By Ed Miseta, Chief Editor, Clinical Leader
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The challenges of conducting a Phase 3 trial and then using that data to get an approval from the FDA are something every head of clinical research knows very well. The clinical team at Agile Therapeutics knows it all too well. The company has been down that road once before, only to come away empty-handed. Before its second attempt, the company hired Elizabeth Garner as chief medical officer and SVP of clinical development to take control of the process.
"The active ingredients used in the patch are already used in multiple contraceptives and have been for more than 25 years,” says Garner. “Those ingredients are levonorgestrel (LNG), which is used as a standard of comparison of venous thromboembolism risk among progestins, and ethinyl estradiol (EE), a synthetic estrogen used in many currently marketed contraceptives. [Because these have been previously used], some of the information required for approval can come from other studies not conducted by or for Agile. We believe our proprietary Skinfusion technology delivers the hormone (EE, a synthetic estrogen) in a more appealing form.”
Measuring the effectiveness of a contraceptive in a clinical trial is not an easy process. These studies are typically single-arm, open-label trials. Since the purpose of the patch is preventing pregnancy, the trials are never placebo-controlled. “We measure exposure over a 28-day cycle of use,” says Garner. “Our studies are generally 13 cycles (one year) in duration, and the FDA requires approximately 10,000 cycles of exposure and a minimum of 200 female participants on the drug for one year.”
To measure the effectiveness of its contraceptive, all contraceptive studies use a calculation known as the Pearl Index (PI). “This index can be affected by many factors,” notes Garner. “There are differences in study design, sensitivity of early pregnancy tests, population, user experience, and inconsistent or incorrect use of the contraceptive method. For those reasons and more, patient engagement is something we obviously spend a lot of time thinking about.”
NO APPROVAL ON FIRST TRY
The Twirla patch, also known as AG200-15, has already been administered to more than 2,100 women in completed Phase 2 and 3 studies. It has been through two Phase 3 studies, one of which was submitted to the FDA for approval and subsequently rejected. Results from those studies have shown the pharmacokinetic profile is consistent with a low-dose contraceptive, it was well-tolerated with a low rate of estrogen-associated adverse events, the Skinfusion technology performed well under normal daily activities (bathing, exercise), and the effectiveness in prior Phase 3 studies has been comparable to approved low-dose oral contraceptive comparators. The problem is, after an extensive Phase 3 study with what the company believed to be promising results, Agile still did not have a product approval from the FDA. “The FDA issued a Complete Response Letter in February 2013 citing insufficient evidence of efficacy and issues with our study conduct. Specifically, it noted the dropout rate and loss to follow-up, subject compliance with the proper use of the study drug (both the patch as well as the pill), and overall data quality. Patients were getting pregnant using a pill that we knew to be highly effective. They requested we complete a third Phase 3 study with better study conduct and improved oversight, support of subject compliance, and avoidance of dropout and loss to follow-up (i.e., patients unaccounted for at the end of the trial).” Long story short: If Agile was to complete a third Phase 3 study, Garner knew she would have to focus on selecting and working with an experienced CRO to ensure the close oversight of the trial the FDA was asking for.
THE HUNT FOR FUNDING A NEW TRIAL
The new Phase 3 trial was initiated in September 2014. This was also a single-arm, open-label study that was set to treat approximately 2,000 subjects for one year (13 cycles), at 102 clinical sites in the U.S. The PI would again be used as the primary endpoint. A main focus would be on correcting the deficiencies noted by the FDA, and the study was scheduled to be completed in the fourth quarter of 2016.
The first thing Agile needed to do was find the funding that would allow it to take on such an immense trial. Company CEO Al Altomari did so by taking the company public. Garner, who was involved in that process, describes going through an IPO as incredibly stressful and now compares it to the challenge of an NDA (new drug application) filing … times three. Despite the challenges faced, the company was able to raise the money it needed.
“To convince the investment partners that we had the right product for them to invest in, we had to demonstrate that we were working with the right CRO partner,” says Garner. “The investors felt some of the oversight issues we experienced in the past were due to the conduct of the CRO. In a few instances, some investors believed that some of the sites being used simply did not have enough experience in contraception. Therefore, we knew the CRO we selected would have to be experienced and well-known in the industry, it would have to have access to experienced clinicians and study coordinators, and it would need to help us enroll the right selection of study subjects. This left us with a very critical decision to make.”
"To convince the investment partners that we had the right product for them to invest in, we had to demonstrate that we were working with the right CRO partner.
Chief medical officer and SVP of clinical development, Agile Therapeutics
AN IN-DEPTH CRO ANALYSIS
But how does a small company the size of Agile go about finding a known and experienced CRO, when your size makes you feel like they won’t view you as worthy of their time and effort? Garner figured the best way to start was by performing some research. She learned 64 percent of post-Phase 1 studies are outsourced. The outsourcing rate was 52 percent for large (top 20) pharma companies, but rose to 88 percent for small companies. Looking at research performed by University of the Sciences in Philadelphia, she was able to better organize her thoughts regarding the top five criteria to look for in a CRO. They are, in order of importance, a CRO your team can work with, a project management team devoted to the study, recent experience in the same indication (a criteria very important to Garner), overall experience in the therapeutic area, and the background of team members.
She also considered the results of other industry surveys which noted cost was not generally a leading criterion, but quality and timelines were, along with the process for issue identification and resolution. The most important quality attributes reported by others going through the same process, she learned, were values, work ethic, and team chemistry. That convinced her of something she had already believed: that outsourcing relationships are really about people. But one concern still weighed heavily on her mind: the size of the CRO.
“Big Pharmas generally outsource to the largest CROs,” she says. “Studies also have found those that do are satisfied with the results. But only about 10 percent of small sponsors spend most of their outsourcing budget on the top five CROs. In fact, 70 percent of small companies dedicate less than 10 percent of outsourcing spend to those top five companies.”
Looking at research performed by The Avoca Group, Garner also found that small and midsize sponsors that used the top five CROs to meet less than 25 percent of the outsourcing needs were more satisfied than those who used the large service providers more liberally. “It seems to me that large companies are more comfortable with the large CROs, and the small companies are more comfortable with small CROs,” she says. “That finding did not really surprise me.”
Overall, that same Avoca study found large CROs excelled at providing a global footprint, standardized procedures, and capacity. The medium and small CROs excelled at value, lower turnover, flexibility, and personal service, all things that she valued highly. Smaller CROs also seemed to have strong experience in specific therapeutic areas and obviously are less likely to have strategic partnerships in place that might take priority over a smaller study.
CHOOSING THE RIGHT PARTNER
Garner’s research seemed to point toward working with a small or midsize CRO, although she knew the Wall Street investors who helped finance the study were looking for a well-known and established service provider. Although she now had a better-structured and researched list of criteria to look for in a partner, Garner was still no closer to selecting the right CRO. So she began a search process that would end up taking about four months to complete.
To make the selection process easier, Garner decided to make a list of the considerations she felt were of greatest importance to her company. The top five criteria she came up with were quality (especially in the data that would be gathered), technology and systems (so as to properly monitor compliance and know when to intervene), experience in contraception studies, name recognition, and finally cost. Although Agile was able to raise funds for the study, Garner notes she still had tight budgets that had to be met.
She also decided on the process she would use to find the right partner, which would consist of an RFP, a detailed review of the responses, selection of candidates for in-person meetings, a formal bid defense of the top candidates, and finally a ranking for each candidate of the key considerations noted above.
“A critical component of the selection process was hearing directly from the candidates we felt would be a good fit,” she says. “Instead of just looking at information submitted, we wanted them to make their best pitch to us in person. Therefore, the in-person meetings contained a lot of information-sharing by the contenders.” Specifically, Garner asked the following questions:
- Why are you the best CRO for this project?
- What is your approach to working with small companies?
- Describe your approach to site selection, monitoring visits, and oversight.
- Describe your experience in women’s health in general and contraceptives in particular.
- How many CRAs (clinical research associates) will be assigned, and what is the CRA/site ratio?
- Elaborate on your approach to subject retention and compliance.
- Provide metrics on study timelines, monitoring, and query/database lock procedures.
The information Garner and her team received was valuable and insightful. In addition to the information obtained, she also was able to observe personal qualities of the presenting teams and their ability to interact and converse with her own team members. “For me, a very important part of this process was truly about understanding the medical monitor and making sure they really understood what we needed and what we were looking for,” she states.
THE RANKING PROCESS
Now that most of her work was complete, the hardest part of the selection process still remained: ranking the contenders and selecting a partner. Garner produced selection criteria for the project, which she notes can also be used for future projects simply by varying the order of importance (which might vary based on the specific needs of a trial).
For this trial, Garner placed therapeutic expertise and experience at the top. With this being the third Phase 3 trial for the patch, she knew success was critical, and that a fourth trial would not be financially viable. In fact, the success or failure of her company was likely riding on it. Rounding out the top five criteria was the CRO’s CTMS (clinical trial management system), past enrollment and site performance, the site selection process, and the risk identification/mitigation process. Other criteria considered were the project management model, proposed EDC (electronic data capture) system, experience with electronic patient diaries, projected enrollment rates, timelines, site monitoring model, metrics quality, study timelines, the project team, and cost. After a very thorough ranking and evaluation process, Agile selected PAREXEL as its partner.
“For each criterion that we looked at, the compatibility with our team, our processes, and our systems were critical factors for us,” says Garner. “The knowledge they had coming in and the proposal they presented were impressive. And even though they are a large company, they had the expertise and name recognition we needed, but as a small company, we also felt they would treat us the way we wanted to be treated. When they made their presentation, it was clear to us that really did their homework, took the time to understand the issues we faced, and they even went so far as to understand what is currently happening in the contraceptive market, and the pros and cons of using electronic diaries. That attention to the things we cared about really stuck with us.”
Agile will continue to have statistics performed by the same vendor who provided those services for the two prior Phase 3 studies. The FDA had no issues with the analysis performed, and Garner felt there would be efficiencies by sticking with the same company they already knew and worked with.
For other small companies going through this process, Garner also recommends thinking about internal team strengths and identifying gaps that might exist. For Agile, medical monitoring, statistics, and patient recruitment were important considerations.
Although cost has to be a concern for any small company, she cautions this should never be a reason to cut corners or consider lower quality work. Instead, she recommends companies consider the potential to save money by sharing tasks with the CRO and therefore ensure the CRO selected is willing to do the same. To properly understand the CRO’s processes, she recommends performing a thorough review of their SOPs.
Finally, Garner acknowledges that issues will arise in any relationship and advises companies to thoroughly explore an issue resolution/escalation plan up front. “Ensure you have a responsive point person at a sufficiently high level,” adds Garner. “They will be your sounding board within the CRO. This is the person who will perform troubleshooting and problem solving, and the person responsible for adding or replacing team members, when necessary. And take the time to explore the company culture. In any relationship, people and relationships will always be the ultimate keys to success.”