PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = THE FUTURE OF DRUG DEVELOPMENT IN PULMONARY FIBROSIS – A REGULATORY PERSPECTIVE JANET WOODCOCK, MD KEYNOTE ADDRESS NOVEMBER 13, 2015

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = AGENDA Encouraging Development of New Therapies for Pulmonary Fibrosis ©2015 Pulmonary Fibrosis Foundation. All rights reserved.2 Biomarkers: Measurements that can speed drug development Clinical trials: How patient and advocates can assist Patient-focused drug development: Putting patient needs at the center; how patients can make this happen

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = First two drugs for pulmonary fibrosis approved in US in Oct 2014 on the basis of an effect on a biomarker—FVC In efficacy trials for both, there was a trend towards a survival benefit Two different mechanisms of action Great news for the field, but like most biomarkers, cannot really know how much slower decline in FVC relates to improved quality of life ©2015 Pulmonary Fibrosis Foundation. All rights reserved.3 BIOMARKERS

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = WHY ARE BIOMARKERS IMPORTANT? Good biomarkers, especially if they change quickly in response to an intervention, attract drug developers into the field Biomarkers might reflect “target engagement”; a “pharmacodynamic endpoint” or indirectly measure a symptom like shortness of breath Biomarkers can also be used as “surrogate endpoints” as in the two development programs This speeds approval but leaves questions about the real impact on patients ©2015 Pulmonary Fibrosis Foundation. All rights reserved.4

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = WHY ARE BIOMARKERS IMPORTANT? Measurement of multiple biomarkers can give insight into how a drug works in a disease It is likely, in pulmonary fibrosis, as in many other diseases, that we may want to use a COMBINATION of treatments to get the maximum effect Biomarkers can help us understand how different drugs might add or synergize with each other ©2015 Pulmonary Fibrosis Foundation. All rights reserved.5

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = WHY ARE BIOMARKERS IMPORTANT? The fact that FVC has been used as a primary endpoint in approval of drugs for IPF means that developers of new products will likely use this endpoint This decreases uncertainty about the development pathway and attracts investment into this disease area Hopefully, more direct measures of quality of life will be available in the future as well ©2015 Pulmonary Fibrosis Foundation. All rights reserved.6

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = CLINICAL TRIALS: HOW PATIENTS AND ADVOCATES CAN ASSIST The expense (time, money, personnel) of conducting clinical trials is a big barrier to development of new therapies The way trials are conducted today is often inefficient, slow, and frustrating for trialists and trial participants Patients and advocates can take steps to improve the trial landscape in their disease Multiple areas where interventions can improve the situation ©2015 Pulmonary Fibrosis Foundation. All rights reserved.7

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = CLINICAL TRIALS: HOW PATIENTS AND ADVOCATES CAN HELP IN TRIAL DESIGN Often trials are designed without asking whether they work for patients This can lead to drop-outs and “missing data” Understanding what is or is not doable from a patient/family point of view can really improve a trial This information can be gathered by patient groups separate from any trial being conducted ©2015 Pulmonary Fibrosis Foundation. All rights reserved.8

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = CLINICAL TRIALS: HOW PATIENTS AND ADVOCATES CAN HELP IN RECRUITMENT Often, getting an answer is slowed because the trial accrues people very slowly This delay is usually preventable Strong Associations, who have identified people with the disease who are interested in enrolling, and have provided them with education about being in a trial, can be very helpful in speeding the evaluation Data can also be collected about stage of disease/what therapies the people are taking, etc., to facilitate getting into trials ©2015 Pulmonary Fibrosis Foundation. All rights reserved.9

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = CLINICAL TRIALS: CENTERS OF EXCELLENCE AND CLINICAL TRIAL NETWORKS There are ways to further accelerate development in a specific disease Centers of Excellence: Establishing sites with specific expertise in treating the disease—requires continuity of funding Clinical Trial Network: Standing up networks of trialists with experience in evaluating treatments for the disease—can support ongoing trials For many diseases, availability of new therapies raises additional questions ©2015 Pulmonary Fibrosis Foundation. All rights reserved.10

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = PATIENT-FOCUSED DRUG DEVELOPMENT: HOW TO PUT THE PATIENT AT THE CENTER Drug development programs often do not evaluate many aspects of the disease that are very important to patients In “PDUFA V”, FDA negotiated to have 20 patient- focused meetings over a 5 year period, supported by user fees In Sept 2014 we held a PFDD meeting on pulmonary fibrosis Well attended in-person and on line ©2015 Pulmonary Fibrosis Foundation. All rights reserved.11

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = PATIENT FOCUSED DRUG DEVELOPMENT Goal: to hear about experience of the disease and current therapies from people living with the disease, and people close to them FDA hopes to hear from a wide spectrum of people with the disease; not just one group FDA writes up the meeting and publishes results “Voice of the Patient” from pulmonary fibrosis meeting published March 2015 ©2015 Pulmonary Fibrosis Foundation. All rights reserved.12

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = WHAT DID WE LEARN? Very similar experiences relayed by many patients and relatives Major symptoms: – Cough – Shortness of breath – Fatigue – Inability to do activities of daily living These symptoms may not be well captured in drug development programs Current oxygen therapy felt to be burdensome and have some unpleasant side effects ©2015 Pulmonary Fibrosis Foundation. All rights reserved.13

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = HOW COULD IMPACTS ON MAJOR SYMPTOMS BE BETTER CAPTURED IN DRUG DEVELOPMENT? Specific reporting on certain key symptoms Patient reported outcome (PRO) measures Activities of daily living Health related QOL Any of these types of measurements could be refined to work well for pulmonary fibrosis symptoms ©2015 Pulmonary Fibrosis Foundation. All rights reserved.14

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = AVENUES FOR DEVELOPING OUTCOME MEASURES Consortia (such as C-Path) work to establish PROs for certain diseases in a public-private partnership arrangement Patient groups can work with academia and industry to develop measures Parent Project Muscular Dystrophy (PPMD) gathered academics, patients, and industry together and created a “guidance document” that they submitted to FDA. This included trial design and endpoint issues. FDA evaluated this and then issued an FDA “draft guidance” on the topic. ©2015 Pulmonary Fibrosis Foundation. All rights reserved.15

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = FDA “QUALIFICATION” PROCESS FDA seeks to assist in creation of new “drug development tools” such as PROs or biomarkers, that can speed and improve evaluation of new treatments Outside groups, often consortia, develop the tools FDA provides advice and input If successful, the tool program results are submitted to FDA and reviewed If FDA finds them acceptable for a certain use, then they are “qualified” for that use: FDA posts a guidance describing this ©2015 Pulmonary Fibrosis Foundation. All rights reserved.16

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = SUMMARY Hopeful time for those fighting pulmonary fibrosis Drug approvals for IPF were based on effects on a biomarker (FVC) Need for additional therapies and treatments to address major symptoms and quality of life Patients and advocates can help advance new biomarkers, clinical trials, and patient-centered outcome measures These will help us all understand the impact of therapies more fully, and spur faster progress in treating this disease ©2015 Pulmonary Fibrosis Foundation. All rights reserved.17

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = Questions?

PFF Teal = MAIN COLORS PFF Green = Light Green = Red = HIGHLIGHT COLORS Light Grey = Dark Grey = Black = Thank you.