Drug, Supplement Industries Need Formal But Timely Guidance - Stakeholders

Food and drug industry stakeholders suggest FDA clarify regulatory expectations and justify requirements through written and finalized formal guidance rather than through speeches and other informal communications.

In comments to the transparency task force FDA announced in June, stakeholders also urge that the agency prioritize developing timely and current regulatory guidance in a variety of areas, including much-needed information on dietary supplement good manufacturing practices inspections and new dietary ingredient notifications.

The task force, headed by Principal Deputy Commissioner Josh Sharfstein, solicited comments through Aug. 7 on how FDA can improve communication and better explain agency decisions (¹ (Also see "Supplement Industry Wants Answers From FDA Transparency Task Force" - Pink Sheet, 8 Jun, 2009.)).

At a Risk Communications Advisory Committee meeting Aug. 14, Afia Asamoah, special assistant to Sharfstein, said FDA will reopen the docket at least through the next task force meeting to be scheduled in the fall.

New policies and regulatory positions announced in letters to individual firms or by agency officials at public meetings are often inconsistent and lack clarity that "could result in compliance challenges," the Pharmaceutical Research and Manufacturers of America says.

"Podium policy" makes "it difficult for the public and regulated industry to learn about new developments," and creates "a very uneven understanding of requirements," the Combination Products Coalition, which represents biological product and medical device manufacturers, agrees in its comments.

PhRMA and CPC suggest FDA adhere to good guidance practices, which prohibit informal communication of new or different regulatory expectations to a public audience for the first time. Through good guidance, policies go through a formal guidance process with public comment before implementation.

The Council for Responsible Nutrition says the regulatory information that industry awaits includes additional guidance on FDA's decision-making process for reviewing NDI notifications and the GMP inspection process.

CRN asks FDA to explain "the evolution and basis for" a recent verbally communicated decision that firms need to submit an additional notification for any new formulation containing a permitted NDI (² (Also see "NDI Notification Guidance To Assist Puzzled Industry Could Emerge In 2009" - Pink Sheet, 12 Jan, 2009.)).

Until now, the industry assumed it could use an NDI for which FDA had no objections in different formulations as long as the ingredient was identical to an NDI submitted to the agency, CRN says.

Why would FDA allow the industry to operate for so long "under a set of seemingly incorrect assumptions?" Douglas MacKay, CRN's VP for scientific and regulatory affairs, asks in the group's comments.

In addition, CRN is concerned that because FDA communicated the new policy verbally instead of through formal, written guidance, there is a "lack of awareness among industry members of FDA's abrupt decision to only recently communicate its interpretation of the law."

CRN acknowledges FDA's resource shortage may have precluded more formal communication, but says, "We also believe that a lack of transparency around FDA's decision-making process" is "an equal contributor" to the confusion on NDI policy.

Groups Seek Additional GMP Guidance

CRN also would like additional compliance guidance for GMPs to help firms better prepare for inspections. In particular, it would like to know how manufacturers should qualify ingredient suppliers, "what proper qualification means" and which company records GMP inspectors can access.

The trade group adds it will work with FDA to develop ingredient supplier qualification guidelines that "could serve as the basis of industry best practices or even future regulation."

The 2007 GMP final rule leaves substantial discretion to supplement firms to establish their own systems for qualifying vendors. The rule says to qualify a supplier, a manufacturer must "establish the reliability of the supplier's certificate of analysis through confirmation of the supplier's tests or examinations" (³ (Also see "Supplement GMPs Leave Vendor Qualification Specs In Manufacturers’ Hands" - Pink Sheet, 3 Dec, 2007.)).

CPC asks for more guidance on how GMPs apply to combination products, noting that existing guidance "has been helpful" but the combination product industry needs additional guidance. It also reminds FDA that it announced "its intent to propose regulations for GMPs for combination products in the spring of 2006."

CPC urges FDA to finalize "important guidance documents left in draft for far too long," including drug adverse event reporting guidance.

The group specifically mentions 2001 and 2003 draft guidances about providing regulatory submissions on post-marketing expedited safety reports in electronic format.

"This new draft guidance is still a draft, eight years after the first draft was released," according to CPC's comments prepared by attorney Bradley Thompson of Washington firm Epstein Becker & Green.

The Natural Products Association also seeks answers on AER guidance. The trade group wants to know why FDA took the "unprecedented step" of mandating through guidance for the 2006 Dietary Supplement and Nonprescription Drug Act that firms print full addresses, or phone numbers and introductory statements on supplement and OTC drug product labels.

Since FDA issued its first draft guidance on supplement AERs in December 2007, NPA and other industry stakeholders have argued the law does not require full addresses and introductory statements on labels and that other FDA-regulated products do not have the same requirement (⁴ (Also see "Final Guidance For Reporting Adverse Events Gets Serious On Definitions" - Pink Sheet, 20 Jul, 2009.)).

"This is just one example as to where we are unclear as to why the agency reached the conclusions that they did," Daniel Fabricant, NPA's interim executive director, said at a June 24 public meeting about transparency.

FDA in December 2008 extended the AER label compliance deadline until January 2010 because guidances for the supplement and OTC industries were not final. The agency has not indicated when it will post final label guidances or whether it will extend the compliance date again.

FDA's Online Policies Unclear

CPC also would like more guidance related to online promotion and on food and nantotechnology.

In the absence of Internet marketing guidance, several drug manufacturers erroneously expected they could provide risk information about a drug within "one click" of paid advertising that appears with results of online searches for certain terms.

In March 2009, FDA submitted warning letters to several firms to include risk information about a product with the first screen of an ad's content (⁵ (Also see "Internet Promotions Must Be Redesigned After FDA Cites Sponsored Web Links" - Pink Sheet, 13 Apr, 2009.)).

CPC argues the agency "could have easily cleared up the policy in this area through guidance" that would have helped "preserve agency resources by disseminating information to a broad public audience," rather than issue individual letters that continue to confuse industry about FDA policy.

Use Web, Conference Calls For Outreach

Guidance is not helpful if it is not known to stakeholders and consumers, the Alliance of Specialty Medicine observes in its comments advocating that FDA consider new outreach initiatives to better educate the medical community about rules, regulations and guidance documents.

It recommends FDA host periodic conference calls on focused topics, similar to how the Centers for Medicare and Medicaid Services holds regular "open door forums" at which stakeholders can learn about and provide input on developing topics.

Another way to improve outreach is to improve FDA's Web site, the alliance adds. Specifically, it asks FDA to repair online links that became inoperable when the agency recently updated its Web site. Repairing the links would facilitate searching for guidance and regulation.

The Union of Concerned Scientists adds in its comments that FDA should redesign the Drugs@FDA database with an easy-to-use portal for finding safety and labeling information about FDA-approved products.

FDA also should add a link on its home page to a page that explains in consumer-friendly language how the agency approves and regulates drugs, says PhRMA.

Protect Appropriate Confidentiality

FDA must carefully balance transparency with appropriate protection of confidential information, many stakeholders caution.

"Increased disclosure requirements that fail to protect trade secrets and confidential commercial information associated with innovative research and development not only will violate existing legal requirements, but also will harm, rather than improve public health," PhRMA says.

PhRMA explains if FDA were to disclose proprietary pre-approval information in the course of clarifying the approval process for specific products, competitors could easily "glean" information from FDA that would compromise a developer's competitive edge. As a result, "the government would markedly decrease the incentive for development in the first place," the group says.

CRN also worries FDA could jeopardize fair competition if it mandates the rapid release of GMP inspection reports.

A "knowledgeable competitor may be able to access key information" from the report "that could affect competition," CRN says.

CRN further argues that it is not clear how releasing inspection results would "benefit the health of dietary supplement users."

The Center for Science in the Public Interest advocates posting online GMP inspection reports within 24 hours.

CSPI suggests firms post the results on their Web pages and FDA create a searchable database for the results, according to a presentation by Sarah Klein, a food safety attorney for the advocacy group, at FDA's public meeting on transparency.

Often guidance and regulations are only as strong as their enforcement. CRN recommends FDA reinforce new policies with more enforcement, including more frequent and intense GMP inspections.

The group explains, "Without the threat of adequate enforcement, there are not perceived consequences for criminal behavior."

- Elizabeth Crawford ( ⁶ [email protected] )