OTC Switch “Blueprint” Could Help Regulatory Navigation – Researchers

Rx-to-OTC switch questions that FDA asked advisory committees over the past 10 years can help guide future sponsors to success, says the lead researcher in an analysis of the agency’s switch actions.

The article seeks to provide “an essential blueprint for designing and implementing any Rx-to-OTC drug development program," says lead author Bill Soller, professor and executive director of the Center for Consumer Self Care at the University of California, San Francisco, School of Pharmacy.

The journal SelfCare published the analysis online Sept. 30. Soller and his colleagues list questions – “OTC Considerations” – based on switch principles FDA set in 1990 and 1998 and questions to post-2002 advisory committees that evaluated first-in-class switches.

Bill Soller, executive director of the Center for Consumer Self Care at the University of California, San Francisco, School of Pharmacy

“These are the questions that FDA has been asking,” said Soller, a consultant and former Consumer Healthcare Products Association executive who also serves as co-editor in chief of SelfCare.

For both drug development teams and FDA, the OTC Considerations “provide a comprehensive framework to consider the evidence base needed by FDA for evaluating switch,” the authors say,

The list reflects materials FDA provided advisory committees and presented at meetings on first-in-class switches from 1992 to 2011. The latest was in 2007.

Less Predictable In Practice

Regulatory consultant Cindy DiBiasi praised the article as “a very well-researched and robust accounting” of FDA actions, but points out that FDA switch decisions sometimes depart from expectations created by the agency’s history and policies.

“While FDA defines the characteristics of over-the-counter medicines in a predictable way, the agency has become far less predictable in practice,” says DiBiasi, a partner at Bethesda, Md.-based 3D Communications.

“What the FDA has done and what companies can expect around their specific applications in the future are two entirely different issues. … That’s mainly because there are so many variables that affect the FDA’s position and the advisory committees’ recommendations,” she said.

Eric Brass, a physician, director of Harbor-UCLA Center for Clinical Pharmacology and a professor at David Geffen School of Medicine at UCLA, also praised the analysis, while noting the complexity and breadth of variables that affect switch considerations.

Applying the OTC Considerations recommendations “in specific circumstances often remains challenging,” said Brass, a former chairman of FDA’s Nonprescription Drugs Advisory Committee.

“The specific form one of these issues takes may require novel data collection methods to address, or disagreement about how much uncertainty about OTC safety is acceptable,” he added.

Soller acknowledges switch decisions can defy expectations.

“Whether it means if they answer all those questions it will be predictable that they’ll get approval, that’s anybody’s guess,” he said.

The authors say FDA “uses its discretion to select areas of concentration for advisory committee discussions on switch.”

Factors influencing the agency’s questions for advisory committees include the novelty and uniqueness of a proposed OTC indication or Rx active ingredient; intrinsic and extrinsic toxicity of a switch candidate; and robustness of published and NDA-derived data and worldwide post-marketing surveillance evaluations, according to the article.

From Drug-Centric to Patient-Centered

The researchers reviewed FDA’s switch activities during Carl Peck’s 1987-1994 tenure as drug center director and from later in the decade through 2001, when Robert DeLap was director of the division that reviewed OTC drug applications.

Soller said the review of Peck’s and DeLap’s work at FDA led to the OTC Considerations list as a “logical construct” of “two very different perspectives on what would constitute the efficacy, safety and labeling considerations for switch.”

While switch evaluations were primarily drug-centric as Peck led the work, under DeLap the agency turned to a more patient-centered approach, emphasizing label comprehension and self-selection studies, he added.

“But 10 years later, no one has put these together. How do we consolidate this along with the most recent thinking, the last 10 years in terms of how FDA has evolved?” said Soller.

Consolidating the information is particularly important for people in industry and at FDA who were not involved with preparing or reviewing switch applications during the 1990s, when 50% more first-in-class and 25% more follow-on switches were made than in the 2000s, according to the study.

“I think it’s useful from that regard because a lot of times the kinds of questions companies are asking I think we answer in this article,” Soller said.

“But I also think for newer regulatory personnel that may not have that history, this forms a good foundation.”

The recommendations also could help marketing staff. While switch projections often identify most Rx products with an indication for a common condition and an approaching patent expiry, the lists could be more realistic if marketers and analysts considered the likelihood of a certain drug being approved to switch.

“The applicability of this list is not limited to the scientific, regulatory personnel within the company, but really extending to the marketing folks in order to have a better understanding of what is potentially feasible. The kinds of questions that they need to be sure they know, their scientific, regulatory people are answering,” he said.

“The reality of the future switch horizon is grounded in these questions.”

Degree Of Difficulty Climbs

Proving a switched product will benefit public health without an accompanying increase in risk has become more difficult for sponsors. In the U.S., drugs for chronic or asymptomatic conditions – such as statins for high cholesterol – have failed to switch successfully as FDA advisors have questioned whether consumers can appropriately self-select their treatment ("Lipitor OTC Switch Would Force Pfizer To Clear Big Research Hurdles" — "The Tan Sheet," Aug. 8, 2011).

The analysis in SelfCare comes a month after FDA published a draft guidance on designing self-selection studies in support of OTC switches. The draft states FDA’s interest in greater insight into consumers’ thought processes and says study sponsors should follow up with medical history questions and additional open-ended queries ("FDA Expects OTC Switch Self-Selection Studies To Probe Consumer Thinking" — "The Tan Sheet," Sep. 19, 2011).

“Recent years have been somewhat dryer than in the 1990s for switch,” Soller said, adding that switch sponsors will have “trepidation” because of “significant efforts that were turned aside.”

Those included Merck’s attempt to switch the cholesterol drug Mevacor Daily (lovastatin) in 2007.

The labeling “became overly complex” and “substantial gaps” were apparent in label comprehension, Soller said.

It was “a very daunting task when you thought about a label comprehension study to really demonstrate that [for] a large proportion of the population, the needle was on the safe side.”

However, since then FDA’s decisions on med guides for Rx products have turned to “only the most essential information,” a shift that might portend “another era where it would be more attractive to attempt to reintroduce” a statin switch, he added.

Will Pharmacy-Only Move Some Switches?

The U.K. and other European Union members have a regulatory option FDA does not to facilitate making drugs available without prescriptions – a third class, known as pharmacy-only or behind-the-counter.

FDA’s drug center director this year noted fewer existing Rx drugs are appropriate for consumer self-selection when she encouraged firms to consider behind-the-counter status for future switches ("CDER Director Sees Behind-The-Counter Switches As Best Bet" — "The Tan Sheet," Apr. 11, 2011).

Soller says intervention by a pharmacist for behind-the-counter drugs essentially solves self-selection questions linked to whether a drug should be available without a prescription.

Self-selection and actual use are not “primary considerations” in the U.K. as they are in the U.S., he said.

However, because a third class is unlikely in the U.S., sponsors and FDA should give more attention to voluntary behind-the-counter switches, Soller said.

The stakeholders need to consider whether a pharmacist’s intervention would improve a drug’s benefit for consumers.

“If that is deemed to be the case … then this behind-the-counter distribution of an OTC may be quite appropriate,” Soller said.

Going behind-the-counter voluntarily could facilitate some switches, Brass observed, but pharmacy-only approval of the first product in a class or category would not mandate the same status for later switches.

“Thus the statement that a company will voluntarily impose such a restriction cannot influence the regulatory decision, as the second company to market could not be held to the same restriction,” he said.

Brass added that no public health benefit from expanding consumers’ access to medicines through pharmacists has been established.

“If pharmacist assessment is required for safe and effective use by the consumer, I think that the drug would not be appropriate for OTC status today.”

“They clearly have the skill sets to be helpful, but are our pharmacies staffed and equipped to provide such services across the U.S.?” Brass said.

DiBiasi also has doubts about voluntary behind-the-counter as a switch facilitator. Enhancing and expanding the information, materials and resources made available with a switched drug could be more effective, she says.

A “more forward-thinking” and “holistic approach” to switches, employing technology and behavioral programs, could help consumers appropriately self-select and use a wider variety of products more safely without the intervention of a health care provider, DiBiasi said.

Models for these approaches include online materials and support groups that accompany smoking-cessation and weight-loss products.

“There is an urgency about this, because while the FDA is not supposed to consider economic issues, with our current health care crisis, we need to make effective medicines more accessible and affordable to people – and getting these medicines over-the-counter is an effective way to do just that,” DiBiasi said.

By Malcolm Spicer