Nearly a year ago, the FDA launched a major initiative, the Electronic Submissions Gateway (FDA ESG).  Resulting from the mandate of the Prescription Drug User Fee Act III (PDUFA) to develop tools to enhance receipt and review of electronic applications, the Gateway is bringing much-needed efficiencies to the submissions process.

Opened in May 2006, the Electronic Submissions Gateway is a single portal for electronic submission of regulatory data to the Agency.  FDA ESG receives, routes, and provides notification of the delivery of an electronic submission, but does not open or review it.  The Gateway is set up to accept submissions of up to 100 gigabytes to the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH).  It also supports receipt of Adverse Event Reporting System (AERS) reports and attachments. 

Gateway software does not have any limitations on transmission format -- all types of binary and markup language-based (SGML, HTML, and XML) submissions can be picked up.  During transmission, folders maintain their actual structure -- a vast improvement over the old ESTRI Gateway, which could only accept single files. 

“The central concept of the Gateway is to allow for a level playing field so that all communities -- drug, device, biologics, foods, veterinary medicine, and all strata of corporate environments, small pharma, big pharma, venture capital, and academia -- can play,” explains Michael Fauntleroy, program manager for FDA ESG, and director of the electronic submissions program at CBER.

To make the level playing field concept a reality, Fauntleroy and his team recognized the need for a low-cost or no-cost option for gaining access.  They selected the commonly used X509 v. 3 class 1 certificate for the public key infrastructure (PKI) certification.  PKI is a system of components that uses digital certificates and public key cryptography to secure electronic transactions and communications.  “This certification can be secured from any number of vendors for approximately $19.95 to $50, and gives the user the ability to send information through the Gateway from a laptop, desktop, or server in a secure fashion,” Fauntleroy comments. 

Obtaining a PKI certification is just one part of becoming a user of the Gateway.  A user, also known as a “transaction partner” must apply for a test account; confirm system requirements; send a successful test submission, 7.5 GB in size; and then apply for a production system account, which allows the user to send submissions to the production system.  Users must also submit a letter of non-repudiation for digital signatures.

System Uptake
One year into the process, use of the system is slow but gaining steadily.  There are between 150 and 200 transaction partners, mostly sponsors (some 96 percent), with the remaining 4 percent coming from CROs and academia.  Submissions are largely from the pharmaceutical sector (64 percent), but biotech and CROs are also players (35 percent and 1 percent, respectively).

The AERS program has the most submissions, followed by CDER, CDRH, and CBER. According to Fauntleroy, AERS figures are high because of the large numbers of adverse event reports submitted by sponsors.  He says, “There are 30 companies electronically reporting a total of 100,000 adverse events to the AERS program annually via the Gateway, mostly one megabyte in size.”

By comparison, submissions to CDER, CDRH, and CBER are far larger, sometimes in the gigabyte range, and are growing in number.  When the Gateway opened, submissions to CDER numbered fewer than 100 per month.  Now that figure has leapt to 600.  Gains have been more modest at CDRH and CBER, with monthly submissions now averaging approximately 180 and 60, respectively.  Whereas submissions to CDER and CBER are truly electronic, CDRH is operating under a pilot program in which a provider under contract with that Center is sending scanned copies of paper documents through the Gateway. 

Big Benefits
Michael Brennan, VP of global regulatory operations at Centocor, says his company jumped on the Gateway bandwagon right from the get-go because it is fast, efficient, official, and secure.  “We made our first submission on May 5, the day after it went into full production,” he remarks.  

Brennan says that Centocor immediately recognized the Gateway’s potential for improving submission operations.  It eliminates the need to publish data to different kinds of media, such as CD-ROM, DVD, or digital linear tape (DLT), followed by transmission via courier to the appropriate division at FDA, where someone date-stamps receipt of the package. 

As Brennan explains, “One of the important steps forward with the Gateway is the beginning of acknowledgement of receipt.  The acknowledgement that we used to get could have been from somebody at a loading dock or a guard at a desk.”  With the Gateway, there are multiple levels of receipt, starting with an official acknowledgement that the submission has been received by FDA, followed by acknowledgement that the information is being loaded into the network, and finally, that it has been received by the reviewing discipline.  “Date of receipt is important because it triggers a lot of regulatory clocks.  A UPS receipt is not an official acknowledgement by FDA,” says Brennan. 

The full value of the Gateway is realized in terms of the amount of time and money saved by no longer having to prepare media, hire couriers, or track down when or whether the package was received by the right individuals at FDA.  According to Brennan, “The greatest return on investment comes from tallying up all the submissions that a company makes for all its products, such as correspondence related to investigator information, protocols, and amendments to protocols.  If you start multiplying all of the times that you are no longer going through the manual process, this is where you see the benefit.”  He adds that before the Gateway, the company had to factor in transit time, which has dropped from hours or days to minutes.

Similarly, Dan Offringa, a consultant specializing in electronic submissions for Biologics Consulting Group, says, “Speed is the most value-add.”  Biologics Consulting Group, a Beta test site for the Gateway, works with both U.S. and non-U.S. based clients who want to make submissions through it.  Offringa explains that clients of all sizes, from small start-ups to large pharmaceutical companies, are becoming attuned to its benefits.  “The Gateway is part of the whole process now.  It’s become a given as to how we do things for our clients,” Offringa adds.

The word is getting out about the Gateway.  According to Fauntleroy, FDA ESG is receiving five to ten requests a week from prospective transaction partners, mostly smaller pharmaceutical and biotech companies wanting to introduce greater efficiencies into the clinical development process.  The Agency has a similar goal.  It is marching toward a paperless or nearly paperless environment as part of the Critical Path Initiative, a directive meant to bring better medical treatment to patients faster by adopting new tools and methodologies.  Together, stakeholders and FDA will continue to partner to expand the use of the Gateway for mutual benefit.    

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