1. Should I Enroll in a Clinical Trial? David N. Assis, MD Assistant Professor of Medicine Yale University

2. I have no disclosures relevant to this presentation.

3. Clinical Trials in PSC PSC is a rare disease –32,000 patients in the US PSC has no proven and approved treatment PSC has many clinical sub-categories –Large duct, small duct, AIH-overlap PSC is associated with IBD It is not clear what to measure to define success in a PSC trial

4. Clear need for improvement in outcomes! Mendes et al. Hepatology 2008;47:1241-7. Drug Development

5. Clinical Trials in PSC New discoveries are more necessary than ever! Requires collaborative efforts by Patients, Advocates, Physicians, Researchers, Industry, Regulators

6. Clinical trials are part of clinical research and at the heart of all medical advances. Look at new ways to prevent, detect, or treat disease. The goal of clinical trials is to determine if a new test or treatment works and is safe.

7. Treatments might be new drugs or new combinations of drugs, new surgical procedures or devices, or new ways to use existing treatments. Clinical trials can also look at other aspects of care, such as improving the quality of life for people with chronic illnesses and delivering quality care to patients.

8. Why do people participate in clinical trials? Healthy volunteers may want to help others and to contribute to science forward –Patients may also want to help others in the future –Patients may want to have potential access to the newest treatments –Patients may also want to receive specialized and additional care and attention from the clinical trial staff.

9. Origin of Clinical Trial Drugs Where do clinical trials originate? –Often from pre-clinical work in a laboratory in which a treatment was tested in a tissue culture plate or in animal models –If a drug shows promise in one are of medicine and there is reason to suspect it might be helpful for another disorder Re-purposed Drugs

10. Models of PSC There is no perfect animal model for PSC! Each model has limitations and is incomplete Mdr2 knock-out model –Spontaneous strictures (scars) at some time points Bile duct ligation model –Surgical procedure to block the common bile duct –Short-term model

11. Clinical Trials in PSC New treatments may not necessarily be found based on animal models although many will be tested in models before humans Re-purposed drugs from other areas of investigation (fatty liver, other metabolic diseases, anti-fibrotic, etc.) may be studied in PSC

12. Components of a Clinical Trial Protocol –A carefully designed plan to guide the process of the trial, to help answer very specific questions. –Specifies who is eligible to enroll –Details about tests, procedures, medications, and dosages –The length of the study and what information will be gathered

13. Components of a Clinical Trial Principal investigator (PI) The person leading the effort, who is responsible for the trial Study Subject –Someone who enrolls in a clinical trial Research team members regularly monitor the the study subjects to ensure the study’s safety and effectiveness.

14. Components of a Clinical Trial Institutional Review Board (IRB) –An IRB is an independent committee that consists of physicians, statisticians, and members of the community who ensure that clinical trials are ethical and that the rights of participants are protected.

15. Components of a Clinical Trial IRB –Some multi center trials have IRB approval sought through the local center while others have a IRB at a single location

16. Components of a Clinical Trial Sponsors –Clinical trials are sponsored or funded by various organizations or individuals Physicians Foundations Medical institutions Voluntary groups Pharmaceutical companies Federal agencies such as the National Institutes of Health and the Department of Veterans Affairs.

17. Components of a Clinical Trial Informed Consent –The process of providing potential participants with the key facts about a clinical trial before they decide whether to participate. –Members of the research team explain the details of the study (purpose, duration, required procedures, and who to contact for further information, risks and potential benefits). –This process continues throughout the study!

18. Components of a Clinical Trial Informed Consent –The participant then decides whether to sign the document. –Informed consent is not a contract. –Volunteers are free to withdraw from the study completely or to refuse particular treatments or tests at any time. Sometimes, however, this will make them ineligible to continue the study.

19. Types of Clinical Trials Natural history studies –How disease and health progress. Prevention trials –Better ways to prevent a disease in people who have never had the disease or to prevent the disease from returning. Screening trials –Best way to detect certain diseases or health conditions.

20. Types of Clinical Trials Diagnostic trials –Better tests or procedures for diagnosing a particular disease or condition. Treatment trials –New treatments, new combinations of drugs. Quality of life trials –Explore and measure ways to improve the comfort and quality of life of people with a chronic illness.

21. Clinical Trial Phases Phase 1 To determine safety 20 to 100 healthy volunteers Duration: days-months Only a portion of candidate drugs may move to the next phase

22. Clinical Trial Phases Phase 2 To determine the optimal dose and side effect profile Several hundred hundred people with the disease Duration: months A smaller number of candidate drugs may move to the next phase

23. Clinical Trial Phases Phase 3 To determine efficacy and monitoring of adverse reactions Up to several thousand people with the disease Duration: years 25-30% of candidate drugs may move to the next phase FDA new drug approvals are based on Phase 3 studies

24. Clinical Trial Phases Phase 4 –Post-FDA approval registries and data collection to ensure the drug is as safe or effective as seen in earlier studies

25. Components of a Clinical Trial Randomization –The process by which two or more alternative treatments are assigned to volunteers by chance rather than by choice. –To avoid any bias with investigators assigning volunteers to one group or another. –When one treatment is found superior, the trial is stopped so that the fewest volunteers receive the less beneficial treatment.

26. Components of a Clinical Trial Single, Double Blind Studies –Designed to prevent members of the research team or study participants from influencing the results –Single-blind studies, only the patient is not told what is being administered –Double-blind study: only the pharmacist knows who gets which treatment –If medically necessary it is always possible to find out what the patient is taking.

27. Benefits of Participation Play an active role in your health care Gain access to new research treatments before they are widely available Receive regular and careful medical attention from a research team that includes doctors and other health professionals Help others by contributing to medical research

28. Risks of Participation There may be unpleasant, serious, or even life-threatening side effects to experimental treatment. The study may require more time and attention than standard treatment would, including frequent visits to the study site, more blood tests, more treatments, hospital stays, or complex dosage requirements.

29. Key Questions to Ask What is the purpose of the study? Why do researchers think the approach may be effective? Who will fund the study? Who has reviewed and approved the study? How are results and safety of subjects checked? How long will the study last? What will my responsibilities be if I participate?

30. Key Questions to Ask What are my possible short-term benefits? What are my possible long-term benefits? What are my short-term risks, such as side effects? What are my possible long-term risks? What other options do people with my disease have? How do the possible risks and benefits of this trial compare with those options?

31. Key Questions to Ask What kinds of therapies, procedures and /or tests will I have during the trial? Will they hurt, and if so, for how long? How do the tests in the study compare with those I would have outside of the trial? Will I be able to take my regular medications while in the clinical trial? Where will I have my medical care? Who will be in charge of my care?

32. Key Questions to Ask How could being in this study affect my daily life? Can I talk to other people in the study? Will I have to pay for any part of the trial such as tests or the study drug? If so, what will the charges likely be? What is my health insurance likely to cover?

33. Key Questions to Ask Who can help answer any questions from my insurance company or health plan? Will there be any travel or child care costs that I need to consider while I am in the trial?

34. After the trial ends… Results are often published in peer- reviewed scientific journals. Peer review is a process by which experts review the report before it is published to ensure that the analysis and conclusions are sound. If a new approach has been proven safe and effective in a clinical trial, it may become the standard of medical practice.

35. Registries Collection of information about individuals, usually focused around a specific diagnosis or condition. Many registries collect information about people who have a specific disease or condition Individuals provide information about themselves to these registries on a voluntary basis.

36. Registries Clinical trials registries collect basic health information from people who agree to be contacted about participating in future clinical trials or studies Volunteering for a registry does not mean a person has signed up for a clinical trial! Participation in a disease registry can sometimes become a first step toward participation in a clinical trial Registries and specific trials are not directly linked.

37. How to look for Trials in PSC ClinicalTrials.gov A searchable registry and results database of federally and privately supported clinical trials conducted in the United States and around the world. Gives information about a trial's purpose, who may participate, locations, and phone numbers for more details. Necessary to register in order to publish results

38. Clinicaltrials.gov

39. FDA Workshop on PSC Clinical Trial Endpoints March 3 and 4, 2016 Patient and Caregiver Participation was Critical!

40. Challenges in PSC Therapy Clinical Endpoints –How to define and measure treatment success? –How long should an intervention be studied? –How to account for Inflammatory Bowel Disease? –How to incorporate endpoints and patient selection? –What is a meaningful surrogate endpoint in PSC? –Who to enroll in studies? What stage of disease?

41. PSC Bile Acids Toxic Injury Inflammation Immune System Self-reacting lymphocytes Inflammation Liver-Gut Axis Altered Microbiome Colitis Bile Duct Scars Progressive Fibrosis Emerging Therapies Bile & Bile Acid Modulators Immune Modulators Microbiome Modulators Anti-Fibrotics

42. Summary Clinical Trials are absolutely essential in order to make progress in the treatment of PSC Engagement and participation of PSC patients and advocacy groups are critical