Driven by congressional reaction to fear of substandard ingredient suppliers in China, FDA is improving its lists of drug manufacturing facilities and products domestically and abroad.

As part of its reaction to disclosures of tainted drug ingredients from China, Congress added drug registration and listing provisions to last year's FDA Amendments Act (H.R. 3580) as well as to pending legislation that is likely to be reintroduced next year.

FDA will use a switch from paper filing to electronic submittal that FDAAA requires of most drug manufacturers as an occasion to make sure it lists all active facilities and marketed products, and none that are not operated or marketed for sale in the U.S.

It will be important for entities such as drug manufacturers, repackers and relabelers to be ready for the switch by a June 1, 2009, deadline.

As a practical matter, that will generally involve finding or establishing Dun & Bradstreet DUNS numbers for every registered facility involved in manufacturing their products.

Drug and facility listing plays an important role in the regulation of drug quality. FDA relies on its inventory of drug facilities and products for scheduling inspections, facilitating recalls, verifying imports and many other activities.

Yet the agency has known for many years that the inventory in its Drug Registration and Listing System (DRLS) is highly inaccurate.

Foreign Facility Registration Data 'in Shambles'

FDA has endured an onslaught of criticism from members of Congress over the past year for shortfalls in its process for registering foreign manufacturing facilities.

The agency requires registration of both domestic and foreign drug manufacturing facilities under an April 1963 rule that implemented Section 510 of the Food Drug & Cosmetic Act. All manufacturers, repackers, relabelers as well as salvagers of marketed drug products must register their facilities under this regulation.

Members of the House Energy and Commerce Committee have raised concerns about registration during recent hearings that focused on ensuring the quality of imported drugs and active ingredients.

Oversight and Investigations Subcommittee Chairman Bart Stupak (D-Mich.) complained in a hearing last fall that FDA doesn't know what foreign firms it needs to inspect or where they are located because its data "is simply in shambles" ("The Gold Sheet," November 2007, p.12).

In findings presented at that hearing ("The Gold Sheet, December 2007, p.12), the General Accountability Office called attention to two key problems with DRLS:

· Facility totals may be inflated by foreign firms that registered for the approval it appears to convey; and

· Data may be confounded by manufacturers that neglected to annually renew their facility registrations or to alert FDA when they stopped manufacturing for the U.S. market.

The committee's ire increased another notch this spring when it came to light that without realizing it, FDA had failed to conduct a pre-approval inspection of the Changzhou SPL facility in China that supplied Baxter with deadly adulterated heparin API. FDA had mistakenly inspected a different facility that had a similar name ("The Gold Sheet," March 2008, p.3).

Draft Guidance Gives a Transition Period

FDA in July 2008 provided draft regulatory guidance detailing how to comply with the electronic registration and listing provision in FDAAA, which President Bush had signed into law Sept. 27, 2007.

The provision added wording to Section 510 of the FD&C Act that requires regulated entities to file their registrations and listings electronically. Waivers could be granted for those who show it would not be reasonable to expect them to file electronically rather than by submitting paper forms.

The agency assured the regulated community in a July 11 Federal Register notice that it would exercise its discretion not to enforce the electronic submission requirement.

Instead, FDA would accept voluntary electronic submissions during a transition period that runs through May 2009. The agency is calling this a pilot program, which it is using to test its new systems for processing electronic submissions.

On June 1, 2009, FDA will stop accepting paper submissions except when it grants waivers. Paper submissions use form FDA 2656 to assign labeler codes and register establishments, form FDA 2657 for drug product listing and form FDA 2658 for registered establishments to report private label distributors.

XML on Drugs

Speaking Sept. 9 at the PDA/FDA Joint Regulatory Conference in Washington, FDA's John Gardner gave manufacturers a preview of the new electronic registration and listing process.

He noted that at the same conference two years before, he had announced plans, since shelved, to field a Drug Facility Registration Module. The agency has decided to rely instead on the structured product labeling (SPL) document markup standard.

SPL is an extensible markup language (XML) standard. XML is similar to HyperText Markup Language (HTML), which tags text so it will display correctly on a website. HTML tags represent factors such as the font, size and color of text. XML tags can represent any factors agreed upon in a standard.

Since Oct. 21, 2005, FDA's Center for Drug Evaluation and Research has required drug manufacturers to submit labeling in SPL format, which renders it machine-readable. CDER had previously accepted pdf files.

The National Library of Medicine posts SPL-formatted labeling information from FDA on its DailyMed website in coded data fields that Gardner noted "are then useable, analyzable and retrievable."

SPL Expanded for DRLS

Last year FDA worked with Health Level Seven and other data standards organizations, adding to the fourth release of the SPL standard "the additional fields we needed for electronic listing, and all the fields we needed for electronic registration," Gardner said.

By using the expanded SPL standard for electronic reporting, the agency will be able "to spend our resources on the regulatory and the safety issues rather than on data entry, and for the last eight or nine years, all we've had the resources to do was basically to type in the forms, with very little quality control and little or no regulatory review," Gardner said.

FDA validates SPL registration and listing files by running them through a series of automated rules, 750 at last count. Most address formatting issues such as whether all the fields are there, in the right format, using the right code.

The automated validation rules will improve over the years, Gardner said, with the focus shifting from formatting to regulatory issues.

If upon submission, the SPL file passes all the validation checks, it posts to the DailyMed website. If it fails, the listing establishment gets a report describing the problems.

New Process Starts With Labeler Code File

FDA will not be transferring data from the paper-based DRLS to the new system. Rather, manufacturers and other establishments will have to re-register and then re-list their products electronically.

"Everything that goes into that data set has to come in through this SPL file submission," Gardner explained.

The process starts with the one-time submission of a "labeler code request" SPL file containing a company's National Drug Code (NDC) labeler code, as well as name and contact information and a Data Universal Numbering System (DUNS) number that can be obtained free of charge from Dun & Bradstreet (see www.dnb.com).

Once FDA validates this file, it can use the labeler code to validate subsequent registration and product listing files.

Facility Registration Comes Next

The second step is to register facilities. Each owner/operator submits a single "establishment registration" SPL file to register all of its facilities.

This file includes the labeler code information, plus for each establishment, its name and DUNS number, as well as its FDA Establishment Identifier (FEI) number, if known.

FDA has used the FEI number to identify facilities for some 20 years, so even as the agency transitions to the DUNS number, it will still need the FEI number to link with historical information about facilities.

One problem with the FEI number is U.S. customs brokers have inadvertently created extra ones by inputting company names differently, for example by spelling out "Incorporated" instead of using "Inc.", GAO's Marcia Crosse noted in testimony prepared for last fall's Energy and Commerce hearing.

That may be one reason the Operational and Administrative System for Import Support (OASIS) database that U.S. Customs and Border Protection uses to track drug imports lists some 6,700 foreign establishments, more than twice the approximately 3,000 in DRLS.

Electronic registration can streamline the inspection process by providing much more detailed information about the types of operations conducted at facilities, Gardner said.

Under the paper-based approach, FDA just asks for the facility's "business type." The options are: manufacturer, repacker, relabeler, distributor, foreign country, analytical lab or other. With electronic reporting, there will be an option to include information about unit operations.

"We're expanding this to look at the actual unit operations that you do at that facility," Gardner said. "Using this unit operation information, we can save you a lot of hassle in your inspection process."

Investigators won't have to waste a day at the site "just collecting information on what you do, what operations you have, and so on," he explained. Also the agency is more likely to send an investigator with the right qualifications "to inspect the types of operations that you do," he added.

If the site is in a foreign country, it must have a U.S. agent, identified by name, contact information and DUNS number.

Also, under the Bioterrorism Act, "you have to submit the names of each person who imports or offers to import each product," Gardner said. "That's been the law since 2002, but we've never done it before in registration, and we've decided we better enforce the law."

Gardner indicated that "in the not too distant future, we're going to validate these names against the import line entries, so that if they aren't there, your product won't get across the border."

DUNS - an Offer You Can't Refuse

FDA will be unable to process electronic registrations and drug listings that lack DUNS numbers. However, if regulated establishments do not supply DUNS numbers, the agency will obtain the numbers on their behalf, an agency spokesman explained.

Efforts are under way in FDA and on Capitol Hill to establish a requirement for use of DUNS numbers and other reporting activities that for now the agency can only recommend. Hence FDA is encouraging industry to follow the recommendations even though, at least for now, they are no more legally binding than agency guidance.

CDER Director Janet Woodcock stressed in her Sept. 15 remarks at the annual regulatory conference of the International Pharmaceutical Excipients Council in Alexandria, Va., that use of the DUNS number in the new electronic DRLS process is purely optional.

"We're evaluating the use of the DUNS number, the Dun & Bradstreet number, as a unique identifier," Woodcock said. "There are other ways to do this. This can't be mandatory. You know it's not required by legislation or regulation. However, we're asking people to send in their DUNS number if they have one, and then we're seeing how well that can serve as a unique identifier."

In his remarks at the PDA/FDA conference, Gardner said he would assume that most companies already have a DUNS number. In any case, it costs nothing to get one, and the process takes only a week or two. He added that Dun & Bradstreet will "do an investigation to verify the information that you submit."

FDA can look to Dun & Bradstreet to keep updated information about corporate officers and partnerships, so companies would not have to separately report such information to the agency.

Dun & Bradstreet identifies businesses around the world with its DUNS numbers, Gardner said. He noted that most European sites have DUNS numbers "and Dun & Bradstreet is working really hard to get China and India and the other areas going."

Using Dun & Bradstreet "will help us avoid problems like we had with heparin, for example, when we reviewed the wrong facility in China because somebody misread the Chinese name. If we have DUNS numbers, we would hope to avoid those kinds of problems in the future."

Drug Listings Can Reference Facilities, Units

Listing drugs involves submitting a separate SPL file for each prescriber package insert. Each insert has a list of NDC numbers for each dosage form. As long as these products have the same labeler code, they can be listed in the same SPL file.

As part of its validation process, FDA will automatically check listing files to make sure the labeler code is in the database. If not, the drug listing attempt will fail.

FDA is recommending that each drug listing also include every facility involved in its manufacture, at least for the types of facilities that must register with FDA, such as the API manufacturer, the control test laboratory and the packaging and labeling facilities.

For each such facility, the drug listing SPL file should show its DUNS number and the types of operations performed at that facility for that product.

In its validation process, FDA will check the DUNS numbers against those of its registrants and if they're not registered, the submittal will fail. "So you have to submit the registration SPLs before you submit the listing SPL," Gardner explained.

"For each NDC, you have to submit the specific information on that product." After listing, manufacturers can update the information simply by changing the file and resubmitting it.

For each specific product, the SPL file will give the NDC number, the proprietary and generic names, the application number, if any, as well as labels, labeling and advertisements.

Also recommended for the listing SPL are the dosage form, repackaged product, source NDC, VA schedule revenue administration, the active ingredients and the moieties, he said. "These are not just names; they're also the uniform ingredient identifier codes, the coded active ingredients, along with their strengths."

FDA also recommends listing the inactive ingredients, coded with the Unique Ingredient Identifiers (UNII) codes. "They don't have to have strengths," he said.

Another recommendation is to include the flavor, color, score, shape, size and an image. FDA is arranging with the National Library of Medicine to photograph each product, and the manufacturer can then include those pictures in its SPL file.

The SPL file also can include marketing information -the application number or the monograph, the marketing status and the date it started marketing or ended marketing.

Registrants can flag information they consider to be confidential, such as the identity of an excipient or a business relationship.

Manufacturers cannot simply take the SPL files they used to post drug product data to DailyMed and use them for listing because all those files used Version 3 of SPL. "In order to get into listing, they need to upgrade to Version 4 and resubmit these to the gateway," Gardner said.

The Electronic DRLS Submission Process

Manufacturers and other registrants can create the SPL files from scratch if they have people who know how. Another option is to use the XForms software tool that FDA developed in collaboration with GlobalSubmit and offers at no charge (see www.fda.gov/oc/datacouncil/spl.html.)

Yet another approach is to work with one of the 20 SPL vendors who can either sell SPL products or provide SPL file creation services, Gardner said.

"We call this the Turbo Tax approach, the same approach the IRS and Securities and everybody else uses," he explained. "Rather than giving you an interface where you have to come in, log in and type in your information, we're giving you simply the data standards so that you can create that data file any way you want and then submit it to us and we run the validations and processing."

Companies submit labeler code requests, followed by facility registrations and finally drug listings through FDA's gateway.

"Files go to DailyMed immediately upon clearing validation. When you submit your file, it takes a day to get it into the system. Two to three days later it should post in DailyMed," he said.

At the same time, the redacted information that posts to DailyMed also goes to a site FDA is creating, Facts@FDA. That site will be fully searchable and will give a url link to each label, which manufacturers can cite in their own systems.

FDA will then manually review the data before posting it to the agency's NDC Directory.

FDA Estimates an Increase in Reporting Burden

FDA estimated that initially, the electronic process would add two hours to the 2.5 hours it estimates are now spent every year on reporting each of 39 new registrations and 3,256 annual updates, each of 1,567 new drug listings, each of 146 new listings for private label distributors, and each of 1,677 pairs of June and December updates to drug listings.

However, the extra time spent reporting would decrease as industry learns how to use the new electronic submission process more efficiently.

Each firm would pay a fee of up to $20 for the digital certificate needed to upload files to FDA's electronic submission gateway.

FDA said it is encouraging, though not requiring industry to obtain free Dun & Bradstreet numbers for each registrant, establishment, U.S. agent and importer.

For recordkeeping, there would be a one-time burden of some 40 hours for each new and existing registrant to establish standard operating procedures, and an annual burden of one hour to maintain those SOPs.

Registration Fees Would Be Beneficial

At the Sept. 15-16 IPEC regulatory meeting, FDA's Edwin Rivera-Martinez illustrated the way manufacturers overseas view FDA registration.

"In many companies actually, as you walk into their lobby, the first thing you see is their drug registration form, implying that that is some kind of facility approval from the U.S. Food and Drug Administration, which is totally false," said Rivera-Martinez, a branch chief in CDER's Division of Manufacturing and Product Quality.

One reason for this problem with DRLS, Rivera-Martinez said, "is that it is essentially a freebie."

He suggested at the IPEC meeting that if the agency could charge a fee for drug registration, "then we could probably eliminate a substantial number of facilities, companies that register simply because it's a good thing to do overseas."

In meetings with congressional staff, FDA officials have been asking for authority to charge a drug registration fee, Rivera-Martinez noted.

He added that as part of FDAAA, Congress authorized FDA's Center for Devices and Radiological Health to charge registration fees.

In January, that center began charging device manufacturers annual registration fees, which "really cleaned up" its domestic and foreign facility lists, Kate Cook, acting associate director for regulation and policy at the Office of the Center Director in CDRH, told "The Gold Sheet."

CDRH charged $1,706 per registration in fiscal year 2008, GAO noted in its September report.

The fees already have made FDA's database of device manufacturers a lot more reliable, Cook said Sept. 10 at the PDA/FDA conference in Washington. "Previously, there was no incentive for a manufacturer to take a facility out of the database, when something could stay in there. So we now have a much better understanding of what establishments are actually manufacturing medical devices."

Legislation Would Establish Registration Fees

House and Senate legislation drafted earlier this year would establish registration fees and expand registration requirements to include drug ingredient facilities.

Both measures would require inspection of foreign facilities and would allow FDA risk-based flexibility on inspection frequency.

The Senate measure would require the use of Dun & Bradstreet DUNS numbers to identify each facility.

The measures take different approaches to achieve similar goals, and would have to be reconciled before they could become law.

The legislation went nowhere in the 2008 session. The House bill was never formally introduced and the Senate bill did not advance beyond its introduction.

New versions of the bills are expected in 2009.

Dingell's FDA Globalization Act Discussed

A draft FDA Globalization Act that House Energy and Commerce Committee Chairman John Dingell (D-Mich.) circulated for discussion in April and revised in July would establish, among other things, an annual registration fee for foreign and domestic drug establishments to defray inspection costs.

Dingell has not proposed the legislation for committee adoption, but he is expected to take it up again next year.

Dingell's bill would take annual registration requirements for facilities that manufacture, prepare, propagate, compound or process drug products and apply them to active pharmaceutical ingredient and excipient facilities as well.

However, neither repackagers nor excipient manufacturers would have to pay the registration fee.

FDA would set the annual fee based on the number of facilities, the cost of inspecting them, the "appropriations base," the inspection rate, inspection-related information technology costs and the ratio of new resources to appropriated funds.

Fees would be waived for small businesses, for those with such limited resources that it would pose a barrier to innovation, and when deemed necessary to protect public health.

The Dingell bill would require initial facility inspections prior to sale of drugs or ingredients in the U.S.

Regular biennial post-approval inspections would be required for all registered drug product, API and excipient facilities, including those outside of the U.S.

However, Dingell would let FDA relax the inspection frequency to four years for facilities the agency determines pose less risk. FDA would make such determinations using a risk information system it would have to establish within three years, and that would consider product class, the date of the latest inspection, the facility's compliance and safety history, and its shipping volume over time.

Registered establishments that have not been inspected would get a two-year grace period.

Kennedy Grassley Bill Takes Similar Approach

A Senate bill would enable FDA to enforce registration of foreign establishments involved in producing drugs for the U.S. market.

Senators Ted Kennedy (D-Mass.) and Chuck Grassley (R-Iowa) sponsored the Drug and Device Accountability Act (S. 3409), which was introduced in the Senate in July.

The Senate bill would apply the registration requirement to makers of "precursor ingredients" of drugs, which would expressly include drug component precursors that are of animal origin or used in the final stages of synthesis or purification.

Six months after enactment, it would remove a regulatory exemption from registration requirements for manufacturers of "harmless inactive ingredients" such as excipients, colorings, flavorings, emulsifiers, lubricants, preservatives, or solvents.

Domestic and foreign establishments would have to pre-register with their names, places of business and DUNS numbers, as well as an emergency email address, and payment of any registration and inspection fees required under a new Section 741.

The requirements for foreign establishments to also name U.S. agents, importers and brokers would continue.

Importers and brokers would have to annually register with their names, places of business and DUNS numbers, as well as an emergency email address. The bill would allow FDA to also require them to obtain licenses and post bonds they could forfeit by violating the FD&C Act or providing false or misleading statements.

Under the Senate bill, facilities could lose their registration if their owner/operators or their agents "refused, delayed or limited" an inspection. The same could happen for foreign facilities if agents of governmental authorities similarly impeded inspections.

The Senate bill would authorize FDA to issue a regulation establishing a risk-based inspection schedule, within certain parameters. Inspection frequency could exceed two years for high-risk facilities, and for low-risk facilities it could drop as low as five years, but no lower.

In setting the inspection schedule, the Senate bill said for FDA to consider whether the facility makes a drug product, API, or precursor or inactive ingredient; the route of administration; and the drug's approved uses.

The agency also would have to consider the adequacy of government oversight and inspection frequency of facilities in foreign countries.

FDA would have to consider certain factors in setting a risk-based inspection schedule: drug safety history, inspection record, and for inactive ingredients, any third-party quality certification.

The Senate bill would expand drug listing requirements. For every finished dosage form, registrants would have to identify all establishments engaged in the manufacture, preparation, propagation, compounding or processing of not just the dosage form but also any active or inactive ingredient and their precursors.

The Senate bill would require FDA to establish and maintain an Internet portal for the electronic submittal of facility registration and drug listing information.

A related database would have to include links between registered establishments and listed drugs, as well as inspection dates and information on the inspectional record and compliance history.

Under the Senate bill, FDA would charge drug registration and inspection fees for all registered facilities. The fees would be set annually based on the amounts established in congressional appropriations.

In its annual fee-setting process, FDA would have to proportionally adjust fees based on inspection frequency, with low-risk facilities on a five-year schedule paying the least. The agency would have to add extra charges to fees for foreign facilities to cover the extra costs for travel, lodging and translators.

Also, the drug registration and inspection fees would be reduced by 83 percent for establishments that only make positron emission tomography drugs. Fees would be exempted for some of those PET drug facilities and certain orphan drug facilities.

Shoe Leather Alternative Pursued

As it awaits fee-based incentives, FDA is taking other steps to enhance its understanding of facilities that are registered to export drugs and other FDA-regulated products to the U.S.

On Aug. 14, the agency awarded two contracts for one to three years of foreign registration verification work that together are potentially worth $3.4 million.

One went to Registrar Corp., of Hampton, Va., which already provides registration services for firms wanting to export food and beverages, medical devices or cosmetics to the U.S. It has offices in 19 other countries, including China.

The other went to Information Systems & Networks Corp., a systems integrator in Bethesda, Md., that does a lot of government contracting.

The contracts, advertised in October 2007 ("The Gold Sheet," December 2007, p.11), supplement FDA's foreign inspection program by addressing "a certain degree of risk associated with firms and their registration information, that we do not have the resources to inspect," FDA said in the solicitation.

The contractors will be available to verify facility registrations and product listings for all five of FDA's centers, including its center for drugs.

This verification will involve "visiting foreign firms, verifying and documenting submitted registration information and verifying that they exist and manufacture the products that FDA import records indicate they export to the U.S.," FDA explained in the solicitation. Contractor staff would photograph facilities, establish GPS coordinates, talk to employees and obtain samples of labeling and packaging.

In response to questions from potential bidders, FDA listed 10 countries that the agency might target in its registration verification project: Mexico, Canada, Germany, Spain, China, India, Ireland, England, Italy and Russia.

The contractor could expect to conduct 50 visits a year, including 10 visits per country, where it would conduct one-day audits of manufacturers. Some visits would be scheduled in advance. Others would not.

FDA stressed that it "will not guarantee the cooperation of foreign governments."

All travel will be pre-approved by a project manager in FDA's Office of Regulatory Affairs. ORA's Division of Field Investigations will coordinate the effort.

Inspector General Has Long Criticized Drug List

Data shortfalls in the drug listing portion of FDA's registration system, which Congress had established with the Drug Listing Act of 1972, drew fire from the Health and Human Services Department's inspector general in 1991 and again in 2006.

In its 1991 study, the IG found the DRLS database failed to include 8,000 marketed drug products and inaccurately listed 1,400. The main reason was that manufacturers were not complying with reporting requirements. Other reasons related to poor quality control at FDA, software limitations and uncertainty about legal authority and data requirements.

The agency improved the listing process, setting internal guidelines, adding automated error checking and increasing staff by more than half.

However, staffing later dropped below the 1991 level even as the database tripled to more than 120,000 products in 2005, the IG said in its 2006 report.

A commercial drug listing product from First DataBank included 9,187 drug products that were on the market but missing from FDA's DRLS database in February 2005, the IG said. In most cases, the IG found that the firms could provide little or no evidence that they had submitted products for listing. In some cases, manufacturers did not claim to have sought listing. In others, the IG was convinced that they sought listing but did not obtain it.

FDA still was ruminating over another 5,150 listings for marketed drug products. Most of these drugs were in its "pending file" because of incomplete or inaccurate submissions. Often there were mix-ups between manufacturers and repackagers/distributors, with the latter submitting incomplete or inaccurate manufacturer information or trying to list products before the manufacturers had registered and listed them.

DRLS was riddled with drug products that were no longer on the market. Of 123,856 listed in DRLS, 34,257 or 28 percent were not in First DataBank's database. Most had been taken off the market. Others had been renumbered.

The cumbersome paper, telephone, email and Internet interface between FDA and manufacturers was a problem. For example, manufacturers could only check listings one at a time on the web site.

Another problem was that FDA had not enforced its facility and drug listing requirements, except when also enforcing other violations.

Drug Coding Confusion

Yet another problem was FDA's lack of control over the coding process for drug facilities and products.

The agency would assign only the labeler code, the first segment of the three-part National Drug Code that is at the heart of DRLS. The labeler code is a unique identifier that FDA assigns each drug manufacturer when it first registers with the agency.

The second segment is a product code and the third a package code, both assigned by the manufacturer or labeler/distributor.

The IG identified 23 companies that had registered with FDA and received a labeler code, but never listed any drugs with the agency, even though they had with First DataBank. One had listed 1,932 drugs with First DataBank for at least eight years.

The IG also found nine companies that listed products in First DataBank with labeler codes that FDA had not assigned to them.

The IG's 2006 Recommendations

FDA should assume greater control over the assignment of National Drug Codes, the inspector general recommended in its 2006 report. "By assigning all parts of NDCs, it might largely prevent NDCs associated with drug products on the market from being omitted," the IG said.

The agency also should continue its efforts to establish electronic filing of drug registration and listing information, the IG said. This way, FDA would not have to employ clerks and contractors to manually enter data from paper forms into DRLS.

FDA also should routinely compare DRLS data with other government and commercial databases to spot unlisted or discontinued drug products, the IG said.

Additional recommendations were to resolve the pending listings, communicate more with manufacturers and take action against firms "that consistently fail to list drug products and update information."

Regulatory Responses Proposed

FDA concurred with the IG's recommendations and later that month proposed a rule that would address many of the concerns.

The agency hopes to publish a final version of the rule in the next year, FDA's John Gardner told the PDA/FDA conference in Washington. However, it is difficult for an administration to approve regulations in its final months unless they are highly political.

The Aug. 29, 2006, proposal would mainly revise Part 207 of Chapter 21 of the Code of Federal Regulations, which implements the Section 510 facility and drug listing provisions of the FD&C Act.

The key proposed changes would:

· require industry to submit electronically all facility registration information and most listing information (as Congress later required in FDAAA).

· require FDA to prospectively assign all three segments of the National Drug Code to drugs lacking NDCs. Existing NDCs would not change unless found noncompliant. Companies would get nine months after passage to review and update them. Then FDA would validate compliance. Also, FDA would change the appropriate NDC segments as drugs change.

· require industry to put the appropriate NDCs on drug labels. Repackers or relabelers would not be allowed to use the original manufacturer's label on repackaged or relabeled drugs.

Massive Data Comparison Effort Considered

FDA in August explored plans to contract with a small business for a data comparison exercise much like the one the IG had recommended, only more extensive.

The agency contemplated a contract that would involve comparing DRLS not only with First DataBank, but also with three other competitors - MediSpan, Gold Standard and Micronetics Redbook - according to a July 30 sources-sought notice. The comparisons would provide data entry validation, quality control and benchmarking.

FDA explained in the notice that industry, on which it depends to maintain DRLS data, "often shrugs off that responsibility even though mandated by law because of a lack of enforcement prerogative." Consequently, FDA said, DRLS and its public counterpart, the NDC Directory, "will remain fragmented and unreliable as a complete data source in the foreseeable future."

The notice went on to suggest that even though FDA's Office of Critical Path Programs has been pressing for the switch to electronic listing authorized by FDAAA, agency staff worry it could be risky to proceed before the August 2006 proposed rule goes final.

The contract FDA was considering would at first involve data entry for some 10,000 registration forms and handling of some 60,000 DRLS forms and other correspondence received annually. Mail volume would decline as industry switches to electronic filing, with a concomitant reduction in contractor staffing levels to five from the prior-year level of eight.

The contractor also would support the phone-tag process, checking phone mail at least three times daily and responding within two days.

A second task of the contract, to be activated if and when funding became available, would follow the transition to electronic filing. This phase would involve verifying the integrity of the data industry enters, either for every record or for randomly selected records.

"Not only is this crucial in order to gain insight as to the ease of industry adaptation to the new business plan," FDA said in the notice, "but sound approaches to identifying real or potential compliance, technical or security issues say a lot about how supportive the electronic systems will be in helping to foment a partnership between FDA and industry in advancing the public health."

'Best Practices' Drug Content Management Sought

FDA on Aug. 27 advertised for drug data content management support, without limiting respondents to small businesses.

The contract will play a key role in FDA's high-profile unapproved drugs initiative.

"FDA currently does not have access to thousands of unlisted products on the market," the agency explained, "so it cannot confront establishments regarding the drugs they do not list."

According to the statement of work, the contract would have three primary tasks and four secondary tasks, corresponding to its priorities for DRLS.

First, the contractor would arrange for the use of a private drug database that lists every prescription drug marketed in the U.S., and grant FDA a license to use it.

On a daily basis, the contractor would compare the private database's drug listings with those of DRLS by NDC number, identifying any drugs on the market that did not appear in DRLS, and any that were in DRLS, but no longer on the market.

On a weekly basis, the contractor would update DRLS, reconciling some types of discrepancies and flagging others for FDA to deal with.

FDA expects the private database to be 98 percent accurate for human prescription drugs and include at least 70 percent of over-the-counter human drug products on the U.S. market.

The contractor will need to be able to differentiate between application and non-application drug products, between prescription and OTC drugs, and between drugs and non-drugs.

The latter is important, FDA said, because some establishments have assigned NDC numbers to devices, nutritional supplements and other non-drugs. "The establishment will be unable to list a non-drug and will be confronted with this the first time an attempt is made to list or relist the non-drug under the electronic system," the agency said.

Second, the contractor would perform quality control and other reviews of data that industry enters into DRLS. To resolve any discrepancies, the contractor would email the listing establishment using the email address the establishment provides.

Taking Pages from 70 Years of the Federal Register

Third, the contractor would build an automated system to help FDA figure out which unlisted drugs are out of compliance.

This will involve collecting all the determinations FDA has ever made in its Drug Efficacy Study Implementation (DESI) review, a retrospective efficacy evaluation of all drugs FDA had approved as safe in 1938-1962. Only those deemed efficacious can be legally marketed.

The contractor will have to find DESI notices that appeared in the Federal Register dating back to 1938, and create keyword-searchable pdf versions of the pre-1994 notices that are only available on paper. Then it will construct a web interface compatible with an Oracle platform so FDA review staff can search it.

The secondary tasks are to:

· help FDA staff check regulatory status and label content and format, emailing listing establishments when there are issues;

· provide email-based help desk services;

· perform data entry for paper forms submitted after the switch to electronic. "There may be a residual amount of forms that continue to be received, but we anticipate the use of forms to dwindle precipitously over the next six months to one year," FDA said; and

· add features to FDA's NDC Directory, such as templated reports, classification, OTC monographs and additional research support with links to other web sites.

Separately, the agency on Aug. 14 solicited bids for legal services to help it conclude the few DESI proceedings that still are pending.

These services were to include: determining the status of DESI proceedings by reviewing related documents; developing an approach, such as issuance of Federal Register notices, for closing out DESI proceedings; providing legal support for complex, innovative decisions related to unapproved new drugs; and reducing the number of pending DESI proceedings and eventually completing them all.

- Bowman Cox (b.cox@elsevier.com )

Electronic Registration to Aid FDA's Quest for Enhanced Global Oversight

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