Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Study Designs to Meet the Challenges of Personalized Cancer Medicine

The  current understanding of cancer biology indicates that cancer is a large number of niche diseases that may be targeted with therapies against specific molecular alterations which maybe common to multiple tumor types. Drug development under this model creates challenges for both the development program and patient care with implications for initial indication selection and for the design and execution of clinical trials from first in man studies through post marketing studies. Among the challenges and topics the panel will address:

• The availability of  biomarkers to stratify trials, select patients and monitor drug response can improve both trial speed and cost. This can also enable  development of companion diagnostics but present more complex validation requirements.
• Design of trials using surrogate end points holds great promise but validation of such endpoints represents another regulatory challenge. Adaptive trial designs for dose response, pK/PD and efficacy hold promise but adoption of such approaches has been slower than many expected.
• The success of cancer immunotherapies creates a significant opportunity for development of combination therapies but the cost of acquiring the approved drug can significantly increase the cost of clinical trials. This may require new approaches to late preclinical development as well as the need to develop biomarkers that are early and accurate indicators of drug response for incorporation in the clinical trial in Phase I/II.
• Finally, the increasing cost of the current and next generation of cancer drugs creates the need to produce and measure both clinical and econometric outcomes in order to justify reimbursement. This may imply a need for larger post marketing clinical studies, including observational trials.

• What is wrong with clinical Trial
• small subgroups if the study is very large – who efficacy can demonstrated
• AVASTIN was approved on endpoints, later no efficacy
• diagnostic test developed at the same time as the drug themselves
• if drug approved wihtout companion diagnostics
• randomized trial – patient fear that they will get into the Placebo

• different end points
• genomic used
• overall survival to demonstrate — not required by FDA  only 24% of drugs are approved based on survival
• big benefit – eligible in an arm for prognostics, genomics support genomics and companion diagnostics
• remove chemotherapy arm and expand the trial to second lines
• combinations drug therapy — many arms
• end point  for efficacy, tumor shrinks due to activity and represent efficacy
• response rate 50% no available therapy or available if agent effective in 10% of Patient
• FDA acceptable single arme by objective response rate and durable response
• Lung Cancer wiht 50 Patients expansion over 1000 patients
• encourage with the right scenario
• two approval – accelerated approval pathway – surrogate meaningful over and above – 10% in oncology wihtdrawal – did not prove benefit, years in advance provide benefit over existing therapy options
• regular approval pathway — direct benefit demonstration
• adaptive enrichment design  – earlier
• guidance on device for companion diagnostics – not always possible
• pronounced benefit – FDA may approve the drug first and a commitment to develop the companion diagnostics after the drug was approved
• patient for drug not drug for patient

• Good and bad of Clinical Trials
• Metastasis and adjuvant Trials
• innovation trials approaches needed not to have Patients waiting for survival
• What is wrong – LOSING Patients during the long trials
• Targeted therapy EGFR – while at AZ for lung cancer – mutation was discovered after the study started – overlapping Meyers Curves for Europe and the US
• Japan regulators ask other requirement that in the US
• Payers have theirs requirements
• rely on diagnostics in order to give the drug to the right patient — ALK adenocarcinoma – 30% response rate  – diagnostics FISH assay another diagnostics was developed right target for the Patient
• if patient has two mutation — to which arm to enroll the Patient – control group needed to known if the right drug was matched with the right Patient
• large trials NCI or CRO 10,ooo of Patients, amount tissue generated, repeated plasma DNA, Data sharing central biobanking
• chemotherapy”: Progression and Survival
• common sense – Hazard ratio do you need a surrogate study given serendipity — not end of data generated
• tool to recall a drug if after market efficacy not found
• Ongoing adaptive trial, add control ongoing, registration fixed to start, max patients 70, endpoints, MRI trial can be stoped after 30 patients – lack of clarity how to register
• confirmation of adaptive trial
• laboratory test not as stringent as a drug
• 60%

• complexity of Biology
• due diligence to select the Patient population
• broader eligibility
• signaling molecules
• adaptive trial design – incorporate learning, confirmatory type 1 error
• elegant statistical ways – uncommon diseases – prospective defined learning – very successful conversation in that framework
• complex phase two trial
• access and particiaption still inadequate

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Surviving Cancer: New Realities, New Needs

Extraordinary treatment advances have turned many cancers from apparent death sentences into manageable chronic illnesses with extraordinary consequences for the entire health care system. In the United States, there are approximately 14 million cancer survivors, up from just three million four decades earlier. Those survivors have unique care requirements, that will put enormous stress on the system and calling out for new technology solutions. The panel will discuss those requirements and the technologies and approaches that can help monitor, guide, and connect patients.