Keeping Adversity At Bay

On December 22, 2006, the President signed into law the Dietary Supplement and Nonprescription Drug Consumer Protection Act. The law amends the Federal Food, Drug and Cosmetic Act with respect to adverse event reporting (AER) and recordkeeping for dietary supplements and nonprescription drugs marketed without an approved application.

The Act applies to all dietary supplements labeled on or after December 22, 2007, and the Food and Drug Administration (FDA) began enforcing the requirements of 403(y) for dietary supplements labeled on or after January 1, 2010.
“Currently, we are required to report To the FDA any adverse event that results in death, a life-threatening experience, in-patient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect or, if it requires based on reasonable medical judgment, a medical or surgical intervention to prevent one of the above described outcomes,” said Eileen Sheets, managing director of Bioforce USA (Ghent, NY).

With these requirements, have manufacturers been able to comply?

Andrew Shao, PhD, senior vice president of scientific and regulatory affairs for the Council for Responsible Nutrition (CRN, Washington, DC), said its member companies have a clear understanding of the law. “CRN has provided education To our own companies, but also has conducted public education through webinars and speaking engagements,” he said. “While many companies have dedicated in-house staff to ensure they’re handling received AERs properly, there are also a number of good thirdparty firms who work closely with an inhouse team, or even substitute for an inhouse team to ensure that manufacturers are compliant when it comes to the AER process. If a company is not sure it is doing things to the letter of the law, it is really important that they get advice from an attorney or company specializing in the AER process.”

“Generally more manufacturers are realizing they have to take it seriously,” said Rick Kingston, PharmD, president,Regulatory and scientific affairs/senior clinical toxicologist with SafetyCall International P.L.L.C (Bloomington, MN), a third-party firm that handles AERs.

Kingston said that under the new good manufacturing practices (GMPs), the FDA is also looking at how they receive adverse events, and during GMP inspections, whether companies are submitting them to the FDA.

“The GMPs give the FDA a reason to look into AERs. It’s often hard to tell if it’s a GMP issue or adverse event related to the use of a product,” he said. “It gets blurry, but the FDA can see how a manufacturer is managing the adverse event experience.”

The FDA recently audited a number of companies that subsequently have enlisted The services of SafetyCall to help them improve their adverse event capabilities, Kingston said. SafetyCall offers full AER services as well as consulting.

Sheets said in the past year Bioforce has not had to report a serious adverse event. “This is not surprising,” she said.

“Bioforce AG in Switzerland instituted [its] AER system in 1988 and have been tracking all products sold worldwide since. In the 15 years I have been with Bioforce, I have never had a serious one that would meet the FDA requirements for filing. Bioforce requires that I file with them any adverse event reported to me—minor ones and even ones that seem like it could not be related to the product at all, and these are only several in a year. So I am not surprised that I have had none to report to FDA.”

Kingston agreed that manufacturers must document all allegations. “Even someone complaining of a stomachache needs to be documented,” though it may not have to be reported to the FDA. And manufacturers must also keep a data archive of all events for six years.

A concern regarding serious adverse events, according to Kingston, is that many manufacturers believe they have the latitude to determine if the alleged effect is related to the use of their product and that determines if they have to report it or not. “That’s not the case,” he said. If someone alleges that a product resulted in a serious adverse event, it makes it automatically necessary to report. If the allegation meets the criteria for serious AER and the cosumer alleges it occured, it must be reported to the FDA. Manufacturers may think the problem couldn’t be caused by their product so they don’t have to report it, but they do. Manufacturers can provide FDA with qualifying information such as a rebuttal, medical opinion or assessment refuting the claim. “That’s where the challenge comes in,” Kingston said.

Products Prone to AERs?

Amgen, Inc. Department of Global Regulatory Affairs and Safety (South San Francisco, CA,) collaborated with the FDA Center for Food Safety and Nutrition (CFSAN) to conduct a one-year prospective surveillance study of dietary supplement-related poison control center calls in 2006. Prompt follow-up of symptomatic cases, laboratory analysis of implicated dietary supplements and causality assessments by a case review expert panel were performed. The results were published in the Journal of Medical Toxicology in 2008.

Of 275 dietary supplements calls, 41 percent involved symptomatic exposures; and two-thirds were rated as Probably or possibly related to supplement use, according to the report. Eight adverse events required hospital admission.
Sympathomimetic toxicity was most common, with caffeine products accounting for 47 percent, and yohimbe products accounting for 18 percent of supplement-related symptomatic cases.Suspected drug-herb interactions occurred in six cases, including yohimbe co-ingested with buproprion (one) and methamphetamine (three), and additive anticoagulant/anti platelet effects of NSAIDs taken with fish oils (one) and ginkgo (one). Laboratory analysis identified pharmacologically active substance in four cases; supplement toxicity was ruled unlikely when analytical testing was negative in five cases.

The study concluded that supplement- related adverse events were minor.
Clinically significant toxic effects were most frequently reported with caffeineandyohimbe-containing products.Active surveillance of poison control center reports of dietary supplement adverse events enables rapid detection of potentially harmful products, which may facilitate regulatory oversight.

But Shao pointed out that best-selling products might receive the most reports. “If you look at sheer numbers, it makes sense that the more popular products would be prone to more AERs, because the universe of consumers is so much larger,” he said. “For example, the multivitamin might have the most number of reports, but that doesn’t mean that multivitamins are more likely to be linked to adverse events.”

Inspiring Confidence

So far, AER requirements have had a positive effect on the dietary supplement industry and have been in line with industry expectations.

“Overall, I feel it has been a good thing for the industry to have to implement this,” said Sheets. “Now that we all must be GMP compliant, the AERs have become a part of the GMP process in our company. It forced us to really take a look at how we handle the AERs—document our process and train our employees on how to handle them—so we can be GMP compliant. In the end, the customer will benefit from our having to go through this process.”

Shao agreed, adding that when Industry lobbied to pass the AER bill, CRN felt it would demonstrate the broad safety profile for the industry, and that has proven to be the case. “If you look at the numbers, they are low, relative to those from other FDA-regulated industries,” he said. “There was concern among some in the industry about how the AER reports were used for the Hydroxycut voluntary recall, and how they could be used in requested recall situations in general, but we have found the agency to be transparent and willing to share their thoughts about how AERs play into situations like this.”

Sheets said at Bio force, it has been the consumer that calls to ask about a reaction or symptom. Improvements needed in the process, she added, included getting the SOP (standard operating procedure) done and others trained on it so that it could be handled properly even if the designated person is not here.

Safety Call is used to working with all types of companies and consumer products in general, Kingston said, which puts the company in a good position for working with supplement manufacturers.

“We work closely with companies that have general consumer products and get calls from consumers reporting adverse events. These are spontaneous events that come directly from consumers.” He explained that for the supplement industry, consumers are contacting manufacturers directly as opposed to adverse events involving prescription drugs where reports come from a health care practitioner such as a physician or from a clinical trial. “There’s not a health care professional prescribing the supplement, so it’s not unusual for the consumer to call the manufacturer directly.”

Shao expressed that responsible manufacturers haven’t been the problem regarding AERs. “What concerns us is the potential for AERs from products that are marketed as dietary supplements, but, in fact, are unapproved drugs— those categories where we’ve seen the most FDA warning letters, where companies are illegally spiking products with prescription drugs,” he said. “Although technically not dietary supplements, those products have the potential to cause serious adverse events.

“Right now our industry needs to focus on how to get bad actors out of The dietary supplement industry,” Shao continued. “The actions of a few who are marketing illegal products and calling them dietary supplements threaten consumer trust and could be the foundation for new and inappropriate legislation.

CRN and other trade associations worked closely together to pass the AER bill because it was the right thing to do. We need to put our heads together and find ways to help FDA enforce current regulation, so all companies, not just the majority of them, are abiding by the law.”

Kingston agreed: “I think organizations such as CRN that bring companies together to share best practices is one of the best things for the industry. It’s the fringe that puts everybody at risk.Good companies want to see the FDA enforce those who do nothing to ensure that their products are safe.” 

FDA Response

As may be expected, manufacturers are concerned about reporting adverse events to FDA, Kingston said. “But just because a company makes a report, doesn’t mean the FDA will shut them down and recall the product,” he added. “Seeing the reports tells the FDA that the company is taking the rules seriously.” And, he agreed that the number of serious events is relatively small for dietary supplements.

In addition, Kingston said manufacturers should keep in mind that not all events are created equal; there are a lot of reasons why people report.
Employing the services of Safety Call ensures having the right kind of expertise to sort out what is and is not serious, what has something to do with the product and what is background noise that has nothing to do with product use.

“Also, a robust adverse event system [can] help companies demonstrate the safety of their products,” Kingston added. “The safety surveillance system can help them demonstrate how safe their products are.”

He added that those answering the adverse event call could go through a computerized questionnaire or be offered an informed discussion. “We’re talking about medical conditions here and having someone who is used to talking to consumers. Oftentimes consumers are asking for advice, and an important component of adverse event reporting systems is knowing what types of questions to ask—it’s all about the nuance of knowing the right type of question and how to document the response.”

Summing up the topic, Sheets said she sees the law as part of the industry’s growing pains. “In Europe, this has been in place for quite a long time and, as a result, these types of products have gained more credibility. I hope it will be the same here,” she said. “From what I have read, the number of AERs reported shows that overall these are safe products. In the end, I hope this will Show that the reports about dietary supplements being unsafe and unregulated are just not true. That will be good for all of us.”