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Setting standards in US drug reviews

While Europe has been getting to grips with standards for presenting drug data, US regulators have been equally busy bringing the industry closer to full electronic submissions

For once, the regulatory spotlight has not been shining so brightly on the US Food and Drug Administration (FDA) as life sciences companies fix their focus on the European Medicines Agency (EMA) and its EudraVigilance Medicinal Product Dictionary (EVMPD) data mandate. Yet the FDA has been far from idle. While drug safety and the enforcement of drug safety laws remain top of the agenda, the FDA is increasingly putting the emphasis on the efficiency and quality of the review process, making clear that it expects industry to step up to the plate.

More consistency
The past year has seen a strong push by the FDA towards standardisation because the agency is eager for more consistent and broader use of existing standards. The FDA has collaborated with standards-setting bodies such as the Clinical Data Interchange Standards Consortium (CDISC) to develop standards for the submission of study data. Today, multiple clinical standards are in place, including the:

  • Study Data Tabulation Model (SDTM) for representation of clinical trial tabulations
  • Analysis Data Model for clinical trial analysis files
  • Standard for Exchange of Non-Clinical Data for representation of tabulations of non-clinical animal toxicology studies.

For the most part, the aforementioned standards have tended to be optional. More and more, though, the FDA has been pushing for CDISC-formatted data with sponsor submissions. For example, the Center for Drug Evaluation and Research (CDER) issued a notice in May 2011 saying 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'. CDER points out that, while it has accepted SDTM data sets since 2004, such data sets have been implemented inconsistently by sponsors, resulting in variability in submissions. From the FDA's point of view, it has set forth standards in keeping with industry's requests; now it expects companies to deliver their submissions accordingly.

Electronic drive
Momentum has been gathering within the FDA for full electronic adoption. While companies have not been required to submit electronically, during the past year-and-a-half the agency has been making public announcements about its efficiencies and its ability to review applications submitted electronically more quickly and thoroughly. The agency's adoption of the electronic Common Technical Document (eCTD) has reached the point where, unless a sponsor tells the FDA it plans to file a submission in paper format, there is an assumption that submissions will be filed electronically. That position is significantly different from, and more assertive than, past positions.

The push towards electronic submission will intensify, as is apparent in both the draft Prescription Drug User Fee Act (PDUFA) guidance and the draft Module 1 specifications.

Preparing for PDUFA
Amid efforts to improve the review process, the FDA has proposed under the PDUFA a requirement for electronic submission of NDAs, IND applications and Biologic Licence Applications.

There is no imminent pressure on industry to hasten implementation. The draft guidance will be issued at the end of next year, followed by a year for public comment before the final guidance would be given at the end of 2013. Even then, companies have 24 months to comply. Once underway, the change to electronicic data should lead to faster reviews.

Nevertheless, there are cost implications for drug sponsors because they may be required to upgrade their software to comply. The FDA is aware of such cost burdens and has indicated it will endeavour to select a format that is most efficient and effective for both applicant and the agency. The changes are likely to be felt most keenly in the area of INDs, since the use of electronic submission for INDs is currently relatively limited, whereas electronic submission of NDAs is fairly widespread.

Modifying Module 1
While still in the preliminary phase, the temporary release of draft guidance is a welcome step forward by the FDA, which has long been expected to update Module 1 of the eCTD. Perhaps most significant for drug sponsors are two aspects of the proposed guidance: first, the introduction of grouped submissions and, second, an indication that the Office of Prescription Drug Promotion (OPDP, formerly the Division of Drug Marketing, Advertising and Communications) is finally backing electronic submissions.

In a sign that the FDA is taking first steps towards Regulated Products Submission, the Module 1 specifications state that submissions may be grouped. This would allow information from more than one product or more than one regulatory activity to be sent in a single package. For companies, the potential time-saving and cost-saving benefits are vast, because companies would no longer need to send separate submissions for information repeated across several products that, for instance, share changes to manufacturing information. The expectation is that this will ease the workload for regulatory departments and reviewers. Above all, it is a change that brings the eCTD closer to resembling human activities, thereby making it more intuitive for companies.

The potential time-saving and cost-saving benefits are vast, because companies would no longer need to send separate submissions

Though few details are currently available, the OPDP's likely introduction of voluntary electronic submission could be huge for companies. Electronic submissions are frequently large and complex, since they must include all aspects of a company's proposed advertising campaign, including, for instance, DVDs for a television slot and recordings for radio. If companies could send electronic versions rather than the physical items, huge amounts of time could be saved. And because companies are eager to get their advertising information approved quickly, anything that speeds the process is likely to be welcome.

However, the marketing industry has not been using the eCTD, so getting this area of the business up and running with the necessary software and training could be time-consuming. Therefore, it is unlikely that a change to electronic would take place quickly. Moreover, there could be resistance from reviewers who may continue requesting the physical items, so it is likely that any change will be phased in when it does happen.

Implications for industry
Even though there may be some apprehension about an entirely electronic-submission environment, it would drive much more transparency from discovery through to marketing. Without being able to fall back on the comfort of a paper submission, the industry will start to experience, right from discovery, a business model that is more efficient and that has the potential for greater clarity around the safety and efficacy profile of therapies and insights into each therapy. That history is all there and easily searchable for those companies that are pursuing the electronic route.

Nevertheless, there are challenges inherent in going fully electronic. Chief among them is standardisation across the enterprise. To adopt an electronic end-to-end model, the enterprise must have the technological pieces in place, along with a plan – from a process perspective – on connecting those solutions so that information flows right from discovery to marketing and beyond. While there is no denying the changes can be difficult for an organisation to implement, once the processes are in place, much of the effort, inconsistency and duplicative work that pervade life sciences organisations can be eliminated.

Going global
Although the ability to submit a single eCTD to several health authorities is a long way off, there is no doubt that adoption of standards will enable companies to take advantage of commonalities. Certainly, regulations will require more and more information from companies, and nowhere is that clearer than with the EVMPD.

Adoption of standardisation across the enterprise could enhance and simplify the process of gathering and processing data for the EVMPD, because, for example, if companies implement strong global regulatory information management programmes, EVMPD becomes an output from those programmes. So, rather than treating regulations around data submission as more hurdles, such regulations can be seen as opportunities to move the company forward.

The Author
Ken VanLuvanee
, director of global professional services, CSC

13th December 2011


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