The implementation of the adverse event reporting bill will present the dietary supplement and nonprescription drug industries with challenges as well as opportunities, experts stressed at a recent United Natural Products Alliance seminar on the implementation of the new law.

UNPA held the seminar in Salt Lake City on Jan. 11, less than a month after the Dietary Supplement and Nonprescription Drug Consumer Protection Act was signed by President Bush (¹ 'The Tan Sheet' Jan. 1, 2007, In Brief).

The AER bill was widely supported by the regulated industries, trade groups and congressional staffers, especially those in the offices of Sens. Orrin Hatch, R-Utah, Tom Harkin, D-Iowa, and Dick Durbin, R-Ill., who worked diligently to get the measure passed (² Also see "Adverse Event Bill Down To The Wire As Congress Wraps Up" - Pink Sheet, 11 December, 2006., p. 8).

According to UNPA head Loren Israelsen, the determination with which the dietary supplement industry pursued passage of the bill "pleasantly surprised" some parties "historically critical of the industry" (³ 'The Tan Sheet' Dec. 18, 2006, In Brief). However, industry cannot sit back and relax, he said.

"There will be scrutiny now; there will be a lot of eyes watching to see how well we do this," Israelsen stressed. "Our credibility is now on the line ... to get this right."

The UNPA seminar is the first educational forum on the implementation of the bill since it was passed; however, it will not be the last as industry trade groups have pledged to provide their members with information and tools to help companies meet the new reporting and recordkeeping requirements (⁴ Also see "Adverse Event Collection Expected To Be In Force By Christmas 2007" - Pink Sheet, 18 December, 2006., p. 4).

The American Herbal Products Association will hold an educational tele-seminar on the implementation of the law Feb. 22, exactly 10 months before the law will be implemented.

The AER bill was signed by the president Dec. 22, and will take effect one year from that date. Sen. Hatch's Chief of Staff Patricia Knight pointed out, however, that firms will have an additional year to bring labeling into compliance with the law.

Therefore, while the recordkeeping and reporting requirements will go into effect Dec. 22, 2007, firms have until Dec. 22, 2008 to bring the labels of dietary supplement and nonprescription drug products into accordance with the law.

"Clumsy" MedWatch Form

Dietary supplement trade associations already have expressed concerns over certain aspects of the implementation of the law, especially the use of the MedWatch form and the training of employees who will work with consumers and healthcare professionals reporting adverse events (⁵ Also see "Adverse Event System Success Will Depend On Trained Reporters, Experts Say" - Pink Sheet, 18 December, 2006., p. 6).

SafetyCall International President and Clinical Senior Toxicologist Rick Kingston, Pharm.D, agreed the form is not optimal for dietary supplements.

"I'm hoping that what we can do is come up with a modified form that's really usable, more streamlined, and really makes a lot more sense for companies to work with," he said.

One aspect of the MedWatch 3500A form that is not conducive to dietary supplement adverse event reporting is that it only has room to list two "suspect products," Kingston said.

"It's very common [for] nutritionally-oriented individuals ... to be taking five or six different things, and each one of those particular products could potentially trigger an event," he pointed out.

AHPA President Michael McGuffin commented during a panel session that he finds the form "clumsy" and is particularly concerned with the fact people filling out the forms "cannot ever leave a blank" space.

"You really have to fill those forms out every time the phone rings, absolutely completely, and if the reporter won't give you some information ... you have to record that you asked them and they wouldn't tell you," McGuffin said.

Anonymously Reported Events

The Dietary Supplement and Nonprescription Drug Consumer Protection Act does, however, allow reporters to remain anonymous.

According to Kingston, this could create a substantial problem for companies, especially in the area of recordkeeping.

Under the law, the company whose name is on a product's label is responsible for the reporting of serious adverse events as well as the maintenance of records related to all reported adverse events, both serious and non-serious, for a period of six years.

Moreover, any information related to the event the company receives within a year of receipt of the report also must be retained.

If a report is received anonymously, it will be very difficult for a company to track the report down if they need to add any additional data, Kingston said.

It will also make it harder to keep track of duplicate reports and identify fictitious reports, he added.

"I'm hoping that maybe we can qualify [the anonymous reporting provision] a little bit in the guidance document that's actually released" by FDA, Kingston said.

Fictitious and Duplicate Reports

Reporting of a fictitious event is illegal, but nobody is responsible for determining whether an event is fictitious, Knight and Kingston noted.

Companies will be able to assign a unique code to each report, however, and that should help firms identify or prevent the filing of fictitious reports, according to Kingston.

At least one attendee was concerned that a competitor could file false reports involving a company's product. The code would aid the firm in controlling and managing "some" of the reporting process, Kingston said.

In addition to anonymous reporting, multiple pathways for a report to be received (through a poison control center or direct to FDA, for example) could create duplicate reports, he pointed out. Additionally, dietary supplement consumers on a multi-product regimen could report a single event to several companies.

Tag, You're "It"

The 15-day deadline for companies to report serious adverse events to FDA is a separate concern for Kingston. "That is an extremely short period of time," he told attendees.

"It's like [the reporter] touch[es] somebody in your company and it's 'tag, you're it' and the clock starts ticking."

Within 15 days after receiving notification of the event within the company, the event must be reviewed, either in-house or by a team of consultants, to assess whether it is a serious event, whether there is sufficient information and whether "you understand what's going on there," Kingston said.

"Then you have to identify your particular product label so you can submit that with the report," he added.

It "seems like a fairly straightforward process ... [but] if you're getting a lot of minor types of events - stomach cramps and things like that - there are a lot of nuances. Even some of those types of effects" might be a reportable event in certain circumstances, Kingston said.

Additionally, the 15-day deadline applies to updates on already reported events the company receives.

"There are not going to be that many serious adverse events that come in .... It's probably the rest of the data that is going to be a bigger issue," he observed.

Media Influence

Kingston informed attendees that at some point the media will probably impact the number of reports industry receives. A report on the news about an ingredient being linked to an adverse health event, for example, will increase the number of calls, he said.

However, the relative intensity of the outcomes will remain the same, Kingston said. In other words, the volume of reports will increase, but the percentages of mild, moderate and severe cases will remain constant.

"It's going to happen. So, you just need to be prepared as to how you present that data and how you track that in the context of your interpretation," he said.

Differences Between OTCs and Rx Drugs

This phenomenon will be increased by a relatively unique aspect of adverse event reporting for nonprescription products. Unlike Rx products, OTC products share ingredients and thus inherit risk from each other, as well as from negative media and studies on an ingredient.

Furthermore, while ingredients may be shared, concentrations and combinations of the ingredients will vary widely. Proprietary blends with undisclosed concentrations will cloud this issue even more.

"It's going to make it difficult for you to fully understand in some circumstances" what is going on with a certain ingredient, Kingston said. "Certainly, it's going to make it difficult for others who are looking from outside to understand."

Adding to the "product versus ingredient problem" is the fact that studies in the dietary supplement industry tend to be conducted on ingredients rather than individual products.

"The safety of supplements and related ingredients will be defined by spontaneously reported adverse events regardless of the quality and integrity of those reports," Kingston stressed.

"So, it's best for you to have a good handle on what it is that you're receiving and what it means to you, your product and the ingredients that are in your products," he said.

Another aspect of nonprescription reporting that differs from Rx reporting is that consumers expect toxicity from prescription drugs but expect safety from over-the-counter products, especially dietary supplements.

Consumer "Desensitization"

Historically, adverse events have been "customer complaints" in the dietary supplement industry, Kingston said. "Now, they're going to be called adverse events, and we've lived in a paradigm of zero tolerance of adverse events with dietary supplements."

"Companies have kind of promoted it, [and] the public has as much as said, 'we don't want any adverse events with something that is supposed to be ... safe,'" he noted. "So, there's going to be a little bit of a nomenclature issue and desensitization of the public that needs to take place."

"People are taking your product because it does something. They're not taking it because it's like water, and it just goes through your system," Kingston pointed out. Therefore, there are going to be adverse events. "There's a physiological response, a pharmacologic response, even though it's not classified like that."

According to Kingston, the trade groups "are going to have the task of educating people as this thing goes on."

Qualifying Data in Reports

Throughout his presentation, Kingston emphasized the importance of including qualifying data in reports.

The less information included with a report, the more it will be taken at "face value," he said. "So, if you can qualify that event, find out what other types of drugs the person is on, changes in therapy, other supplements, other lifestyle things," it will benefit the firm by putting it in context.

"If you get called in by the FDA, they will give you the opportunity to present your side of the story, and they're going to be open to it," Kingston said.

Additionally, more information will help FDA as the agency tries to determine cause and effect.

Other data a company will want to have in its "back pocket," is the total number of doses in the marketplace or total amount of product in the marketplace. This will help put the number of serious adverse events reported in context.

This information is very important "for data normalization and, ultimately, product defense," he said. However, firms want to use discretion when reporting this information to FDA, Kingston said. He recommends firms determine a trigger point at which they will send this data to the agency to put the number of events in context.

Firms should not get into cause and effect in the reports, McGuffin stressed. "There is no cause and effect requirement," and AHPA advises "strongly" against a firm telling FDA whether it thinks its product had anything to do with the event, he said.

"From a strict liability point of view, your obligation is satisfied when you" report the serious adverse event to FDA, he emphasized.

Kingston and other industry stakeholders will be talking with the Center for Food Safety and Applied Nutrition to figure out "how to have a give-take relationship without sharing all your confidential data," he said.

In fact, Kingston will be talking about the development of the guidance with "some officers from CFSAN" following a February Institute of Medicine committee meeting on the monitoring of dietary supplement adverse events in the military community.

"Fly-By-Night" Firms

At the end of the seminar, Israelsen added one more concern to Kingston's list.

"There is another part of our industry that, in my judgment, has no intention of complying with this law or any other," he said.

Furthermore, these firms are often companies marketing the type of stimulant products that are likely to cause adverse events, Israelsen said (see ⁶ Also see "Multi-Ingredient Caffeine Products Easily Top Adverse Event List, Study Finds" - Pink Sheet, 29 January, 2007.).

"That is our big problem," he told attendees.

The implementation of the AER bill and the future GMP requirements will cause some "major shifting" in the dietary supplement industry, Israelsen predicted.

The Good Side

"There are a lot of strengths, too, and I don't want to minimize that," Kingston said.

"When you collect spontaneously reported data, you get a good safety profile of what's happening with your product," he said. Additionally, "the fact that you've got this critical mass" increases the likelihood that firms will discover serious events, as well as the adulteration of products.

"When you're looking at a safety profile, you want to make sure that you have sufficient 'penetrance.' What we mean by that is, if there was an adverse event, what's the likelihood that you'd know about it and that it would be reported," Kingston said.

"With this particular law, I think we can make a pretty good argument to the public and health professionals that for the first time everyone's on a level playing field."

The collection of adverse event reports will also allow firms to monitor their products and discover, for instance, if a specific batch of raw ingredient is contaminated with bacteria, which would be indicated by a rise in gastrointestinal adverse events being reported after the firm begins working with a new supplier, Kingston said.

On the other hand, this benchmarking capability also means FDA is likely to "have an expectation that you would be monitoring and watching that." As Kingston pointed out, FDA likely will be evaluating firms' compliance on a performance-oriented basis (⁷ Also see "FDA Likely To Take Holistic View Of AER Bill Compliance, Expert Says" - Pink Sheet, 22 January, 2007., p. 3).

The additional data, however, will help companies design research protocols "as more companies are getting involved in that process."

Knight pointed out the law does not apply overseas, a requirement the industries were "adamantly against" but was supported by FDA. The agency "regularly" suggested the bill apply overseas, she said.

Dick Griffin, an insurance industry veteran and principal at Grifcon Enterprises, said one thing that companies likely will not have to worry about is high insurance rates.

Many people in industry have been concerned that the new adverse event requirements would lead to an unmanageable rise in the cost of insurance, Griffin and Israelsen noted.

However, "from an insurance point-of-view everything is quite bright right now," Griffin said. The rates currently are in freefall and are expected to go down for the next five to 10 years, he said.

The AER bill is important to industry and public health, but really has little to no impact on insurance, Griffin said.

The price of insurance is "not falling because you're doing a much better job. It's falling principally because ... right now [insurance companies] are making a lot of money because they're not suffering any type of claims that are of great importance ever since 9/11," he said.

Additionally, the dietary supplement industry has never had a loss ratio greater than 8 percent, and "8 percent is absolutely wonderful from the insurance point of view."

In-House or Outsource?

When a firm is trying to decide whether to manage the reporting and recordkeeping requirements in-house or outsource it to a third party like SafetyCall International, "take a look at what kind of staff you've got," Kingston said.

"Do you feel comfortable with their ability to receive, document, put together a good ongoing system and maintain the stuff, and do they have the expertise that's necessary to respond to these types of events and classify the incidents?"

Additionally, firms should be aware that if they have one person designated to handle the reports, that person cannot be available all the time. On the other hand, if they have multiple people responsible, the firm needs to make sure that the reports are being received and maintained in a consistent fashion.

If a dietary supplement firm, in particular, decides to outsource, the company needs to make sure the third party "understands how your products are used and the importance of those products."

The firm should also have a relationship and good reputation with FDA and other agencies. "If they end up being called in to discuss something, you" want them to get a "friendly invitation and a friendly reception."

The third party should also be appropriately insured, Kingston said.

The requirements of the new law will likely be more difficult for medium-sized companies than small or large firms, one participant at the conference pointed out.

Small firms will have a higher degree of control over their employees, and large firms will have the resources to have an in-house team or contract the process out, he explained.

Another participant at the conference pointed out that firms, especially smaller firms, marketing a functional food or beverage as a dietary supplement may want to begin marketing the product as a conventional food to avoid the new requirements.

- Katia Fowler

Experts Give AER Prep Course, Discuss Potential Potholes At UNPA Seminar

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