Regulatory Issues - US

1. Regulatory Issues - US Claudio Dansky Ullmann, MD Head, Thoracic and Head & Neck Malignancies, Melanoma and Other Skin Cancer Therapeutics Cancer Therapy Evaluation Program National Cancer Institute

2. Development of New Therapies • Drug development is an orderly process designed to minimize risk and determine benefit • Clinical studies are required by the FDA to produce the evidence to determine risks and benefits to humans • Clinical development is most effective with understanding and communication between all involved

3. A Collaborative Effort Against Cancer

4. Government Involvement-Regulatory Perspective • Registration of trial in national database • Evaluation of trial before it opens • for patient safety • For adequacy of trial design to prove efficacy for new agent or device • Ethical review • National, regional, and/or local • Ongoing review of toxicity/adverse events

5. NCI Pathways - Development of New Agents NCI Industry Academia Agent Review Data NExT DTP CTEP Development Plan IDSC review CTA/CDA Preclinical Development Clinical Development Developmental Therapeutics Program Cancer Therapy Evaluation Program Activity Formulation Toxicology Clinical Trials under CTEP IND Development

6. Regulatory Affairs Branch (RAB) Drug Regulatory Group • Preparation and submission of Investigational New Drug Applications (INDs) • Review of protocols/protocol amendments • Liaison with FDA • Liaison with intramural and extramural investigators Agreement Coordination Group • Liaison with pharmaceutical companies • Preparation of agreements (CTAs and CRADAs) for clinical development of agents • Coordination of company interactions with NCI and investigators • Preparation of MTAs for basic research with investigational agents in clinical trials • Investigator’s Handbook

7. Collaborative R&D Agreements with CTEP • Clinical Collaborative Agreements provide the framework for clinical trials and non-clinical studies sponsored by the NCI with agents provided primarily by industry collaborators and some academic investigators. • The purpose of the R&D Agreements is to set the stage for the exchange of funds, materials and information between NCI, industry, and academia, while addressing issues such as human safety, cGCP, data sharing, intellectual property, etc. • The key clinical agreements are CRADA, CTA and CSA.

8. 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

9. 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

10. 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

11. Regulatory Approval • Approval of trial by national trial regulatory agency (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

12. Central Institutional Review Board The NCI CIRB Initiative Target questions: • Could a CIRB reduce the significant local administrative burdens for multi-site trials while maintaining a high level of human subjects protection • Would a CIRB enhance the protection of research participants by providing consistent expert IRB review at the national level before the study is distributed to local investigators

13. OHRP Model Options • Model A– Central IRB review only • Appropriate where no local IRB exists • Understanding of local context obtained via site visits, audits, teleconferences • Model B– Central IRB review with some local IRB review • More appropriate where local IRB exists • Value of this model: LIRB provides understanding of local context and avoid expense of site visits, etc.

14. CIRB - Selecting a Model - Division of Responsibilities • NCI chose Model B for practical reasons • Local IRBs already exist and NCI chose to interface with them • Who better to understand local research context than local IRB Chair/members? • This model permitted NCI to offer its CIRB free of cost to local sites • CIRB and LIRB share regulatory responsibilities • The CIRB’s primary function is initial and continuing review of studies • The local institution’s primary function is consideration of local context, oversight of local performance, review of locally occurring adverse events

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

16. 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 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

17. 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

18. SPONSOR • Primary organization that oversees implementation of the study and is responsible for data analysis • Industry • Government • Cooperative Group • Academia

19. Sponsors Responsibilities - Regulatory • Ensuring proper monitoring of the investigation(s) • Ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND • Ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug • Ethical review • Maintaining an effective IND with respect to the investigations Code of Federal Regulations 21CFR312

20. Sponsor Responsibilities: Informed Consent • Ensuring that an informed consent document accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations and the ICH require that “the information that is given to the subject or the representative shall be in language understandable to the subject or the representative.

21. Sponsor Responsibility • Same responsibilities across industry, government, academia • Priority and focus may differ, but all play a unique role cancer research

22. Clinical Trials Provisions for All CTEP Collaborative Agreements

23. NCI- Cooperative Group- Industry Relationship: Summary of Obligations and Guidelines • Proprietary Agents • Confidentiality • Indemnification/Liability • Intellectual Property and Extramural Inventions • Exclusive access to Proprietary Data • Procedures under which Collaborator may contact Coop Groups, Member Institutions or Individual Clinical Investigators • Contact of Cooperative Groups by NCI • Nature and form of information supplied to the Collaborator • Cooperative Groups – Collaborator Agreements (w/out direct NCI involvement) • Publications • Financial Disclosure

24. 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)

25. Approvals - FDA • FDA remains committed to the accelerated approval pathway • 49 new oncology indications since 1995 • 3.3 oncology indications per year since 2005 • AA has provided early access to clinically beneficial cancer therapies (i.e. pemetrexed, sunitinib, bortezomib) • 27 oncology indications have confirmed benefit in post-marketing trials • Made available a median of 3.6 years prior to the verification of their clinical benefit

26. 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

27. Muchas Gracias Por Su Atencion