FDA Considers Rx-to-OTC Switch of Antihistamine Drug Products

Date: May 14, 2003


Since the meeting described below, the debate over the regulatory status of Claritin® (loratadine) has been resolved. On November 27, 2002, FDA approved Schering's supplemental New Drug Applications to provide for the over-the-counter (OTC) use of Claritin® Tablets, Syrup, and RediTabs®. Schering initiated the Rx-to-OTC switch of Claritin®, despite its initial resistance, in large part because the patent protection would expire in late 2002, opening the door to generic competition and reducing Schering's sales regardless of the products' status. Since November 2002, other companies have received FDA approval of OTC loratadine and are on the market. The WellPoint Petition remains pending with respect to Aventis' Allegra® (fexofenadine) and Pfizer's Zyrtec® (cetirizine). Some media reports indicate that FDA has concluded it has the legal authority to force the switch of these drugs to OTC status, although there has been no formal decision from the Agency. Any such action will almost assuredly be challenged in court.

The Food and Drug Administration's (FDA) Nonprescription and Pulmonary - Allergy Advisory Committees held a joint meeting on May 11, 2001 to consider a Citizen Petition submitted by Blue Cross of California (now WellPoint Health Networks) in July 1998.  WellPoint's Petition requests that FDA switch the non-sedating antihistamines (NSAs) Allegra, Claritin, and Zyrtec from prescription to over-the-counter (OTC) status.  As was widelyreported by the mainstream news media, the Panel voted 19 to 4 that both Claritin andZyrtec could be safely used OTC, and 18 to 5 in support of Allegra.  However, the discussion over the course of theday-long meeting reflected much greater uncertainty than the final vote would indicate,and there are substantial legal and regulatory obstacles that must be overcome before anyswitch is accomplished.   In addition, onesurprising element that was not reported is that FDA suggested that it might reconsiderthe active ingredients permitted in the OTC antihistamines monograph.

The Petition

WellPoint's Petition is unusual since it represents a party other than a drugproduct's sponsor requesting that FDA change the product's status fromprescription to OTC.  Although FDA has aregulatory procedure that allows for such a switch to be done without a New DrugApplication (NDA), FDA last used this process in 1971 and, as far as can be determined,has never switched a drug's status over the objection of the drug's sponsor.  One such switch was attempted in 1982 (switchingmetaproterenol sulfate as part of the OTC bronchodilator monograph), but was rescindedfollowing very strong objection from industry and the medical community.  The WellPoint petition contains surprisinglylittle in the way of data to support the request.  Basedon our experience with FDA, the petitioner does not appear to have provided FDA withsufficient information to support the action requested.  However, the fact that FDA decided to convene a joint Advisory Committeemeeting to consider the issue indicates that the Agency is at least open to thepossibility of taking the requested action.  FDA'spresentation and discussion at the meeting made it apparent that the Agency appearssupportive of the move (at least from a scientific/safety standpoint).

The Hearing on May 11, 2001

FDA made clear in advance of the meeting that the Agency was seeking only the Panel'sscientific advice on the safety of the drugs in question, and did not want it to considerissues of health care costs or FDA's legal authority to implement such a switch.  Nevertheless, many of the presentations to thePanel made conflicting arguments as to whether or not the NSAs would cost less and be morewidely accessible if they were available OTC.  Asone of the Panel members commented, all sides involved seemed disingenuous in theirarguments.

WellPoint's presentation emphasized how much "safer" the three NSAs werein comparison to the OTC monograph ingredients and how OTC status would make the productsaccessible to more patients.  The Panelmembers were profoundly critical of WellPoint for the minimal amount of informationprovided to support its conclusions and the fact that its two primary studies were notpeer-reviewed or otherwise published, and had not been made available to the Panel by thetime of the meeting.  [WellPoint presented theresults of (1) a meta-analysis of published randomized controlled studies of selectedantihistamines and (2) a cost-effectiveness model based on the effects of sedation onmotor vehicle accidents.]

Not surprisingly, Schering-Plough and Aventis, the NDA holders for Claritin andAllegra, respectively, made presentations emphasizing how little information was knownabout the safe use of the NSAs in an OTC setting and how the petitioner had provided nosuch information.  [Pfizer, the sponsor ofZyrtec, declined the opportunity to appear at the meeting and its views were not formallypresented.]  The fact that these products hadbeen on the market for eight years or fewer added to their concerns about potentialeffects that simply had not yet had time to be uncovered. The Panel members expressed considerable frustration over the sponsors'assertions of safety issues, while at the same time the companies failed to identify aspecific concern or any particular investigations they were conducting to evaluatepotential concerns.

FDA's safety presentation focused on the data submitted in the NDAs for the threeNSAs and a review of the published literature and the pharmaceutical Adverse EventReporting (AER) system.  Surprisingly, FDAstated that it did not believe an OTC "actual use" study or a "labelcomprehension" study would be needed to support the OTC use of the NSAs.  For virtually all of the Rx-to-OTC switchessought by manufacturers in the past several years, however, these studies were conductedand generally viewed by the Agency as crucial to documenting the safe use of the drugunder OTC conditions.

The Panel was asked to vote on whether the three NSAs have "a safety profileacceptable for OTC marketing , i.e., can [they] be used safely without a learnedintermediary?"  However, the questionswere presented in the context of whether the Panel members felt there were any possiblescenarios under which the products could be used, in which case the members were to vote"yes."  Any reservations aboutspecific issues (e.g., lack of data for use in certain populations, concerns aboutspecific drug-drug interactions or other side effects, etc.) would be consideredseparately by FDA and were not to preclude a "yes" vote.  Following the voting, two of the Panel membersspecifically commented that they voted "yes" based on the instructions given,but were very uneasy about supporting OTC use because of the general lack of availabledata.

OTC Antihistamines Monograph

As part of the open public hearing portion of the meeting, numerous medical, consumer, andbusiness organizations expressed their opinions on the proposed switch.  Although some parties were in favor, the majorityof the groups, particularly the medical organizations, opposed the switch, primarily outof concern that consumers may not be able to appropriately self-diagnose and distinguishseasonal allergic rhinitis from other, more serious conditions that might also showsymptoms of runny nose and watery eyes.  Oncethe Panel deliberations began, however, FDA specifically took the question of adequateself-diagnosis off the table, arguing that the issue had already been resolved by the OTCantihistamines final monograph. 

However, FDA strongly indicated that it might re-evaluate the OTC antihistamineindications and ingredients currently permitted by the OTC monograph (developed in the1970s and in effect since 1992).  FDAacknowledged that the scientific understanding of allergies has evolved considerably sincethe monograph was originally  developed.  While no time frame was suggested, it bearswatching to see what action FDA will take on this front. 

Issues Not Yet Resolved

Despite the news reports suggesting that the OTC switch is practically a "donedeal," there are numerous legal and regulatory questions that still must be resolved.  For example, it is argued, but is uncertain, thatFDA would need to provide the NDA sponsors with a formal administrative hearing prior tochanging the NSAs to OTC status.  If so, thisprocess could drag on for years (with the assurance of court challenges if FDA rulesagainst the sponsors).  In addition, it is notclear that the government can force a manufacturer, over its objections, to subject itselfto potential legal/product liability exposure it does not want to assume.  The scientific questions addressed at the meetingare likely to be the "simplest" issues to resolve.  Considerable effort and heated debate lie ahead.

For further information about FDA's OTC drug regulatory requirements or theWellPoint Citizen Petition, please contact Frederick A. Stearns at 202-434-4288 or via e-mail at stearns@khlaw.com