As electronic regulatory submissions take hold, large and small companies alike scramble to keep up with technology and guideline advancement. As Cathy Brode explains, it's all about maximising market opportunities for new drugs and treatments.
Individuals involved in getting a new drug to market are used to hearing the constant and unwavering statement that life sciences organisations need to maximise the market opportunity for new drugs and treatments.
These products prolong and improve life and, we cannot forget, make company shareholders wealthy. This simple statement of amaximising market opportunity' has forever been a complex process. Today we are facing the unprecedented opportunity of globalisation. Bringing drugs to market more quickly in all regions is not free of technological and regulatory challenges. Delivering clear evidence of drug safety and efficacy in the form of a regulatory submission can be a daunting task.
The paper puzzle
The pure paper process of submitting a dossier to an agency is undoubtedly a manual one. In most cases, regulatory affairs (RA) departments are responsible for compilation and publishing of a submission. Often times they have little knowledge of the status of critical documents needed to make up the submission. It can be the last hour before a deadline that a referenced document or report is turned into RA by the clinical or pre-clinical departments.
Once the document is delivered its format becomes an issue. How was it created? Will the section or volume of the submission have to be re-paginated due to the late inclusion or change? If so, will the table of contents have to be updated? It is amazing to contemplate that after millions of dollars and human hours have been spent on developing a promising drug that millions of dollars could be lost if there is a delay getting the submission into review. Regulatory affairs is left to piece together years of related product documentation manually.
First things first. Documentation is received by RA and sorted into volumes. Tabs and slip sheets are inserted and the volumes are paginated. Once paginated, the volumes are duplicated and each copy must go through a QC process. Cross references are inserted, tables of contents generated and each page must be hand stamped and signed by an authorised individual. Once all this is complete, each copy is bound and labelled. The headache of the inevitable last minute changes is immense as these must becross-checked, as well as page numbers and cross references updated and tables of contents retyped.
This process is resource intensive and costly when you factor in the copying of the thousands of pages and the binding into volumes. These then must be shipped to the agencies and stored for reference. It doesn't stop here. Submissions of the drug application to other agencies need to meet the individual agency regulatory requirements. This means that though most of the content will remain the same, the format of the content as well as the presentation will change. This means repeating the same manual process over again.
When the submission reaches the agency the key challenge is retrieval of information and navigation through the truckloads of paper. One of the major hurdles in the review process of a paper submission is the cross references. For example, a reviewer may be reading a section that references another volume. If they need to review the referenced volume they will have to physically find and retrieve the volume. This referenced volume may not be readily available as it may be in use by another reviewer.
The Food and Drug Administration (FDA) reported that for new drugs that gained marketing approval in 2002 the average time spent in review was about 18 months. For new biologics approved in 2002 it was about 30 months. Life sciences organisations must make the review process as convenient as possible for the reviewers in order to minimise time in review. Not only must safety and efficacy be proved effective with solid research and results, but also the way in which this data is presented and the format in which it is delivered must match the suggested guidelines issued by the agencies.
Steadfast paper it's not going away
With the electronic world at hand, it would seem unrealistic that life sciences organisations are still using the paper process. However, as with all major transitions within organisations, there are many obstacles.
In some cases the comfort level with the paper process is the biggest resistance to change. RA departments sometimes conclude that at the particular point in which the decision is to be made it is the wrong time due to lack of expert resources the risk of transitioning to the electronic solution is greater than the risks associated with a manual process.
Companies are also confused about regulatory guidelines. At the moment, most agencies are not making an electronic submission mandatory though they are preferred. However, with the International Conference on Harmonisations' initiative for the common technical document (CTD) and the electronic common technical document (eCTD) to bring a common format to the way in which global organisations submit to the three regions of the USA, Japan and the EU, companies need to start formulating a transition strategy in order to be ready when these formats are required.
With both agency and industry in a state of transition, paper is not going away anytime soon. Many companies are using a partially electronic process. For example, organisations submitting to the FDA may choose to submit the extremely large Items 11 and 12 of the NDA (case report forms and case report form tabulations) electronically and the rest of the submission in paper.
There are also companies taking the hybrid approach. Progressive companies are utilising the five module format of the CTD to compile and submission and are then mapping the content to an eNDA and eBLA format. This practice allows companies submitting on a global scale to reuse content submitted in the EMEA as a CTD to be used in a FDA submission with all the convenience of the electronic format.
It is also a practice used by companies with a clearly defined strategy for eCTD. Since the eCTD is based on the CTD modules, the internal affect the eCTD transition will have on an organisation will be much less if they are experienced in submitting CTDs as well as electronic submissions.
According to CDC Solutions' Annual Regulatory Submissions Trends Survey 2002, only 7 per cent of survey respondents indicate they are now using a fully electronic submissions system, while more than a third are using a system that is a combination of paper and electronic. However, the pure paper process was the overriding practice with almost40 per cent of respondents not having made the electronic transition (Fig. 1).
Automated systems
In recent years many organisations who submit paper dossiers have made the transition to an electronic infrastructure to streamline the manual practices. The use of a Document/Content Management System (DMS/CMS) provides a centralised repository for documents with associated ease and control of access.
This can also provide an electronic process for the review and approval of the documents and dossier as a whole. The use of authoring templates and the review and QC of the electronic documents result in improved quality and consistency. If you combine this with an electronic regulatory publishing system, organisations can get the maximum benefit of the highest quality paper output. Electronic compilation of the paper submission removes the need for manual volume compilation, pagination, cross referencing and table of content generation. Late changes become much easier and the ability to reuse information in another report, submission or amendment is a great benefit.
According to John Cogan, Head of IS, Group R&D Applications, at Shire Pharmaceuticals, the Regulatory Operations group shaved weeks off of its traditional manual compilation of the clinical study reports (CSR) included in a recent sNDA submission to the FDA.
With the use of EZsubs, CDC Solutions' electronic regulatory publishing solution, Cogan managed to streamline his CSRs, 150-page reports that total800-2000 pages with attachments. Before these reports could be used in a submission, they must be reviewed by the quality assurance (QA) group at Shire and signed by the principal investigator.
"With EZsubs, the time taken for CSR assembly will be minimal. Now QA and the principal investigator can easily navigate and find references within the 800-2000 page reports,“ said Cogan. "Before implementing EZsubs and Documentum, we had a time consuming manual paper process, collaboration was difficult and version control of our documents was very challenging,“ he added.
Shire is one of the many companies to have streamlined paper submission processes with electronic systems. Shire plans to stick with this practice until it is forced or incentivised to submit electronically.
The company's electronic submissions strategy is to wait until the eCTD is closer to being implemented globally and continue to work onits authoring and template processes which are the key to successful paper or electronic submissions. Cogan explained Shire would only have to changeup that process again once the eCTD becomes mandatory.
Why go electronic the industry view
If the global regulatory agencies have not made an electronic submission mandatory what are the benefits?
It all comes back to the simple statement that life sciences organisations need to increase their speed to market and maximise the market opportunity. Once the organisation has rolled out a set of standards and implemented and trained the best resources for the process, it will realise a significant advantage in terms of getting their submission into review before the competition.
With the entire management and publishing process automated, tasks such as late changes, cross referencing and printing, that once took weeks or months, can now take hours or days. If the authors and publishers work together to agree on a template structures and standards, this time can be reduced even further.
Some of the keys to successfully planning your electronic submission strategy include:
* Agree definition of eSubmission-readinesscross-functionally and globally to support multiple markets.
* Identify templates structures for authoring.
* Identify bookmark standards.
* Agree document naming conventions (such as CMC, Pharmtox).
* Define a cross reference strategy.
The agency reviewer's view
Since there are multiple agencies and agency reviewers of all types the agency perspective on electronic submissions is hard to pin down.
However, it is easy to deduce that the process of reviewing an electronic submission at your fingertips as opposed to truckloads of paper has significant benefits. Cross references are a click-away and the information is always readily available. According to the December 2002 issue of DIA Today, Armando Oliva, Neurology Team Leader, CDER, FDA, surveyed reviewers to assess their opinions of the advantages and disadvantages of electronic submissions. The majority of reviewers say that the advantages are substantial and the disadvantages can be resolved as systems improve and if reviewers get updated hardware that is more functional and more ergonomic.
DIA Today found the top five advantages of electronic submissions to be:
* Easier to search and to find and retrieve information.
* Easier to work with overall than paper submissions.
* Take up less room in CDER's small Rockville offices.
* Can copy and paste tables, figures, facts into review.
* Save trees.
The top five disadvantages were found to be:
* Need more navigational aids, bookmarks, hypertext links.
* Table of contents not sufficiently detailed.
* Lack of standardised variables and variable names.
* Difficult to cut and paste from Acrobat to Word.
* Electronic document room is slow and crowded.
Preparing for the ae' transition
As with all electronic systems used in getting a drug to market the validation of your DMS and publishing systems and implementing best practices for21 CFR Part 11 is crucial.
21 CFR Part 11 provides the criteria under which FDA will consider electronic records to be equivalent to paper records, and electronic signatures equivalent to traditional handwritten signatures.It is an FDA regulation, but global companies submitting to the FDA and companies implementing best practices should always follow theregulation.
According to CDC Solutions Annual Regulatory Trends Survey 2002 only about 12 per cent of respondents were already compliant, while42 per cent are planning to become complaint. A small 6 per cent had no plans to become complaint (Fig. 2).
In addition to 21 CFR Part 11 challenges, devising an eCTD strategy sooner rather than later will help organisations realise significant benefits. Though neither the US or EU have a review tool in place for the eCTD as of yet, the transition is gaining considerable momentum.
This new approach to publishing across the entire life cycle of the product introduces new complexities. To optimise the integration of documentation into an eCTD submission, standardisation of electronic document and file formats will be necessary throughout the organisation and product development process.
Building hyperlinks within individual pre-clinical and clinical study reports during initial preparation is critical and will streamline the final compilation of these documents into the eCTD, as opposed to building these links into all reports as an end-on publishing process. If the correct steps are taken, an eCTD can be assembled and published in parallel to the product development process with great potential time and resource savings.
When asked if they had plans to migrate to an eCTD submission process 35 per cent of respondents said they have plans to migrate the submissions process to the eCTD. 20 per cent said they are uncertain while just 12 per cent said they have no plans (Fig. 3).
The certain fact that life sciences organisations can count on is that the industry standard is rapidly moving towards electronic regulatory submissions and ultimately the eCTD.
When a proper strategy and technologies are set in place and RA has inter and intra departmental buy-in, implementing a streamlined electronic process will help organisations realise significant benefits with process efficiencies and ultimately help them get new products to market faster it all comes back to maximising market opportunities for new drugs and treatments.
Cathy Brode is the Director, Product and Customer Advocacy at CDC Solutions. She can be reached at cathy.brode@cdcsolutions.com or +44 1249 705 300
About CDC Solutions Annual Regulatory Trends Survey: 5000 surveys were distributed throughout USA and Europe via hard copy and electronically to regulatory and IT professionals involved with regulatory submissions. 110 responses were received via fax and the CDC Solutions web site. For more information on the survey please email marketing@cdcsolutions.com
