Getting closer to regulatory harmony in a shrinking pharma world
This article was originally published in SRA
Gill King and Joel Finkle explore some of the key developments relating among other things to document submission that have taken place over the past year in major pharmaceutical markets and what those developments mean for the industry.
The life sciences industry has more on its plate than ever before. It’s no secret that companies have been struggling with shrinking pipelines, heightened competition, greater budgetary and staff constraints and more comprehensive, more stringent regulatory requirements.
Working within the established markets – the industry’s bread and butter – the industry has some clear advantages: namely, the International Conference on Harmonisation, which has brought about greater cohesion among the three major markets: the US, the EU and Japan. But even between those ICH partners there are still differences in interpretation involving submission formats, such as the electronic common technical document (eCTD). In addition, the increasingly global nature of the industry requires that companies ensure their submissions meet the evolving formats, standards and regulations of numerous regions.
US takes a tough stance
Safety in the headlights
In the past year or so, the US Food and Drug Administration has placed an emphasis on two areas: improvement in patient safety and modernisation of the review process.
Since the May 2009 appointment of Margaret Hamburg as FDA commissioner, the agency has been focusing far more heavily on safety and enforcement. That’s not to say that safety and enforcement haven’t always been priorities at the FDA, but in the past the agency tended to adopt a more consultative approach to working with industry sponsors in its search to find mutually acceptable solutions. In the past year, the agency has taken a much more aggressive stance in terms of policing the multiple aspects of safety – from manufacturing and quality control through efficacy and safety claims for approved drugs. While worrying for an already embattled industry, this development serves to underscore the importance of knowing and adhering to guidelines and regulations.
Emphasis on modernisation
The FDA has been working collaboratively with standards-setting bodies – in particular, the Clinical Data Interchange Standards Consortium (CDISC) – to develop standards for the submission of study data. The efforts of such bodies have resulted in the development of numerous clinical standards, such as SDTM (Study Data Tabulation Model) for representation of clinical trial tabulations, ADaM (Analysis Data Model) for clinical trial analysis files and SEND (Standard for Exchange of Non-Clinical Data) for representation of nonclinical animal toxicology studies tabulations.
Although adoption of standards has been voluntary, the FDA has been urging that submissions be made by using CDISC-formatted data. In May 2011 (updated in December), for example, the agency's Center for Drug Evaluation and Research said it “strongly encourages IND [Investigational New Drug] sponsors and NDA [New Drug Application] applicants to consider the implementation and use of data standards for the submission of applications”1. CDER has accepted SDTM data sets since 2004, but data sets have not been implemented consistently by sponsors, resulting in variability in submissions and increased review times at the agency. The FDA’s point of view is that it has built standards in accordance with industry’s requests, and it now expects companies to adopt those standards more consistently.
The FDA has certainly not rested on its laurels with regard to modernisation. This is apparent with electronic submissions. Even though companies are still permitted to file paper submissions, the agency has said that in the near future it will require that all submissions be filed in eCTD format. The agency is giving industry plenty of notice, flagging 2015 as a deadline and allowing steady uptake, starting with NDAs and then moving to other submission types. There are valid reasons for that decision, such as the desire for greater efficiency and the need to ease the burden of having to store paper submissions.
The signs are that the industry is becoming comfortable and familiar with the eCTD, so it is likely that an eCTD mandate, once it finally comes, will not be too onerous for most companies. In fact, CDER now receives 400 to 600 electronic submissions per day; 70% of NDAs are eCTDs, and even INDs are gathering momentum, with 52% of INDs now filed as eCTDs2. Breaking that 50% mark was an important milestone for the agency and augurs well for the future.
Module 1, Version 2
Each agency participating in the ICH eCTD standard has its own requirements for the Module 1, or regional section. The FDA has just released draft guidance for an updated version of its Module 1 specifications3. For drug sponsors, two aspects of the new Module 1 guidance are perhaps the most significant: the introduction of bundled submissions and the decision to bring marketing submissions into the eCTD fold.
The ability to bundle submissions could bring huge time and cost savings for the industry, allowing information from more than one product or regulatory activity to be sent in a single package. This is most frequently an issue with manufacturing – especially with regard to drug substances, when the same information might apply to multiple applications. With the change, companies would be able to send one set of files for a number of applications, thereby easing the workload for regulatory departments and reviewers, as reviewers will not need to examine the same documents multiple times.
Marketing submissions, too, have undergone modernisation and reform. First, the FDA department that handles marketing submissions has been overhauled. The Division of Drug Marketing, Advertising, and Communications was renamed the Office of Prescription Drug Promotion, with the FDA elevating it from simply a division to an office in its own right and separating the professional and direct-to-consumer functions.
Under the new format, OPDP has expanded the headings and hierarchies regarding the documents and data being sent and classifies a submission according to whether it is promotional material to be sent to healthcare professionals or whether it is direct-to-consumer advertising4. Further headings help refine the document type and determine the type of form that has to be used.
Most significantly for sponsors, once the new Module 1 has been implemented, OPDP will accept eCTDs through the electronic gateway. Also, the use of new headings and a new hierarchy means companies will have to use only one kind of software to send material to the FDA. Theoretically, this is a cost- and time-saving move, but companies have raised some concerns. In the real world, those who send promotional material to the FDA are not, typically, the same regulatory operations personnel who send INDs, regulatory updates, periodic safety reports and so forth. Moreover, marketing personnel could be located in a different building or a different state and not have access to the same systems or information. In addition, there could be confusion over sequence numbers or over the fact that a large number of promotional filings would consume sequence numbers for a particular application.
At this stage, however, Module 1 is under review. The FDA had requested comments from companies be made by 27 December 2011; the agency will review those comments and possibly make changes to the guidance. It has said final guidance will likely be issued at the end of 2012 and that implementation is unlikely until January 2013. During that period, the agency will be ensuring its review systems get updated to handle the new Module 1. The FDA has also stated that the old Module 1 will continue to be accepted for some time after the implementation5.
Bundle of EU surprises
Mixed eCTD uptake
The eCTD is now well established at the European Medicines Agency. The agency mandated eCTD for the centralised procedure as of January 2010 and, despite certain earlier concerns, companies are now comfortable with the format. Today, the overwhelming majority of submissions to the centralised procedure are now sent in eCTD format — in keeping with requirements6. But the centralised procedure accounts for only 11% of EU submissions. Of the remaining 89%, 12.7% are under the mutual recognition procedure, 23.8% are under the national procedure and 61.8% are under the decentralised procedure.
Unfortunately, the eCTD has had far less traction under the other procedures – and for good reason. When companies submit under the centralised procedure, the EMA is the health authority. It is the EMA that sets the guidelines and, if issues with other health authorities arise, the EMA handles them. Thus, companies can submit full-fledged eCTDs in the knowledge that the agency will be happy.
This is not the case with the mutual recognition procedure and the national procedure, wherein companies are subject to the whim of every health authority in the EU. As a result, companies end up with slightly different formats that contain country-specific documentation for the same product submission in various countries.
Variations meet resistance
The EU has also struggled to gain much buy-in for what has become known as the Variations Regulation (Regulation No 1234/2008), implemented at the beginning of 2010. Companies have spent the past 12 to 18 months getting used to a very different way of working with EU health authorities: In the past, no matter what change was being made to a product licence, companies had to get approval first. In an attempt to minimise the administrative burden, the EMA said companies could begin to go ahead and implement variations, simply submitting an annual report to the health authority within 12 months of making the change.
In theory, this is a time saver, but the processes that were instituted at most companies in Europe do not allow for an automatic trigger that tells when to send something to the health authorities. Thus, for example, how does a company know that if something has been changed, the regulatory affairs person is going to submit at the end of the year? While this is a relatively easy problem to resolve, companies need to take those steps in the first place.
The regulation went further still – to cover work-sharing procedures and grouped variations (which FDA is just catching up to with its draft Module 1 specification’s Bundled Applications). This is akin to cross-company collaboration on certain activities and companies simply are not used to working that way. The group variations have also been problems for industry because the part of the guideline that covers group variations was written with no consideration for the eCTD. So, if a company has, say, five different variations going on in one eCTD, there is uncertainty as to what happens if one of the variations does not get approved. What sequence would the company use and how does that work? The uptake has been slower than the agencies would perhaps have hoped. In addition, the EudraVigilance Medicinal Product Dictionary mandate7,8 has thrown a further spanner into the works, since this is where companies are focusing their energies and efforts.
Eyes on the EVMPD
The requirement that marketing authorisation holders submit by 2 July this year EVMPD data for every medicinal product authorised in the EU has created a flurry of panic and activity.
The task facing companies is vast. The EVMPD affects every authorised medicinal product in Europe and includes both product information and structured-substance information, which means companies must supply the data on products as well as the ingredients, including active ingredients and excipients. Further adding to the burden on companies is the fact that the EMA has not met its own deadlines. The agency had said it would release the structured-substance part of the regulations by September 2011 but announced in November that that part would not be forthcoming until the end of 2011 [it has still not appeared - Ed]. The delay makes getting ready for the deadline even more difficult — as if it already were not next to impossible.
Smooth sailing in Japan
The eCTD is now well accepted by Japanese regulatory authority, the Pharmaceuticals and Medical Devices Agency, and to date the agency has received 106 official eCTDs9. The PMDA has been eager to ensure sponsors submit Modules 1 and 2 in Japanese and, in particular, has stated that, so as to increase review efficiency, adverse events apply the same rule to both Japanese and foreign studies. The agency has requested that all adverse-event terms be written in Japanese10. In the past, tables and figures were allowed to be in English if the original documents were written in English11.
The PDMA updated its eCTD question-and-answer section in April 2011 and announced that industry could now e-mail questions to the agency12. In addition, the agency released eCTD validator v.2.0. in February 2011 – the first time the tool had been revised since its release two years earlier. The new release streamlines processes and makes it more adaptable for companies. In July 2011, the agency released the fourth edition of the eCTD Creation Guide, which included not only updates by the Japanese authority but also industry best practices and experience. Companies are also better able to share information through the Japan eCTD Forum, which in October 2011 introduced an English home page. The forum is open to companies that have submitted eCTDs and, to date, all 37 companies that have submitted eCTDs to the authority have joined.
Australia follows EU example
In early 2011, the Therapeutic Goods Administration decided that, rather than adopting the eCTD right away, it would ease into electronic submissions by following the EU example, and so it released guidance on the non-eCTD electronic submission (NeeS). The intent is to eventually switch to eCTD, though no time frame has been set. The TGA released version 2.0 of the guidance in March 2011 and set aside a consultation period, which closed on 1 May 201113.
An update was expected on 1 July, but the TGA received an overwhelming response from companies – particularly with regard to the structure of the Module 1 folder, which did not follow the normal ICH convention for naming the folders in Module 1. As a result, the TGA is still in the evaluation process and has not yet issued updated NeeS guidance, which would mandate the requirements.
There has been a mandatory requirement since November 2010 to submit in electronic format all Category 1 and Category 2 applications. (Category 1 is an application for a new chemical entity or generic drug; Category 2 can be used when an application has previously been approved in two acceptable countries, and therefore the evaluation is not as rigorous. Acceptable countries include Canada, the Netherlands, Sweden, the UK and the US.) However, because the NeeS guidance has not been finalised, the submissions being filed – while electronic – do not necessarily follow the NeeS format. Among the biggest problem areas are: (1) tables of contents that do not include hyperlinks to the documents; (2) security settings that make it difficult for reviewers to access documents; and (3) scanned PDF files that have not been rendered text searchable via optical character recognition. At present, the guidance has not yet been finalised and, even though applications are not being rejected, once that guidance has been issued, such submissions are likely to be issued with an ineffective-submission notification.
For industry, one of the main components of the new release of the NeeS guidance will be the TGA’s making available the folder structure for the Australian Module 1. At present, companies have to use third-party tools or build the folder structure internally to create that folder structure for Module 1. There is a lot of variability with these approaches, however, because the architecture of the folder structure in the current guidance was not sufficiently defined. The expectation is that the new guidance will make the filing process easier.
Electronic on agenda for China
Over the past 14 months, China’s State Food and Drug Administration has taken firm steps to adopt processes that are more in line with international submission standards, and it has been looking at ways of implementing the eCTD14.
In September 2010, the SFDA issued its requirements on application dossiers in CTD format for pharmaceutical products; in June 2011, it developed the electronic document standards in CTD format for pharmaceutical information on chemicals. In addition, the agency issued the format and filing codes of drug registration and application dossiers.
Currently, the SFDA is still a combination of electronic and paper. While most submissions are still required to be in paper format, the agency has taken several steps toward electronic adoption. For one thing, it provides an electronic application form, which includes summaries of each of the different parts of the submission. At the evaluation stage, the agency requests certain elements in electronic format, including quality specifications, packaging and labelling, the manufacturing process and the clinical databases. At the marketing phase, companies are being asked to submit electronic copies of their adverse-drug-reaction reports, their quality specifications and their ongoing package inserts.
Efforts to date demonstrate that the SFDA is promoting the CTD format, is eager to move to electronic and is even working to set up a safe e-submissions gateway – similar to the FDA’s electronic submissions gateway. Before it does so, however, it needs to prepare its own internal systems to handle the electronic components. The agency does intend to proceed one step at a time by first refining the CTD format standard before introducing eCTD submissions.
All of this will go a long way to appease multinational companies that have been eager for China to adopt ICH standards. At present, companies filing in China are finding they have to reformat entire submissions, and standardisation would certainly serve to assist with the submissions process.
Conclusion
The past year to year-and-a-half has seen continued efforts to create greater global standardisation around the way submissions are formatted, though there is still a long way to go. Nevertheless, with many countries now firmly electronic and several important markets seeking to move in that direction, the outlook for global regulatory submissions is sunny.
There remains the longer-term goal of harmonising the submission process – at least among ICH member nations – through the regulatory product submission (RPS) . The standard development group has been working to get the third draft of release 2 into Draft Standard for Trial Use and is hopeful of achieving this with a ballot in January 2012. If all goes as planned, the expectation is that the RPS will get to a normative standard by January 2013, with adoption by the FDA a year later. The RPS working group will also work to earn ISO (Organization for International Standardization) certification — one of the conditions the rest of the ICH requires for its adoption. It is then hoped that the EU and Japan will adopt the standard by 2015, allowing RPS to become the first true internationally ratified standard.
References
1. CDER Common Data Standards Issues Document Version 1.0, May 2011, updated Version 1.1, December 2011, http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM254113.pdf
2. Presentation, Ginny Hussong, CDER, Drug Information Association (DIA) Electronic Regulatory Submissions meeting, San Diego, California (US), November 2011
3. CDER Common Data Standards Issues Document Version 1.1, December 2011, www.fda.gov/downloads/Drugs/.../UCM254113.pdf
4. Presentation, Marcie Kieste, OPDP (FDA), DIA Electronic Regulatory Submissions meeting, San Diego, California (US), November 2011
5. Presentation, Mark Gray, CDER (FDA), DIA Electronic Regulatory Submissions meeting, San Diego, California (US), November 2011
6. Presentation, Hans-Georg Wagner, EMA, DIA Electronic Regulatory Submissions meeting, San Diego, California (US), November 2011
7. Marr A, EMA sheds new light on requirements for the EudraVigilance medicinal product dictionary, Scrip Regulatory Affairs, 17 November 2011
8. Marr A, EMA mandates Eudravigilance medicinal product dictionary for all authorised products in Europe, Scrip Regulatory Affairs, 4 July 2011
9. eCTD in Japan, Atsushi Tomaru, Kyowa Hakko Kirin Co. Ltd, 5 December 2011
10. Format for Preparing the Common Technical Document for Submission of New Drug Applications to Reduce Total Review Time, Ministry of Health, Labour and Welfare, 17 January 2011
11. Presentation, Masako Kiya, Regulatory Affairs Department 2, GlaxoSmithKline, DIA Electronic Regulatory Submissions meeting, San Diego, California (US), November 2011
12. See Reference 9
13. Section on Australia from 6 December 2011, interview with Nick Ward, principal consultant, Pharma to Market, Queensland, Australia
14. Section on China from 7 December 2011, discussion with Jeanie Kwon, regulatory operations director, CSC Life Sciences
Gillian King is head of global consulting, global professional services, CSC Life Sciences, based in the UK, and has more than a decade of regulatory experience in the life sciences. Joel Finkle is senior strategist, regulatory informatics at CSC Life Sciences, based in the US, and a member of the Health Level Seven International Regulated Clinical Research Information Management working group that is developing regulated product submissions standards. Website: www.csc.com/health_services. Contact emails: