Navigating the FDA Approval Maze
Sirion's Durezol: a blueprint for success.
BY JERRY HELZNER, SENIOR EDITOR
The business of developing drugs and shepherding them through clinical trials is not for the faint of heart. The process requires tens of millions of dollars, lots of patience and the ability to meet the FDA's many requests and requirements. Even then, according to the Hastings Center, a nonpartisan research institution, only about one drug in five that begins the lengthy clinical trial process is eventually approved by the FDA.
Pharmaceutical companies are willing to accept those long odds for two primary reasons. One, a pharmaceutical company's future depends on bringing new drugs to market. A company that can't develop new therapies will eventually fail as its older compounds lose patent protection. And two, the payoff for commercializing a successful drug can be huge. For example, in the ophthalmic arena, Genentech's market-leading treatment for wet AMD, Lucentis (ranibizumab), achieved almost $900 million in worldwide sales in 2008.
Assessing the Approval Process
Given the high stakes associated with drug development, Ophthalmology Management set out to determine just what it takes to obtain an FDA approval. While the FDA process has in the past has appeared to some to be a labyrinth, with drugs at times receiving so-called "approvable" letters that don't lead to approval, the agency has recently taken several steps to remove any confusion or doubt about its overall process.
For example, the FDA has imposed stricter conflict of interest standards on its expert advisory committees. These committees get to review most major new drug applications and have a significant influence on whether these drugs get approved. In addition, the agency has changed the way advisory committee members vote on drug applications — from consecutively to simultaneously — so that no committee member's vote can influence a succeeding voter.
And in regard to those "approvable" letters, an FDA spokesperson told Ophthalmology Management that the agency has now ended the confusing "approvable" designation for drugs that need more study and replaced it with what the Agency calls "a complete response." Though both evaluations detail all of the issues that caused a drug to not be approved, the designation "complete response" ends the confusion embodied in the word "approvable." A small change, but a step in the right direction.
As you can read in the sidebar below, the FDA drug approval process, while complicated, can be broken down into 10 basic steps.
Clearly, a drug that displays safety, efficacy and other positive qualities in pivotal clinical trials, demonstrating itself to be a superior or advantageous treatment, has the best chance of being approved. But aside from that obvious fact, there are other strategies that companies can employ that raise the chances of a successful New Drug Application (NDA).
This article will attempt to explain the challenges of the FDA approval process and provide examples of companies that have brought investigational drugs before this often-daunting federal agency.
Targeting Unmet Medical Needs
It is instructive that a key element in Genentech's stated mission is to strive to develop effective treatments for major unmet medical needs. When Genentech first put ranibizumab into clinical trials in the late 1990s, there was no therapy available that could even remotely claim to reverse vision loss caused by wet AMD. Thus, Genentech met one of the FDA's key approval criteria by focusing on providing a treatment that was superior to anything available at the time.
Ranibizumab's progress through clinical trials was not easy. While the efficacy of the compound was demonstrated in both early studies and two pivotal phase 3 trials, questions were raised about safety and the potential that the antiangiogenic agent could create systemic problems by disrupting blood vessel formation in parts of the body where new blood vessels were needed. In granting approval for ranibizumab, the FDA weighed the drug's huge benefits against the relatively small number of adverse reactions reported.
It's also interesting to note that Eyetech Pharmaceuticals not only beat the odds by obtaining FDA approval for its wet AMD treatment Macugen (pegaptanib sodium), it also received its approval well ahead of the Genentech drug. But as this example proves, successfully navigating the FDA approval process is not much of an advantage when a competing treatment is more effective.
| 10 Basic FDA Drug Review Steps |
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| Though the FDA drug approval process can take more or less time with individual compounds, the agency requires that all drugs go through the following basic steps of the approval process: 1. Animal testing. The animal testing occurs before an investigational new drug application (IND) is submitted to the FDA. 2. Investigational new drug application (IND). The IND outlines what the sponsor of a new drug proposes for human testing in clinical trials. 3. Phase 1 studies. These typically involve 20 to 80 people. 4. Phase 2 studies. These typically involve a few dozen to about 300 people. Some treatments for serious and/or life-threatening diseases have been given accelerated approval by the FDA following phase 2 studies when they offer a satisfactory treatment where none has previously been available.* 5. Phase 3 studies. These pivotal studies typically involve several hundred to about 3,000 people, but usually a lower number in ophthalmic drug studies. 6. The pre-NDA period. This occurs just before a new drug application (NDA) is submitted. It is a common time for the FDA and drug's sponsors to meet. (Steps 7 through 10 take place almost simultaneously) 7. Submission of an NDA. This milestone is the formal step asking the FDA to consider a drug for marketing approval. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's research on the drug's safety and effectiveness. 8. Labeling review and facility inspection. The FDA then reviews information that goes on a drug's professional labeling (information on how to use the drug). The FDA also inspects the facilities where the drug will be manufactured as part of the approval process. 9. Approval decision. If the FDA decides the benefits of a drug outweigh the risks, it will receive approval and can be marketed in the United States. But if there are correctable problems with an NDA or if more information is necessary to make a determination, the FDA will let the applicant know what is needed to resolve the deficiencies. 10. Resolving issues. Some drugs can still be approved if specific issues are resolved first. This might involve the sponsor and the FDA coming to a final agreement on what should go on the drug's labeling, for example. It could also involve more difficult issues, such as the adequacy of information on how people respond to various dosages of the drug. An applicant may need to conduct additional studies — perhaps studies of more people, different types of people, or for a longer period of time. *Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available. Instead, less traditional measures called "surrogate endpoints" are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs. Gleevec (Novartis), an oral treatment for patients with a life-threatening form of cancer called chronic myeloid leukemia, received accelerated approval. The drug was also approved under the FDA's orphan drug program, which gives financial incentives to sponsors for manufacturing drugs that treat rare diseases. Gleevec blocks enzymes that play a role in cancer growth. The approval was based on results of three large phase 2 studies, which showed the drug could substantially reduce the level of cancerous cells in the bone marrow and blood. |
The Advisory Committee: A Major Hurdle
By the time a drug reaches one of the FDA's 48 technical and scientific advisory committees, the treatment has gone through years of animal testing, preclinical studies and human clinical trials. As much as a decade of expensive, company-funded effort has already taken place.
Sirion's Durezol had a smooth path to approval.
The FDA tasks its expert committees with reviewing all the relevant data associated with the drug and listening to presentations by both the applicant and the FDA staff. Committee members then ask questions that draw out information that the FDA needs to make a final decision on the drug. The advisory committee usually votes on recommending approval or rejection. The vote is not binding on the FDA but does carry significant weight.
Ellen Strahlman, M.D., M.HSc., chief medical officer of GlaxoSmithKline, was selected as the non-voting industry representative to the FDA's Dermatologic and Ophthalmic Advisory Committee in April of 2008. An ophthalmologist, she was nominated by the PhRMA Association and accepted by the FDA. She will serve a 4-year term.
Dr. Strahlman has the kind of strong credentials that the FDA looks for in selecting advisory committee members.
She has a Bachelor of Arts degree in biochemistry and mathematics from Harvard University and earned her medical degree at the Johns Hopkins University School of Medicine, where she completed her internship in general surgery and residency in ophthalmology. She also has a Master of Health Sciences degree in epidemiology and statistics from the Bloomberg School of Public Health at Johns Hopkins.
Dr. Strahlman has broad industry and government experience. Before joining GlaxoSmithKline, she held leadership positions at Pfizer, Virogen, Merck, Novartis and Bausch & Lomb. She also served as senior medical officer at the National Eye Institute of the National Institutes of Health.
A Panelist's Priorities
"I believe part of the reason for my being selected is my experience with scientific data and in public health," Dr. Strahlman told Ophthalmology Management. "I have also been before FDA advisory committees from the drug development side, so I know the process."
Dr. Strahlman places a high priority on the benefit/risk assessment. "As advisory committee members, we have to weigh issues such as the seriousness of the disease, the urgency of the need for an effective treatment and the age of the patient population," she asserts. "You would probably accept a little more risk with Lucentis than you would with a glaucoma drug."
Dr. Strahlman believes it is important to point out that the FDA can award priority review status (review within 6 months) to drugs that have the potential to meet a serious medical need.
Asked whether presenters who have experience in coming before an FDA advisory committee can help a drug's chances, Dr. Strahlman notes that the drug must stand or fall on its merits but that having experienced presenters is "helpful" when the committee members begin firing questions. "The experienced presenters hold up better under questioning," she concludes.
How Sirion Succeeded
When Tampa-based Sirion Therapeutics was formed in 2005, the drug-development company had already dealt with the experience issue. Company management emphasized the fact that it had put together a team of seasoned professionals with a record of success in obtaining FDA approvals.
A little less than 3 years after being founded, Sirion had its first FDA approval, preceded by a positive endorsement from the advisory panel. The agency gave the green light to Durezol (difluprednate ophthalmic emulsion), a corticosteroid treatment for pain and inflammation associated with ocular surgery. Shortening the approval process was the fact that Senju, a Japanese pharmaceutical company, had developed the compound and conducted several clinical trials in Japan before licensing the drug to Sirion. The FDA allows clinical trials held outside the United States to be used to support a new drug application if the data is deemed applicable to the U.S. population and the study results can be documented.
Sirion's task then was to conduct two pivotal phase 3 trials and combine its positive data with Senju's in its presentation to the FDA.
| FDA Advisory Committees |
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| FDA Advisory Committees often play a key role in the drug approval process. The advisory committee members are selected for their knowledge and for being able to make an unbiased recommendation. Though the FDA is not bound by the vote of its advisory committees (indeed, it is not required to even have such a vote), the recommendations of the committees carry a great deal of weight in the agency's final determination. In response to specific questions, The FDA provided Ophthalmology Management with the following guidance on how committees are chosen and employed in the approval process. Overall Role "The Dermatologic and Ophthalmic Advisory Committee generally reviews issues related to ophthalmic drug products. We will augment the committee membership with specific expertise as needed. Most ophthalmic NDAs are not brought to the Dermatology and Ophthalmology Advisory Committee. Applications that are distinctly new indications are usually brought to the Committee. Applications for new molecular entities are also usually brought to the Committee, although we may not continue to bring applications where multiple other members of the class have already been approved and there are no specific issues with the application. The FDA evaluation (review) process is prepared to deal with new products that are submitted. The first ‘antisense’ product was approved by the ophthalmology group over 10 years ago. Similarly, the ophthalmology group has previously approved prodrugs." The Agency has prepared a draft guidance entitled Guidance for the Public and FDA Staff on Convening Advisory Committee Meetings. This addresses the general issue of when FDA will decide to convene an Advisory Committee meeting. The Web address for this is www.fda.gov/oc/advisory/aclawsregs.html. Membership Selection "We receive committee-member nominations from a variety of sources, including professional medical associations, past members, self-nominations and (other sources). Members serve for up to a 4-year term." (Editor's note: As of this writing, the FDA's Dermatologic and Ophthalmic Committee has a number of vacancies, which the Agency is currently attempting to fill.) Compensation "Advisory Committee members receive a daily salary for attending an Advisory Committee meeting. In addition, they receive reimbursement for their travel and lodging/meal expenses." Influence on FDA "We do not always take all of the advice provided by individual members, although we internally discuss their recommendations. It is also important to understand that we do not always ask the committee whether or not the drug product should be approved." Historically, the FDA has usually followed the recommendations of its Advisory Committees in regard to approving or rejecting new drug applications. |
A Winning Strategy
"In our pipeline are five drugs that we have licensed and three that we have discovered in-house," says Sirion CEO Barry Butler. "We want to do both. But to get the company growing quickly we started with Durezol. It was a good choice because it offered many advantages over available therapies. Plus, all of the animal studies and the earlier clinical trials had been done in Japan."
Mr. Butler says licensing drugs can be a successful strategy "if you spend a lot of time analyzing market needs, shop well and find products that are clearly best-in-class."
Durezol's passage through the FDA approval process went well, he says, because of several factors.
"First and foremost, Durezol performed extremely well in our clinical trials. It is always an easier process when your drug clearly meets the endpoints," asserts Mr. Butler.
"Secondly, the Durezol NDA was chosen to be included in the FDA Good Review Management Pilot Program that emphasized ongoing communication between the company and the FDA. We had a really smooth process that included a lot of open communication with the reviewers," notes Mr. Butler.
Finally, all clinical trial data was captured electronically in real time, keeping investigators on track and immediately catching any possible errors. "With paper charts, it might take weeks to catch errors or be able to raise questions about something that didn't look right," asserts Mr. Butler.
In making its presentation before the FDA advisory committee, Sirion primarily relied on its chief medical officer, Roger Vogel, M.D., and senior vice president of drug development, Christine Miller, PharmD.
"This was Christine's eighth NDA approval and Roger's eleventh," notes Mr. Butler, "so we definitely had people with experience in going before the FDA."
Comments from a Lead Investigator
Michael Korenfeld, M.D. of Washington, Mo., who served as a lead investigator for the two phase 3 trials that Sirion conducted for Durezol in the U.S., had a great deal of confidence in the company's game plan for the drug.
"If the leaders of a U.S. pharmaceutical company are active in seeking out opportunities, clever about identifying a need in the market, and prescient about which partially-developed drug to license, then this method for drug development in the United States is quite wise," says Dr. Korenfeld. "The leaders at Sirion played this hand very well."
Dr. Korenfeld believes it was advantageous for Sirion to in-license Durezol from Senju for several reasons:
► Senju conducted extensive and robust preclinical and clinical testing, which takes years in drug development.
► By licensing a drug that had already been proven in two inflammatory disease states (postop inflammation and moderate to severe uveitis), Sirion was able to offset costs of having to conduct this research internally.
► Because of the known clinical outcomes in Japan, Sirion was able to take most of the risk off of the table when conducting the trials that were submitted to the FDA.
► The Senju results allowed Sirion to choose a dose to study and select an appropriate sample size for their phase 3 trials. It was because of the positive results from the Senju trials, seen in both the postoperative and uveitis setting comparing Durezol to betamethasone (a strong steroid used outside of the United States), that Sirion decided to move directly into the phase 3 trials that would be submitted to the FDA for the ultimate approval of the drug.
Trials Lead to Approval
The two phase 3 trials submitted as part of the approval were identical in design and had similar results. Both trials included two Durezol treatment arms — one Q.I.D. and one B.I.D., and two placebo arms dosed in the same fashion. Patients in the trial included those undergoing ocular surgery and presenting with more than 10 cells in the anterior chamber 1 day after surgery. No NSAIDs were allowed in the trial.
The endpoints, which included clearing of anterior chamber cells and flare and elimination of pain, were the same in each trial. In each of these trials, both Durezol B.I.D. and Q.I.D. were found to be more effective at reducing inflammation and pain than placebo. The B.I.D. and Q.I.D. arms had numerically similar results in the clearing of anterior chamber inflammation, although they were not powered to be compared to each other.
The Q.I.D. Durezol arm performed slightly better then the B.I.D. arm in the elimination of pain at day 8, and a Q.I.D. dosing regimen was approved by the FDA.
"Successful drug development is a tricky game of chess," asserts Dr. Korenfeld. "The playing field is forever protean, so when you commit to selecting a drug for development, you really have no idea what other drugs might emerge in the pipeline at other pharmaceutical companies while you are developing yours. That's why licensing a drug can be advantageous; it may shorten the time to approvability and the drug may already have been proven safe and effective in other non-U.S. venues."
In discussing his role as a lead investigator, Dr. Korenfeld notes that "once the drug company has clarified the protocol and strategies for what it contains, then it must convey these issues to the investigators and make sure that they conduct the clinical trial in strict accordance with the protocol. The protocol is the distillation of lots of hard work at the level of the drug company's scientists and the folks at the FDA."
The overall result of this strategy was that Sirion, which had initially targeted June 2008 for Durezol approval, received its FDA approval in June 2008.
Summing up Sirion CEO Butler's basic advice in going through the approval process:
► Clinical studies should showcase the strengths of your product.
► Be flexible. The FDA will lay down specific ground rules. Be prepared to adjust to meet their requests.
► Negotiate. Interaction with the FDA requires a certain amount of bargaining.
When Approval is Difficult
But not every drug has as smooth a journey as Durezol. For instance, Inspire Pharmaceuticals has encountered delays in the approval process for its dry eye drug Prolacria (diquafosol tetrasodium). The drug received two "approvable letters" and is now beginning another confirmatory clinical trial after Inspire consultation with the FDA.
"Allergan received two or three approvable letters for Restasis before it conducted a confirmatory trial and was finally approved," said one industry source. "The problem is that the symptom data for dry eye can be very subjective and often depend on how a patient feels on a particular day."
Looking Ahead
There are no hard and fast rules that can be said to lead to a smooth and speedy drug approval. Much depends on the specific drug, the indication for which approval is being sought and the ability of the company to have ongoing and productive communication with the FDA.
The good news is that the FDA has been willing to work to create a more transparent and streamlined process that offers companies a greater chance of success — but that only helps if the drug being brought to the agency is safe, effective and provides advantages over available therapies. OM
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