I am stealing a quintessential line from the movie “The Russians Are Coming, The Russians Are Coming”, to explain the emergent nature of the FDA’s proposed revision to its labeling rule to permit unilateral changes in safety information for certain applications for which the Federal Food Drug and Cosmetic Act (FDCA) clearly precludes such changes.  So those of you in industry you have a choice – either raise your voices and raise them loudly, or contact your liability carriers and raise your limits and secure good defense counsel.

The Proposed Rule, which will publish on November 13, 2013,  “is proposing to amend its regulations to revise and clarify procedures for application holders of an approved drug or biological product to change the product labeling to reflect certain types of newly acquired information in advance of FDA’s review of the change. The proposed rule would create parity among application holders with respect to such labeling changes by permitting holders of abbreviated new drug applications (ANDAs) to distribute revised product labeling that differs in certain respects, on a temporary basis, from the labeling of its reference listed drug (RLD) upon submission to FDA of a “changes being effected” (CBE-0) supplement. The proposed rule would create parity among application holders with respect to such labeling changes by permitting holders of abbreviated new drug applications (ANDAs) to distribute revised product labeling that differs in certain respects, on a temporary basis, from the labeling of its reference listed drug (RLD) upon submission to FDA of a “changes being effected” (CBE-0) supplement. The proposed rule describes the process by which information regarding a CBE-0 labeling supplement submitted by a new drug application (NDA) holder, an ANDA holder, or a biologics license application (BLA) holder would be made publicly available during FDA’s review of the labeling change and clarifies requirements for all ANDA holders to submit conforming labeling revisions after FDA has taken an action on the NDA or ANDA holder’s CBE-0 labeling supplement.”  And in a change from the existing Physician’s Labeling Rule, the Proposed Rule “rule also would amend the regulations to allow submission of a CBE-0 labeling supplement for certain changes to the “Highlights of Prescribing Information” for drug products with labeling in the “Physician Labeling Rule” (PLR) format.  DATES: Submit either electronic or written comments.”

The preface to the Proposed Rule goes onto state: “The proposed rule would enable ANDA holders to update product labeling promptly to reflect certain types of newly acquired information related to drug safety, irrespective of whether the revised labeling differs from that of the RLD. An ANDA holder would be required to send notice of the labeling change proposed in the CBE-0 supplement, including a copy of the information supporting the change, to the NDA holder for the RLD at the same time that the supplement to the ANDA is submitted to FDA, unless approval of the NDA has been withdrawn.  This proposal would ensure that the NDA holder for the RLD is promptly advised of the newly acquired information that was considered to warrant the labeling change proposed for the drug in the CBE-0 supplement.”

FDA plans to review changes to an ANDA where there is no marketed NDA and will make all of the CBE-0 changes available on a new web site or modify an existing FDA web page to assure that the most current safety information is available to the public and health care practitioners.

After affirmative approval of the label change for the innovator, the ANDA applicant would have 30 days to submit a CBE-0 supplement with conforming labeling changes associated with the RLD labeling. In addition, the Proposed Rule would permit a CBE-0 for changes to the “Highlights of Prescribing Information” section of the labeling, which under the current Physician Labeling Rule, requires a prior approval supplement.  This change is being made to remove that obstacle to getting current important information into the label quickly.   “Finally, FDA regulations provide that FDA may take steps to withdraw approval of an ANDA if the generic drug labeling is no longer consistent with the labeling for the RLD, subject to certain exceptions specified in the regulations. The proposed rule would amend the regulations to add a new exception for generic drug labeling that is temporarily inconsistent with the labeling for the RLD due to safety-related labeling changes submitted by the ANDA holder in a CBE-0 supplement.”

The FDA states in its Proposed Rule that “[t]he Mensing decision alters the incentives for generic drug manufacturers to comply with current requirements to conduct robust postmarketing surveillance, evaluation, and reporting, and to ensure that the labeling for their drugs is accurate and up-to-date.”  However, those reporting requirements always have remained the same.  How the Agency came up with this assertion is beyond me.  It is FDA’s role to assure that all generic firms are meeting their postmarketing surveillance requirements and they have used various means of incentivizing Firms such as the issuance of FDA 483 observations, Warning Letters, and other enforcement measures.

The Proposed Rule would permit ANDA applicants to make CBE-30 changes to labeling and issue “Dear Health Care Provider” letters, something that the Supreme Court has already said could not be done.  Maybe it is just me, but the FDCA does require labeling to be the same as the RLD, and the preamble to FDA ANDA regulations explained that consistency among labeling of the RLD and ANDA was essential to avoid confusion in the marketplace.  But now, FDA is proposing to create the confusion in 2013 that it sought to avoid for the past 30 years.  Their reasoning isthat the marketplace has changed since the passing of Hatch-Waxman, and over 80% of all drug products dispensed in this country are generic products.  I say their proposed actions are misplaced and will lead the drug industry to systematically engage in “defensive labeling” by both generic and brand name manufacturers to include any ADE that might have been reported, even if it was not positively determined to be caused by the drug product in an effort to reduce liability exposure, and thus, avoid “Failure to Warn” claims by Plaintiffs.  This could potentially dilute the impact of label warnings to a point where consumers or practitioners do not pay attention to the warnings or adverse events themselves.  Worse yet, one could imagine a scenario where, if there are 10 generics and a brand name manufacturer on the market for the same drug product, you could theoretically have 11 different labels floating around in the marketplace, each with a subset of different warnings waiting for FDA review, modification, approval or denial.

While this scenario might be something I am certain the Plaintiff’s bar would savor, I am also certain that the confusion it would cause will certainly have significant unintended consequences.  Having seen many of these liability suits firsthand as an Expert Witness (which I vowed I would no longer do), I can easily imagine suits for Firms failing to submit a CBE-0 for a warning, once one generic applicant makes the change and prior to another doing so.  The window of opportunity for such suits would never be closed as it is unlikely that any Firm would have a complete idea of what CBE-0 warnings or label revisions would ultimately be approved, altered or denied by FDA.

The FDA’s proposed answer to avoid this confusion is for the Agency “to establish a dedicated Web page (or, alternatively, to modify an existing FDA Web page) on which FDA would promptly post information regarding the labeling changes proposed in a CBE-0 supplement while FDA is reviewing the supplement (see proposed §§ 314.70(c)(8) and 601.12(f)(2)(iii)). The public may subscribe to FDA’s free email subscription service to receive an email message each time there is an update to this proposed FDA Web page. The FDA Web page would provide information about pending CBE-0 supplements for safety-related labeling changes, including but not limited to: The active ingredient, the trade name (if any), the application holder, the date on which the supplement was submitted, a description of the proposed labeling change and source of the information supporting the proposed labeling change (e.g., spontaneous adverse event reports, published literature, clinical trial, epidemiologic study), a link to the current labeling for the drug product containing the changes being effected, and the status of the pending CBE-0 supplement (e.g., whether FDA is reviewing the proposed labeling change, has taken an action on the CBE-0 supplement, or has determined that the supplement does not meet the criteria for a CBE-0 supplement).”  We could call this web page the Plaintiff’s Full Employment Act of 2013, as it would provide a simple road map to the courtroom.

If FDA feels strongly about assuring that appropriate changes to generic labeling are made in a timely manner that are consistent with what the science supports, then perhaps they should have a Division staff thatreviews only proposed changes for such proposed warnings, but handles them as prior approval supplements, wherein all applicants are required to make the change within a specified period of time if FDA determines such change is appropriate.  Then, only after FDA’s affirmative approval, would all manufacturers be required to make the change.  To me, that makes more sense and provides for a process that would remove the potential for confusion in the marketplace and would also avoid a tremendous increase in workload for both the FDA and industry that may spend much of its time continually making CBE-0 changes to avoid liability concerns. 

It took 30 years to get to the Mensing decision – a clarification consistent with the Hatch-Waxman Statute and the regulatory framework that was “hatched” (pardon the use of the term) from a delicate balance of the rights and responsibilities of the brand and generic industry in turn for certain period of patent and market exclusivity.  Let’s make certain we don’t create a bigger problem when trying to solve one that might have a more simplistic solution.   Perhaps the FDA and Congress should look more towards a program like the national vaccine program to compensate patients injured by generic drugs. 

The Generic and Brand Name Industry should review this Proposed Rule closely to assure that it does not become the undoing of the pharmaceutical industry.  I am certain that its impact, if finalized, will ultimately be felt in the pocketbooks of the consumers who will likely be paying significantly more for their prescription drugs due not only to label change costs but most certainly to cover the litigation costs. . While many might not agree with my view point, I am sure there are many that will. The proposed procedures outlined in the rule are quite complex and FDA Is asking for public comment.  The text of the full Proposed Rule can be found here