Posts

Dieter Schlaps, ITCLS

SMS, G-SRS, GINAS, EU-SRS Current Status July 2018

SMS, G-SRS, GINAS, EU-SRS Current Status of the IDMP Substance Submodel Implementations in Europe and the US

By Dieter Schlaps for IDMP1-News July 2018

The SMS, G-SRS, GINAS, EU-SRS Current Status as of July 2018 is beeing summarised in this blog article.

FDA’s G-SRS System

In FDA2‘s G-SRS1 system, the substance is registered per type, as defined in the IDMP4 standard (e.g. chemicals, proteins, polymers, structurally diverse, nucleic acid, etc.) and then, certain criteria apply to distinguish substances in each category from one another (e.g., chemical structure, DNA sequence etc.). When enough information is available and validated, a substance is assigned a unique identification (UNII- Unique Ingredient Identifier) code, which can be used as a quick way to refer to that substance in the future. Until the UNII code is defined, the substance exists in G-SRS as a “concept”.

In last week’s GINAS[1] meeting, FDA[2]‘s and NCATS[3]‘ teams reported about the current status of FDA’s implementation of the IDMP[4] substance standard [1], and, indeed, a lot has been achieved:

  • The final versions of the ISO Standard 11238 on Substances (https://www.iso.org/standard/69697.html ) and its Implementation Guideline 19844 (https://www.iso.org/standard/71965.html ) with all annexes are published in this month (July 2018)
  • Version 2.2 of G-SRS is now in productive use at the FDA
  • The version 2.2 of the public G-SRS will be released in a few weeks, watch website https://tripod.nih.gov/ginas/#/.
  • The currently available version 2.1 of the public G-SRS already hosts more than 100.000 substances and concepts.
  • Programmatic communication with the G-SRS database is possible through the GINAS RESTful[5] API[6] (https://tripod.nih.gov/ginas/#/gsrs/api ), allowing substance searching, registration, browsing, updating. Figure 1 shows and example that downloads substances with all details in a simple query.
  • Version 2.2 allows individual configuration by the registered user, e.g. which properties of a substance and which substance types are to be listed in the G-SRS views.
  • With version 2.2, G-SRS has become more modular and more extendable than previously, which also should make interfacing and synchronization with other substance databases easier.
  • For the production versions, from now on FDA will only support UNIX-based platforms, however. But Windows-based systems will be available for test and/or development environments.
    At the same time, interested parties, that would be interested to develop and maintain a Windows-based G-SRS are welcome and should contact FDA’s GINAS team.
G-SRS API Example
Figure 1: G-SRS API: Example Download of substance details in JSON format. The URL <uri>https://ginas.ncats.nih.gov/ginas/app/api/v1/substances?view=full</uri> retrieves the full data of the first ten substances as a single JSON file.

The following figure shows a screenshot of FDA’s internal G-SRS system, that links information about the product, its registrations and the substance information in a common interface.

FDA Internal G-SRS API
Figure 2: FDA’s internal G-SRS System, where product registration information is linked to IDMP substance information ([1])

An updated G-SRS data set will be available end of July.

For versions 2.3ff. FDA now plans to address the following topics [1]:

  • Inclusion of Orphan Drug Application Codes, indications and other product-related information
  • Develop modules for Specified Substance Groups 2-4
  • Start entering Specified Substance Group 1[7] information
  • Continue to develop better forms and presentation of data
  • Expand quality (impurities) and pharmacology (targets, metabolite, cyp and transporter information)
  • Deploy full instances with all public data at Open FDA and NLM
  • Establish mechanism for system-system communication
  • Integrate G-SRS into a clinical trial registry system (C-DISC)

European Activities around SMS and EU-SRS

The following activities concerning the SMS, G-SRS, GINAS, EU-SRS Current Status are carried out in Europe:

Substance Pilots to assess the validity of Article 57 substances and carry out mappings to G-SRS:

In Europe with the (IDMP-non-compliant) substance information being available in Article 57 database, there is first-of-all the need to map these information into the IDMP data model, to clean-up the data and then to match it against the G-SRS system.

The following figure shows how the EMA team led by Dr. Herman Diederik (Medicines Evaluation Board, Amsterdam, Netherlands) is carrying out this challenging task:

Substance Mapping XEVMPD to G-SRS
Figure 3: Substance mapping from xEVMPD/ Article 57 to G-SRS ([1])

Business Case and Implementation of a European Substance Registration System (EU-SRS)

The business case that was presented to the 92nd Heads of Medicines Agencies (HMA) (19 – 21 June 2018, Sofia, Bulgaria) describes why an IDMP-compliant Substance Management System is regarded indispensable for a successful implementation of SPOR, the European Framework for IDMP. Without unique identification and reliable characterization of substances used in product compositions, extensive additional efforts will be continuously be spent to check, correct and communicate substance data provided by industry to regulatory agencies.

The data lists that are used today for the selection of the substances and/or the declaration of strength for product composition in electronic Application Form (eAF), as currently provided by EUTCT / EudraVigilance are highly error-prone and not unambiguous.

At last, the HMA meeting endorsed the business case which now allows to start the EU-SRS project.

The Dutch Medicines Evaluation Board will lead the implementation of EU-SRS.

European Substances Validation Group (SVG)

The HMA meeting also endorsed the establishment of the European Substances Validation Group (SVG), which will assemble European (NCA/EMA) substance experts that will govern the contents and enable Europe-wide use of substance information, and it also endorsed the full cleansing of the current substances list to a baseline of quality that supports the required processes.

The role of SMS vs. EU-SRS

The Substance Management Service (SMS) within SPOR will be the “substance list” that is to be used when substances are to be selected for an electronic submission. It will hold a key set of fields on substances for use in related regulatory use cases (SPOR). In contrast to SMS, EU-SRS will support unique identification of substances using a more extensive data model, validation rules as well as validated content. EU-SRS will generate the final identifier to the substance and will distribute this to SMS for use in regulatory processes.

EU-SRS will also be the primary tool for the SVG and will enable alignment and synchronization with the FDA substance system (G-SRS) to allow for maximal re-use of already characterized substances. [2]

Conclusion and Outlook to the SMS, G-SRS, GINAS, EU-SRS Current Status

In the first half year of 2018 there has been significant progress in IDMP substance management activities around the globe:

The IDMP standard and implementation guidelines for Substances 11238 and 19844 are in process of being published by the International Standards Organisation (ISO), FDA has made some significant achievements in the implementation of their G-SRS system and EMA has now finally endorsed a project to establish Europe’s first IDMP-compatible Substance Management System (EU-SRS).

The implementation of EU-SRS will last probably one year or more, but will ultimately lead to a better and more effective regulatory decision making in the Network, from which patients, regulators and industry will profit.

References:

[1]  Overview of ISO IDMP, Substances and HL7 Patient Care WG (allergy-intolerance)
Joint HL7 Biomedical Research & Regulation WG and Patient Care WG Meeting, May 10, Madrid, Spain
Panagiotis Telonis (EMA), Christian Hay (ISO/GS1), Herman Diederik (EMA/CBG),
Larry Callahan (FDA), Frank Switzer (FDA), Tyler Peryea (NCATS/NIH), Noel Southall
(NCATS/NIH). Link: http://wiki.hl7.org/images/2/2d/PT_CH_LC_HD_IDMP_HL7_Joint_BRR-PC_May_2017.pdf [2]  Business case for implementation of EU-SRS – IDMP compliant substance management.
92nd Meeting of Heads of Medicines Agencies (HMA) (19 – 21 June 2018, Sofia, Bulgaria)

Abbreviations:

[1] GINAS is the project name of FDA’s substance database project and stood originally for “Global Ingredient Archiving System”. The system’s name name has been changed in the meantime into G-SRS, “Global Substance Registration System”, but the old project name is still in use.

[2] FDA: Food and Drug Administration

[3] NCATS: National Center for Advancing Translational Sciences

[4] IDMP: ISO Standard for the Identification of Medicinal Products

[5] RESTful: The REST (“Representational State Transfer”) architecture has been defined to allow “stateless” machine-to-machine communication between clients and web-based applications. “Stateless” means that all information that is needed to conclude the API request must be contained in the url (“uniform resource locator”) string. Methods like “GET”, “PUT”, “POST” etc. are provided by G-SRS for that purpose. The web application therefore does only need minimum access rights management and no further session management due to its stateless character.

[6] API: Application Program Interface – Set of functions for communication and data exchange with the G-SRS database

[7] IDMP Group 1 Specified Substances are multiple substance materials (Coatings, Colorants, Flavorants); Physical Form; Extracts

Dieter Schlaps, ITCLS

How FDA intends to introduce IDMP through the backdoor

How will FDA introduce IDMP?

FDA proposes structured data for the CMC Module 3 of the eCTD standard

(Blog content by our partner Dieter Schlaps)

A few days ago, FDA has circulated a remarkable document for commenting, entitled “Pharmaceutical Quality/Chemistry Manufacturing and Controls (PQ/CMC) Data Elements and Terminologies”[1]. The document is the result of a study, in which FDA exploits the extensive use of structured data to describe the chemical, manufacturing and quality aspects of a drug product/ drug substance as it is described (currently only in text) in the Quality module 3 of the Common Technical Document (CTD).

news ectd fda
FDA-2017-N-2166-0002.pdf

The FDA project team identified and prioritized pharmaceutical quality/chemistry, manufacturing and controls (PQ/CMC) information that would benefit from a structured submission approach. This information would be submitted in the Common Technical Document as defined by the International Council for Harmonisation’s (ICH) Common Technical Document (CTD)[6].

The goals of this project were:

  • identifying pieces of PQ/CMC information that are already available in product applications, that are important for the evaluation of an application, and are “common denominators” across the various application types,
  • recommending standardized categories and data types necessary for application review. In this, the substance and product identifiers as described by the International Organization of Standardization for the Identification of Medicinal Products (ISO IDMP) standards are key.
  • The project team consisted of Subject Matter Experts (SMEs) from the Center for Drug Evaluation and Research (CDER), the Center for Veterinary Medicine (CVM), and the Center for Biologics Evaluation and Research (CBER).

The circulated draft document provides a first set of key data elements and terminologies associated with PQ/CMC subject areas and scoped to some of what is currently submitted in Module 3 of the electronic Common Technical Document (eCTD)2 submission. The set is not comprehensive and does therefore not cover all eCTD product quality information, as there are currently only limited existing data standards and terminologies for PQ/CMC data.

Benefits for the Submission Review

It is expected that with the submission of structured data in a standardized format, the efficiency of FDA’s review of PQ/CMC data contained in the Module 3 of eCTD submissions shall be increased significantly.

Not only the New Drug Application (NDA) would be impacted, but also:

  • Investigational New Drug Application (IND),
  • Biologics License Application (BLA),
  • Abbreviated New Drug Application (ANDA),
  • New Animal Drug Application (NADA),
  • Abbreviated New Animal Drug Application (ANADA),
  • Investigational New Animal Drug (INAD),
  • Generic Investigational New Animal Drugs (JINADs),
  • and Master File (MF).

Proposal of a structured representation of the CMC Quality eCTD Module 3

The draft document is structured in three sections:

  • Section 1 introduces the PQ/CMC information elements to be included as structured data.
    The information elements are arranged in CMC domains as “Specification”, “Quality Control”, “Batch Information” etc.
  • Section 2 described which controlled terminology is to be used for the information elements from section 1.
  • Section 3 contains a glossary of the terms used.

Whereas some information elements are to be represented as text fields still, others are drawn from established sources like the NCI Thesaurus (Field “Container Type”), CAS[1] or INN[2], and some already make use of identifiers in the same way as IDMP does, e.g.

  • Substances – to be coded according to the Unique Ingredient Identifier (UNII), currently used in the FDA’s Substance Registration System (SRS) which is going to be replaced by IDMP-compliant Global Substance Registration System (G-SRS),
  • Manufacturer and testing sites – to be coded according to the Data Universal Numbering System (DUNS), which is said to be the primary system for Marketing Authorisation Holders and Drug Manufacturers Identifiers for the US implementation of IDMP,
  • Units and measures – to be coded based on the SPL Units of Measure (UoM) list, which is a subset of the Unified Code for Units of Measure (UCUM) values
  • Other data fields are to be coded based on HL7 SPL controlled vocabularies, e.g. for “Closure Type”, “Container Type”, and “Dosage Form”. As HL7/SPL has been used in the ISO IDMP implementation guidelines it is very likely that these will also be the controlled vocabularies for the US implementation of IDMP.

Conclusion and Outlook

Both EMA as well as FDA obviously have chosen a pragmatic approach to introduce the IDMP concepts and identifiers – either already existing or being introduced identifiers – into (upcoming) electronic submission standards:

  • In Europe, where EMA has just rolled out the Organisations and Referentials Management Systems (OMS resp. RMS) of SPOR[3][3], the organisation identifiers and some of the controlled vocabularies are already integrated into a next version of the Electronic Application Form (eAF), replacing some of the text fields by codes from OMS and RMS.
  • In the US, where G-SRS will be released with a new version this fall potentially serving as the basis for the first New and Specified Substance Submissions by Industry, more and more sections of the submission dossier will be augmented by structured data.

In the long run, this will lead to a situation, where dossier documents will be increasingly replaced by structured information, and where “dossier submissions/ variations” will be replaced by much more efficient and painless online database updates.

 

References:

[1] Pharmaceutical Quality/ Chemistry Manufacturing and Controls (PQ/CMC) Data Elements and Terminologies, círculated by the FDA in August 2017 for annotation and review [2] Dieter Schlaps: Identification of Medicinal Products (IDMP) Standards Part 1: Impact on the Regulatory World, Regulatory Affairs Professional Society, December 21, 2016 [3] Dieter Schlaps: Identification of Medicinal Products (IDMP) Standards Part 2: The Implementation Roadmap, Regulatory Affairs Professional Society, February 28, 2017 [4] Dieter Schlaps: Identification of Medicinal Products (IDMP) Standards Part 3: Steps to Prepare for IDMP implementation, Regulatory Affairs Professional Society, April 26, 2017 [5] Dieter Schlaps: Identification of Medicinal Products (IDMP) Standards Part 4: Technical Approaches to IDMP, Regulatory Affairs Professional Society, June 10, 2017 [6] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH):
The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality – M4Q(R1). Quality Overall Summary of Module 2. Module 3 : Quality, September 12, 2002

 

 

 

[1] Chemical Abstracts Service

[2] International Non-Proprietary Name

[3][3] SPOR: Substances, Products, Organisations and Referentials, the four pillars of the European IDMP implementation