Same Rod, Bigger Fish

The traditional strongholds of the pharmaceutical industry-the United States and Europe-are currently experiencing a slowdown in growth, roughly 6 percent a year by some estimates. Difficult economic conditions are not the only cause of this slowdown. Other factors include the loss of marketing exclusivity in a number of major therapeutic categories, lower contributions from new products because of increased scrutiny of their value, and slower uptake by doctors and healthcare systems.

This confluence of issues is causing sciences organizations to look into emerging markets as a way to maximize revenue streams, save on production costs, and conduct clinical trials. These markets-the BRIC nations of Brazil, Russia, India and China, as well as Mexico, Turkey and South Korea-currently boast growth rates of 12 to 13 percent.

But targeting new markets presents a challenge. Requirements vary significantly from country to country, multiplying the administrative hurdles pharmaceutical companies have to clear to get their products to market. The time it takes to navigate these differences is critical, because firms looking to break into new markets need to be ahead of the game if they want to gain early ground over their rivals.

Getting to Market
With the average drug discovery-to-market cycle taking as long as 15 years (and costing around $1 billion), prolonged time-to-market can also translate into huge financial losses. Up until recently, most pharmaceutical companies have focused their efforts to slash development timetables on clinical trials, but new regulatory standards in drug submissions have companies looking at the regulatory function in more strategic terms and earlier in the development process.

Companies are now leveraging the harmonization of regulatory standards to reengineer decentralized processes and teams, and make strategic decisions about how to reuse data, including which countries they will submit to first, and how they will roll out subsequent filings. This approach to regulatory filings can be attributed to harmonization of regulatory standards, specifically the Common Technical Document (CTD) and its electronic version, the electronic Common Technical Document (eCTD). CTD and eCTD promise to synchronize the submissions process, making it possible to share and reuse data-thereby simplifying submissions to multiple regulators.

Regulatory Changes, US and Abroad
The most significant regulatory change on the U.S. front was FDA’s eCTD-only initiative for electronic submissions. Since January 1, 2008, the Center for Drug Evaluation and Research (CDER) division of the FDA no longer accepts electronic submissions in formats other than eCTD, unless waivers are granted. (CDER does allow eCTD waiver requests for new drugs for certain types of submissions.)

Despite advance warnings of the deadline, industry was been slow to get on board, and eCTD submissions have suffered. According to CDER, the quantity of eCTD submissions has increased throughout the course of the year, but many have contained fundamental errors that could have been avoided with proper planning. FDA advocates a planned approach to eCTD, and is willing to work with sponsors to make the transition to the new format less onerous.

Given the challenges industry is experiencing with domestic submissions, it is easy to see how submissions made to multiple regions would cause additional struggles. Varying stages of technical maturity and eCTD acceptance may be the chief reason for confusion, but they’re not the only issue. International Conference on Harmonisation (ICH) guidance on CTD/eCTD does not address technical aspects or content required in different regions. Without clear guidelines that cut across regions, it’s difficult to reuse an accepted submission in a second (or subsequent) region.

The technical approach to reusing a submission is to clone the application for another region by making alterations based on the specific regulatory requirements of that market. The eCTD format requires that documents are organized into five modules- Administrative Information and Prescribing Information; Common Technical Document Summaries; Information on Quality; Nonclinical Study Reports; and Clinical Study Reports.

While module 1 of the CTD changes from region to region, modules 2 through 5 generally require modifications that vary depending on the requirements of the regulatory body. The added benefits that come along with standardization include submission granularity and life-cycle management, which further improve operational efficiencies. Altering submissions in this way-rather than starting from scratch each time-allows sponsors to focus on fine-tuning their CTD or eCTD for future submissions.

Organizational Change
Although regulatory changes and nuances appear on the surface to create administrative burdens, they actually provide a valuable catalyst for organizations to transform processes, and invest in new technologies and/or outsource areas that do not constitute true competitive advantage. Organizations need to understand the drivers for efficient global eCTD/CTD filings in order to make critical decisions. Among the criteria to consider are patent timelines, competition, required translations, document status, and product potential.

Once criteria have been evaluated, an organization can make decisions about technology tools, outsourcing options, and business processes. If done correctly, organizational change can reap benefits including faster document retrieval, review and transfer times; Web-based document access that allows for simultaneous review and global collaboration; and the ability to repurpose clinical trial data and documents for various regional requirements. The end result is more efficient review process which could potentially result in faster approval timetables.

Whether managed internally or via an external agency, the best way to ensure multi-regional efficiencies is to embrace processes and technologies that are flexible enough to accommodate a variety of filings-CTD, eCTD and/or paper. It’s also imperative to be able to address each country’s requirements as they currently stand, making it important to invest in a solution that can manage these.

Since many countries still use paper or mixed submission formats, any technology solution must be able to cater to a variety of formats, while being able to draw all of the information together so that it can be tracked and repurposed effortlessly and accurately. Submission tracking and licensing management must be a key feature to fulfil the information management requirements of the regulatory affairs department.

As downward pricing pressure on drug development increases, there is a rising need for flexible regulatory affairs departments that can get drugs to multiple markets quickly.  As more regulatory bodies require electronic submissions, there will be new costs from technology infrastructure projects to fit the requirements.  This means that pharmaceutical companies will have to be all the more vigilant in their data management and business process design. With discipline and commitment, pharmaceutical companies that create a smooth, standardized development pipeline free of data-caused delays will be the leaders going forward.

Sidebar: Best Practice
One shining example of an efficient, multi-region submission comes from Alexion Pharmaceuticals, a biotech firm that recently launched its first commercial product, Soliris-the only FDA-approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a condition affecting fewer than 200,000 people in the US. Because of this limited consumer demographic, the product is classified as an orphan drug, giving the manufacturer exclusive marketing rights for a seven-year period.

Having developed a groundbreaking treatment for a rare but debilitating blood disorder, Alexion wanted to take full advantage by submitting simultaneous licensing applications in the US and Europe in both electronic and paper formats. It was vital, then, that the company get the submission process right the first time. With the average eCTD submission to the FDA containing roughly six gigabites of data, Alexion needed to optimize the operations of its relatively small regulatory and medical writing staff to create a simultaneous eCTD submission process for both target markets.

Alexion decided to outsource both its submission and medical writing services to ISI. To simplify the documentation process, Alexion wanted help collating data and scanning and cleaning up any hard copy documents-often an issue when drawing on data from clinical trials held a decade or more earlier-as well as electronic data into guidance-compliant formats. Documents could then be assembled for submission, with content tracking for both the company and the regulators.

Behind the scenes, the granular nature of the eCTD helped Alexion manage huge volumes of data while ensuring the proper foundation to make filing updates.  Handling the eCTD granularity-whereby the document is split into smaller pieces to improve clarity-and the life-cycle management can sometimes be a burden for smaller companies. Companies must manage granularity, establishing the life cycle approach for submission management to ensure updates, changes, additions and submissions for new indications or to other regulators can be managed quickly and easily. Leveraging this content granularity, Alexion was able to submit variations of its paper and electronic submissions in both the U.S and Europe within one month of each other. It has since submitted an application to Australia, and will submit to Japan and Korea later this year, taking advantage of the widest possible market for its niche drug.