Making the Switch

Dr. Doug Bierer felt like he was in a courtroom, waiting for the jury to render its verdict. It was June 2002, and executives from Procter & Gamble and its partner AstraZeneca had just finished presenting their bid to FDA's Non-Prescription Drugs Advisory Committee (NDAC) to market the popular heartburn medication, Prilosec (omeprazole), as an over-the-counter (OTC) drug.

Doug Bierer, former regulatory chief for P&G

The crowd buzzed with anticipation. Reporters shuffled papers as they prepared to record the committee's decision. A sudden hush came over the room as the panelists began to vote.

"Yes."

"No."

"I vote yes."

"Yes, with some reservations."

"Yes for approval."

Bierer, then-regulatory chief for P&G's personal healthcare products, was one of the main presenters at the hearing. He had spent years working on the Prilosec switch, and months preparing for the NDAC hearing. As the panelists' votes stacked up in favor of the switch, Bierer knew the effort had been worth it.

The Prilosec Rx-to-OTC switch was P&G Consumer Healthcare's single most important initiative in a decade. It was the first over-the-counter switch in the proton pump inhibitor drug class, and the first OTC product for the treatment of frequent heartburn. And since FDA leans heavily on NDAC's recommendations, a "yes" vote with the committee—while not a guarantee—was a good indicator of eventual FDA approval.

News Flash

More Rx brands are expected to move over the counter in the next decade. Several forces are driving that trend: With 15 blockbuster drugs set to lose patent protection by 2008, the industry sees these switches as a way to salvage shrinking profits on big-selling prescription drugs. Consumers also expect to save money, since OTC products usually cost less than branded pharmaceuticals (even for patients with insurance). Regulators, too, want to make medications more affordable. FDA has even said that it wants to increase the number of drug switches by 50 percent from previous years, and will accept foreign safety and efficacy data in support of Rx-to-OTC petitions.

But experts like Bierer say gaining approval for Rx-to-OTC switches is becoming increasingly more difficult, and that it may be harder to secure a switch than a FDA approval for an entirely new prescription drug. After all, sponsors applying for an OTC switch must satisfy both the Review Division, which oversees Rx drugs, and the OTC Division, which reviews all switches. They must also show FDA that the drug is safe and effective, and that consumers can use it correctly without a doctor's supervision.

There are also new barriers to overcome. Traditionally, marketers of drugs that treat symptomatic conditions, like allergy and pain, have had the best shot at proving OTC claims, mostly because the symptoms help consumers remember to take the pills. But tomorrow's OTC marketplace may include newly switched drugs for chronic conditions like high cholesterol, where the symptoms and subsequent relief are less obvious to consumers. In fact, at least two manufacturers of prescription statins are planning to apply for OTC status in the near future.

This could make the Rx-to-OTC process even more complex and challenging. This article helps guide pharma companies through the switch process, and prepare for the main event—the advisory committee meeting.

John Dent, former director of R&D at GSK Consumer Healthcare

Talk to FDA Early and Often

In the Rx-to-OTC switch process—as with the development of any new, prescription drug—FDA may well take a different perspective of the data from the sponsor. But viewing the agency as an adversary can be a big mistake.

"We're not here to be an obstacle," said Charles Ganley, MD, director of FDA's division of OTC drugs. "FDA is charged with speeding access to safe and affordable medicines, and we have an obligation to help companies figure out a way to do that."

The difference between success and failure may come down to simply talking to FDA early on in the application process—preferably, before submitting the Investigational New Drug Application (IND) for the Rx-to-OTC switch. These early meetings allow sponsors to determine whether their proposed OTC clinical development program—efficacy and safety trials, and possibly comprehension studies to determine the accessibility of the label—is adequate for FDA to approve the switch.

The agency is generally very open to these types of meetings, as long as the objectives are clear and sponsors have a proposed OTC clinical-development plan. Companies may not always get the answers they want. But the interaction provides sponsors a chance to share their views with FDA—and more importantly—to fully understand the agency's perspective on the data.

"It is best to identify and confront issues head-on and try to negotiate a win-win situation," said Bierer. "Failing to fully understand the FDA's position—whether the issue is dosing, duration of therapy, or anything else—just causes a loss in time and frustrates both the sponsor and FDA."

Did You Know?

As time goes on, sponsors should request follow-up meetings with FDA, and share their own evolving rationale for the switch. Companies should also continually ask regulators if they agree with their analysis.

If they don't, Ganley advises sponsors not to give up, but rather to ask what additional information FDA would need to approve the switch.

Ganley sees such negotiations as an integral part of FDA's decision-making process for potential Rx-to-OTC switches. "It's easy to just say, 'No, the switch can't be done,'" said Ganley. "It's much more scientifically challenging [for FDA] to have to explain their specific objections and then figure out what data might be necessary to overcome them."

Mission Possible: The Right Label

Consumers buy OTC drugs right off the shelf, without the benefit of physicians' or pharmacists' advice. Therefore, FDA ranks consumers' ability to read and follow a product's label—including its Drug Facts section—as one of the most critical elements to consider during an Rx-to-OTC petition. The label must contain all the information consumers need to decide if this is the right medicine for them and how to use the product appropriately.

"It's quite challenging to get all of the necessary information into the very small space on the label," said Louis Cantilena, MD, a professor for the Uniformed Services University of the Health Sciences. Cantilena served as a member of the original NDAC, and chaired that committee from 2001 to 2005. He also serves as a consultant to the pharma industry. "I advise companies to develop clear and consistent messages about the product's safety and efficacy, how it works, who is supposed to use it and how they should use it, very early in the process and make certain that the wording in Drug Facts clearly conveys this information to consumers," said Cantilena.

Developing the right OTC label can be a long, iterative process. Companies must repeatedly test to determine whether consumers—including those with limited reading skills—will understand it. FDA's OTC Division may also require special behavioral studies, called Actual Use Trials (AUTs), to see if consumers will follow label instructions in the real world.

"We need to see AUTs when there are no other drugs with the indication already out there," said Ganley. "In Prilosec's case, it was the first drug of its kind to go over the counter, so we had to be sure it would be taken correctly and by the right population."

The Big Event: The Advisory Committee Meeting

Often, FDA will turn to one of its advisory committees for advice on whether or not to switch a drug over the counter. For companies, that means that, after years of conducting studies and investing millions of dollars, much of the decision about whether consumers can use a drug safely and effectively without a prescription winds up in the hands of about a dozen people.

Therefore, for companies, making an impression comes down to the FDA Advisory Committee hearing. That is where sponsors present their rationale and data to support the switch and address any lingering questions from committee members. And, since FDA usually follows the committee's recommendation—as it eventually did in Prilosec's case—convincing the committee is critical, and strategic preparation is key.

Start early A successful advisory committee meeting does not just happen by itself. The preparation process should begin as the company is finalizing its application for FDA review.

"You cannot start the process of preparation too early," said John Dent, former director of R&D at GSK Consumer Healthcare and leader of the team that successfully convinced an advisory committee to recommend the Rx-to-OTC switch of the weight loss drug Xenical (orlistat). "In the ideal world, you should start preparing your presentation for the advisory committee hearing as you prepare your NDA submission."

Other experts agree. "The case must be built brick by brick, from the first pre-IND all the way through post-marketing," said behavioral scientist Saul Shiffman, who also presented at the orlistat hearing. "Building the Rx-to-OTC case is not just about the science—you also have to consider the politics, public, and media, because these factors influence how science is seen."

Build an expert team To truly shine at the committee meeting, companies must build a team of expert advisors that includes scientists and academicians, and regulatory, marketing, and FDA communication specialists. Each of these disciplines offers a unique perspective, and helps ensure messages are credible, accurate, and resonate with committee members.

"Try to assemble a team with track records of success with advisory committees, and strike a balance between scientific and marketing experience," said Jerry Gardner, MD, who spent 20 years at NIH and now analyzes data for pharma. "Each specialty is important and should have a seat at the table."

A balance of internal and external presenters is key. Internal presenters tend to best know and understand the data, while external thought leaders add credibility to the presentation. "Experienced clinicians provide an objective perspective on safety, efficacy, and labeling," said David Peura, MD, associate chief of gastroenterology and hepatology at the University of Virginia Medical School, whom P&G enlisted in the Prilosec switch. "Because they are on the front lines, they can answer questions from fellow clinicians on the advisory committee."

But working with physician thought leaders and other outside experts can pose challenges. Outside presenters must learn the data, be willing to participate at meetings and rehearsals, and work closely with FDA communications specialists to develop their presentations and craft answers to questions the panel members may ask. The entire process usually takes months, and patience is critical. "It is essential to communicate the likely time requirements to outside presenters up front," says Dent, "to make sure they can give you the time you need."

It's not what you say—it's how you say it As with any presentation, spokespeople must be credible and true to the science. But an FDA Advisory Committee presentation is like a regular scientific presentation on steroids—presenters must compel and convince the committee with their delivery.

"Scientists underestimate the importance of a strong delivery," said Bierer. "You need to show the advisory committee that you are confident in your data and passionate about your positions. If they see you truly believe what you say, it will help convince them too." It is here that Bierer believes communications experts can make the biggest impact: They know how to organize and deliver content most effectively.

Know who is in the audience Just as two divisions of FDA are involved in switch decisions, Rx-to-OTC advisory committees are actually two committees put together: the Non-Prescription Drugs Advisory Committee and the committee representing the indication, which in Prilosec's case was the Gastrointestinal Drugs Advisory Committee. Consequently, sponsors must win over two separate committees, each with its own agenda.

To add to that complexity, within the advisory committees themselves, there are a potpourri of specialty physicians, scientists, statisticians, epidemiologists, toxicologists, and industry and consumer representatives, each interested in obtaining a different slice of the data.

"It is helpful to analyze each of the committee members to find out his or her specific interests, concerns, and biases," said Dent. "This allows you to target your presentation to those specific issues, as well as to anticipate negative questions."

Build a cohesive, convincing case FDA typically grants sponsors an average of 75 minutes to present all of their data, and another half hour or so to answer questions from committee members. Companies can submit a briefing document beforehand, but members usually don't have a lot of time to read and process that information. Therefore, sponsors must develop a clear, convincing, and laser-focused case for approval.

"No matter how great your data, dumping years of it on the committee without context won't convince them," said Gardner. "Guide the panel through it in a logical and persuasive way."

The case for an OTC switch and the data that support it should be largely shaped around the questions FDA provides to the advisory panel at the start of the hearing—similar to a judge "charging" a jury. FDA sends those questions to sponsors anywhere from a month to the night before the hearing—so companies should be prepared to scramble and change their presentation to accommodate the questions, if necessary.

Companies should assign a team to compile Q&As and "drill" presenters before the hearing. In particular, when it comes to the negative questions, companies should ensure that presenters have appropriate data-driven answers. "You can win or lose on Q&A," said Gardner. "I've seen companies go down in flames because their answers were confusing. You've got one shot to answer the question and get your point across."

Practice makes perfect In the end, engaging in a successful advisory committee meeting comes down to practice—as individual presenters and as a team.

The Rx-to-OTC team should hold a few "mock" advisory committee hearings. The panels should be composed of thought leaders in both the specialty area and OTC medicines in general, to reflect as closely as possible the make-up of the advisory committee members. The mock panels should be staged realistically, with the room arranged like a typical advisory committee hearing to help presenters visualize the big day.

In addition, presenters should practice in front of the organization's senior management, who can sometimes see critical points that were omitted by the team. All this input should then be used to better prepare the team to face FDA.

If You Don't Succeed, Try Again

Even with all this preparation, the Advisory Committee may not decide in favor of the switch. But losing with NDAC doesn't mean a company should stop trying. It took the Prilosec team two appearances before the committee to win a positive vote. The first time, in 2000, the panel asked for more data. The second, in June 2002, the vote was an overwhelming 16-2 in favor of recommending approval.

"We definitely learned from the first time around," said Bierer. "The second time, our team started preparing earlier, defined our OTC target population more clearly, sharply focused our messages, and drilled on Q&A five times as much."

All the work paid off. FDA approved Prilosec OTC in June 2003—one year almost to the day the advisory committee voted "yes."

Penny Daniels, Carmie McCook, and Jim DiBiasi are principals of 3D Communications, an agency in Bethesda, Maryland that consults on regulatory issues. They can be reached at www.3dcommunications.us