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Topical, authoritative and business-critical coverage of pharmaceutical and medical device regulatory affairs

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ElEctronic SubmiSSionS

2 September 2015 www.scripregulatoryaffairs.com © Informa UK Ltd 2015

As international regulatory bodies continue to make great strides towards standardizing the format

and content of drug approval dossiers, pharmaceutical companies are coming under increasing pressure to improve the efficiency and quality of their regulatory operations and submission teams, particularly as any failure to comply can lead to costly penalties.

Pharmaceutical organizations must increasingly be able to manage simultaneous, multi-market product launches. Global, timely and complex submissions require thorough knowledge of all the prevailing regulatory requirements as well as streamlined internal processes ranging from document management through to mitigation of potential deadline delays. This all requires open communication between submission departments and all dossier content authors/stakeholders.

The industry has made great progress towards harmonizing these requirements. The adoption of standards like the common technical document (CTD), the electronic common technical document (eCTD), and non-eCTD electronic submissions (NeeS) has simplified and streamlined interactions between companies and regulators in many regions around the world including the EU, the US, Japan and Canada.

But more is needed, and companies will have to take action to comply with the evolving regulatory mandates, cope with higher volumes and manage the resources that are spread across multiple geographies.

Emerging Systems & ProcessesSuccessful compliance-driven companies are optimizing their processes, adopting standards and deploying technology solutions with the global market in mind. Electronic submissions (eSubs) are becoming a way of life, from both the regulatory and efficiency standpoints. While

eCTD software has transformed many of the previously manual processes, the emergence of new systems and processes requiring a new skillset means that technology alone is no longer enough.

In the US, the Food and Drug Administration has given applicants the option of submitting CTDs in an electronic format (eCTD) since 2003. This format not only provides an interface for industry-to-agency transfer of regulatory information, but also facilitates the creation, review, lifecycle management and archiving of the eSubs1.

In 2014, the FDA said that all regulatory submissions would have to be made electronically to facilitate a more effective review process and information sharing2. In May this year, the FDA released a final guidance on the submission document types detailed in Section 745A (a) of the Federal Food, Drug, and Cosmetic Act FD&C Act that would have to be submitted electronically – ie, certain investigational new drug applications (INDs); new drug applications (NDAs); abbreviated new drug applications (ANDAs); and certain biologics license applications (BLAs)3. In this guidance, the agency stated that industry would have until the first quarter of 2017 to implement a full transition to eCTD for all submission document types listed in Section 745A (a)4.

Compliance can be achieved by ensuring operational excellence through optimized processes, a thorough understanding of various global standards, and well-trained experts, ultimately resulting in timely approvals. As companies move to eSubs, the people who are involved in the work will require a different skillset than those who work with paper submissions.

Emerging required SkillsetsRegulatory submissions dossiers are not the sole creation of one single department within a pharmaceutical organization, but

are rather the end result and compilation of work done across multiple functional groups. These range from R&D and clinical teams through to submission specialists.

As with any project shared amongst a plethora of different stakeholders, the planning and outlining of responsibilities and processes has a direct correlation with the success of a product submission development. Regulatory operations executives and teams must recognize the importance of the department’s involvement in creating new and pivotal roles, skillsets and expertise in ensuring realistic expectations are established regarding team capabilities.

The documents specialist will need to have advanced technical expertise and experience with the following: virtual document (Vdocs) creation/submission/archiving (e.g., templates to create clinical study reports); document management systems (e.g., FirstDoc, ddms); publishing software (e.g., Insight Publisher, DocuBridge); and other software (e.g., TRSToolbox, OCR and file optimization, TRSWriter, MS Word including macros).

In addition, they will need in-depth knowledge of eCTD guidelines from the International Conference on Harmonisation and the content of common regulatory documents (CSRs, IBs, etc.) so that they can independently assess the quality and completeness of typical components (main body, appendices, attachments, etc.).

The eSub publisher will need to be skilled in creating electronically published reports, regulatory documents, and regulatory dossiers using a variety of software (MS Word, Adobe Acrobat Professional, AutopageX Adobe plug-in, Reference Manager, InSight Publisher, TRSToolBox, TRSWriter, eCTDXPress, eDMS, etc.). They will need to perform critical QA (quality assurance) compliance checking, formatting, hyperlinking, bookmarking and

Building An Innovative And Streamlined Approach To End-To-End Regulatory eSubmissionsOrganizations working in the pharmaceutical sector need to take action now to ensure that they have internal processes and systems in place that allow them to be compliant with rapidly evolving global regulatory requirements, particularly the growing use of electronic submissions by the major world regulators, says Darryl Clarke.





review of documents that results in the rendering of multiple documents to PDF. They will also require experience and knowledge of publishing of Modules 1-5 in eCTD format in order to provide component-level publishing and submission support to ensure conformance to e-submission standards utilizing electronic document management and publishing tools.

Finally, the submission manager will need to maintain effective interactions with all publishing and submission contributors, to ensure timely delivery of submission ready documents.

In addition to obtaining new skillsets, organizations will need to implement new processes.

The old paper submission process is depicted in Figure 1.

The new electronic submission process is depicted in Figure 2.

benefits and challenges of eSubmissionsThe standardization that eSubs has brought about will allow for much greater consistency not only for the FDA, but also for pharma organizations. Both parties will benefit by having all data in a common electronic environment, and it will also allow them to manage the documentation and oversee products more efficiently, eliminating the difficulties with accessing, searching through and finding data in paper format. Other benefits of a common global standard for eSubs include5:• enhancedabilitytoefficientlyorganize,

prepare and manage submission content;• reducedstoragecostsassociatedwith

producing and storing paper dossiers;• streamlinedworkflowsindevelopment,

regulatory and marketing departments while increasing collaboration between teams;

• streamlinedreviewprocessallowingformultiple reviewers and a more efficient review process; and

• reuseofdocumentsandsubmissioncomponents.

Despite these benefits, the compulsory switch to eCTD presents companies with several challenges. The costs, both in initial capital and annual expense of building, validating and operating an electronic publishing system, together with the training and administration required to develop organizational competency, present significant barriers to adoption. The effort required to establish and maintain an

in-house system can be considerable, and a team of people is typically required to document the requirements; research and evaluate options; procure, install, configure and test the system; and validate documentation and execute the full solution. Even though each organization’s implementation project plan is different, a typical timeframe to complete the required steps is estimated to be 9-18 months depending on the system size and configuration complexity.

A new Approach to eSubmissionsAs a result of growing submission needs and ever-changing regulatory requirements, successful organizations are developing new strategies and a proactive approach to eSubs. And these companies are increasingly looking to specialized

outsourcing vendors to oversee, manage and perform regulatory operations tasks as part of this approach. This can provide cost-effective and flexible means to manage the varying degree of regulatory submissions demands, such as expertise and knowledge, resource flexibility, additional capacity, process improvement and process standardization. Companies need to take a more rounded approach to the regulatory submission process through engaging earlier in the process and by setting up submission infrastructure capabilities with submission managers to align processes and timelines.

The future is electronic, seamless, interconnected and automated. A global regulatory best practice model not only reduces costs and increases efficiencies, but it also enhances an organization’s ability to

Paper output is quality

controlled (QC’d) and put

into binders

3 copiesof the paper

submission are sent to the RA

by courier

2 copies of thepaper submission

are sent toarchive

Approx. 2-4 weeks

after submission, sponsor receives

confirmation letterfrom RA that

submission was accepted

Documenttracking sheet

and contentis created

Contentis finalizedand sent to publisher

Publisheruses tracking

sheet to ensure that all submission

content was sent

Publisherimports all submission

content into paper publishing

software

5 copies ofthe submissionare published

(3 copies for regulatory authority (RA) and

2 for archiving)

Figure 1. Paper Submission Process

DS ensures allsubmission

internal links and bookmarks

are created

DS notifies publisher that submission is

ready to publish

Publisher uses tracking sheet to

QC vDoc and submission

content

Publisherimports

submissionvDoc into

publishingsoftware

Documenttracking sheet

and contentis created

Virtual document

(vDoc) build request sent to

document specalist (DS)

DS usestracking sheet

to createsubmission vDocs

and importssubmission

content

DS ensuresthat all

submission content is submission

ready

DS usestracking

sheet to ensureall submission

components arein the vDoc

Publisher performs all

publishing tasks (external links,

QC internallinks and

bookmarks)

Publisher publishes

submission

Final published output created

and QC’d

Finalsubmission

output is sent toRA via eSubmission

gateway orCD/DVD

Figure 2. Electronic Submission Process




respond to changes in the FDA final guidance. A best practice model can be customized for each project, taking into account the company’s requirements and the size of the project, and can offer enhanced productivity and quality through the use of innovative processes, people expertise, and technology.

Small ProjectsFor small projects, such as clinical study reports, advertising and promotional material submissions, small supplements and amendments (under 1,000 pages), a document specialist should be put in place to work directly with a team of content creators/authors to ensure that all pieces of the submission are created and finalized according to the required timelines and guidelines. The process for delivering the project should commence with the content creators/authors who are responsible for authoring, reviewing and approving all submission content. The initial content should be handed to the document specialist to oversee and facilitate all document control procedures, including:• formattingalldocuments;• ensuringdocumentsare"submissionready";

• creatingsubmissionvirtualdocuments(vDocs) and linking all submission components to vDocs;

• creatingasubmissiontrackingtooltoensure all components of the submission are processed and accounted for; and

• qualitycheckingthesubmissionoutput.

An optimized best practice electronic submission process flow for small projects is depicted in Figure 3.

medium to large ProjectsFor medium to large projects, which include INDs, NDAs, BLAs and Canadian

new drug submissions (NDSs), a submission management team should be added to this structure to liaise with the document specialist and the content creation team to ensure that all projects are completed and published successfully. Within the model, the submission management team should work with the document specialist to ensure that submissions are ready within the required timelines together with the management of the submission tracking tool on all major submissions.

In the final step of the process, the publisher will receive the final submission after a high-level quality review process, utilize the submission tracking tool to ensure that all components are accounted for, and publish the submission. The publisher will then work with the document specialist and content creation team to quality control the final published output. Once everything is checked and confirmed to be correct it can be transferred to the regulatory authority.

An optimized best practice electronic submission process flow for medium-to-large projects is depicted in Figure 4.

DS ensures all submission

internal links and bookmarks

are created

DS notifies publisher that submission is

ready to publish

Publisher uses tracking sheet to

QC vDoc and submission

content

Publisherimports

submissionvDoc into

publishingsoftware

Documenttracking sheetand vDoc buildrequest sent to

document specialist (DS)

DS usestracking

sheet to create submission vDoc

and imports submission

content

DS ensuresthat all

submission content is submission

ready

DS usestracking sheet

to ensure all submission

components arein the vDoc




bookmarks)

Publisher publishes

submission


and QC’d

Finalsubmission


gateway orCD/DVD

Figure 3. Small Projects Process

Document tracking sheet and vDoc build request sent to

document specialist (DS)

DS uses tracking sheet

to create submission vDoc

and imports submission

content

DS ensures that all

submission contentis submission

ready

DS uses tracking sheet

to ensure all submission

components are in the vDoc

Projectcoordinator (PC)

is notified of new project

PC workswith regulatoryaffairs projectmanagement

(RAPM) todetermine

project team

PC works withRAPM to create

project plan,timelines andtracking sheet

PC andRAPM have a

kick-off meetingwith project team

to go over responsibilities

and timelines

DS ensures all submission internal links

and bookmarks are created

DS notifies publisher that sumbission is

ready to publish

Publisher uses tracking sheet

to QC vDoc and submission

content

Publisher imports

submission vDoc into publishing

software




bookmarks)

Publisher publishes

submission


and QC’d

Finalsubmission


gateway orCD/DVD

Figure 4. Medium to Large Projects Process






SummaryThe adoption of the eCTD electronic submissions has simplified and streamlined interactions between companies and regulators.

While much progress has been made within the industry towards harmonizing requirements, in order to comply with the evolving regulatory mandates and manage the resources that are spread across multiple geographies, it is important that organizations urgently take the opportunity to change their model and how they work. Bearing in mind that what may be working for now may not work in the future, the change needs to start now.

The future is becoming increasingly digital and submitting documents electronically benefits all parties involved. However, the costs and regulatory operations expertise associated with the operational changes and new technologies required to remain compliant are of chief concern for

pharmaceutical and biopharmaceutical companies across multiple geographies.

Looking forward, life sciences companies should already be preparing for electronic submissions. It should be a priority for all companies to have the appropriate systems in place, or to be working with a service company that meets their needs, so that they are adopting a proactive approach to electronic submissions. This best practice model will ensure that organizations successfully achieve compliance with the regulatory requirements while also increasing efficiency and reducing costs associated with the submission process.

references1. EMA, eSubmission, eCTD, website accessed

Aug. 10, 2015, http://esubmission.ema.europa.eu/ectd/

2. US FDA drafts 5-yr plan to strengthen e-submission of drug applications, data, Scrip Regulatory Affairs, Jan. 3, 2014

3. US FDA, Guidance for Industry, Providing Regulatory Submissions in Electronic Format

–Certain Human Pharmaceutical Product Applications and Related Submissions Using eCTD Specifications, May 2015, www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm333969.pdf

4. US FDA, Guidance for Industry, Providing Regulatory Submissions in Electronic Format – Submissions Under Section 745A(a) of the Federal Food, Drug and Cosmetic Act, Electronic Submissions, December 2014, www.fda.gov/downloads/Drugs/Guidances/UCM384686.pdf

5. Onyszchuk G, 2010, Outsourcing: A Rapid, Cost-Effective Option for Electronic (eCTD) Submissions, 2010, Beckloff Associates whitepaper

Darryl Clarke is Head of Global Regulatory Operations at Sciformix Corporation, a scientific process organization providing knowledge-based services to pharmaceutical and biopharmaceutical, generics, consumer products, medical devices and other healthcare companies. Email: [email protected].



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