FDA Proposes Controversial Rule Allowing ANDA Applicants to Change Drug Labels

November 15, 2013

On Nov. 13, 2013, the Food and Drug Administration (FDA) published a Proposed Rule in the Federal Register. The title of the Proposed Rule is “Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products.” Whereas currently, the label of an abbreviated new drug application (ANDA) must be identical to the innovator product’s label, the Proposed Rule would permit ANDA applicants to distribute revised product labeling that differs in certain respects, on a temporary basis.

In our view, this rule has monumental implications not only for ANDA sponsors, new drug application (NDA) sponsors, and biologics license application (BLA) sponsors; but for health care providers (HCPs) as well as patients. The proposed rule undermines the entire concept of the generic drug program, which is based on the principle that “products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product” (the Orange Book, 33rd ed., 2013, p. vii). To obtain approval of an ANDA, an applicant does not need to provide independent evidence of safety and effectiveness but, instead, relies on the finding of safety and effectiveness for a drug that has been previously approved (an innovator product, the reference listed drug (RLD)). An ANDA must have the same active ingredient, strength, dosage form, route of administration and conditions of use as the RLD. In addition, the ANDA applicant must establish that its drug is bioequivalent to the RLD.

In view of the aforementioned requirements of an ANDA, it is difficult to envision the ANDA product as having a different safety profile from that of the RLD. The development and approval process of the RLD, as well as the extensive marketing prior to marketing of a generic version, surely would have uncovered safety issues with the active ingredient and/or the innovator product. If new, previously unobserved, safety issues arise with a generic product, it should raise concerns about the bioequivalence of the generic product. Since ANDA products do not need to have identical inactive ingredients, are the previously unobserved safety issues emanating from the different inactive ingredients or some interaction of the different inactive ingredients with the active ingredient? Or is the historically accepted concept of bioequivalence not a guarantee of therapeutic equivalence? In our review of the Proposed Rule, we were surprised by the total lack of any scientific discussion as to how a generic product that was deemed bioequivalent to the RLD could have a different safety profile.

In our experience, review of reports of new safety information is not a trivial matter. In fact, innovator companies have pharmacovigilance experts and staffs who continually monitor the safety profile of approved products including signal detection, issue evaluation, updating of labeling, and liaison with regulatory authorities. In addition, there are Standard Operating Procedures specifically for safety signal evaluations with a series of steps to be taken over time, i.e., a dedicated process that requires considerable scientific and medical judgment. ANDA applicants do not have the in-house staff to fully evaluate the adverse event reports which they may receive and determine if the report should trigger an immediate change to the label of their product and if it would require a submission of a changes being effected (CBE-0) supplement to their ANDA. The CBE-0 supplement process permits a prompt update of the labeling to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a casual association with a drug. How will an ANDA applicant evaluate a report as being a clinically significant hazard and ascertain if there is reasonable evidence of a causal association with their drug? We don’t believe that at the present time, ANDA applicants have the in-house capability to perform these functions. The Proposed Rule will require the ANDA applicant to notify the NDA holder of the RLD so that the NDA holder may consider the new information of the CBE-0 labeling supplement as part of its review and evaluation of postmarketing data. We can envision a scenario where the NDA holder reviews the copy of the information (published literature, spontaneous adverse event reports) sent by the ANDA holder that supports the labeling change described in the CBE-0 and concludes that the safety information that was reported to the ANDA holder does not apply to the NDA product.

The Proposed Rule acknowledges that there may be times when the labeling of the ANDA holder that submits the CBE-0, the NDA holder and other ANDA holders of the same drug may differ. It also states that HCPs are unlikely to review product labeling for each generic drug that may be substituted for the prescribed product when making treatment decisions with their patients. Currently, the expectation of a prescriber and dispensing pharmacist, as well as patients, is that the substituted generic has the identical safety and efficacy profile as the prescribed innovator. Will the difference in labeling increase the potential liability of the prescriber and/or pharmacist? The FDA proposes to establish a dedicated website on which the Agency would promptly post information regarding the labeling changes it receives in a CBE-0 supplement while they are reviewing the supplement. Once the CBE-0 supplement is approved, the approved label would be made available through a link to FDA’s online labeling repository at https://labels.fda.gov. In our experience, reviewing labels on that repository is overly confusing as not only approved labels from NDA and ANDA applicants are listed, but also the labels of numerous distributors. Furthermore, it does not appear that the repository is updated in a timely fashion. For example, on Nov. 8, 2013, the FDA approved six ANDAs for rabeprazole sodium tablets but as of the publish date of this post, the labels of only three are available on that site.

The issues discussed above are the ones we consider to be the most controversial. However, there are many others, including the Agency’s gross underestimate of the net annual social costs of the Proposed Rule. In conclusion, if the pharmaceutical industry, both innovator and generic, as well as health care providers, don’t voice their strong opposition to this Proposed Rule, they will have only themselves to blame for the significant impact it will have once the regulations are codified.

If you have any questions or thoughts on this blog post or others, please contact us.


April 3, 2013

Waivers for Carcinogenicity Studies? Not So Fast!

The recently published request for comments regarding the Proposed Change to Rodent Carcinogenicity Testing of Pharmaceuticals signals intent by regulatory agencies to alter what Sponsors consider in...

February 26, 2014

Rethinking the OTC Monograph System

When the OTC drug review was undertaken in the 1970s, it was deemed the best solution available at the time for efficiently assessing the safety and efficacy of the countless drug products being sold...

April 24, 2017

FDA Changes Labeling Requirements to Protect Children from Pain & Cough Medicines

On Thursday, April 20th, the FDA issued a statement announcing a number of changes that are being made to the labeling requirements for two opioids – codeine and tramadol. The Agency’s statement...