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Celgene Corporation uses the PHT Corporation SitePad System and StudyWorks to collect patient-driven eData for OTEZLA (apremilast) tablets approved by the FDA in March 2014
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of novel therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation.
Celgene evaluated the safety and effectiveness of OTEZLA®, an oral inhibitor of phosphodieasterase-4 (PDE-4), in three global clinical trials involving 1,493 patients worldwide with active PsA. The FDA approved OTEZLA® in March 2014.
Celgene wanted to determine whether patients treated with OTEZLA® would show improvement in signs and symptoms of PsA, including tender and swollen joints and physical function, compared to placebo. Celgene chose to use the SitePad® System eCOA (electronic clinical outcome assessment) tablet from PHT Corporation to collect data about patient symptoms as observed by physicians through the ACR assessment which was used to assess efficacy. The eCOA tablet was used to collect quality of life data including SF-36, EQ-5D, MOS Sleep Scale, and WLQ-25.
In addition to QOL data, the patient also recorded the HAQ-DI, a patient’s assessment of pain and a global assessment of their disease. Patients with axial disease also completed the BASDAI. Sites completed the 76/78 Joint Assessment, a physician’s global assessment of disease, a dactylitis assessment, the MASES, and the PASI for patients who had more than three percent of psoriasis.
Over the course of 3.5 years Celgene collected 4.5 million data points. Celgene chose to use an eCOA tablet instead of paper because it enables clinicians and patients to record real time clinician and patient outcome data electronically from the start. Once entered onto the tablet the data is transmitted into PHT StudyWorks, a secure online portal of all electronic clinical outcome assessment (eCOA) data, and was available for review and report on subject compliance, safety and retention. This significantly reduced monitoring and data cleaning costs. Elisabeth Kurkimilis, Senior Study Manager at Celgene, said, “Convert that into monitoring time and expense, because once the information is directly entered into the tablet, that's your source.”
While Celgene did have a paper backup system in place, the number of paper instances Celgene used was less than 2% across the global studies.
Celgene collected clinician and subject outcomes. Both groups used the tablet to enter their assessments, capturing study-specific clinician and patient assessments at the investigator site.
Supporting Patients – The program included patients who were “Snowbirds,” spending summer in Canada and winter in Florida. To handle this issue and transfer of a patient across sites, Celgene put an entire patient transfer document into place to make sure patient data were transferred so they could capture the additional data for Snowbird patients when they transferred. Celgene took the data from PHT and transferred it to their CRO, who performed a manipulation and delivered two datasets for Celgene’s review. Various programming checks on the data looked for mismatches and made sure everything lined up.
Improving Patient Retention and Compliance – The secure online reporting and monitoring portal helped Celgene improve patient retention. When patients came in for site visits monitors could show them where their symptoms started, where they were at the moment, and the difference. If patients said they weren’t sure they were doing well the investigator could show them how they had progressed throughout the course of the study. To assess potential patient fatigue Celgene asked study coordinators and internal staff, some of whom had not seen the questionnaire before, to see how long it took them to complete it. Most people spent between 30 and 40 minutes on the complete set of patient questionnaires. To minimize impact from potential patient fatigue Celgene ordered questionnaires by importance for secondary endpoints, so the first questionnaire patients saw on the tablet was the key questionnaire Celgene needed.
An eCOA tablet handles the volume and allows your CRAs to spend more time at your sites paying attention to issues at hand. For us that was a huge, huge saving.”
= $3,250,000 saved per study X 4 studies
Total savings across the program = $13 million dollars
As of December 31, 2013 Celgene had completed over patient 17,800 visits. There were over 166,000 expected questionnaires and assessments on the eCOA tablet: The completion rate was over 99%. For Celgene’s primary endpoint they achieved a 99.5% effective completion. “From our standpoint having that data readily available was phenomenal,” Elisabeth said. “The assessor endpoints were 98.5%. Imagine the problem trying to achieve that number on paper. You miss a questionnaire, you miss certain questions within a questionnaire, and if you lose two questions on an SF-36, you start losing pieces of domains you can analyze.”
Celgene did not provide training eCOA tablets to CRAs at the IM, but allowed them to take them back with them after the IM. “We provide so much information to CRAs at the IM it’s hard for them to comprehend all of it and to understand what they’re supposed to do once they get back,” Elisabeth said. After the IM, they can sit with a physician or study coordinator and walk through how to assign a patient and how to do assessments with the trainer.
After submitting the NDA, Celgene preplanned for their sponsor inspection, and conducted inspection readiness training for about a year before inspections occurred, so they had all documents inspectors requested. Elisabeth spent a number of hours with the inspector going through a point-for-point comparison of the source data for primary endpoints. The StudyWorks portal gave the Celgene team the confidence to know they were presenting high quality data and they could answer questions about the data throughout the trials and during their inspection quickly. Because Celgene trained sites before they had a health authority inspection, each site was aware of how to access requested data related to any aspect of the trial.
While preparing for inspection, Celgene had a weekly meeting with program suppliers and eventually reduced the schedule to every two weeks. It took about 30 minutes each month to discuss four studies. “Having that time built into your calendar and having the buy-in from your cross-functional team to attend those calls is vital so everybody knows what they need to do,” Elisabeth said.
Plan Ahead, Plan Again – The best laid plans encounter pitfalls, what is important is how you react and work through problems: “Plan, plan, plan with your internal team, your partners and your vendors,” said Elisabeth. For example, it took about seven weeks to get wireless access hubs into Russia because Celgene had to go through so many lines of approval. “Preplan with your vendor, and you’ll be ready for any obstacles,” is a key recommendation for managing a large global trial with complexity.
Develop a Database Lock Plan – Elisabeth recommends before you get to database lock, make sure you have a database lock plan in place. What are you going to do? What's going to be acceptable? Once you lock your database, you don't want to unlock it. It needs to be clean before you lock it. “If you have an endpoint and a lock coming up, plan your reviews early so if you need to make updates to the system sites can make them early to allow for smooth data reconciliations.”
Casebooks are Different than eCOA Archives – Casebook Preparation was very important for Celgene. PHT has its own format for providing data for archives, as do other vendors. Celgene determined how to integrate all the pieces of data so when they provided their information to a health authority according to the standard, and were able to look at one patient and all their data as a whole.
Closely Monitor the Data Change Queues – If you have DCFs you want to make sure they don’t mount up on you. At Celgene’s first meeting with PHT they had about 70 DCFs or site questions. They reduced the list to a manageable three or four. “Old ones fall off and new ones will come in, but that's a very manageable level as you're working into a database lock,” she said.
Consider Data Entry Requirements Up Front – “The review of the specifications will carry a trial through,” Elisabeth explained. “Have this done early so if when you start getting your transfers and you see a problem you can recommend, remediate, and make changes to that transfer document to get what you need.” When it comes to reviewing data the biggest piece of advice Elisabeth has is about how often data is reviewed: “When you're doing site and patient assessments, if your site is a little quirky and doesn't tend to follow the rules, you want a lockout to make sure the data are entered within a specific visit. We worked with PHT to build those lockouts in the system, with a generous 16-hour post visit window to complete questionnaires and assessments.”
Don’t Underestimate Training – This is the one of the most important parts of a clinical trial in general and an eCOA System in particular “You want to ensure the CRAs working on your program are adequately trained so they know how to use the SitePad and what StudyWorks can do for them,” Elisabeth said. “When CRAs understand the process and how to use the SitePad, it makes it easier for the group and makes your job as sponsor/manager much easier.” Celgene allocated training time at IMs. “Think early on about what kind of training you want to do and how often you want to do it – in-person, webinar, small group training – and get your team that information.” The training engaged coordinators: When Celgene started the program many coordinators said their physicians would never do assessments on an eCOA tablet, but would only use paper. After the first six months of the study, principal investigators asked if they could use the SitePad in their regular practices and get output from StudyWorks.
Getting Comfortable with Technology – Elisabeth recommends getting the eCOA tablet in as many hands as possible to see if they can break it, if people need extra training, or if they have issues with how questions are worded. Celgene asked its team members to go all the way through physician and patient assessments. Then Celgene gave the SitePad to some of its physicians and asked them to follow the flow of the physician assessments, and report on how it worked. Getting their input told Celgene ahead of time how they might experience adoption in the field. That exercise was very beneficial because Celgene was able to make changes to make it easier for its sites to use the SitePad.
Reporting– “The sponsor and CRO need to review reports,” Elisabeth explained. “For Celgene the metric for questionnaire completion by visit report was hugely important. We stayed on track and on the same page by using StudyWorks to compare the date of the subject visit vs. when they completed their ePRO and ClinRO assessments.”
Over the course of 3.5 years Celgene collected 4.5 million data points.
Celgene conducted the program in 23 countries and 26 languages, with English for primary endpoint.
There were 126 subject and 188 assessor questions. There were over 17,800 visits completed.
The study achieved a completed questionnaire and assessment rate of 99.16%, with 166,702 expected and 166,301 completed.
Celgene achieved a 99.5% completion rate for the primary endpoint across the program, with 98.5% completion for assessor endpoints.
The number of paper instances Celgene used was less than 2% across the study, with between 1.4% and 1.6% of paper instances out of over 166,000 entries.
In this brief video Elisabeth Kurkimilis discusses the OTEZLA®® (apremilast) clinical program: http://bit.ly/1wMgBIH
Elisabeth says, “Our steps for success were to plan, train, document, and remember that everybody is on the same team. And you can make mistakes as long as you don't put a patient's life in jeopardy. Learn from mistakes and make improvements. That’s key to the success of any program.”
Sheila Rocchio, MBA, is Vice President of Marketing and Corporate Strategy at PHT Corporation. She can be reached at [email protected]. Carolyn Peterson is Senior Marketing Manager at PHT Corporation. She can be reached at [email protected].