By Cindy Dubin
A report by Deloitte on the world’s 12 largest drugmakers shows that the average cost of bringing a product to market rose by more than 25% to greater than $1B in 2011, from $830M in 2010. And, for new drugs, it typically averages 10 to 15 years from discovery to enter the marketplace. With the time and monetary investment, it is no wonder that the number of late-stage drugs in development dropped to 18 from 23, on average, per company, from 2010. And, 10 of the 12 firms actually saw a decline in investment returns from R&D, resulting in an overall drop to 8.4% from 11.8% last year.
But there are success stories: 35 new medications were approved during the FDA’s 2011 fiscal year, the second-highest number in a decade. Industry pros say that those who have received FDA approval were careful to dot all their “i”s and cross all their “t”s during clinical studies, communicate with regulatory bodies, and choose the right sales and marketing team.
Begin With The End In Mind
According to Gene Haley, CEO and founder of Wilmington Pharmaceuticals (which develops and out-licenses fast-dissolving formulations for established medicines), a successful process begins with the end in mind. “Bringing a drug to market is not an exercise in imagination but a process that aims to satisfy an unmet need within the market for patients, physicians, and managed care and brings with it economic value.” Haley says when you start with the end in mind, it is much easier to communicate the goal and gather a team that has the capability to carry out that goal.
The team should represent a variety of skill sets — formulation, clinical design and trial, regulatory, and manufacturing. “Any drug approval process is more than one person deep,” agrees Jim Hauske, Ph.D., president and founder of Sensor Pharmaceuticals, a virtual drug discovery and development organization focused on molecules affecting the nexus of inflammation and metabolic disease. Hauske is not a novice when it comes to bringing a drug to market; he was part of the team associated with discovering and developing Zithromax. “Bringing a drug to market is a team sport that requires all the skills of a highly diversified team.”
Clinical Trials: When To Stop
To promote the development of innovative new therapies, the FDA has made advances in regulatory science a top priority. For example, the agency is working to improve the science behind certain clinical trial designs. It has issued a draft guidance document on “adaptive trial designs” that makes use of early results of a trial to modify the design, making the study more likely to detect whether a drug works. The FDA also is working on a guidance document on “enrichment designs,” studies that make use of patient characteristics to identify people for whom the drug is likely to be effective. These designs allow smaller studies to be successful and target the treatment to patients who will benefit the most.
About 50% of drugs entering Phase 3 trials fail because of lack of benefit and sometimes because of unacceptable side effects that were not seen in Phase 2. “That fact is just amazing to me,” says Robert Temple, M.D., CDER’s (Center for Drug Evaluation and Research’s) deputy center director for clinical science. “The FDA understands that when the drug is exposed to more people during a Phase 3 trial, this opens the possibility to see more adverse events, but a large failure rate for effectiveness suggests inadequate Phase 2 trials. I encourage pharma to take a close look at their Phase 3 failures to identify why a failure occurred.”
One area Temple says requires a closer study during Phase 3 is dose response. While no one wants to give more drug than necessary to do the job, studying a range of doses can mean the difference between success and failure. “There was one drug, Alosetron for diarrhea caused by irritable bowel syndrome, that caused severe constipation, which sometimes needed to be treated surgically, as well as ischemic colitis,” relays Temple. “During the course of clinical trials, patients were dropping out because of the constipation. One would have thought the drug company would have tried a lowering of the dose study, but no.”
The International Conference on Harmonization (ICH) urges that different dosing regimens be evaluated during Phase 3. Often companies study a few dosing regimens in Phase 2 and then study only one dose in Phase 3, which Temple says is often a “terrible mistake.”
In addition to studies of more doses, Temple recommends that clinical trials encompass a range of patient populations. In addition to relatively healthy patients, seniors and people who have diseases other than the one being the focus of the study should be included. This, says Temple, will provide more and better data related to drug interactions and drug metabolization. It is also important to test various patient populations for drug side effects. A randomized withdrawal study with responders who are randomized to continued treatment or placebo is a very efficient way to test for the persistence of effect over time.
One major difficulty pharma companies face is knowing how much time to spend conducting Phase 2 and Phase 3 trials, says Temple. “Sometimes it is tempting to overinterpret data and perform subset analyses and decide you already have enough information, but this leads to inadequate dose finding and poor Phase 3 studies,” says Temple. “The saved time is wasted. Better Phase 2 data, perhaps using careful adaptive procedures and a full range of doses, is often a worthwhile investment.”
On the other hand, resist the temptation to overanalyze and collect too much data. “There is no need to collect lab data every month in a Phase 3 study; maybe every three months is sufficient,” says Temple.
One way to see if clinical protocols for Phase 3 trials are sufficient is by way of a special protocol assessment (SPA) by the FDA. While not a guarantee of eventual drug approval, an SPA is a way to come to an agreement with the FDA on the design of protocols related to animal carcinogenicity, final product stability, and pivotal Phase 3 trials.
Getting FDA agreement (read: buy-in) on your Phase 3 protocol can be critical to your development plan. It means the FDA is familiar with your program and feels that the protocol is adequately designed to address the endpoints proposed. Having an SPA can give you and investors confidence in your program.“The advantages of submitting an SPA seem obvious, yet many companies do not avail themselves of the process, which does not seem prudent,” says Temple.
FDA Approval Comes Down To Sound Data
The FDA often gets the reputation of slowing down the approval process. Yet, historically, the agency has put many guidelines in place to attempt to do just the opposite. For example, a report by the National Organization for Rare Disorders says the FDA’s flexible standards for approving drugs targeted at rare disorders have made it easier for those drugs to reach patients in need.
“Oncological development is presented with fewer hurdles than other therapeutic areas, so the regulatory process is more straightforward,” says Habib Skaff, CEO of Intezyne, a specialty pharma firm that was founded in 2004 with the goal of developing better cancer treatments. “Regulators know these patients are terminal, and it is important to get therapies available to them as soon as possible.”
Intezyne’s work involves substantially changing the pharmacokinetics of already approved drugs, which is unique when it comes to clinical trials. “Our risks in clinical trials are not the same as those associated with the development of a traditional new chemical entity (NCE) because the API in our NCE has already been clinically proven,” says Skaff.
But others remain skeptical of how much the FDA can handle and how quick the approval process really is. “The FDA’s workload can be an impediment to a rapid review process,” says Tom Aluise, CFO, Wilmington Pharmaceuticals. “The process gets delayed because the agency doesn’t have the time and people to answer questions. NDA (new drug application) filing used to involve meetings and a Q&A process with the FDA, but now the agency doesn’t have the time for personal meetings, so we receive written responses, which can be open to interpretation. Collaboration is largely gone.”
Temple adds, “Many pharma companies are knowledgeable and have discussions with us about areas of their studies that might cause trouble. And sometimes, disagreements arise, but we are willing to disagree, and companies should feel free to push the issue with us. Despite what many believe, disagreeing with the FDA won’t harm the chances for drug approval.”
According to Dr. Ron Hargreaves, VP, regulatory affairs at Ferring Pharmaceuticals, “Gaining FDA approval is, and probably should be, a challenging procedure. While we aim for the smoothest process possible, we expect and are prepared to face the challenges.” The challenge Ferring knew it would face is one that faces all companies making a submission to the FDA — the agency’s increasing criteria for the demonstration of safety and/or efficacy. This is particularly the case when a new product or a new claim is introduced into an existing class of products. According to Dr. Paul Korner, senior VP, U.S. development at Ferring, “This has to be expected in product development, and studies need to be designed to allow for such rigorous criteria.”
It is important to have a thorough understanding of what products have been approved in the area of interest and, if possible, what issues were encountered during the development and approval process. Additionally, communicate with the FDA early and at key points during the development process to ensure a successful program outcome. Finally, the project team must respond quickly, clearly, and completely to FDA questions or comments, particularly in the final stage of the review process.
Treading carefully from drug discovery to commercialization is essential. And once you’ve been through the process, don’t get too comfortable. There will always be an “i” left undotted and a “t” left uncrossed. “When launching a product, you don’t know what you don’t know,” says Hauske.