November 15, 2009 (Vol. 29, No. 20)

Agency Takes a Tough Stance on Hype, Defines Combinations, and Issues REMS Guidelines

FDA reads your press releases, and it reviews your promotional materials and websites. It doesn’t just give them a cursory glance either, it scrutinizes them. As a result, biotech/biopharma companies are advised to fight the urge to dwell on or embellish the positives, especially in press releases where negative news actually predominates. This clouding of the truth is viewed by FDA as misleading and violative. 

In fact, the former CEO of InterMune, which has an approved biologic license, was convicted of wire fraud for issuing a press release in 2002 that positively spun the results of failed clinical trial. The company characterized the Phase III data as “demonstrating survival benefit” and reducing “mortality by 70% in patients with mild to moderate disease.”

According to the Department of Justice, this conviction demonstrated a commitment to hold accountable those corporate executives who provide false and fraudulent information about pharmaceutical trials.

“Pharmaceutical executives who promote drugs using false and misleading information should not be allowed to hide behind a corporate shield,” said Kim Rice, special agent in charge of FDA’s Office of Criminal Investigations. “Pharmaceutical companies do not run themselves, and those who engage in criminal conduct will be held personally accountable.”

What is important here is that the FDA and the Department of Justice are clearly establishing a standard for information disclosure about clinical trials data. Companies issuing a clinical trial result press release should be extremely wary of embellishing where there are obvious negatives, and they should seek legal input on the appropriate wording of press releases. 

That said, firms should not attempt to hide behind the sign-off of outside legal FDA counsel. In another legal skirmish, the SEC brought action against a company and its management for a press release that sounded too positive after rejection of a Biological License Application, even though outside FDA counsel had signed off on the wording. 

FDA is also cracking down on hype in promotional materials. It has sent warning letters to companies about the omission of risk information or the broadening of the indication of an approved drug on a company website. FDA’s position is that promotional materials are misleading if they fail to reveal material facts when recommending the use of a drug.

One company was recently reprimanded by the FDA when its website presented an “unbalanced picture of the benefits and uses [of an approved drug]”. After FDA alleged that the website was violative because of the omission, it then alleged that the company had failed to submit Form FDA-2253 for transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human Use.


The Federal Court recently reaffirmed that the “responsible corporate officer,” regardless of whether they have knowledge of FDA noncompliance in the corporation, will be held to strict criminal misdemeanor liability. The relevant case centered around liability and civil penalties for the failure of a company to submit product failure reports to FDA. These failures were first identified during a cGMP inspection.

The FDA expects CEOs/presidents to adequately supervise their company’s compliance efforts in quality control, quality assurance, regulatory, and clinical studies. The initial judgment for civil penalties was assessed by a Department of Health and Human Services (HHS) administrative law judge against the company and its president, was subsequently affirmed by the HHS Appeals Board, and then affirmed by the 10th Circuit Court of Appeals. 

The level of liability exposure to senior and middle management was further demonstrated on October 29, when the former president of Stryker Biotech and three of its current sales managers were indicted for illegal promotion, misbranding, making false statements to FDA, and wire fraud. These defendants allegedly promoted OP-1 products mixed with an unapproved excipient, Calstrux, for implantation, resulting in patient deaths and serious medical problems. Additionally, Stryker has a number of outstanding warning letters that have not been closed, which could mean more FDA compliance issues for Stryker corporate.

Combination Products

FDA has issued a proposed rule that defines a combination product as being either one that is physically combined or copackaged, and also, one established by cross-labeling where the components are separately manufactured or packaged, but expressly labeled for use with each other (See 21 CFR3.2(e)(1)-(4)). 

Furthermore, the constituent parts of the combination (drug, biologic, or device) retain their individual cGMP requirements when combined during manufacturing; thus, a manufacturer combining a drug and device must demonstrate compliance with drug cGMPs and also design controls provisions. Companies developing combination products, particularly those containing devices, need to be especially cognizant of the new proposed rule (74 Fed. Reg. 48,429, September, 2009). 

Risk Strategies

At the end of September, FDA issued extensive risk evaluation and mitigation strategies (REMS) guidance with examples of REMS elements. Instructions on how to modify approved REMS were also provided. The importance of this guidance for biotech/biopharma companies is multifold. First, there are an ever-increasing number of pharmaceutical products and classes of products now being subjected to REMS regulatory requirements. Companies need to anticipate whether their product will be subjected to REMS and plan for it. 

Second, though FDA adamantly denies any correlation, many believe that therapeutic products that provide clinical benefit but have some FDA-perceived safety risks can more easily be approved/licensed when subjected to REMS.

In fact, the guidance allows that a proposed REMS can be submitted in the original drug application, as a supplement to an existing application or as an amendment to an original application. A senior FDA official has said that the REMS requirement might affect priority drugs disproportionately as compared to standard NDA applications as FDA is less likely to impose REMS on a drug that does not offer a clinical advantage over an approved drug. It is interesting to note that priority-rated NDAs continue to get reviewed and approved much faster that standard NDAs.

Pharmaceutical companies developing new products obviously favor those indications that will receive priority-rated NDAs, given the faster approval times. In choosing such indications, companies now need to consider the implications of having to comply with REMS guidance.

Although most pharmaceutical executives are frustrated by REMS, it does have its benefits, as acknowledged by a biopharma executive under a consent decree requiring dissemination of REMS-mandated information. The executive said that he did not mind the requirements to disseminate such information to physicians since it actually enhanced the companies’ ability to interact and build creditability with the prescribing physicians.  

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:

Previous articleMaking Sense of Antisense and Its Rebound Potential
Next articleSpherix’ Preliminary Late-Stage Data Bodes Well for Oral Antidiabetic