In 2008, the dietary supplement industry must decipher FDA guidance on the good manufacturing practices regulations final rule while developing standards for areas the agency intentionally left vague, United Natural Products Alliance Executive Director Loren Israelsen says.

FDA provided the industry with insufficient clarity in its guidance on GMP compliance since it published the final rule in June 2007, he says (¹ Also see "Supplement GMPs Stress Responsibility, Put Firms In Driver’s Seat For Testing" - Pink Sheet, 25 June, 2007., p. 3).

"It's very tough for industry to understand whether FDA's post-publication statements in the forms of tele-seminars or public statements at conferences or whatever [are] to be taken as personal opinion or as agency policy, enforcement policy. That's most unhelpful," Israelsen said.

"FDA's subsequent comments have been mostly confusing, with respect to head counts for example."

The agency's stated approach to measuring head count in determining a firm's size for the purpose of setting compliance schedules over the next three years has raised concerns among stakeholders (² Also see "FDA Using GMP Head Count Method That May Shorten Compliance Schedules" - Pink Sheet, 25 February, 2008., p. 3).

FDA officials say that if firms contract with companies to manufacture their products, or are subsidiaries of larger companies, the other firm's employee totals would be included in their head counts.

"Companies quite honestly do not know what their compliance deadline is," he says. "It appears if we added up all of the contract manufacturers that we use ... a significant percentage of the industry would at least be in the 24-month if not the 12-month compliance group," Israelsen said.

Further, the planned GMP head-count method violates a central tenet of the final rule, he says.

"FDA went to great lengths in the regulation to say, 'We've made extraordinary efforts to accommodate small businesses, recognizing that the vast majority of companies covered by the rule will be small businesses.' Then FDA says, 'By the way, you have to add up the head counts of your contract manufacturers,'" Israelsen said.

"That is contradictory to the intention that was manifested in the regulation itself," he said. The uncertainty puts pressure on firms to act conservatively and use the earliest possible compliance date, he added.

FDA Needs To Put It In Writing

The uncertainty is compounded by FDA officials describing the agency's plan in public comments rather than with guidance published for public comment.

"The agency needs to put something in writing, in my judgment. These public statements just are not suitable," Israelsen said.

Supplement firms have little information to use for making production plans under the GMP final rule, but compliance is crucial to those plans, he says.

"If I was a CEO I'd say, 'I'd like to see something in writing before I start committing millions of dollars and demanding that my down-line supply chain meets compliance obligations all based on an unwritten statement that clearly contradicts the overall intention of the regulation.' But I've not heard FDA come back with any further clarification in writing or verbally that would correct that," Israelsen said.

He added that FDA officials' advice to firms to confer with the agency's district or regional representatives to determine compliance schedules is an "invitation for confusion" because it allows for individual interpretation at those levels.

This patchwork approach "fails to provide adequate notice and guidance to industry" and is likely to lead to enforcement actions that would not withstand a challenge in court. "Should FDA assert that something is a GMP final rule violation, I think a company could quite readily say, 'Based on what?'" Israelsen observed.

Firms receiving ingredients or contracting for other services with multiple companies in different FDA districts could be particularly disadvantaged, he says.

"This is a federal regulation that requires a national standard, that is not driven by regional opinions of FDA staff who individually have very little experience with dietary supplement manufacturing."

Enforcement: Bumps In The Road Ahead

Another GMP complication is FDA's enforcement capabilities. Although the final rule came 13 years after it was required by the Dietary Supplement Health and Education Act, the agency in that time did not become prepared to execute enforcement of the regulation, Israelsen says.

However, the industry's supply of products to the market will be directly affected by how effectively and consistently FDA enforces GMP regulations.

FDA's "expertise in the field is such that it will take time ... through a series of inspections, to get a good understanding of what they believe GMP compliance looks like. I would expect them in the early phase here, as of June this year, that there will be some bumps in the road. There will no doubt be some disagreement between industry and FDA inspectors as to what is compliant and what is not," Israelsen said.

FDA's lack of supplement manufacturing expertise is mitigated by their crafting the final rule to allow industry to lead in developing GMP standards, he says.

"We have several certifiers for dietary supplements, all of them competent. I would expect that that would continue as the operating software for the industry. That's how it will actually show up in the marketplace as the evidence of compliance."

Consumers are also driving the industry's creation of internal standards, he says. "The consumer is becoming more active in wanting to know, 'How can I trust a product?' In general, the retailer will look to the manufacturers and vendors for that confirmation and certification will be the principal tool to do that."

AER Label "Pejorative" Preamble Contested

FDA gave firms until January 2009 to comply with the serious adverse event reporting law labeling requirements, and in the meantime, firms still have issues with the agency's interpretation.

UNPA does not support FDA's guidance to include "preamble language" in front of the address or phone number on product labels.

"The major disagreement is on the ... language that FDA has suggested industry use, which is 'to report a serious adverse event call or write the following.' We find that unacceptable both because it is suggestive and pejorative that a consumer would look at this product and think, 'Wow is there something I should know about this?' and to predispose someone to think about a problem that does not exist."

Israelsen said he is not aware "of any other class of product that has a predicate statement to report a serious adverse event."

"We simply disagree with that and believe that it contradicts the report language that accompanied the AER legislation, where this issue was discussed and it was agreed by the negotiators in Congress that that kind of language would not be expected or appropriate. We clearly disagree with FDA on that."

Israelsen suggests firms should simply follow FDA's guidance as it relates to including full address information on labels.

Some stakeholders maintain "that the standard requirement of business name, city, state and zip code will be adequate if you're in the phone book," he said. "My personal view is that it's in the interest of all companies, not just dietary supplement companies, to provide as much contact information as can be effectively used by a consumer."

Eye On Legislation

The industry should follow closely any attempts in Washington or at any state legislature to limit access to vitamins or other supplements because of unfounded suspicions linking the products to controlled substances such as anabolic steroids.

"Is it possible that an enthusiastic state legislator sees himself as being a champion of an issue and he ends up trying to slip in one or more supplements? I can't imagine at the moment what it would be that there would be concerns about, but ... you just really can never anticipate what somebody is going to do," Israelsen said.

Like Congress' investigation of the use of steroids in professional and college sports, drug testing of athletes during the Summer Olympic Games in Beijing this year is likely to generate claims of tainted substances causing positive test results (³ Also see "Industry Says MLB Players Union Off Base Linking DSHEA To Steroid Violations" - Pink Sheet, 21 January, 2008., p. 6).

"The Olympics are probably going to be the interesting thing to look at to see whether or not there are any hiccups along the way with athletes claiming that they had testing problems and blaming supplements for that. That is possible, but as we have seen with Major League Baseball, the claims of players that they were somehow duped into taking what they thought were supplements is disingenuous at best."

As for the elections, while he expects "substantial turnover in the House and Senate," Israelsen says the leading proponents and opponents of the supplement industry are not likely to lose their seats.

Sens. Orrin Hatch, R-Utah, and Tom Harkin, D-Iowa, are long-time nutritional product advocates; on the other hand, Sen. Dick Durbin, D-Ill., and House Democrats Rosa DeLauro, Conn., John Dingell, Mich., and Henry Waxman, Calif., are frequent critics.

Further, if Democrats retain a majority in both chambers, the industry likely will face continued scrutiny on the quality of its products.

"It's counterintuitive. You would think with a stronger Democrat majority that that would historically favor our industry, but that has not been the case. The more Republican the Congress, the less that issues have been raised with respect to supplements," Israelsen said.

"But I think that is really partly a result of historical players being there for a very long time, pre-DSHEA, during DSHEA and all of the post-DSHEA issues."

- Malcolm Spicer (m.spicer@elsevier.com)

GMP Guidance Puzzle Is Chief 2008 Challenge For Supplement Firms – UNPA

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