May 8, 2013 | By Márcio Barra
Regulatory week continues at full steam, today with a short article detailing the CTD, and some of the differences between a standard CTD and a CTD of a generic drug. As always, please share this if you enjoy it!
The Common Technical Document
A CTD, or Common Technical Document, is a document that contains all the efficacy, safety and quality information of a pharmaceutical drug product for which a MAA is intended.
The CTD was created by the ICH in 1996, under the multidisciplinary guideline M4, and was launched in 2003 (1). The CTD is a document comprised of four modules for quality, non-clinical and clinical information, plus one regional module specific for each region. It applies to all types of drug products and all kinds of applications. The introduction of the CTD was a big step in harmonizing submission procedures, as it made the exchange of information among drug regulatory authorities in the U.S., Japan and Europe easier. It’s no coincidence that, since 2003, both EMA and the FDA have had confidentiality agreements in place, where both entities can exchange confidential information as part of their regulatory and scientific process(2).
The arrival of the CTD (and more recently, its electronic substitute, the eCTD (3)) helped these communications, as both agencies receive the submissions for a new drug in the same standardized format. As for the industry, the CTD has eliminated the need to reformat the information for submission to the different ICH regulatory authorities.
By providing a common organization for the contents of a marketing or licensing application, the CTD has led to almost complete harmonization in marketing authorization application in the three regions. The implementation of the CTD standard format also extended ICH’s harmonization to non-ICH countries, thus playing an important part in normalizing regulatory processes and promoting a faster access to new drugs in these countries.(4)
A recent development in the CTD format was the introduction of the eCTD format, and electronic version of the CTD. The eCTD is defined as an interface for industry to transfer between agencies of regulatory information, while at the same time taking into consideration the facilitation of the creation, review, lifecycle management and archival provided by the electronic format and submission (3).
Module 1 – Administrative and Prescribing Information
This module contains documents specific to each ICH region. Its content and format requirements can be specified by the relevant regulatory authorities.
Module 2 – Summaries
This Module should begin with a general introduction to the drug product, including its pharmacological class, mode of action and intended clinical use. Also, a summary of the quality, and a summary and overview of the nonclinical and clinical modules must also be included.
Module 3 – Quality
This section contains the pharmaceutical documentation and general information regarding the drug substance, its manufacturing process, characteristics, validation methods and excipients, among others.
Module 4 – Nonclinical Study Reports
The reports of the non-clinical studies, like pharmacology or toxicokinetics, conducted for the drug are included here.
Module 5 – Clinical Study Reports
All Clinical Study Reports for clinical trials conducted for the drug go in this module.
From the information provided above, it’s easy to see that a CTD for a new drug product is a very complete document, containing all the information pertaining to the drug product created in its development. A CTD for a generic product, on the other hand, due to the drug product being an identical version of the original drug, might not need so much information in its CTD. A CTD for a generic product contains the following modules, albeit with some key differences:
– Module 1
– Module 2
– Module 3
– Module 5
Looking at this short list, it seems that the only difference between a CTD for a standard MAA and one for a generic MAA is that the latter doesn’t have Module 4. Let’s look closely now at each module to see the differences.
In Module 1 of a CTD for a generic MAA, applicants (in the case of Europe) should provide in section 1.5.2 a concise document, no more than 5 pages, summarizing the grounds and evidence used for demonstrating that the medicinal product for which an application is submitted is a generic of a reference therapeutic product. This summary must include details on the generic drug product, the qualitative and quantitative composition in active substance, pharmaceutical form, bioequivalence information and its safety and efficacy profile in comparison to the reference medicinal product.
Module 2, like in a normal MAA, must include the Quality Overall Summary, Non-clinical Overview and Clinical Overview. The summaries of the non-clinical and clinical studies however, are only mandatory if new studies have been conducted for the generic drug.
As for the overviews, they should have a summary of impurities present in batches of the active substance, an evaluation of the bioequivalence studies conducted, new published information relevant to the active substance, and information on whether different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives than the ones found in the reference medicinal product were used, and, if so, details on their safety.
Module 3, the Quality Section of the CTD of a generic drug has to be filled and presented as described in ICH M4Q and WHO’s Guideline on submission of documentation for a multisource (generic) ﬁnished pharmaceutical product (FPP): quality part.
Module 4 doesn’t need to be included in a CTD for a generic drug, as non-clinical development of generic drugs is, for most cases, not warranted, since all relevant non-clinical information for the active substance of the drug product is already documented. Some exceptions may apply, of course, and in these cases these studies should be included.
Module 5, however, is included, seeing that most generic drug products market applications are supported by one or more pivotal comparative bioavailability studies, in order to assess their bioequivalence to the original drug product. Also, if different salts, esters, ethers, isomers, complexes or derivatives of the active substance of the reference medicinal product are used, information should be provided in this module detailing their safety.
Since no other clinical studies are required for generic drug products, this module is much shorter than the one for an original drug product(6).
Since the introduction of the CTD, the industry has made leaps and bounds in harmonizing the authorization procedures for a drug throughout the three ICH regions and more. The eCTD is the natural evolution of this document that further contributes to the harmonization efforts of the ICH. While in the surface, the differences between a CTD for a standard MAA and a generic MAA might not seem much, at closer inspection the differences are noteworthy, and the savvy regulatory affairs professional must be sure to take them into account.