FDA’s dietary supplement program chief says the under-reporting of adverse events is “evidence of systemic issues” of noncompliance in the industry even though the number of AERs from manufacturers doubled in 2011 and could double again this year.

Division of Dietary Supplement Programs Director Dan Fabricant and other agency officials raised eyebrows April 17 at the Oxford (Miss.) International Conference on the Science of Botanicals with estimates on rates of compliance with the good manufacturing practices final rule, the new dietary ingredient notification requirements and mandatory reporting of serious adverse events to the agency.

Noncompliance “looks fairly systemic,” Fabricant said in an interview. “We’re seeing it pretty much across the major programmatic areas: claims, current good manufacturing practices, adverse event reporting, NDI requirements,” he said.

When he started at FDA in early 2011, Fabricant let industry know the agency expected tighter compliance with AER requirements Also see "FDA Says Supplement Adverse Event Under-Reporting Should Feed Growth" - Pink Sheet, 22 August, 2011..

And the AER totals show more frequent compliance with submitting serious adverse events to FDA within 15 days of receiving the reports, a rule effective in January 2008 Also see "Adverse Event Collection Expected To Be In Force By Christmas 2007" - Pink Sheet, 18 December, 2006..

The annual number of AERs from the supplement industry grew from 677 in 2008 – the first year firms were required to submit the reports to FDA – to 705 in 2009, 985 in 2010 and 2,019 in 2011, according to FDA records.

“The way it’s looking right now, it may get close to doubling again in 2012,” Fabricant said.

But based on the volume of nutritional products sold in the U.S., supplement AERs remain under-reported, he said. Although firms are submitting substantially more AERs, many more serious adverse events likely are being reported but are not being forwarded to FDA, he said.

The volume of supplement and vitamin product sales in the U.S. is the primary indicator that AERs for the category are under-reported, but FDA says some firms’ failure to investigate adequately adverse event information they receive and to conduct post-market surveillance contribute to under-reporting.

“It’s a consumer product – for any consumer product being sold, you’re going to get adverse events. … This notion that we don’t have any serious adverse event reports because we make dietary supplements just doesn’t hold water,” Fabricant said.

A separate FDA presentation at the Science of Botanicals conference reported a 31% overall violation rate for the 175 GMP inspections the agency conducted in fiscal 2011. Center for Food Safety and Applied Nutrition officials also note that violations are spread across firms in the three size groups delineated in the GMP final rule: small – fewer than 20 employees; medium – 20 to 499 employees; and large – 500 and more employees.

“We find that many firms are noncompliant regardless of size or business model,” according to CFSAN.

FDA Supplement Surveillance Impeded

At the conference, Fabricant said another recurring problem with supplement AERs is insufficient or inaccurate information in case reports.

Both under-reporting of AERs and incomplete reports impede CFSAN’s ability to determine whether a threat to public health is linked to a supplement ingredient.

Fabricant said at the conference that CFSAN also needs more data on rates of adverse events reported to supplement firms but found not to be linked to their products, and on the extent of a particular population’s exposure to a supplement ingredient.

“It’s just a matter of looking at the data, looking at the trends and looking at the marketplace,” he said.

Ikhlas Khan, assistant director of the National Center for Natural Products Research at the University of Mississippi, which hosts the annual conference, said the researchers in attendance were “shocked and set back and dismayed” at the persistent noncompliance.

“But on the other hand, they were very positive” because they are prepared to help supplement manufacturers improve their compliance records, Khan said.

Manufacturers need to ask for compliance assistance, though. “We have a feeling that … a majority of the companies are really not exploring the options on how to improve their situation,” Khan said.

Prioritizing and executing regulatory compliance pays dividends for supplement firms, said Rick Kingston, AER service firm SafetyCall International’s president for regulatory and scientific affairs and senior clinical toxicologist.

For AER compliance, firms should do more than record information from consumers or other parties reporting adverse events and then forward the serious events to FDA, he said.

“You need to know what the experience is out there, whether it’s good, bad or indifferent. You need to have a sensitive surveillance system so the company has a good feedback loop to find out what the consumer experience is,” Kingston said.

Alacer Corp.’s Chief Scientific Officer Robert Kay said a firm risks losing customers if it becomes known for not effectively tracking complaints.

“They would probably never buy the product again. Yet, for some unknown reason, there are folks in the industry who … when it comes to their business regarding their supplement, they think it’s okay to not have the systems, which is kind of bizarre,” Kay said.

The Many Facets Of Investigating AERs

FDA offers these “lessons learned” since submitting serious adverse event reports became mandatory for supplements:

Follow-up investigations are critical when insufficient information is reported to determine clinical evidence of an adverse event
A determination can be made when only enough pharmacological or clinical evidence is known to “support the plausibility” of serious adverse events linked to certain ingredients and products
Data on a consumer’s exposure to an ingredient or product may be less important if there are plausible events that satisfy the evaluation criteria for serious adverse events.

The agency also makes these suggestions for a firm’s analysis of adverse event information:

Know the expected incidence rate for all adverse events, broken down by age and outcome
Track the expected rate for trending to determine an accepted range and to flag unexplained variations outside the range
Based on a product’s toxicology and design, know what kind of adverse event reports to expect
Determine a benchmark for how often the expected AERs should occur
From AERs received, determine those that are predictable based on previous general use patterns consistent with a product’s toxicology
Determine the incidence rate for such predictable events
After determining expected rates and benchmarks, determine which reports meet high or low levels of integrity for strengths of association between product use and the reported effect.

Industry Not Operating In A Vacuum

FDA reported 25% of supplement GMP inspections are prompting “official action indicated” letters to firms and a slightly higher rate for “voluntary action indicated” letters.

“It shows a pretty good trend of noncompliance when you add the two together,” Fabricant said.

An OAI finding can result in warning letters or "voluntary" recalls, while a VAI finding means "objectionable conditions were found and documented but the agency is not prepared to take or recommend such regulatory action "since the objectionable conditions do not meet the threshold for regulatory action," according to the agency website.

An FDA presentation at the Science of Botanicals conference included statements that while roughly 4,000 vitamin and supplements products were available in the U.S. when the Dietary Supplement Health and Education Act was passed in 1994, research shows more than 1,000 new products are being introduced annually. But the total number of new dietary ingredient notifications under DSHEA is around 700.

Fabricant’s conference presentation also noted Sen. Dick Durbin’s, D-Ill., November 2011 request that the Government Accountability Office assess the effectiveness of the AER requirement for supplement firms. He said he mentioned Durbin’s request to remind industry stakeholders that members of Congress scrutinize information on the safety of supplement products Also see "Durbin Requests GAO Inquiry On Supplement Adverse Event Reports" - Pink Sheet, 14 November, 2011..

“To think that we’re operating in a vacuum out here isn’t the case. Congress is very influential in this town. If they’re looking at the adverse event issue, then we as public servants are looking at it too,” Fabricant added.

Supplement AER Under-Reporting Marks Tip Of Compliance Iceberg – FDA

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