Pharmaceutical companies will be asked to provide postmarketing drug usage information in their periodic safety update reports, including use in off label indications, under a proposed FDA rule due out later this year.

"A major component of this is the estimation of patient exposure...that goes for really getting a better understanding than we do now with the traditional periodic reports of how...drugs are being used [and] who's using them," FDA Office of Postmarketing Drug Risk Assessment Director Peter Honig, MD, said at a recent Drug Information Association/FDA satellite workshop on minimizing pharmaceutical contributions to medical errors.

"There are major gaps in our understanding [of drug use patterns]," Honig noted. "If we can make this a useful document, [it] will largely shift the burden to industry to tell us how these drugs are being used," he added.

The Suspected Adverse Drug Reaction proposed rule will "codify and implement" International Conference on Harmonization regulation E2C, Honig explained, and will "have a major impact on...periodic reporting." The 15-day expedited report requirements will be only moderately affected, Honig said.

The rule is part of FDA's effort to revamp postmarketing drug risk surveillance following the November 1999 Institute of Medicine report on medical errors and patient safety, which attracted extensive media and congressional attention (¹ Also see "FDA Post-Marketing Drug Risk Surveillance Requires More Funding, IG Says" - Pink Sheet, 20 December, 1999.).

"This is a very large rule. It is affectionately internally referred to as 'The Tome,' approaching 500 pages including the preamble," Honig noted. "We will obviously be looking for comments from industry about this particular document once it is out."

The agency is currently focusing on a number of risk management initiatives, including developing updated standards for drug labeling, packaging and naming; incorporating post-marketing safety considerations into advisory committee meetings; and examining risk and efficacy profiles of older drugs to assess whether they should remain on the marketplace (² Also see "Risk Management Assessments Will Be Part Of Advisory Committees - FDA" - Pink Sheet, 3 July, 2000.).

A major reason FDA has lagged in compiling accurate postmarketing drug use information is its traditional role of looking only at the approved indication for any given drug, Honig pointed out.

Now, however, FDA is interested in "looking at...those off label situations," Honig said. "Many times, the benefits are undocumented, but the risks are just the same or greater than for the approved indication."

Off label drug use often extends to vulnerable populations, Honig noted, such as children, the elderly, and renally/hepatically impaired populations. "These...particularly susceptible individuals may not be contained in the approved indication for the product, but we acknowledge the fact that [drugs] may be being used in these situations, and we need to know about that."

Safety evaluations for such populations are the kind of information FDA will ask industry to provide in PSURs, along with analyses of drug interactions and data about long-term drug usage.

Gaining access to such information should not be a stretch for industry, OPDRA Medication Error Prevention Associate Director David Graham, MD, remarked.

"Frequently, we are not aware of studies that industry is conducting looking into the safety of products once [they] are in the postmarketing realm. We only learn about it if a particular issue comes up, and they have a study that maybe presents their position in a favorable light," Graham observed. "And so [the new reporting requirements] will give us an idea, a better handle on what the full scope of things are that are happening in the real world."

Most data provided by industry would be considered confidential and would not become accessible through the Freedom of Information Act. The only exception would be any information that may warrant a public health alert.

The SADR proposed rule will also emphasize a thorough summary of adverse events in the conclusion section of the PSUR. "This is where we really expect some thought to be put into the document, rather than the periodic reports that we receive now, which are essentially data dumps," Honig said. "We would hope that this document is going to put it all together, be thoughtfully composed, and really tell us what's new and...different about the safety profile of these products."

The final SADR rule, which will make PSURs a requirement, is not expected to be released until 2002. Honig encouraged companies to take advantage of the existing waiver mechanism that allows them to submit PSURs being prepared for other (usually foreign) regulatory jurisdictions in place of the traditional periodic reports.

He said companies can request such a waiver and that FDA will be looking forward to working with these firms and providing them with feedback on the usefulness of submitted documents.

FDA plans to work with the international community to implement the ICH-E2C document so that the agency and industry may "work smarter, not harder." A July ICH meeting in Brussels will address expectations for PSURs and "what message we want to send back to industry," Honig said.

"We owe it to industry...to work with our other regulators out there to develop some clear consensus of what our expectations are going to be, and not necessarily ad hoc the industry to death on these documents," he remarked.

OPDRA Drug Risk Evaluation II Division Director Evelyn Rodriguez, MD, added that although many different opinions on risk management are likely to be exchanged during the regulators' meeting in July, "our colleagues in industry...don't need to worry that it's going to be a knee-jerk response around the globe. But rather we need to use our social and political context and our own public health agenda to really drive decisions."

Companies are not the only resource FDA will be tapping for drug use information. The agency plans to issue a request for proposals in the near future to find an organization that can provide more comprehensive data on drug use.

The drug use statistics FDA currently receives are compiled by IMS Health and are based largely on ambulatory use. FDA is seeking more information on inpatient and longitudinal use, as well as use by special populations.

OPDRA is also working on an adverse drug reaction electronic submission rule, Honig said, "which will propose to require that adverse drug reaction reports/expedited reports initially be submitted to the agency electronically." FDA hopes to publish the proposed rule by the beginning of next year.

FDA's Adverse Event Reporting System, "with enhanced functionalities over the spontaneous reporting system that was in place until late 1997," should be completed within one year, Honig said.

OPDRA expects that the database will be able to accept electronic submissions by October 31, known as "D-day" at the agency, he indicated. However, no requirement will yet be in place for electronic ADR submission at that time, and therefore "D-day should not be ominous [for industry]. D-day is a liberation day for us, but it is hopefully a dawning of a new era for everyone."

Another OPDRA initiative to maximize drug safety is the new trade name review process, launched in October 1999 to reduce prescribing errors due to name confusion, (³ Also see "Proprietary Name Evaluation Guidance Will Detail New FDA Review Process" - Pink Sheet, 27 March, 2000.).

To facilitate the review of proposed names, OPDRA Medication Error Prevention Associate Director Jerry Phillips encouraged companies to submit "data or studies to support the safety of that name at that time for us to look at."

Such studies may include focus groups, and evaluations of a trade name's propensity to be confused. Homophonic sound recognition software could also be developed.

It takes FDA about 60 days to complete a trade name review, and name information may be submitted anytime from the end of Phase II trials through the NDA stage, Phillips said.

To further postmarketing surveillance efforts, FDA plans to seek increased funding as part of PDUFA III, to be negotiated as PDUFA II expires in 2002 (⁴ [A#00620240006]).

FDA's initiative to reduce medical errors and adverse drug events also includes a $15.9 mil. appropriations request for FY 2001, while the Pharmaceutical Research & Manufacturers of America, on its part, is getting ready to release a set of recommendations for reducing medication errors for member companies, due out imminently (⁵ Also see "PhRMA Medication Error Reduction Plan Slated For July Release" - Pink Sheet, 13 March, 2000.).

Off Label Drug Use Data To Be Required In Periodic Safety Updates - FDA

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