CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVALOTEZLA® (apremilast) tablets approved for Active Psoriatic Arthritis in Adults

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2CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

MOBILE eCOA TABLET DEVICES COLLECTED ALL DATAPrimary and secondary endpoints were collected using clinician and patient-reported assessments on the eCOA Tablet. On-device calculations, branching and restricted reporting time intervals helped Celgene ensure the completeness and quality of data collected, reduce monitoring time and costs and expedite database lock. ERT EXPERT® provided easy access to real-time study data with reports on patient enrollment, compliance and safety.

ERT eCOA Tablet collects consistent data with universal screen features and functions, mitigating data adjustments reconciliation

3CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

STUDY PURPOSE 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.

> Study: Global Phase III Program for OTEZLA® (apremilast) comprising three mid-to-large studies

> Therapeutic area: Active psoriatic arthritis (PsA) in adults

> Patients:1493, (2503 screened, 2026 randomized)

> Technology: ERT eCOA Tablets and ERT EXPERT

> Instruments that collect PRO: SF-36, EQ-5D, MOS Sleep Scale, WLQ-25, HAQ-DI, BASDAI, MASES, PASI Patient-Specific Index

> Instruments that collect CLINRO: 76/78 Joint Assessment, PASI Psoriasis Area and Severity Index

> Approval March 2014: OTEZLA® (apremilast)—First oral therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with active psoriatic arthritis

4CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

STUDY OBJECTIVESCelgene 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 eCOA tablets to collect data about patient symptoms as observed by physicians through the ACR assessment which was used to assess efficacy. The eCOA tablets were 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.

SUMMARY > Celgene evaluated safety and

efficacy of OTEZLA in 3 global trials

> 1,493 patients worldwide with active PsA

> ERT eCOA Tablets used to collect primary and secondary endpoints

> ERT EXPERT used to review and report on subject compliance, safety and retention

IMPACT > Using eCOA Tablets ensured

completeness and quality of data collected

> Reduced monitoring time and costs

> Decreased time to database lock

> FDA approved OTEZLA in March 2014

5CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

OVERVIEW Over the course of 3 1/2 years Celgene collected 4.5 million data points via ERT eCOA Tablets. Celgene chose to use the eCOA Tablets instead of paper because the device enables clinicians and patients to record real-time clinician and patient outcome data electronically from the start. Once entered onto the eCOA Tablet, the data are transmitted to the ERT Server for fingerprint verification before tablet data are erased. Verified data are copied to ERT redundant servers and immediately available for review and reporting on ERT EXPERT. This significantly reduces 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 eCOA 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.

IN 3 ½ YEARS, CELGENE COLLECTED 4.5 MILLION DATA POINTS

6CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

TRIAL INSIGHTS & BEST PRACTICES 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, 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 ERT 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 ComplianceOnline data access via ERT EXPERT improved 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 eCOA Tablet was the key questionnaire Celgene needed.

QUESTIONNAIRES WERE ORDERED BY IMPORTANCE FOR SECONDARY ENDPOINTS TO MINIMIZE PATIENT IMPACT

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THE eCOA SYSTEMCollecting patient and clinician data on the same eCOA Tablet was efficient for both patients and study coordinators. ERT worked with study coordinators to design the eCOA Tablet, which has a large touch screen and user-friendly interface. Each device supports 500 patients. “With the eCOA Tablet you don’t really need to do a lot of monitoring,” said Elisabeth. “Where you spend your time is reviewing DCFs and focusing on some other important areas. The 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 savings.”

COLLECTING PATIENT AND CLINICIAN DATA ON THE SAME eCOA TABLET WAS EFFICIENT FOR BOTH PATIENTS AND STUDY COORDINATORS

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Study design and eCOA Tablet functionalities enabled Celgene to achieve record diary and questionnaire completion rates

ASSESSOR ENDPOINT COMPLETION98.5%

OVERALL COMPLETION RATE

PRIMARY ENDPOINT COMPLETION99.5%

RESULTS As of December 31, 2013, Celgene had completed over 17,800 patient visits on eCOA Tablets. There were over 166,000 expected questionnaires and assessments on the eCOA Tablet, putting the completion rate at over 99%. For Celgene’s primary endpoint they achieved a 99.5% effective completion rate on the eCOA Tablets.

“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 devices to CRAs at the Investigator Meeting (IM), but enabled them to bring their devices back to their site. “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. 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."

9CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

SITE AUDIT PREPARATION 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. eCOA Tablets 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. “ERT EXPERT is an excellent source of information,” Elisabeth commented. 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 including ERT, 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.

eCOA TABLETS PROVIDED CONFIDENCE IN HIGH‑QUALITY DATA FOR NDA SUBMISSION

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Plan ahead, plan againThe 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.

Plan for database lock 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.”

TOTAL COST SAVINGS

$13M

$200K

$50K

x4=

+

+$3M

TOTAL SAVINGS

STUDIES

STAFF ENTRY OF PAPER SOURCE

DECREASE IN QUERY RATES

MONITORING COSTS

SAVINGS PER STUDY

Lower monitoring costs, decrease in query rates and reduced need for manual staff entry across 4 studies resulted in $13M total savings

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LESSONS LEARNED

11CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

Prepare casebooksCasebook preparation was very important for Celgene. ERT 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, they were able to look at one patient and all their data as a whole.

Closely monitor the data change queuesIf you have DCFs you want to make sure they don’t mount up on you. At Celgene’s first meeting with ERT 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.

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“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.”

—Elisabeth Kurkimilis, Senior Study Manager, Celgene

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Consider data entry requirements up front“The review of the specifications will carry a trial through,” Elisabeth explained. “Have this done early so if 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 ERT to build those lockouts in the system, with a generous 16-hour post visit window to complete questionnaires and assessments.”

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BUILD LOCKOUTS IN SYSTEM TO ENSURE DATA ARE ENTERED WITHIN A SPECIFIC VISIT

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Don’t underestimate trainingThis 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 eCOA Tablet and what ERT EXPERT can do for them,” Elisabeth said. “When CRAs understand the process and how to use the eCOA Tablet, 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 the eCOA Tablet, but would only use paper. After the first six months of the study, principal investigators asked if they could use the eCOA Tablet in their regular practices and get output from ERT EXPERT.

6“When CRAs understand the process and how to use the eCOA Tablet, it makes it easier for the group and makes your job as sponsor/manager much easier.”

—Elisabeth Kurkimilis, Senior Study Manager, Celgene

14CELGENE LEVERAGES ERT eCOA DATA FOR FDA APPROVAL

Get comfortable with technologyElisabeth recommends getting the ERT device 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 eCOA Tablet 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 eCOA Tablet.

Review study reports"The sponsor and CRO need to review EXPERT 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 ERT EXPERT to compare the date of the subject visit vs. when they completed their ePRO and eClinRO assessments.”

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8GET TECHNOLOGY IN AS MANY HANDS AS EARLY AS POSSIBLE

ABOUT ERT

ERT is a global data and technology company that minimizes uncertainty and risk in clinical trials so that customers can move ahead with confidence. With nearly 50 years of clinical and therapeutic experience, ERT balances knowledge of what works with a vision for what’s next, so we can adapt without compromising standards.

Powered by the company’s EXPERT® technology platform, ERT’s solutions enhance trial oversight, enable site optimization, increase patient engagement and measure the efficacy of new clinical treatments while ensuring patient safety. Since 2014, more than half of all FDA drug approvals came from ERT-supported studies. Pharma companies, biotechs and CROs have relied on ERT solutions in 10,000+ studies spanning more than three million patients to date. By identifying trial risks before they become problems, ERT enables customers to bring clinical treatments to patients quickly — and with confidence.

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