration of digital technology. DX might even move technology and processes to the edge of what is currently possible, the last mile where technologies meets, where process collide. An area for any business destined for improvements.

But what has that to do with the equine world?

DX takes place in other areas, not just high-tech; the veterinary world is just one example. Technology has been used to monitor performance during horse racing for years, but with DX in addition, opportunities seem endless to improve equine health and wellbeing. Although it might mean to walk away from more traditional thinking or long-standing processes, there are advantages that can only be realised by taking DX seriously. DX might be simply a piece of technology such as a sensor, or it could be a piece of software to monitor heart rate or data analysis presented in real time. The ability to adapt quickly is one of the challenges in business, but also one that can be addressed by DX; the equine world is no exception.

There are only a few animals close to humans that represent beauty, agility, strength and sometimes freedom quite in the same way as hoses do. Although the place and role of horses has changed over hundreds or even thousands of years, horses have demonstrated their adaptability from farm worker to athletes. But did technology advance with them in a similar way?

Example: pressure sensors

For a long time, humans “experimented” with different types of saddles, but without taking into account the horse’s comfort, health and agility. The somewhat heavy and more sturdy western saddle for example could weigh up to 30kg, in contrast the traditional English saddle is lighter and more flexible. However, most saddles were made with the rider in mind; they were designed to provide comfort for the rider and the ability to control the horse with ease, sometimes for going long distances. But what about the horse?

With DX taking place, new technology in the form of pressure sensors has been developed, allowing measurements with greater accuracy and in a timely manner. At long last, it will be possible to determine whether a saddle fits too tightly putting unnecessary pressure on the horses back and making it uncomfortable; or checking the saddle is only using a fraction of its surface creating undesirable effects. However you look at it, getting a better understanding of the optimal fit will benefit the rider as well as the horse leading to a much better partnership.

Example: 3D printing

Another example is 3D printing. The 3D printing process creates a three-dimensional “object” by building successive layers of “objects” produced for example by CAD (computer-aided design) drawing or an MRI (Magnetic Resonance Image). 3D printing is already widely used in healthcare for example by dentists to create crowns in a fraction of the time it takes a lab relying only on manual labour. The flexibility of 3D printing allows the alteration of the final “object” more simply. Personal devices are another good example for 3D printing as these devices can be matched to each patient’s physique.

But how might 3D printing benefit the equine world?

3D printing could be used to create bespoke horseshoes where accuracy is of higher importance than speed of application. 3D printing would enable a farrier to create horseshoes on the fly with minor alterations possible even on the day. Perfectly fitted, lightweight racing shoes made (for example) from Titanium are already been produced. Other areas of application would be for bone substitutions, a welcome change to the historic euthanasia in the case when a horse suffers an unfortunate bone fracture.

In summary

Digital Transformation (DX) is not only happening in high-tech companies, it will have an impact on many businesses. DX will help in many areas such as Regulatory Information Management via sensors to 3D printing by expanding via the use of leading-edge technology and processes to improve everybody’s life, including that of horses.

Transitional arrangements for Regulation (EU) 2019/6 for Veterinary Medicinal Products

On 19/July/2021 the CMDv released document EMA/CMDv/181154/2021 entitled “Transitional arrangements for the entry into application of Regulation (EU) 2019/6 for veterinary medicinal products registered under national, mutual recognition and decentralised procedures”. CMDv has prepared this document to assist Marketing Authorisation Holders (MAHs) as well as National Competent Authorities (NCAs) in the management of the transition from Directive 2001/82/EU to Regulation (EU) 2019/6. The CMDv provides this guidance mainly for the Mutual Recognition Procedure (MRP) and Decentralised Procedure (DCP).

The release of the CMDv document follows publication 2021/C 274/02 from the European Commission “Commission Notice on marketing authorisations for veterinary medicinal products for which the expiry of the 5‐year period of validity falls on or after the date of entry into application of Regulation (EU) 2019/6”, which clarifies some practical steps, mainly for the centralised procedure with some aspects also applying to the national procedure.

What do these documents contain?

Both documents are addressing MAs for Veterinary Medicinal Products (VMPs) that require renewals, either under the current Directive 2001/82/EU or under the new Regulation (EU) 2019/6 and their Marketing Authorisation (MA) validity.

What is the main difference of these documents with regards to MA validity?

With regards to MA validity, the main difference between Directive 2001/82/EU and Regulation (EU) 2019/6 is the timeframe for MA validity. Directive 2001/82/EU limits the validity of MA for Veterinary Medicinal Products initially to five years, MA regulated under Regulation (EU) 2019/6 will have an unlimited validity (exceptions apply). Both documents clarify the provisions already contained in the applicable legislations. A new one-step process for acquiring an MA for VMPs for an unlimited duration will replace the previous two-step process.

Sample clarifications

For the Centralised Procedure (CP), MAHs with MA for VMP that expiry on or after 28/January/2022 will receive a letter from the EMA concerning the expiry date. With a positive reply from the MAH, the EMA will initiate steps to ensure unlimited validity of the MA. In the case of no (or a negative) reply, the MA will expire.

For the CP, MA submitted before 28/January/2022 but yet undecided will be dealt with under Directive 2001/82/EC.

What happens to MAs with validity after 28/January/2022 but with MA granted before 28/January/2022? As renewals should be submitted at least six months before the MA ceases, MAs will be handled according to Directive 2001/82/EC. In the case of the validity of the MA ending after 28/January/2022 with a submission date also falling after this date, no renewal application is required. The validity for the MA will be amended by the NCA.

In summary

With the New Veterinary Regulations now only months away, MAHs have to decide on when best to submit VMP renewals to make the most of the unlimited validity of MA under Regulation (EU) 2019/6. Replacing the two-step process under Directive 2001/82/EU with a one-step process under Regulation (EU) 2019/6 is certainly an improvement, but rules will apply. However, this is one final step to get to an unlimited validity of the Veterinary Medicinal Product more quickly….

FDA Guidance for Industry: Development of Abbreviated New Drug Applications during the COVID-19 Pandemic

In April 2021 the FDA released a new question & answer guidance document for the industry, specifically addressing Generics and their challenges during the COVID-19 pandemic. As the guidance is coming into effect immediately without prior public comments, it is worth having a closer look.

The FDA has issued this guidance to provide general recommendations to (prospective) applicants of abbreviated new drug applications (ANDAs) related to generic drug product development and regulatory submissions. The FDA has collated the questions and is presenting the responses in this guidance document for the benefit of all stakeholders. The FDA intends to revise/update this guidance as appropriate.

What does the guidance contain?

The guidance document has been structured into the following categories:

A) Generic drug product development;
B) Submission and assessment of ANDAs; and
C) Marketing and exclusivity.

Each category addresses different areas of concerns.

Category A: Generic drug product development

Questions in this category are mainly about bioequivalence studies and how any study interruption can be handled and whether multiple batches of reference products can be used in particular circumstances.

Category B: Submission and assessment of ANDAs

Questions in this category mainly address concerns about ANDA submissions for medicinal products that help with the COVID-19 public health emergency and possible site inspections that cannot take place because of restrictions invoked by the COVID-19 pandemic.

Category C: Marketing and exclusivity

Questions in this category address tentative drug approval and any impact of COVID-19 on timelines, specifically on exclusivity for Generics.

What other support is available for Generics?

Although not directly linked to the COVID-19 pandemic, the FDA has just launched the “Generic Drug Cluster” to improve global regulatory alignment among agencies, specifically in countries with focus on development of generic medicines. The “Generic Drug Cluster” aims to increase scientific alignment with the following objectives:

• Achieving a common understanding of each Agency’s regulatory requirements for approval and current thinking on topics related to generic drug development through information sharing on approval requirements and recommendations conveyed in guidance documents.
• Offering a confidential forum for exchange of discussion on policies in development, including draft guidances for industry, and the scientific basis for decisions on those policies.
• Provision of a forum for a discussion of general and product/class-related scientific review issues and fostering alignment in approaches to scientific evaluation whenever possible.
• Addressing long-term safety issues to ensure a global safety net for generic drugs through confidential sharing of reports.

Hopefully other agencies will also see a benefit in this forum to support global generic drug development.

In summary

With this Q&A guidance for industry, the FDA has addressed some of the questions faced by the Generics industry, in particular about the possible impact of the COVID-19 pandemic. The FDA provides some of the options available to the industry for handling studies and batches used to conduct bioequivalent studies as well as inspections. For Generics it will be a relief though that the FDA is not automatically rejecting applications that include sites that cannot be inspected because of COVID-19 restrictions. Approval decisions will be based on the entire information available. A key point is that marketing of a tentatively approved ANDA will not be possible.

With the recently launched “Generic Drug Cluster”, the FDA opened a communication forum for the world’s leading regulatory agencies to address generic drug development globally. Let’s hope that other agencies will also see a benefit in this forum and participate.

EMA’s new veterinary product information template

To be able to support the new veterinary regulations coming into effect in January 2022, the EMA updated the product information template that can be accessed here . The new template includes a new section on restrictions on the use of antimicrobials and antiparasitic veterinary products in an attempt to reduce resistance.

The other thing to notice is that the new template will address the need for Marketing Authorisation Holders (MAHs) to address any environmental issues. One notable example is the need to include information on special precautions for the protection of the environment – this information will help users of the medicinal product to better defend the environment.

What are the timelines?

One of the main aspects of the new template is that it supports the requirements under Regulation (EU) 2019/6, coming into effect 28/January/2022. Therefore, template version v9.0 should be used for all initial marketing applications after 28/January/2022. For product information of medicinal products placed on the market in accordance with Regulation (EC) 726/2004, template v8.2 may be used until 29/January/2027.

Please note that QRD template v.8.2 was revised in December 2021 to specify Northern Ireland as a local representative.

What does the new template v9.0 contain?

• a new structure of the SPC labelling and package leaflet with the order of sections aligned as far as possible;
• information only to be included in the package leaflet that was formerly in the labelling, simplifying the outer and immediate labelling;
• a consolidated section on ‘minimum particulars to appear on small immediate packaging units’ which now incorporates blisters and strips;
• a new section on any restrictions on the use of antimicrobial and antiparasitic veterinary products. This includes restrictions on conditions of use that are not in accordance with the terms of the marketing authorisation (MA);
• expanded guidance text in many sections to improve clarity for applicants and regulators;
• standard text for “marketing authorisation” granted for veterinary limited markets and under exceptional circumstances;
• reference to national collection systems for disposal of waste veterinary medicines.;
• guidance on specific content for novel therapies;
• increased flexibility in some sections;
• consolidated section for all contact details.

EMA also simplified the SPC and package leaflet sections on ‘frequency and seriousness of adverse events’.

In summary

It is clear that a big effort has been made to align the QRD template with the NVR coming into effect in January 2022. Although we can expect finalisation of the combined label-leaflet QRD in the fourth quarter of 2021, companies can already align their data and processes with the new template v9.0.