Pharmaceutical Medicine (2020) 34:381–386

https://doi.org/10.1007/s40290-020-00364-7

CURRENT OPINION

Current Challenges in Labelling for Generic Medicinal Products:

Company Core Data Sheet (CCDS) Development and Maintenance
Marion Mueller1 · David J. Lewis2,3 · V. Kishore K. Darisi4 · Sebastian Horn5

Accepted: 24 October 2020 / Published online: 8 December 2020

© The Author(s) 2020

Abstract
Labelling of pharmaceutical products plays a vital role in the safe and effective use of approved medicinal products. This
information may be provided to end-users including patients and/or prescribers, and it needs to be made available in multi-
ple formats including printed forms (patient information leaflets, pack inserts, etc.) or web portals of the product, based on
national authority guidelines. The Company Core Data Sheet (CCDS) serves as a key document representing the pharma-
ceutical company’s position on the product and is used as a reference document for national labels. Content from national
labels may differ from the CCDS for different reasons including implementation of national authority requirements in the
serving market and findings from local markets. In the current article, we discuss the process, challenges and key concepts
in creating and maintaining CCDS documents for generic products. We highlight key parameters that are worthy of process
improvement in generic products’ CCDS updates. In addition, we argue that labelling harmonisation across multiple regions,
especially safety section-related information, plays a key role in promoting end-user safety and would help communicate risks.
We also strongly believe that the topic is worthy of the International Council for Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use (ICH) consideration, and propose that this is the key area that requires standardisation
and harmonisation.

Key Points

The Company Core Data Sheet (CCDS) serves as a key

document representing the pharmaceutical company’s
position on a generic medicinal product.
Some challenges in the generic labelling processes are
highlighted, including common procedures and opinions.
Opportunities for improvement are discussed, including
* Marion Mueller
labelling harmonisation and IT solutions.
Marion.mueller@novartis.com
1
Manager Safety Risk Management, Global Drug
Development, Novartis Pharma GmbH, Holzkirchen,
Germany
2
Chief Medical Office and Patient Safety, Global Drug 1 Background
Development, Novartis Pharma GmbH, Wehr, Germany
3
Department of Pharmacy, Pharmacology and Postgraduate Labelling of a pharmaceutical product plays a vital role in
Medicine, University of Hertfordshire, Hatfield AL10 9AB,
Hertfordshire, UK the safe and effective use of that product. Such informa-
4
tion must be provided to end-users, including consumers
Safety Labeling Manager CDS&SD, Global Drug
Development, Novartis Healthcare, Hyderabad, India and prescribers, for decision making on the usage of the
5
pharmaceutical product, and must be available in multiple
Global Drug Development, Head Patient Safety Generics,
Novartis Pharma GmbH, Holzkirchen, Germany formats (online and print format) based on the region [e.g.

Vol.:(0123456789)
382 M. Mueller et al.

USPI (United States Prescribing information) for prescribers on originator labels as they did not own complete infor-
and PIL (patient information leaflet) for consumers]. mation about the product and it is difficult to provide jus-
It is the responsibility of the marketing authorisation tification for label updates as they did not own complete
holders (MAHs) to manage labelling of documents based on information.
relevant national authority requirements and health authority The process becomes especially difficult when the origi-
recommendations in the regulatory market. nator updates the labels with their internal safety and clinical
The Company Core Data Sheet (CCDS) is a master label- data, which is not publicly available at the time of update.
ling document maintained at a central level by the MAH to The complexity of harmonising safety information starts
represent the company’s position on the product, and from with the evaluation of multiple aspects as described below.
which local/national labels will be prepared.
Pharmaceutical products are classified into originator 3.1 Identification of Right Originator Label
products and generic products. Originator products are
medications that were first authorised worldwide based on Since originators may market their products in multiple
clinical efficacy and safety studies. Generic products are countries, it becomes difficult for generic pharmaceutical
composed of the same qualitative and quantitative active companies to consider which national label is available in
substances as a reference molecule and are registered based the public domain to consider for CCDS update. Labels that
on bioavailability and bioequivalence studies. Typically, are publicly available might have been prepared based on
there will be no other additional clinical studies for generic national authority recommendations, which may not ide-
products. ally represent the originator company’s position. In these
Generic product labels are prepared based, broadly, on instances, generic pharmaceutical companies use multiple
content from their reference products and additional infor- major labels to compare information and to establish the
mation from health authorities is also considered. company’s position in the CCDS.

3.2 Lack of Harmonised Label Structure

2 Current Approach for Generic CCDS
Updates Currently, there is no defined harmonised template/structure
for CCDS. Major pharmaceutical companies prepare their
In general, CCDS preparation starts when the product’s Mar- CCDS templates adapting from major labels like USPI or
keting Authorisation is granted, and is prepared by generic SmPC (Summary of Product Characteristics) style whereas
companies based on the reference product, followed by some pharmaceutical companies create either a hybrid
updates, which are usually triggered by sources such as: model or novel stand-alone model based on their internal
decisions.
• Recommendations from health authorities Since there are no common guidelines for CCDS, their
• Changes in originator label structure is dependent on the pharmaceutical company’s
• Product updates from internal resources (quantitative and discretion [1]. Consequently, differently structured local
qualitative findings from internal databases) labels can serve as a reference for signal evaluation or label
updates. Comparing these documents, finding new safety-
As soon as signals are identified and classified for a prod- relevant information, and transferring this information into
uct, they will be further evaluated to judge whether or not a CCDS is time-consuming and marginally supported by
the information qualifies for updating the CCDS. The MAH comparison applications. Fundamentally, it can be debated
performs a medical evaluation to establish a relationship whether any of the templates are appropriate to maintain
between the use of the product and the conditions that were safety information.
noted, and it evaluates other factors that could be attributed
to the signal. 3.3 Differences in Procedures

The process and conventions for updating the CCDS dif-

3 Current Challenges in CCDS Update fer between pharmaceutical companies, as no harmonised
guideline/structure needs to be followed and companies also
Currently, pharmaceutical companies prepare/update their follow their convention when updating the CCDS.
generic product CCDS documents with alignment of origi- Usually, the effort involved in updating generic CCDS
nator product labels that are publicly available on Health is not comparable with originator product label updates.
Authority websites. Generic product companies face diffi- Significant effort is required to update labels; such updates
culty in providing justification for the changes made based are dependent on internal data, which can be ‘owned’ by
Current Challenges in Labelling for Generic Medicinal Products 383

multiple functions across the organisation. For originator be differences in opinion while adapting such information
label updates, cross-functional teams are required for label based on the company’s internal assessment and based on
updates and the process will be treated as a shared effort; the availability of background data that were considered for
for example, the preclinical safety team provides updates label updates.
from animal studies and the pharmacokinetic department
provides updates on product pharmacokinetic parameters
3.5 Conversion of Information between Different
from advanced studies or other resources. The major differ-
Formats
ence between originator and generic labels are the sources
of information that are used to update labels. In general,
The structure of the label and the process of updating safety
originator companies have more data than the generic com-
information affects the evaluation of that information.
panies, as they have access to more data from preclinical
A comparison of the structure of the EU SmPC and the
and clinical studies, which provides sound scientific justifi-
US PI demonstrates the complexity involved in uniting infor-
cation for adaptation. Consequently, within a generic label
mation derived from two major markets (see Table 1). Some
health authority recommendations can be implemented, even
sections directly lead to another, while other sections are
though an originator label might have been adapted to inter-
not represented in both documents or have separate titles.
nal clinical study results that are not available to the public
Therefore, it must be carefully evaluated if the content is
or competitors. Even if both generic and originator compa-
covered or if it is expressed differently.
nies plan to implement changes according to health authority
recommendations, it is possible that, based on differences in
processing the variations, the generic label is available more 3.6 Class Effects
quickly than the originator label.
As a result, health authorities do not normally accept that A recent example demonstrates the medical evaluation com-
the generic MAH copies the safety-relevant sections from plexity in the risk of severe cutaneous adverse reactions
the referenced originator product label. The MAH must (SCARs) associated with the use of beta-lactam antibiot-
ensure that the product information is up-to-date based on ics. In September 2018, the Canadian regulatory authority
current scientific knowledge, including assessments and (Health Canada) issued a recommendation, aimed at har-
recommendations made public via the European medicines monising all beta-lactam labelling by implementing con-
web-portal [2]. sistent terms for SCAR in all relevant beta-lactam labels
The non-availability of decision-making documents cre- [3]. Although the authorities provide supporting publica-
ates additional efforts for generic companies for considering tions, these scientific papers described only the suspicion
the changes made by originator companies and sometimes of an association and did not establish a causal relationship
it is difficult to justify the changes, especially if the changes between SCAR and all beta-lactams. This is not an issue for
are done based on the originator company’s internal data. the two countries specified, as MAHs in both are obliged to
follow the recommendations. However, implementation in
3.4 Differences in Opinion the CCDS should be based on a solid foundation of clinical
evidence if the company Core Safety Information is to be
The majority of the information in the labels is adapted from credible as the basis for regulatory safety variations. Justi-
originator labels by generic companies; however, there might fication documents prepared by MAHs must be acceptable

Table 1  Comparison of Section in EU-SmPC Section in USPI

EU Summary of Product
Characteristics (SmPC) and US 4.3. Contraindications 4. Contraindications
Prescribing Information (USPI)
4.4. Special warnings and precautions for use 5. Warnings and precaution
4.5. Interactions 7. Drug interactions
4.6. Pregnancy and lactation 8. Use in specific popula-
tion
8.1. Pregnancy
8.2. Lactation
8.3. Females and males
reproductive potential
4.7. Effects on ability to drive and use machines 5. Warnings and precaution
Undesirable effects 6. Adverse reactions
Overdose 10. Overdosage
384 M. Mueller et al.

for each respective market where a generics company has during inspections, as failure or delays in the submission of
approval. safety variations can affect patient safety.
The following is a scenario, where the situation was It should be kept in mind that the CCDS is a document for
complex and difficult to manage. The originator products use by MAHs that does not require approval by any author-
(and their respective labels) for a large number of registered ity. However, the national labels require approval from the
beta-lactams were nearly all taken off the market. Evalu- responsible authorities.
ation of in-house investigations including broad literature In case of non-acceptance (i.e. deficiency letter to the
research for published evidence resulted in a high workload MAH), the national labels must undergo an internal review
as the medical concept (SCAR) includes about 50 Preferred process often requiring additional investigations and evalu-
Terms within the Medical Dictionary for Regulatory Activi- ation (e.g. literature review, medical evaluation of line list-
ties (MedDRA) terminology (MedDRA Preferred Terms). ings, etc.). Depending on the complexity of the authority’s
The application of this broad medical concept across a large comments, this evaluation can be very time-consuming.
group of active ingredients made it especially clear that from In case of acceptance, new information must be included
the perspective of the global labelling group there was a in the Marketing Authorisation (product license) and
rapid and significant increase in workload to maintain the throughout the production system, resulting in the inclusion
CCDS documents for products containing beta-lactams. of up-to-date printed material in package leaflets and other
As a result, harmonising the labels for a substance class publishing material.
company-internal is nearly impossible when the reference Altogether, it can take several months before newly
labels are different, outdated or not applicable. Even though detected information finally reaches the patient. There are
additional internal signal detection could provide evidence also technical aspects (e.g. ‘just-in-time’ manufacturing pro-
for a harmonised update in terms of a company position, it cesses) that are not described in this article but may impact
is not guaranteed that this can be implemented on a national the labelling process.
level.

3.7 The Company Position 4 Opportunities for Improvement

The content within a nationally approved label for generic 4.1 Information Technology
products is generally reliant on two primary sources. First,
the company’s position on the safety profile of the product, In the area of generic safety labelling, the use of advanced
which should be backed by supporting data and would typi- methods like digital systems is not yet widely established
cally be described in a CCDS. Second, there is a depend- and it is the key area where health authorities or pharma-
ency on the nationally approved text, which is governed by ceutical companies must be focused. The need to establish
the health authority, which may differ from the company’s a comprehensive solution to improve the maintenance of
description in the CCDS. Such content differences may arise CCDSs was identified by the European Medicines Agency
for a variety of reasons, including differing medical prac- (EMA). Unfortunately, the initiation to develop suitable
tices, ethnic or patient variability, availability of competitor technology was not successful [EMA’s Product Information
products, or differences in opinion between health authori- Management (PIM)] [7].
ties and the MAH [4]. Hock et al. [8] proposed the use of new technologies to
Therefore, the CCDS for bioequivalent drugs often dif- support the maintenance of the CCDS using XML-Author-
fer. Concerns about the safety of generics are not limited to ing. The CCDS is viewed as a data container (or database)
patients but extend to other stakeholders including physi- that holds the textual content of the label in a highly struc-
cians and pharmacists [5]. Physicians are aware of differ- tured, hierarchical manner and provides the possibility
ences in perception and regulators consider new strategies to store information beyond the written text (attributes)
for harmonising bioequivalent labels [6]. related to each module of the hierarchy (e.g. pharmaceuti-
cal form, route of administration, core/non-core informa-
3.8 Compliance tion). The tracking system includes medical and regulatory
assessments for all information collected and collated by
The basic goal of continuous label maintenance is to make the MAH. National labelling documents are derived from
sure that the product updates will swiftly reach end users for the CCDS and reflect the national requirements in terms of
better decision making on product use. However, safety data structure and wording [8].
management and management of reference safety informa- The approach of maintaining a virtual CCDS within a
tion is a common area of non-compliance for many compa- database, instead of updating single CCDS documents is a
nies. Health authorities usually focus more closely on this promising concept and might gain support from IT vendors.
Current Challenges in Labelling for Generic Medicinal Products 385

Technically, it would be possible to extract information Not all health authorities have the resources to review
according to the intended purpose. An IT solution, such as changes to the national label of each licensed product based
the one proposed, could offer customisation according to the on the CCDS that the MAH has submitted for approval.
MAH’s structure and requirements. The system could enable In different regions and countries, some health authorities
the automated creation of different text documents (or just in require the MAH to base their national label on an approved
terms of reusable modules) and reduce administrative work label in a “major market”. Often, health authorities only
globally and locally (e.g. text formatting), whilst increas- approve variations to the label when there is evidence that
ing document compliance. Finally, the accelerated creation the reference market health authority has already approved
of CCDS updates via a repository for safety information them. This practice is prevalent in many emerging markets
would offer: and can be considered a form of labelling harmonisation
[4]. Within the EU, participation in specific registration
• Expedited communication between global and national procedures [i.e. mutual recognition procedure (MRP), cen-
stakeholders tralised approval procedure (CAP), decentralised approval
• Improved approval procedures procedure (DCP)] across many countries is a further step to
• Distributed safety information quicker to patients and harmonisation within an emerging market. However, label-
healthcare professionals (HCPs). ling harmonisation across regions, particularly safety-related
information, represents a key factor in promoting patient
Depending on the structure and workflows within a com- safety, risk communication, and risk minimisation measures;
pany, this approach might also serve as a basis for a “One hence, it is an important topic for consideration in the future.
Product Safety Master File” as described by Furlan [9]. The
authors describe overlapping and redundant information in 4.3 Interchangeability
multiple safety documents including Periodic Safety Update
Reports (PSURs) and Development Safety Update Reports Data publishing/exchanging is one of the key things that
(DSURs), Risk Management Plans (RMPs) and Signal pharmaceutical companies/health authorities should con-
Detection Reports [9]. A database collecting safety infor- sider while updating labelling documents. The PSUR work-
mation from various pharmacovigilance departments could sharing scheme that was adopted within the European Eco-
also provide approved documents for many other objectives nomic Area (EEA), as well as the PSUR synchronisation
such as the scope of case processing and preparation of edu- project, resulted in a reduction of administrative burden
cational material. [10]. We hope that regulators will also consider the aspect
The major objective would be the elimination of manual of harmonisation of labels as an essential topic to improve
processes and to make content re-usable, instead of copy- public health.
ing and pasting the content into various formats that conse-
quently leads to redundant work.
It must determine what IT solution would best fit a 5 Conclusion
generic approach. The value of an IT solution would be that
it could provide a full package of creation, maintenance, The challenges in the field of CCDS maintenance process
tracking, and approval features, as well as a complete audit for generic medicines are complex and an end-to-end solu-
trail of changes and derivatives. These approaches could tion covering all aspects will be promising. The authors
start with CCDS maintenance and even bring informa- believe that the creation of data exchange platforms creates
tion to consumers and prescribers in terms of e-labelling a widely accepted solution to address challenges in CCDS
approaches. maintenance and to create high-quality documents across the
However, the benefits in terms of cost effectiveness and industry that improves patient health. In addition, authors
time savings need to be evaluated carefully. Consideration believe that there is a huge need for a harmonised process for
must be given to the fact that, although changes can be easily label updates across the industry and clear guidance needs
implemented, that data entry into a complex IT system and to be provided for pharmaceutical companies in maintaining
associated approval steps might impact time expenditure. CCDS updates.
Approaches by MAH might include reduction of admin-
4.2 Harmonisation of Labelling istrative and bureaucratic workload by referring to new IT
solutions and on other hand support the companies in focus-
The creation of a common template and a detailed guide- ing on medical and scientific evaluation of the available evi-
line would be beneficial for the MAHs when creating/updat- dence. Although some IT solutions seem to be very promis-
ing respective documents but also for the health authority ing, the main limiting factor might be budget availability.
inspectors. However, the benefits and risks of public health, litigation
386 M. Mueller et al.

and reputation of outdated reference safety information far Commons licence, unless indicated otherwise in a credit line to the
outweigh any financial risks/factors. material. If material is not included in the article’s Creative Commons
licence and your intended use is not permitted by statutory regula-
The conclusion is that there are many alternatives to the tion or exceeds the permitted use, you will need to obtain permission
status quo. Not all of the proposed solutions have been or directly from the copyright holder. To view a copy of this licence, visit
will be successful; some of them may not be applicable, http://creativecommons.org/licenses/by-nc/4.0/.
others are over-ambitious or are practically unaffordable
for a generic company. However, some methods are prag-
matic and have a strong possibility as the operating model of References
choice. The aim of MAHs should be to work more efficiently
to maintain harmonisation, and up-to-date labels for generic 1. Agency EM. How to prepare and review a summary of product
characteristics. 2019. https:​ //www.ema.europa​ .eu/en/human-​ regul​
substances, to support generic substitution and facilitate atory​/marke​ting-author​ isat​ion/produ​ct-infor​matio​n/how-prepa​re-
choices made by prescribers and patients alike. revie​w-summa​ry-produ​ct-chara​cteri​stics​. Accessed 17 Mar 2020.
2. European Union Pharmacovigilance Legislation. Directive
Acknowledgements We thank Julie Gabriel for her careful reading of 2001/83/EC of the European Parliament and of the Council.
our manuscript and her many insightful comments and suggestions. 2001. https:​ //www.ema.europa​ .eu/en/docume​ nts/regula​ tory-​ proce​
dural​-guide​line/direc​tive-2001/83/ec-europ​ean-parli​ament​-counc​
il-6-novem​ber-2001-commu​nity-code-relat​ing-medic​inal-produ​
Declarations cts-human​-use_en.pdf. Accessed 15 Nov 2019.
3. Health Canada. Summary Safety Review—Beta-lactam antibi-
Funding This article was not funded. otics—Assessing the potential risk of severe skin side effects.
2018. https​://www.canad​a.ca/en/healt​h-canad​a/servi​ces/drugs​
Conflict of interest The authors work for different departments of a -health​ -produc​ ts/medef​f ect-canada​ /health​ -produc​ t-infowa​ tch/healt​
pharmaceutical company undertaking work related to the content of h-produ​ct-infow​atch-octob​er-2018.html. Accessed 24 Oct 2018.
the article. 4. Yoshida S, Matsui R, Kikuchi C. What drives adoption of
national labels as global reference labels? A case study with
Ethics approval Not applicable. the JPI. Ther Innov Regul Sci. 2018;52(6):724–30. https​://doi.
org/10.1177/21684​79018​75508​4.
Consent to participate Not applicable. 5. Dunne SS, Dunne CP. What do people really think of generic
medicines? A systematic review and critical appraisal of liter-
Consent for publication Not applicable. ature on stakeholder perceptions of generic drugs. BMC Med.
2015;13:173. https​://doi.org/10.1186/s1291​6-015-0415-3.
Data availability Not applicable. 6. Duke J, Friedlin J, Li X. Consistency in the safety labeling of
bioequivalent medications. Pharmacoepidemiol Drug Saf.
Code availability Not applicable. 2013;22(3):294–301. https​://doi.org/10.1002/pds.3351.
7. European Medicines Agency. European Medicines Agency closes
Author contributions MM conceived of the presented idea. MM, KKD PIM project. 2011. https:​ //www.ema.europa​ .eu/en/news/europe​ an-
collected the data and prepared the article. SH and DJL supervised and medic​ines-agenc​y-close​s-pim-proje​ct. Accessed 04 May 2019.
reviewed this work. All authors discussed the information in the article 8. Hock S. The company core data sheet in light of XML-authoring
and contributed to the final manuscript. and IDMP master data implementation. Ther Innov Regul Sci.
2017;51(3):342–51. https​://doi.org/10.1177/21684​79016​68025​5.
9. Furlan G. Using resources for scientific-driven pharmacovigi-
Open Access This article is licensed under a Creative Commons Attri- lance: from many product safety documents to one product
bution-NonCommercial 4.0 International License, which permits any safety master file. Drug Saf. 2012;35(8):615–22. https​://doi.
non-commercial use, sharing, adaptation, distribution and reproduction org/10.2165/11631​290-00000​0000-00000​.
in any medium or format, as long as you give appropriate credit to the 10. European Medicines Agency and Heads of Medicines Agencies.
original author(s) and the source, provide a link to the Creative Com- PSUR Work Sharing and Synchronisation Project. 2002. https​://
mons licence, and indicate if changes were made. The images or other www.hma.eu/348.html. Accessed 15 Nov 2019.
third party material in this article are included in the article’s Creative