September 15, 2009 (Vol. 29, No. 16)

Two Recent Actions that Amend Guidelines Illustrate Growth in Political Support

The FDA Commissioner recently signaled that cGMP/GCP/GLP compliance will be the catalyst for the issuance of Warning Letters within 15 days after an inspection has been completed. Currently it can take two to four months for a Warning Letter to be issued. Usually, companies with a significant FDA 483 Notice of Observations can ameliorate the severity by providing a voluntary 483 Response Letter listing corrective actions that have been or will be taken. 

The new 15-day timeline will require companies to act immediately and get a 483 response to the FDA within 48–72 hours in order to have any potential impact.

This paradigm shift is a clear sign that FDA believes it has the political support to act more aggressively than it did under the previous administration.

The underlying legal/regulatory threat  is that FDA will issue Warning Letters regardless of the corrective-action promises made. The agency will do this in order to build a record upon which it has the option to take more serious action, including consent decrees, indictment of management, and civil penalties. When the response to a 483 is delayed or incomplete, it could be interpreted as a lack of commitment from the company. In contrast, an immediate and thorough response shows that a company is trying and is not recalcitrant.

This new initiative will require that companies shift more resources, manpower, and economics into quality control and assurance. Such actions will be more difficult where the nature of the 483 noncompliance shows a systemic cGMP problem. In this case, a company will need to show FDA that it has a creditable immediate plan of action with measurable time points. 

The FDA has hired 450 new field inspectors/investigators. These new hires include recent college graduates, individuals with advanced degrees, and industry experts. The frequency and thoroughness of field inspections is likely to increase as a result of this enhanced staffing. 

Recently, I have seen a greater number of FDA field personnel in attendance at inspections, especially for-cause inspections. With an increased FDA presence, companies need to step up their employee participation as well. Firms must now train more staff members on how to handle inspectors, as well as have more support personnel to retrieve FDA-requested documents. Having such trained people will be critical to mitigate and facilitate the inspectional process.

Under the new Warning Letter procedures, it is critical that companies thoroughly prepare for the exit interview, where observations will be shared and companies expected to respond to each observation. Usually as an inspection is under way, FDA inspectors will identify their concerns to the company representatives in attendance. These concerns will likely appear on the 483, and having knowledgeable personnel attend the inspection will give the firm invaluable advance notice. 

After the FDA leaves the company for the day (usually at 3:00 pm), company officials need to spend several hours discussing potential observation(s) and developing reasonable strategies for corrective action to be articulated to the FDA inspector(s) during the exit interview at the conclusion of the inspection.

FDA investigators will note in the 483 document the company’s willingness to make corrective action or explain why the observation is not accurate. I believe it is beneficial for companies to prepare an extensive document on what, how, and when they are going to take the required actions. It is crucial to get the FDA inspector to add this to the internal Establishment Inspection Record, which accompanies the 483 during the FDA’s administrative review process.

If FDA suspects major noncompliance that presents a public health risk, local and state inspectors, who may have greater authority to immediately shut down a company, will be contacted. This risk is particularly strong in states that more aggressively regulate biomedical companies. 

It would not be surprising if in the near future there were major criminal complaints filed against companies that FDA feels lack serious commitments to compliance. At least two major medical-device companies have experienced a number of facility inspections with 483s and Warning Letters being issued.

Biomedical companies need to reassess their allocation of resources to address this new paradigm. One immediate action that companies should consider is significantly increasing the frequency, scope, and thoroughness of their internal audits to identify potential problems and implement corrective actions to upgrade their compliance level. Companies should also use audits as mock inspections to test their readiness for the real thing.

Truth in Product Promotion and Physician Education

When draft guidance on “Presenting Risk Information in Prescription Drug and Medical Device Promotion” is finalized, companies that minimize risk in their advertising promotions (written, oral, and Internet) to consumers and physicians are at compliance risk. FDA has found that the most frequent violation is either omitting or minimizing risk information provided to consumers and even physicians.

This draft guidance follows the regulatory tenets previously expressed in the Division of Drug Marketing, Advertising and Communications’ Warning and Untitled Letters. The regulatory standard for drugs, biologics, and devices in judging the adequacy of the products’ promotional materials is the “reasonable consumer standard” which FDA has been using for foods and dietary supplements, a.k.a., nutraceuticals. The guidance provides a number of good examples of promotional language deemed by FDA to be inadequate in presenting risk information.  

I recommend that corporate compliance staff members provide copies of this guidance to their sales/marketing colleagues. It is essential that sales and marketing departments understand the seriousness of this action and that several large medical-device companies have recently been convicted of or plead guilty to criminal violations of FDA regulations. In addition, Wall Street analysts are now reading 483s, resultant Warning Letters or absence thereof, and criminal indictments/convictions of sale and marketing people to arbitrage the value of biomedical companies.

Bruce F. Mackler, Ph.D., J.D., a senior advisor in FDA matters, is lead contributor to GEN’s “Spotlight on the FDA” column. Web:

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