Regulatory Issues International Perspective

1. Regulatory Issues International Perspective Claudio DanskyUllmann, MD Head, Thoracic and Head & Neck Malignancies, Melanoma and Other Skin Cancer Therapeutics Cancer Therapy Evaluation Program National Cancer Institute

2. NCI Organization Chart

3. CANCER THERAPY EVALUATION PROGRAM Jeff Abrams Operations & Informatics Branch Steve Friedman Clinical Grants and Contracts Branch Roy Wu Clinical Investigations Branch Meg Mooney Regulatory Affairs Branch Jan Casadei Investigational Drug Branch James Zwiebel Pharmaceutical Management Branch Charles Hall Clinical Trials Monitoring Branch Gary Smith

4. Cancer Therapy Evaluation Program - CTEP Therapeutics Development Program Specialty Resources /Other Basic Resources Adult U01 Phase 1 Program (14 phase 1 sites) *Clinical Center, Phase 0/ Expl IND *Cancer Centers Phase 1 Pediatric Phase 1 Consortium CNS Consortia Pediatric, NABTT, NABTC N01 Phase 2 Program (9 phase 2 sites) Phase 2 *SPORES, R21, R01, P01 Cooperative Groups *CCOPs Phase 3 *Non-CTEP Funded Resources

5. Essential Elements for a National CancerClinical Trials Network – Basis for Collaboration • Qualified investigators from qualified institutional sites with important scientific/therapeutic hypotheses and experienced in clinical trial conduct • Infrastructure for protocol development and conduct of clinical trial in multi-institutional setting(Operations Office) • Infrastructure for collecting and quality-checking data (Data/Statistical Center) • Biological tissue specimens/correlative studies • Financial support • Patients

6. Group Collaborations – Opportunities – Types of Trials • Studies whereby an efficient process is required • Large RCT’s • Strategic Phase II trials • Uncommon diseases or less common presentations of common diseases • Integrate new agents into standard regimens • Compare two or more approaches to an accepted standard • Multimodality treatments • Translational studies. Incorporate correlative science and quality of life • “Pooled” resources • Tissue banking

7. Challenges in Clinical Trial Research • Enrollment often is not representative of the general population Factors affecting enrollment are multiple and complex • Well designed controlled trials are necessary to identify sometimes small benefits • Important time and human and infrastructure resources are invested in the conception, launching, and execution of a clinical trial. AVOID DUPLICATION IS CRITICAL • Timely completion of trials is key • Well developedregional, national, and international networks and collaborations are important to obtain definitive results to advance cancer research and patient management

8. Challenges for Coordinated Efforts • Standardizations of definitions for efficacy endpoints • Harmonized Data Elements • Identify and standardize translational research data elements to be commonly collected across trials • Specimen collection SOPs • Data Sharing System • Share electronic data files to allow for the study of specific questions across trials • Create a system that provides a data mining capability that should allow more contemporaneous and frequent analysis of pooled resources from contributing groups • Publication guidelines

9. Hurdles to International Collaboration • Scientific agreement on clinical study design • Close communication and interaction essential • U.S. requirement for international institutions to obtain Federal Wide Assurance (FWA) • If receiving U.S. funds or exchanging patient data • Technical agreement on data collection and submission • Requirements for auditing of collaborating international institutions • Tissue banking – Analysis • Drug distribution across borders and other regulatory issues

10. International Regulatory Issues • Harmonization of clinical practice across all sites • Registration of investigators • National and local regulatory approval • Harmonization of data collection • Reporting of adverse events • Insurance requirements • Global variation in regulations

11. International Committee of Harmonization (ICH) It is ICH’s mission to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration, thereby reducing duplication of testing and reporting carried out during the research and development of new medicines. http://www.ich.org/home.html

12. ICH • Drug regulatory authorities and pharmaceutical trade associations of Europe, Japan, and the United States discuss scientific and technical aspects of product registration. • QSEM • Quality • Safety • Efficacy • Multidisciplinary .

13. Harmonization of clinical practice • Patient eligibility: pathologic diagnosis, imaging studies, laboratory tests • Surgical treatment • Chemotherapy and biologic treatment • Radiation therapy • Supportive care • Surveillance and follow-up

14. Patient Selection – Lab Assays • Nowadays in the era of personalized medicine: it is critical that patient selection based on a specific biomarker is done using properly standardized assays • Are we really testing what we want to test? • Are we really categorizing adequately? • EGFR mut, BRAF mut, EML4/ALK, ERCC1, Risk classifiers • Standardization and Validation • Important ethical and regulatory implications

15. Registration of investigators & sites • Harmonization of registration • US FDA 1572 form or equivalent • Copies of curriculum vitae and medical licenses for physicians • Financial disclosure forms for physicians • Certification of laboratories for clinical tests • Inspection of study site before trial opens

16. Regulatory approval • Approval of trial by national trial regulatory agency (equivalent of US Food and Drug Administration) • Approval by independent ethics committee • National, regional, or local • In some cases, approval by scientific review committee • Documentation of approvals required

17. Harmonization of data collection • Case report forms • Collection by mail, fax, or internet • Collection of images (CXR, CT, etc) • Collection of pathologic specimens • Tumor, plasma, blood, normal tissue • Central review of images and pathology? • Core laboratories

18. Harmonization of data collection • Important for all trials • For registration trials, some specific data to be collected may originate from discussions and agreement between the lead institution, the sponsor, and the country’s regulatory agency based on a particular trial, drug or claim • Case Report Forms, Central review of images

19. Global variation in regulatory requirements • European Union Clinical Trials Directive: • Directive 2001/20/EC • Required each member country in EU to pass national legislation concerning clinical trials which evaluate new medications • Problems • Little harmonization: 27 different laws for 27 countries • Covers all trials (even without new medications) • Barrier to international participation

20. FDA Approvals • Regulatory approval: substantial evidence of clinical benefit demonstrated prior to approval based on prolongation of life, a better life or an established surrogate of either of the above • Accelerated approval (AA): designed to hasten the delivery of products appearing to provide a benefit for serious or life threatening illnesses lacking satisfactory treatments • AA regulations 1992 • 21 CFR Part 314, Subpart H (for drugs) • 21 CFR Part 601, Subpart E (for biologics)

21. Critical Elements of Accelerated Approval • Serious or life threatening diseases • Provides a benefit over existing therapies • A surrogate reasonably likely to predict clinical benefit • Subject to the requirement to verify benefit • Post-marketing trials would usually be underway • Applicant should carry out studies with due diligence If post-marketing studies fail to demonstrate clinical benefit or applicants fail to perform required post-marketing studies with due diligence, FDA may withdraw approval, following an open public hearing

22. EMA Approvals • Approval types: • Normal, Exceptional, Conditional • Conditional Marketing Authorization(CMA): • Demonstrates positive benefit:risk based on preliminary evidence • “Specific Obligations” to provide further data necessary to become Normal approval • Authorization valid for one year (renewable) • Clear information to patients and providers on the conditional nature of the approval • Financial penalties if fail to observe obligations

23. Data Reporting: Regulatory Requirements • Method of data reporting • Multi-center guidelines • Reporting requirements • Collaborative agreement language

24. Reporting of adverse events • All clinical trials must collect data on adverse events associated with the trial. • Some adverse events must be reported immediately, within 48-72 hours. • Adverse events must be reported to the study sponsor, the independent ethics committee, and the national regulatory authority. • The toxicities which patients experience may require modification to the trial.

25. NCI Common Toxicity Criteria & Adverse Events (CTCAE) • Recently underwent 3rd revision (CTCAE v4) • Grade I: mild • Grade II: moderate • Grade III: severe • Grade IV: life-threatening • Grade V: death • ~30% de la toxicidad es basada en sintomas> el resto en parametros de laboratorio o hallazgos clinicos

26. Trial Data Monitoring Data Monitoring Committee (DMC) of Data Monitoring Safety Board (DMSB) To review safety and efficacy data from phase III trials on a continuing basis Recommendations to the trial “steering committee” Closing the trial in case of large therapeutic benefit Closing a trial for futility or safety Changing the trial design / eligibility criteria Early publication Closing a poorly accruing trial Decisions with ethical, regulatory, commercial implications Dagher RN and Pazdur R, in Anticancer Drug Development Guide, 2004; Chapter 20 p408

27. Trial Data Monitoring – Early Closure Process If DMC/DMSB recommends early closure for safety, futility, efficacy, there is a regulatory process to be followed: Communications between government, leading group, pharma Dear doctor letter Dear patient letter Communication to other stake holders/partners Communication to FDA Different regions/countries, may have different sop. Dagher RN and Pazdur R, in Anticancer Drug Development Guide, 2004; Chapter 20 p408

28. Insurance Requirements • Institutional insurance • Protects local institution from claims that institution made mistakes in giving therapy on trial or that the therapy on the trial was incorrectly designed • Patient insurance • Provides insurance to cover treatment of complications associated with trial • Requirements vary from country to country

29. Model Agreements • Confidential Disclosure Agreement (CDA) • Cooperative Research and Development Agreement (CRADA) • Materials Cooperative Research and Development Agreement • Clinical Supply Agreement (CSA) • Material Transfer Agreement (MTA) • Pediatric Preclinical Testing Program MTA

30. Global variation in regulatory requirements: I • National and local regulatory approval • Length of time required for review varies from country to country • Some countries have established principle for only one fast review • Adverse event reporting • US and European Union have slightly different requirements • New US CTCAE version 4.0 should be more consistent with European Union & ICH rules

31. Global variation in regulatory requirements: II • Drug importation (import) • paperwork required to import experimental drugs varies from country to country • Legal rights to experimental drug can vary from region to region; Often one company has the rights to a drug in the US, while a second company has the rights to the drug outside the US • Transportation of specimens • Some countries do not permit specimens to be shipped to another country

32. Room for improvement: Accrual • How can we strengthen international collaboration and complete trials faster? • If a trial accrues too slowly, then the trial result may no longer be important when the trial is finished. • If a trial accrues too slowly, then doctors and patients lose interest in the study (in particular if a study of high complexity).

33. Room for improvement: Overcoming barriers with a collaborative effort • If we work together, then we can complete larger trials faster. • If we work together, then we can complete trials for patients with a specific molecular biology or with a rare tumor or with a less common stage of cancer. • If we work together, then we can study the impact of pharmacogenomics on cancer treatment.

34. Room for improvement: Better planning, harmonization, and coordination • We must plan our clinical research together: • Complementary trials • Joint trials • We must harmonize regulation • Fast review, approval and activation of trials • Adverse event reporting • Insurance requirements

35. Regulatory Structure: Conclusions • Regulatory structure needs both to protect patient safety and facilitate clinical research • Clinical trials help define optimal cancer care and guide public policy • Government, academia, patients, public, and industry must collaborate to strengthen clinical trials

36. Building a National Network Investments to Conduct National Trials • National dialogue among cancer scientists, clinical investigators and practitioners • National awareness campaign regarding cancer and clinical trials • Develop national infrastructure • Establish common registration, data submission and document approach • Establish data submission network • Establish quality assurance program

37. Building a National Network Depends on what you have… and what you want • Population available and accrual potential • Number of advanced care centers & community hospitals • Number of investigators and research nurses • Private practice component in cancer care • Cancers to be investigated • Phase II or phase III trials • Studies involving specific treatment modalities • Single network or multiple networks (competing studies requires adequate patient base) • Stable infrastructure

38. Building a National Network Steps forward… • Participate in international clinical trials by experienced cancer trial organization (e.g., EORTC) • Experience, GCP standards, data submission, submission of biological specimens, oversight • Commercial trials • Experience and revenue for infrastructure • Explore governmental and charitable funding

39. Websites For Clinical Trials Resources and Information

40. Muchas Gracias Por Su Atencion