1. The Fundamentals of Clinical Research Prepared by Christine Hunter, BSN Baylor College of Medicine and Karen Williams, CCRP Northwestern University 1

2. What is research? Research is defined by the Department of Health and Human Services as a systematic investigation, including research, development, testing, and evaluation designed to develop or contribute to generalizable knowledge. Systematic Defined procedure for data collection process Primary and secondary endpoints are defined prior to data analysis Data is gathered and then analyzed Generalizable Hypothesis is tested Research outcomes are shared 45 CRF 46 Common Rule 2

3. Types of Research Interventionalobservational A study that uses an intervention to modify the health of the subjects Administration of a drug or device; medical procedure Manipulation of the environment intended to change the course of a subject’s medical condition A study without clinical intervention (i.e. survey or questionnaire) An evaluation of patient condition (i.e. PPMI) An assessment of data collected on an individual or group of patients (i.e. PPMI) 3

4. Clinical Trials SponsorFunder The person, company, or group who wrote the protocol and takes responsibility for the initiation, management, reporting, and document preparation of the trial, as per FDA requirements. Source of funding to support the conduct of the trial; funding may come from the sponsor or another source. 4

5. Industry SponsoredInvestigator SponsoredGrant Funded Clinical Protocols for a clinical investigation that are written and initiated by a person or agency outside of the institution Protocols for a clinical investigation are initiated and conducted by the same person, usually a faculty member A clinical investigation that is funded by the NIH or other granting agencies The person or agency does not actually conduct the investigation, but pays clinical investigators for their participation Investigator initiated trials carry the same regulatory requirements as industry sponsored trials, so the investigator takes on ALL sponsor responsibilities Subject to further restrictions and requirements that are placed on all federally funded project The external sponsor takes responsibility for the initiation, management, reporting, and document preparation of the trial Funding sources could be externally funded, grant funded, or unfunded The NIH uses activity codes (e.g. R01, R43, etc.) to differentiate the wide variety of research-related programs they support Clinical Trials 5

6. Human Subjects A human subject is a living individual about whom an investigator obtains data through intervention or interaction or identifiable private information. HIPAA regulations cover research on all human subjects, living or deceased Identifiable specimens or records of deceased subjects may require approval by the IRB 45 CRF 46.102 6

7. Primary Investigator An individual who actually conducts a clinical investigation, i.e. under whose immediate direction the test article is administered Eligible to serve as the PICase-by-Case DeterminationNOT Eligible to serve as the PI Curators Instructors Librarians Non-tenure-track research and clinical faculty Tenure-track faculty Senior research investigators Adjunct faculty Visiting faculty Visiting scholars Contact the Associate Vice President for Research via email to request permission for such faculty. Please include your CV. If approval is granted, upload the confirmation email as a supporting document into the eIRB+ application. Postdoctoral fellows Research assistants Graduate students Research associates Undergraduate students 7

8. PI Responsibilities 21 CRF 312.6021 CRF 812.100 An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs under investigation. An investigator shall, in accordance with the provisions of part 50 of this chapter, obtain the informed consent of each human subject to whom the drug is administered, except as provided in 50.23 or 50.24 of this chapter. An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator's care, and for the control of devices under investigation. An investigator also is responsible for ensuring that informed consent is obtained in accordance with part 50 of this chapter. Additional responsibilities of investigators are described in subpart G. 8

9. Components of a Budget Start-up fees ▫Pharmacy  $300 Federally funded and investigator initiated studies  $3000 Sponsored studied ▫IRB, sponsored research only Clinical Care Expenses Study Team Effort Indirect Costs ▫Non-federally funded ▫Federally funded 9

10. STUDY DOSING FEES INDUSTRY SPONSORED NON-INDUSTRY SPONSORED* Prescription$50 / prescription $15 / prescription IV$100 / dose – low $250 / dose - high $45 / prescription OPERATING FEES INDUSTRY SPONSORED NON-INDUSTRY SPONSORED* Initiation$3,000$300 Annual Maintenance High Medium Low $1,000 $700 $300 $50 Drug Compounding $60/hour$30/hour Pharmacy Fees 10

11. NATURE OF SPONSORED ACTIVITYON/OFF CAMPUS FY 2015 09/01/14 - 08/31/15 FY 2016 09/01/15 - 08/31/16 AND THEREAFTER (PROVISIONAL) Sponsored ResearchOn Campus Off Campus 54.5% 26.0% Department of Defense (DoD) Contracts On Campus Off Campus 55.5% 26.0% Sponsored Instruction/Training On Campus Off Campus 51.0% 26.0% Other Sponsored Activity On Campus Off Campus 36.0% 26.0% NATURE OF SPONSORED ACTIVITYON/OFF CAMPUS FY 2015 09/01/14 - 08/31/15 FY 2016 09/01/15 - 08/31/16 AND THEREAFTER (PROVISIONAL) Sponsored Research On Campus Off Campus 64.4% 31.3% Sponsored Instruction/Training On Campus Off Campus 78.3% 51.9% Other Sponsored Activity On Campus Off Campus 42.8% 31.8% Industry- Sponsored Clinical Trials On Campus Off Campus 30.0% (TDC) FACILITIES AND ADMINISTRATIVE RATES Federally FundedNon-Federally Funded **Check institutional rates as these vary by institution 11

12. Clinical Trials: From Concept to Implementation 12

13. Pre-Clinical Drug Discovery Compounds are extracted from natural substances or synthesized in the lab and analyzed for therapeutic value Pre-clinical testing: ▫Pharmacology  Pharmacodynamics  Pharmacokinetics ▫Toxicology ▫Animal testing 13

14. Pre-Clinical Testing Pharmacodynamics The observed effect resulting from a certain drug concentration Pharmacokinetics Describes the drug concentration-time courses in body fluids resulting from administration of a certain drug dose ▫Absorption ▫Distribution ▫Metabolism ▫Excretion Toxicology Tests the toxicological effects of an agent, including carcinogenicity Animal Studies Common animal models for studying compound safety and efficacy include mice, rats, pigs, dogs, and monkeys 14

15. Research & Development Statistics The average cost of R&D for every successful drug is $800,000,000-$1,000,000,000 For every 5,000-10,000 compounds in the R&D pipeline, 1 receives FDA approval The Pharmaceutical Research Manufacturers of America (PhRMA) estimates that only 5 in 5,000 compounds that enter pre-clinical testing make it to human testing, and 1 of those 5 might be safe and effective enough to reach pharmacy shelves 15

16. Pre-Clinical Testing Results When a drug has undergone sufficient laboratory and animal testing, the sponsor must submit an application to the FDA prior to testing the new drug in humans The FDA will review the pre-clinical data and the proposal for human clinical trials design 16

17. Essential Elements of a Protocol 17

18. Managing Bias 18

19. Blinding The FDA considers blinded clinical trials ethical if they meet the following criteria: Patients are fully informed of the protocol and treatment options Treatments cannot be denied that could prevent irreversible injury or alter survival Continuous monitoring looks for negative or positive results 19

20. Clinical Trial Blinding Human behavior is influenced by what we know or believe. In research there is a particular risk of expectation influencing findings, most obviously when there is some subjectivity in assessment, leading to biased results. Blinding (sometimes called masking) is used to try to eliminate such bias. Double blind, usually refers to keeping study participants, those involved with their management, and those collecting and analyzing clinical data unaware of the assigned treatment, so that they should not be influenced by that knowledge. Double-Dummy, two active compounds, blinding is possible using the this method. For example, if we want to compare two medicines, one presented as green tablets and one as pink capsules, we could also supply green placebo tablets and pink placebo capsules so that both groups of patients would take one green tablet and one pink capsule. Single blind trials (where either only the investigator or only the patient is blind to the allocation) are sometimes unavoidable. Open (non-blind) trials. In trials of different styles of patient management, surgical procedures, or alternative therapies, full blinding is often impossible. 20

21. Investigational New Drug (IND) IND Submission contents When to submit an IND Introductory statement Investigational plan Investigator’s brochure Protocol Pharmacology information Toxicology information Summary of previous experiments Chemistry, manufacturing, and control information Form 1571 New indication Significant change in marketing A new route of administration Dosage level change New subject population Changes that significantly increase the risks associated with use of the investigational product The FDA will notify the PI of approval via formal correspondence containing an IND number and a date of approval. All correspondence and original submission materials should be maintained in the regulatory binder. 21

22. Investigator’s Brochure Includes information and cautions derived from pre-clinical research Serves as the official labeling for an investigational drug prior to FDA approval; subsequently, the approved package insert becomes the official labeling 22

23. Investigational product is tested in human for the first time Small cohort Closely monitored Healthy targets and patients with targeted disease states Often Unblinded Uncontrolled Dose escalation If safety or efficacy concerns arise, human research is discontinued Phase I 23

24. Evaluation of safety and disease treatment effects 100-300 subjects Specific disease condition Continued research regarding safety and less common side effects Phase II 24

25. Treatment evaluation Thousands of subjects Multi-center design Treatment vs. Placebo Controlled Study intervention compared to or combined with standard treatment Phase III 25

26. New Drug Application (NDA) Submission requesting FDA approval to market a new drug Review of all pre-clinical and clinical trial data Assess safety and efficacy FDA may audit sites to verify data submitted in the NDA If approved, the drug can be marketed and sold to the public under the FDA guidelines for marketing and distribution 26

27. Post-marketing studies Long-term safety Affects on different cohorts ▫Dosing ▫Race ▫Gender The sponsor must continue to report Adverse Events (AEs) and finding to the FDA via MedWatch Forms If dangerous side effects are found, the drug is taken off the market or a Black Box may be added Phase IV 27

28. IRB Submission All IRB submissions are done electronically using the institutional IRB system or a Central IRB as allowed by the institution (such as WIRB, Quorum) IRB submissions will not be approved without an approved budget from the Office of Sponsored Research (OSR) (sequence depends on institution) The following documents are included in the with the IRB submission: ▫Protocol ▫Budget (Department/Institutional requirements) ▫Investigator’s Brochure ▫Recruitment Materials ▫Informed Consent ▫Research Supplemental Submission (if applicable) 28

29. Research Responsibilites Contract: Contracts analyst OSR, Coordinator, Investigator, Sponsor Budget: OSR, Coordinator &/or Regulatory specialist Informed Consent: Coordinator &/or Regulatory specialist Regulatory: Coordinator &/or Regulatory specialist IRB Submission: Coordinator &/or Regulatory specialist 29

30. Critical Regulatory Documents CDA executed 1572 CVs for all research staff involved in the study (signed and dated within 2 years) Medical Licenses Protocol Amendments Investigator’s Brochure Protocol Signature Pages Critical Correspondence Test Article Records and Drug Accountability Delegation of Responsibility Log IND Safety Reports Laboratory Certifications Laboratory Reference Ranges Lab Director’s CV and License Telephone Logs Site Signature Logs Monitoring Log Financial Disclosures Conflicts of Interest Enrollment & screening logs 30

31. The IRB: What you need to know You must complete CITI training prior to being added to a protocol You must be added to a protocol with the IRB prior to obtaining patient consent or doing any protocol related tasks You must have documented training on each protocol No study procedures can be completed prior to obtaining informed consent 31

32. The IRB: What you need to know Unanticipated Problems If you encounter a serious event that meets the following criteria, work with your PI to report the SAE to the IRB: ▫Unexpected ▫Related or possibly related ▫Suggests the research places subjects or others at risk of unknown harm 32

33. The Impact of Research “Scientific Research has produced substantial social benefits. It has also posed some troubling ethical problems.” Belmont Report 1979 33

34. The Impact of Research Berlin Code of Ethics: World’s first official regulation of human experimentation, barring non- therapeutic interventions without voluntary consent, as well as experiments on minors and others judged vulnerable or incompetent. The Nuremberg Code: International code of ethics established in response to inhumane Nazi human experimentation during WWII. The Nuremberg Code established four principles: ▫Informed Consent ▫Absence of Coercion ▫Properly formulated scientific experimentation ▫Beneficence towards experiment participants 34

35. The Impact of Research Kefauver-Harris Drug Amendments: Passed to ensure drug efficacy and greater drug safety; drug manufacturers are required to prove to the FDA effectiveness of their products before marketing them and tests for safety during pregnancy are required before a drug can receive approval for sale in the U.S. As a result, the FDA is given closer control over investigational drug studies and FDA inspectors were granted access to additional company records. 35

36. The Impact of Research Declaration of Helsinki: A statement of ethical principles stating that in medical research on human subjects, considerations related to the wellbeing of the human subject should take precedence over the interests of science and society. This document is widely considered the cornerstone of human research ethics. The Belmont Report: The National Research Act led to the Belmont Report, which outlined 3 basic principles: ▫Respect for persons ▫Beneficence ▫Justice 36

37. Principles of The Belmont Report Respect for persons: Informed Consent Individuals should be treated as autonomous agents… capable of deliberation about personal goals and of acting under the direction of such deliberation Persons with diminished autonomy are entitled to protection. Requirements to acknowledge autonomy and the requirement to protect those with diminished autonomy. 37

38. Principles of The Belmont Report Beneficence: Benefits in research should outweigh the risks Do not harm the human subject. Maximize possible benefits. Minimize possible harm. 38

39. Principles of The Belmont Report Justice: Equality in selection and opportunity to participate in research Each person should have equal share according to: ▫Individual need ▫Individual effort ▫Societal contribution ▫Merit 39

40. The Impact of Research International Conference on Harmonization (ICH): Good Clinical Practice (GCP) set as the international standard, providing public assurance that trial subjects are protected. 40

41. Form 1572 The 1572 is an investigator’s signed contract with the FDA, agreeing to uphold federal clinical study obligations No investigator may participate in an investigation until a 1572 is signed Device studies use an Investigator’s Agreement Form, which is the equivalent to the 1572 Name and address of the investigator Education, training, and qualifications of investigator Address of research facilities and clinical laboratories Name and address of the IRB Name of co-investigators and research staff Protocol number and title Commitments Signature Date 41

42. Form 1572 The PI agrees to personally conduct or supervise the described investigation The PI agrees to maintain adequate and accurate records in accordance with 21 CRF 312.62 and to make those records available for inspection in accordance with 21 CRF 312.68 The PI ensures that all associates, colleagues, and employees assisting in the conduct of the study are informed regarding their obligation to meet all commitments of the study 42

43. Guidelines and Regulations Federal Regulations ▫Code of Federal Regulations (CFR)  CFR Title 46 Part 46: Outlines federal policy for the protection of human subjects in research, establishing mandates for institutional review boards (IRBs) and additional protections for vulnerable populations.  CFT Title 21 Part 50: Specifies that research on human subjects at institutions that hold Federal wide Assurances (FWAs) requires IRB review; this CFR specifies the minimum level of review for different types of research. International Guidance ▫International Conference on Harmonization – Good Clinical Practice (ICH GCP E6) Local ▫Institutional (IRB) versus Central IRB (usually selected by sponsor but can be WIRB, Quorum or others) 43

44. Institutional Review Board The Institutional Review Board (IRB) was established in accordance with federal regulations governing the use of human subjects in research. The IRB reviews and surveys research to ensure the protection of the rights and welfare of all research subjects. Investigators cannot initiate or change research protocols until they have received IRB approval. 44

45. Good Clinical Practice Training All faculty or staff listed on a protocol with the IRB must have documentation of training (may be specific requirements at institution) Required: CITI Web Based Training or other similar program Required: GCP for Clinical Trials with Investigational Drugs and Medical Devices (U.S. FDA focus) is suitable for individuals proposing to conduct clinical trials of drugs and devices primarily in the U.S. and/or who would prefer a more U.S. FDA- centric curriculum. Recommended: Clinical Research Coordinator (CRC) CITI Program's CRC course provides a foundational training specifically focusing on operational and regulatory elements necessary for the ethical conduct of clinical research, while at the same time it is specifically tailored for the needs of clinical research professionals. It offers learners a foundation that expands beyond but is directly connected to the Human Subjects Research (HSR) and Good Clinical Practice (GCP) ICH training. https://www.citiprogram.org/ 45

46. Additional Training Protocol specific training ▫Expectations for clinical and research specific procedures, such as laboratory assessments, EKG, vitals, etc. ▫Expectations for standardized and non-standardized study data collection methods or assessments, such as questionnaires ▫Sponsor specific training for EDC, Specialty assessments, diary training, specific assessment devices ( these may take place at Investigator meeting but most often by additional training modules/webinars ) Shipment of Hazardous Materials (IATA) Blood Borne Pathogens 46

47. Investigator’s Meeting (IM) Prior to study recruitment many sponsors hold IM to train, cover AE and SAE reporting, lab procedures, certify investigators and/or staff in assessments and provide a background on the sponsor and protocol. These may be in person meetings or via Webinar or combined with the Site Initiation Visit (SIV). 47

48. Site Initiation Visit (SIV) Following the IM and prior to study start-up, sponsors will hold the SIV to train, cover AE and SAE reporting, lab procedures, certify investigators and/or staff in assessments, collect regulatory documents, verify the Delegation of Authority log and answer questions all site personnel may have about the conduct of the study. 48

49. Screening and Enrollment The protocol will specify when a subject is considered enrolled in a study. Screening and enrollment logs to be maintained and provided to sponsor per protocol. ▫Separate enrollment log with complete subject identification is necessary, to be filed in regulatory binder but not released to sponsor as it includes subject PHI. Signature on informed consent before any study related procedures are completed. Randomization per protocol Treatment dispensed per protocol (if a treatment trial) 49

50. Consent Process Document Required Elements of Informed consent Information must be provided to the subject in a language and level understandable to the subject (7 th grade level) Introduction Study involves research Purpose of research Duration of subject involvement in the study Description of study procedures Identification of any experimental procedures Potential risks/ discomforts Potential benefits to subjects or others 50

51. Consent Process Document Alternative procedures or treatments (that are already available to the potential subject) Confidentiality of subject records (e.g. access to sponsor, FDA) Compensation for injury and treatment in event of emergency Who subject can contact Participation is voluntary New-March 7, 2012: “A description of this clinical trial will be available on https://www.clinicaltrials.gov/, as required by U.S. Law. This web site will not include information that can identify you. At most, the web site will include a summary of the results. You can search this web site at any time.”https://www.clinicaltrials.gov/ 51

52. Consent Process Document Unforeseen risks statement Reasons for involuntary termination Additional costs to subject Consequences of decision to withdraw (e.g. impact on their health, treatment, personal welfare etc.) New findings will be communicated Approximate number of subjects in the study Payments to the subject are to be included in the document and when they will be paid (e.g. incentive, travel costs etc.)* 52

53. Consent Process Document It is critical to document the consent process for your site. Some sites include in subject EDC chart or have a separate consent process document including that the subject has had time to review the ICF, all questions were answered and the subject received a copy of the signed consent document for their records. Example of a consent process document on the next slide. 53

54. Consent Process Document Patient Name: D.O.B. Consent Process Document: Potential risks, benefits and side effects of protocol # _____ have been explained. Subject understands and denies further questions. No protocol procedures were conducted prior to obtaining consent. Inclusion and exclusion criteria have been reviewed by PI and subject meets/continues to meet criteria for participation. The subject has initialed, signed and dated the appropriate informed consent documents. Patient received a copy of the signed consent form for their records. Consenting Site Staff’s Signature: Date ______ Consenting Site Staff’s Printed Name: _______________________________________ Consenting Site Study PI Signature: Date ______ Consenting Site Study PI Printed Name: _______________________________________ 54

55. Routine Monitoring visits Based on CRO/sponsor requirements study monitors will be asked to come to the site generally within 2 weeks of initial enrollment then every 4-6 weeks. These requirements vary from sponsor to sponsor, may be impacted by enrollment numbers and phase of study. Frequency of visits may decrease in the open extension phases of study. 55

56. Research Drug/Investigational Product Drug storage: Investigational drugs will be stored in the appropriately secured location (i.e. refrigerated or frozen compounds). Accurate and complete drug accountability records MUST be maintained. ▫Investigational drugs, which are dispensed to patients, shall be dispensed only by authorized personnel (under the supervision of the study physician or registered nurse) and in accordance with all state and federal, and institutional regulations as required by law. Investigational Drug Disposal: Investigational drugs shall be returned or destroyed according to the protocol and drug company policy. If destroyed on site follow your institutional or facility policies for hazardous waste. Temperature logs: All logs for drug cabinets, refrigerator and freezer must be maintained and available for review by the sponsor or designees. Some sites use and institutional research pharmacy and the logs are maintained there. Study Drug Blind Envelopes: In a separate binder, appropriate personnel have access to the blind envelopes for all studies. These blind envelopes are maintained until retrieval by study monitor at closeout. Sometimes these blinds are on the I/P container itself rather than a separate folder. They are however, available to designated study personnel in the event of an emergency. Every effort is made to keep the studies blinded and the sponsor is notified before the blind is broken. 56

57. Research SOP’s Important to develop site specific Research SOP’s. Include record retention policies, location of offsite storage if applicable, drug destruction policies and plan, specific location of temperature logs and archives of these, maintenance of equipment logs (annual recalibration) Outline site specific responsibilities for research requirements Disaster Plan if one is applicable 57

58. Access for Monitors ▫Access for monitors to patient electronic records may be based on institutional requirements. ▫Some will have certified copies of the patient records printed and dated and provided by the coordinator. Other sites may actually allow sponsor designees “read only” access to patient records. ▫Submit requests 2-3 weeks in advance  Monitor full legal name  Date of Birth  Last four digits of Social Security Number  IRB approval letter  Department  Start date for access ▫EPIC: 1 year (varies by institution) ▫Powerchart: 90 days  Signed Confidentiality Agreement 58

59. Questions? 59