FDA Needs To Track Actions Built On Supplement AERs – GAO Report

A GAO report says FDA “may be able to expand” its use of supplement adverse event reports if it can track its use of the data to support actions it takes to protect consumers. The report makes five key recommendations for the agency to improve its approach to AERs.

FDA needs to create a system to track its use of dietary supplement adverse event reports to prompt consumer protection actions to provide clear direction for its future use of the data, the Government Accountability Office finds.

GAO arrived at five recommendations in its March 18 report on FDA’s use of AERs in overseeing dietary supplements (see table below).

Among other objectives, GAO set out to look at the extent to which FDA is using AERs for consumer protection actions. The office also looked at the number of AERs collected since 2008, the source of the reports, the types of products involved and the extent to which the agency has implemented recommendations GAO made in 2009 for improving oversight of supplements. The office conducted the report at the request of Sen. Dick Durbin, D-Ill.

While FDA has taken enforcement actions – including warning letters and inspections – in response to some supplement AERs, the agency “may be able to expand” its use of the data, GAO found.

FDA “does not systematically collect information on how it uses AERs,” GAO explains in the report.

“Such information could improve FDA’s ability to assess whether the agency is using AERs to their fullest extent in consumer protection actions and make improvements as needed.”

The executive responsible for the report, Alfredo Gomez, GAO’s director, Natural Resources & Environment, notes FDA “has six separate data management systems that are used to monitor consumer protection actions related to dietary supplements, but FDA does not track AERs across all of the systems.”

“Having a system in place to track consumer protection actions would enable FDA to know how frequently AERs initiate or support consumer protection actions,” Gomez notes.

The Council for Responsible Nutrition supports GAO’s recommendation to create a system that tracks enforcement actions linked to AERs.

CRN President Steve Mister notes a tracking system could help address the question, “how does FDA go about determining whether this is a signal versus a random report off the street?”

FDA easily could monitor AERs to know whether similar product reports were coming through other channels, says Rick Kingston, regulatory and scientific affairs president at AER system consultancy SafetyCall International P.L.L.C.

“What should happen is that whenever events come in they should be vetted on whether they have particular information, and if you see a lot of adverse event data, it’s easy to figure out if there’s something there, if it’s collected in a proper manner,” he said.

AERs And Actions

From the start of mandatory reporting of serious adverse events for supplements in 2008 through 2011, FDA received 6,307 reports of health problems linked to supplements – 71% from industry. Most of the reports were linked to supplements containing a combination of ingredients, such as vitamins and minerals or substances that otherwise were not classified within FDA’s product categories.

“However, FDA may not be receiving information on all adverse events because consumers and others may not be voluntarily reporting these events to FDA,” GAO says.

FDA suspects under-reporting of serious AERs is widespread in the supplement industry. Recent warning letters show some supplement makers lack formal systems for recording complaints as required by the good manufacturing practices final rule. The agency plans to emphasize AER processes in GMP inspections (Also see "GMP Inspectors Will Scrutinize Adverse Event Reporting Compliance" - Pink Sheet, 25 Feb, 2013.).

EAS Consulting Group President Dean Cirotta agrees there is a concern that consumers do not realize they can file AERs to FDA for supplements as they can for over the counter and prescription drugs. “I think there’s an education opportunity. FDA’s concerned that is not happening yet, and I still think there’s a feeling that AERs are unreported on the whole,” Cirotta said.

The report also notes that FDA has increased its monitoring of supplement firms through inspections – from 120 in 2008 to 410 between January and September of 2012 – and has hired additional investigators.

GAO officials identified three warning letters and 15 import refusals FDA initiated from 2008 to 2011 for noncompliance with the requirement that a supplement label include domestic contact information that consumers can use to report an adverse event.

Additionally, an injunction was ordered against ATF Fitness Products after the firm ignored warnings about GMP violations in 2011. ATF’s alleged violations include failing to submit reports of serious adverse events, including one in which a customer claimed to have suffered a mild heart attack after using one of the firm’s products (Also see "Enforcement In Brief" - Pink Sheet, 5 Dec, 2011.).

FDA uses AERs to develop consumer communications and most recently issued safety alerts in 2008 and 2009 related to AERs associated with Total Body Essential Nutrition Inc.'sTotal Body Formula and IovateHealth Sciences Inc.’ Hydroxycut products (Also see "FDA Says Supplement AERs Will Be Subject To Lower Threshold Before Action" - Pink Sheet, 11 Jan, 2010.).

But most supplement AERs “do not initiate or support [enforcement] actions because it is difficult to establish causality between the product and the health problem based on the limited information in an AER,” according to the report.

Going Public

The report also suggests FDA determine what information about supplement AERs could be made public on its website. But FDA’s response suggests the agency does not plan to follow that suggestion, and supplement industry stakeholders argue that making more information available could do more harm than good.

The agency stated simply that it “will continue to make reports available through” Freedom of Information Act requests.

The American Herbal Products Association noted that FDA requires FOIA requests before releasing AER information on any regulated product. If FDA provides public access to AER information on supplements, it should do the same for other products subject to AERs, said AHPA President Michael McGuffin.

“FDA may at some time determine to make AERs more easily accessible to the public, and should provide similar access across product categories,” McGuffin said in the trade group’s release.

CRN urges caution when considering the recommendation. Because any event associated with the use of a supplement can be reported, a lot of misleading information about the products could be published, which could lead to frivolous litigation and damages to a firm’s reputation, said Mister.

“If there is more availability to consumers, I’d hope that FDA provides context for them so that media and consumers understand that the existence of a report is not a determination of causality,” Mister said.

FDA will ask experts for input on effectively communicating AER information about all regulated products at a Risk Communication Advisory Committee meeting April 29-30, at agency headquarters in Silver Spring, Md.

A Plea For Poison Center Data

GAO also recommends FDA have access to information on supplement products reported to poison control centers. While FDA officials are interested in reviewing poison center raw data to understand what it includes and whether it would be useful for their analysis, the agency is unable to review the data without purchasing it.

According to the American Association of Poison Control Centers, from 2008 through 2010 the centers received 145,775 calls from consumers or other parties related to supplements, including cases in which a consumer used more than the directed amount of a product and accidentally ingested a product as well as used a product as directed but experienced an adverse event.

GAO notes the association’s records show 4,863 cases of supplement-related adverse events from 2008 to 2010, compared to the 3,827 FDA received during the same period. This suggests some consumers may be bypassing FDA but contacting poison control centers about “some of these events,” GAO says.

CRN agrees that poison center data potentially could enhance FDA’s use of supplement AER information. But the agency must narrowly define the poison control information it will review because AERs submitted to FDA have little similarity to reports the centers compile, said CRN’s Mister.

“We would assume that if they talk to each other, they’d understand they’re apples and oranges. We’d agree that FDA and poison control centers should connect and look for patterns and signals across the two,” Mister said.

Food and drug law attorney Anthony Young said accessing poison center information could help “so long as it is recognized that such reports do not mean that a dietary supplement caused the event.” Overall, the GAO report does not expand beyond what already is known about the supplement AER system, said Young, of Washington firm Kleinfeld, Kaplan and Becker.

Kingston does not consider poison control centers to be good sources for the information FDA needs in order to learn more about supplement adverse events.

“You’re looking in an area because there’s data, not because it’s where you should be focusing your attention. It’s like looking under a streetlamp for your wallet that you lost in the dark. That’s the place where it’s most lit, but it’s not where you’ll find your wallet,” Kingston said.

According to AAPCC’s National Poison Data System, 35,297 calls in 2010 mentioned a dietary supplement. The reports included four deaths.

Kingston pointed out that 58% of the supplement-related calls to poison centers involved children aged 5 years and under and likely related to accidental ingestion and not to product safety.

“The reality is that there is an awful lot of adverse event information that is shared of minor nature, but it doesn’t signal there is something wrong with the product,” he said.

However, GAO’s Gomez said that because the poison control centers received more than 1,000 more supplement-related adverse event reports than FDA did over a three-year period, it is conceivable that not all adverse events are reported to FDA. “It would be useful for FDA to have access to the poison center data to verify this,” he said.

Gomez said the recommendation is for FDA to explore options to obtain the data if the agency determines the information could influence the agency’s ability to identify safety concerns from AERs.

“FDA would need to assess whether it found these data useful. To that end, FDA had requested to see the raw data from AAPCC, but was unable to review it without purchasing it. How it streamlines the data once obtained would be up to FDA,” he said in an email.

Compliance Before Expansion

Kingston questions GAO’s call to expand the system, saying a more crucial issue is the large number of supplement firms that are not complying with AER reporting regulations.

“More companies need to be in compliance – that is the take-home message. Many are putting systems in place or complying with the law as it is written, and I don’t know if expanding it beyond serious adverse events will do anything. I’d rather see FDA work with those companies who see potential signals,” he said.

Cirotta said the report also did not address the issue that some companies do not have staff to take adverse event information from consumers or other parties and fill out a MedWatch 3500 form used to submit the material to FDA. These and other reasons could drive the under-reporting, he said.

Some firms do not understand that the law is intended to prompt more supplement manufacturers to report AERs, not to imply a causal relationship between an incident and a product.

“We’ve worked with companies that think because there is no causal relationship, they don’t have to report. So education is needed by companies – it’s never because you can identify or not identify” a causal link, Cirotta said.

“You have to have so much more data and information to take action besides having just an adverse event. If anything, an increased number may lead to further investigation, maybe an inspection or a review, but I don’t know if adverse events in and of themselves could directly lead to regulatory action,” Cirotta said. “It’d be difficult to draw conclusions, but it would be useful in pursuing investigations.”

GAO Follows Up

GAO determined FDA “partially implemented” all of the office’s 2009 recommendations, “such as issuing guidance for new dietary ingredients, clarifying the boundary between dietary supplements and conventional foods and expanding partnerships to improve consumer understanding.”

However, the report recommends FDA finalize several guidances, thus allowing firms to “be able to make more informed product development and marketing decisions, which could ultimately reduce FDA’s enforcement burden in these areas (see table).

Sen. Durbin said in a same-day release that the report shows the impact of the 2006 legislation he authored that made submission of serious AERs mandatory for supplement firms and for manufacturers of OTC monograph drugs (Also see "AER Bill Will Provide Documented History Of Supplement Safety – Industry" - Pink Sheet, 17 Jul, 2006.).

However, he said FDA needs more information on supplements and more should be made available to consumers. Legislation he introduced in 2011 and will re-file this year, the Dietary Supplement Labeling Act, would require manufacturers to register supplement products at FDA with a description of each one, a list of ingredients and a copy of each product’s label (Also see "Durbin Bill Would Narrow Definition Of Dietary Supplement" - Pink Sheet, 4 Jul, 2011.).

“This would improve the information available to consumers and help the agency respond to health risks posed by certain products or ingredients,” Durbin said.

GAO said FDA should request additional authority from Congress to require firms to self-identify and provide information to the agency on each of their products, updated annually.

GAO Recommendations And FDA Responses
Below are GAO’s recommendations and FDA’s comments, submitted through the Department of Health and Human Services.
GAO recommends FDA	Agency response
Develop a system to track when the agency uses AERs to support and inform consumer protection actions, including “surveillance, advisory and regulatory actions.”	Strongly agrees. Such assessments can be divided into those that use analytical criteria to evaluate whether a signal from the AER system is more or less likely to reflect illness or injury from a specific product or type of product and those that measure the extent to which the AER collection ends up supporting FDA action. FDA will continue to use AER data as the basis for investigating potentially unsafe products.
Determine what information about supplement AERs could be provided to the public on the agency’s website.	Will continue to make reports available through FOIA requests.
Complete the agency initiative to facilitate electronic reporting of supplement AERs.	Building a web-based data-entry form, similar to MedWatch, possibly available by mid-2014.
Explore options to obtain poison control center data if the agency determines the data could inform FDA’s ability to identify potential safety concerns from AERs for supplements.	Will discuss feasibility and costs of sharing data from AAPCC’s systems. IT also is working on whether data on CFSAN-regulated products in the Substance Abuse and Mental Health Services Administration’s Drug Abuse Warning Network and the Centers for Disease Control and Prevention could be integrated with the FDA system.
Establish a timeframe for issuing final guidance for the draft new drug identification guidance clarifying whether a liquid product may be labeled and marketed as a supplement or conventional food with added ingredients.	Regards the completion of both guidances as a priority. Comments received on the NDI draft guidance revealed that certain parts of the draft guidance were misinterpreted; therefore, FDA concluded the best course of action would be for it to seek public input on the revised draft. Revised drafts on both are being developed.
Source: GAO report, “FDA May Have Opportunities to Expand Its Use of Reported Health Problems to Oversee Products”

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