Narrative: It is about showing Safety and Efficacy. You demonstrate Safety by monitoring AEs and Efficacy by documenting how a Patient feels, functions and survives. For both you need outcomes and technology drives outcomes. (Icons need to be updated in the slide. They need to represent imaging, wearables, hand-held devices and eCOA)
The choices are overwhelming: From RECIST to Lugano, Pulse Oximetry to spirometry, Halter monitoring to blood pressure, Magnetic Resonance Imaging to Optical Coherence Tomography, Bone density to muscle volume, Lung Texture Assessment to Cardiac Output Measurement, Patient Reported Outcomes to Clinical Outcome Assessments.
There are three classes of questions that demand answers: Safety, Efficacy, and increasingly important, Effectiveness, including efficiency. We have already discussed the first two. Effectiveness means that we answer questions related to how new treatment addresses an unmet medical need and is economically feasible for patients and insurers. As we tend to be overwhelmed with the choices of technology and outcomes we must never forget that we need to start with the right questions first. With the advances in technology we find ourselves increasingly in a position to ask questions that never before could be answered. Increasingly, effectiveness questions are asked in earlier phase trials. Questions asked in early phase trials can inform trial design in approval trials.
Narrative: In the past collecting data was constrained by the need to have subjects visit an investigator site, where a limited number of outcomes could be assessed. Now technology can go home with the patient, opening up new study designs and the data flood gates. Again, choices must be outcome driven, not technology driven.
Eligibility readを行わないとsiteとcentralの差異はは１０％～１５％。Eligibility readを行った場合は３％程度 Confirmation of PD ２０～２５％の差異。差異の半分は施設の判断で脱落させるが残り半分は救われる
Confidence intervals Bar is long = サンプル数が少ない
Now that Rick as described how central imaging review has played a role in breakthrough approvals to date I will discuss the best practices we have instituted. We have interviewed all of the project managers about what made their studies successful when the worked on breakthrough studies that received approval. These tenents are important for you as Sponsors to consider when selecting vendors for a breakthrough therapy designation trial, or any trial for that matter as you may never know when the designation will be granted.
Of course experience, price, relationship, connection that you already may have will come into play, however we have determined that …. Are key characteristics that have contributed to breakthrough therapy success stories. And I will go through a few case studies to illustrate this.
Flexibility: Sponsor required imaging data early to identify if preliminary clinical evidence existed PAREXEL created a paper process overnight backed by full documentation and performed independent reviews Results were shared with Sponsor and regulatory Preliminary Clinical Evidence was exhibited in the imaging results and led to a breakthrough therapy designation Instituted a rigorous phase 3 design with validated Analysis Application after receiving the designation
Documentation: We cannot be successful if we are not nimble as we just discussed…however, documentation about why we instituted the processes we did is KEY to the FDA. The FDA and other agencies want to see why we did what we did. It is crucial that each decision be documented and shared regularly between Sponsor and vendor. At PAREXEL we instituted a project journal on each study to log all decisions, this has well received by the FDA. Additionally, we assign a project quality lead to each study who is responsible for making sure studies are audit ready at all times.
A process, even a simple paper based process that was designed in a day, can pass regulatory scrutiny if we document why we did what we did.
Project Log Audit Support Who, What, Where, Why, and When?
Commitment: Finally, commitment is key to your success. The FDA expects senior members of both Sponsor and Vendors to be available around the clock for requests. We had a situation on breakthrough therapy designation trial where the FDA requested specific data on a Friday. The CEO of the company called our project managers cell phone on a Saturday to see if she could urgently provide the information. The project manager immediately got her staff to work over the weekend and provided results to the Sponsor and the FDA by Monday morning.
Project Managers, or a designee, must be available outside of working hours for urgent requests and not doing so could result in missing a critical FDA request. Requiring this level of commitment is not unrealistic and will not overburden vendor staff IF they have proper contingencies, back-ups, and scalability. When selecting a vendor for a breakthrough therapy drug, it behooves you as Sponsor to identify if your vendor is cognizant of the importance of this level commitment and has the global resourcing to ramp up and respond at the FDA’s pace.
The process of developing a drug is science but sponsor and vendor cooperating in a partnership to bring drugs to approval is truly an art. And it may feel trite to say that this, but complete commitment and ownership by your vendors is essential to bringing these important and life saving drugs to market faster. Senior level representation FDA expects senior members of both Sponsor and Vendors to be available around the clock for requests Vendor commitment and Project Manager Fast turnaround requests are to be expected and resourced proactively 24 hour coverage – global lab PM or designee available around the clock Need for and length of regulatory audits are reduced when contracting with an Imaging lab that is familiar to the FDA – Speeds process
Leveraging Imaging and Wearable Technology For Agile Clinical Trials