eDiary System’s Importance in a Clinical Trial for Female Sexual Dysfunction

Palatin Technologies is a biotech company focused on developing targeted, receptor-specific, peptide therapeutics for the treatment of diseases with significant, unmet medical needs and commercial potential. Currently Palatin is developing bremelanotide for the treatment of female sexual dysfunction (FSD), of which there currently is no approved drug on the market for FSD.

Study 54, PT-141-54, was a large, complex Phase IIb study which looked at three different indications of FSD: female sexual arousal disorder (FSAD), hypoactive sexual desire dysfunction (HSDD), and those with a combination of both arousal disorder and desire disorder. The study comprised 397 randomized and 394 dosed (1,142 patients recruited) across 67 U.S. sites. The study’s primary endpoint was the change from baseline in the number of satisfactory sexual events experienced by patients using bremelanotide.

Palatin chose the LogPad® System from PHT Corporation to capture all efficacy endpoints. Study 54 had eight patient reported outcomes (PROs) with multiple data points in each. The LogPad® System included a number of different assessments:

     · A diary completed at home by patients after every sexual event

     · A clinic-based questionnaire completed by the patient

     · A clinic-based questionnaire completed by a clinician

These instruments gathered data for:

     · Global sexual function

     · Distress associated with that sexual dysfunction

     · Satisfactory sexual events (SSEs), a count from event-based questionnaire data

Palatin collected subject reported data on each sexual encounter including a single question regarding whether the encounter was satisfactory. In-study analysis, using pre-programmed, blinded data reports, the percent of satisfactory events and the number of doses revealed if patients were dosing more as they improved, or as they increased the number of satisfactory events. Palatin also used this at-home data as a tracking mechanism toward the end of Study 54 to determine each patient’s status in the study.

There was one LogPad® System mobile device per patient, with different logins for patients and clinicians providing clear separation between the at-home and in-clinic portions. All efficacy endpoints were based on data collected via questionnaires and the LogPad® System application required completion of all questions. This resulted in 100% completion of required information and prevented discrepancies in the data entered.

The protocol included two time points for screening evaluation: The first was at Visit 1, and contained questionnaires completed as part of the diagnosis and initial screening assessments. The second was during the screening month between Visit 1 and Visit 2. This was a one-month period with no study drug treatment during which the diagnosis was confirmed using data collected at home following sexual activity. Using data collected at the in-clinic Visit 1 and during the at-home screening month, screening questionnaire scores and percentage satisfaction rates during the one month, at-home screening period were calculated and displayed in a summary report. Palatin used a pre-programmed color coding system in the summary report to call out numbers or values that did not meet the screening criteria.

In an always available, episode-based eDiary report, patients recorded the time of a sexual encounter and the time of the study medication injection. There was also a reminder question which was available from 6:00 AM to 11:59 AM, prompting the patient to enter data if there was anything to report (i.e. any sexual activity). The alarms were selectable between 6:00 AM and 11:00 AM with reminders every 30 minutes. Real-time access to encounter and dosing times provided insight into both time to onset for the medication effects and study compliance. Palatin noted 64% of events recorded occurred between 8:00 PM and 12 AM and made sure the diary was available during those hours. In addition, the study drug and encounter times data were able to show that of all the encounters which occurred in the 1.75 mg and placebo dose arms in the double blind period of bremelanotide Study 54 (1,471 encounters), approximately 72% (1,054 encounters) of those occurred within 16 hours of dosing.

Lessons Learned

Privacy of eDiaries--Data collected in FSD trials is very sensitive. Giving patients the LogPad® System to answer questionnaires provided anonymity which allowed participants to be honest in their responses. Cheryl Van Walsh of Palatin explained, “If patients had to go and sit with their doctor at every visit and talk about the number of sexual encounters and satisfaction levels and arousal, we would not have collected the same quality data. In indications in which sensitive data are collected, it’s so very important to make patients feel comfortable. An ePRO system lends itself to collecting good quality data for this type of indication.”

Training Ensures Compliance--Ongoing, proactive eLearning and communication with sites was a key to the success of Study 54. Going onsite and to investigator meetings, and using an adaptive training strategy for site and CRA staff, had tremendous value.

Palatin and PHT conducted ongoing training during the key enrollment period of the study, offering training sessions to all sites at a scheduled time for about seven weeks. Site staff were invited to participate as many times as they wanted. Palatin also required the CRAs to moderate these trainings, ensuring that the CRAs were following up with the sites, that they understood the training sites were receiving, and that they could effectively assist sites with any issues that occurred. Palatin spent a good portion of CRA meetings talking specifically about issues that arose during site calls to PHT on anything sites were seeing in the data or devices. Cheryl Van Walsh, former Clinical Operations Project Manage for Palatin, commented that this “level of detailed information gathering and sharing helped the team know what they were looking for and how important it was.”

Palatin also invited PHT to include messages for sites in Palatin’s regular newsletters, such as information PHT may have learned from analyzing help desk calls from the study sites or discussing common sources of data change requests.

Reporting, Compliance, and Study Design

Palatin used StudyWorks™, a secure, online reporting portal of all eCOA data collected by any PHT device, to create and review compliance reports by site, patient and country, along with other detailed data. Reports included diary data collected from each patient, such as [or] including screening criteria, continuation decision, date of continuation decision and the patient’s current status.

Patient eDiary compliance was critical to study success as efficacy data was collected via the LogPad® System. As visits were monthly, Palatin did not want to wait 30 days to learn a patient was not completing her diary. It was critical for sites and CRAs to use StudyWorks™ to track patient compliance between visits and proactively monitor and manage compliance to maximize the return on investment for the ePRO System.

Analysis of PHT operational data across numerous eCOA studies indicates sites that review StudyWorks™ frequently have higher compliance rates. Palatin trained CRAs on StudyWorks™ and encouraged them to use it to obtain real-time data and standardized reports on significant study metrics like patient compliance and enrollment. Palatin’s CRAs worked with the site staff to remind patients during a mid-month call to complete their diary. This greatly improved patient compliance and produced quality PROs.

Van Walsh explained, “It’s critical that the site knows the sponsor is invested in the study and is looking at the data on a daily basis. When you have that level of confidence from the site that their specific activities are making a difference it boosts

their investment in following study procedures, facilitates problem solving, and prevents loss of data. StudyWorks™ helps sites and CRAs be vigilant when reviewing data. By using StudyWorks™, SmartReports™ Compliance Reports and alerts, a site coordinator can rapidly identify patients that have not been sending data and can follow up with that patient to provide support and answer questions so they can more easily comply with the protocol.”

Real-Time Data, Study Revisions

During the first third of the trial, Palatin saw a high number of screen failures based on one aspect of one questionnaire: the total FSFI score, which is a global measure of sexual function. They started receiving calls from investigators reporting that these patients did, in fact, have decreased desire disorder but were being screened out because of the total FSFI score. By analyzing data made available through StudyWorks™ Palatin was able to see the issue early in the study and make the necessary revision to their inclusion and exclusion criteria, change the protocol and improve enrollment by not inadvertently screening out desire-only patients.

Summary

Palatin had robust, consistently positive data across all the questionnaires in the Phase II study, including the primary and secondary endpoints.

Rob Jordan, Executive Director of Clinical Operations and Project Management at Palatin, said, “Study 54 was a great example that successful trials are the result of collecting quality data utilizing solid technology and strong collaborative efforts between the sponsor and service providers.”

He offers these insights:

   · Patient centricity is here to stay, but balancing that with clinically meaningful information is an ongoing challenge. PROs are a significant part of the focus on the patient.

   · Electronic data capture is sophisticated and provides flexibility to collect a significant amount of quality data          very easily. ePRO provides the ability to plan an eDiary availability window around the most likely time the          event will occur. It is important to leverage ePRO to gain efficiencies in your study and capture accurate,                reliable data.

   · eDiaries give patients privacy and anonymity. Not having to do face-to-face reporting with the sites, especially      regarding sensitive topics can result in increased data capture.

   · Reminders such as audio alarms and on-screen messages help maximize data collection.

   · Ongoing training is vitally important for improving site and patient compliance.

Palatin has initiated its Phase III program for bremelanotide in pre-menopausal women with FSD.

Van Walsh said, “We’re taking everything we learned in this trial and transferring it over into Phase III. Those things we did well we’ll try to do again. Those things that could be improved, we’ll change. But the biggest takeaway is that we have built such a good foundation and relationship with PHT through the Phase II study, we will realize efficiencies and robustness is our very important PRO data collection necessary for Phase III.”

Sheila Rocchio, MBA, Vice President of Marketing and Corporate Strategy, PHT Corporation