Fundamentals of Clinical Research Overview
Clinical research fundamentals cover topics like research definitions, types (interventional, observational), clinical trials (sponsorship, industry vs. investigator-initiated), and funding sources (grant-funded, industry-sponsored). Understanding these basics is crucial in the realm of medical research.
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1 The Fundamentals of Clinical Research Prepared by Christine Hunter, BSN Baylor College of Medicine and Karen Williams, CCRP Northwestern University
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. 45 CRF 46 Common Rule 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
3 Types of Research Interventional observational 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)
4 Clinical Trials Sponsor Funder 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.
5 Clinical Trials Industry Sponsored Protocols for a clinical investigation that are written and initiated by a person or agency outside of the institution The person or agency does not actually conduct the investigation, but pays clinical investigators for their participation Investigator Sponsored Protocols for a clinical investigation are initiated and conducted by the same person, usually a faculty member Investigator initiated trials carry the same regulatory requirements as industry sponsored trials, so the investigator takes on ALL sponsor responsibilities Funding sources could be externally funded, grant funded, or unfunded Grant Funded Clinical A clinical investigation that is funded by the NIH or other granting agencies 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 The NIH uses activity codes (e.g. R01, R43, etc.) to differentiate the wide variety of research-related programs they support
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
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 PI Curators Instructors Librarians Non-tenure-track research and clinical faculty Tenure-track faculty Senior research investigators Case-by-Case Determination Adjunct faculty Visiting faculty Visiting scholars NOT Eligible to serve as the PI Postdoctoral fellows Research assistants Graduate students Research associates Undergraduate students 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.
8 PI Responsibilities 21 CRF 312.60 21 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.
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
10 Pharmacy Fees STUDY DOSING FEES Prescription INDUSTRY SPONSORED $50 / prescription $100 / dose low $250 / dose - high INDUSTRY SPONSORED NON-INDUSTRY SPONSORED* $15 / prescription $45 / prescription IV OPERATING FEES NON-INDUSTRY SPONSORED* $3,000 $300 Initiation Annual Maintenance High Medium Low Drug Compounding $1,000 $700 $300 $60/hour $50 $30/hour
11 FACILITIES AND ADMINISTRATIVE RATES Federally Funded Non-Federally Funded FY 2016 09/01/15 - 08/31/16 AND THEREAFTER (PROVISIONAL) 64.4% 31.3% FY 2016 NATURE OF SPONSORED ACTIVITY Sponsored Research 09/01/15 - 08/31/16 AND THEREAFTER (PROVISIONAL) 54.5% 26.0% NATURE OF SPONSORED ACTIVITY Sponsored Research FY 2015 09/01/14 - 08/31/15 64.4% 31.3% FY 2015 ON/OFF CAMPUS On Campus Off Campus 09/01/14 - 08/31/15 54.5% 26.0% ON/OFF CAMPUS On Campus Off Campus Department of Defense (DoD) Contracts On Campus Off Campus 55.5% 26.0% 55.5% 26.0% Sponsored Instruction/Training On Campus Off Campus 78.3% 51.9% 78.3% 51.9% Sponsored Instruction/Training On Campus Off Campus 51.0% 26.0% 51.0% 26.0% Other Sponsored Activity On Campus Off Campus 42.8% 31.8% 42.8% 31.8% Industry- Sponsored Clinical Trials On Campus Off Campus 30.0% (TDC) 30.0% (TDC) 30.0% (TDC) 30.0% (TDC) Other Sponsored Activity On Campus Off Campus 36.0% 26.0% 36.0% 26.0% **Check institutional rates as these vary by institution
12 Clinical Trials: From Concept to Implementation Drug Pre-Clinical Drug Discovery Animal Research In Vitro Tests In Vivo Tests Development IND submitted to FDA for use of therapy in human clinical trials Investigational New Drug Phase I Small Cohorts Healthy Volunteers Dose Escalation Toxicity Phase II Disease Specific Drug vs. Placebo Safety Phase III Large Cohorts Drug vs. SOC Efficacy Clinical Research Approval for marketing based on clinical trial results New Drug Application Phase IV Long Term Safety data Diverse Populations Observational Registries Post-Marketing MEDWatch reporting by consumers and physicians Ongoing Drug Safety Monitoring Monitoring
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
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
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
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
17 Essential Elements of a Protocol Objectives should be clearly stated as hypotheses to be tested Sufficient background information should be included so that the rationale for the study is clear Objectives Background Patient Eligibility Criteria Pharmaceutical Information Inclusion and Exclusion criteria should be explicitly stated Information should include product description, storage requirements, stability, route of administration, and toxicity information
18 Managing Bias Controlled Trials Randomization Blinding Single Blinding: the patients do not know whether they are receiving study drug or placebo Study Drug vs. Placebo Subjects are randomly assigned to a specific arm of the study Similar Age and Weight Double Blinding: the patients, investigators, study staff, and data analysts do not know whether they are receiving study drug or placebo The investigator does not control randomization Same Stage of Disease
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
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.
21 Investigational New Drug (IND) When to submit an IND IND Submission contents 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.
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
23 Phase I Objectives 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 Determine Safe Dose Range Toxicity Levels Pharmacodynamics Pharmacokinetics Dose Limiting Toxicity (DLT) Maximum Dose Tolerated (MDT)
24 Phase II Objectives Evaluation of safety and disease treatment effects 100-300 subjects Specific disease condition Continued research regarding safety and less common side effects Determine disease response to study drug Drug-drug interaction Efficacy at various doses Patient Safety
25 Phase III Objectives Treatment evaluation Thousands of subjects Multi-center design Treatment vs. Placebo Controlled Study intervention compared to or combined with standard treatment Compare study interventions to standard treatment for disease Phase III information used for drug labeling Data is analyzed and findings are submitted to the FDA
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
27 Phase IV 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
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)
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
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
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
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
33 The Impact of Research Scientific Research has produced substantial social benefits. It has also posed some troubling ethical problems. Belmont Report 1979 1949 International Code of Medical Ethics of the World Medical Assembly 1962 1966 FDS 400 BCE Hippocratic Oath 1938 Food and Drug Act 1947 1964 Helsinki Declaration 1979 Belmont Report 1996 ICH Kefauver- Harris Amendment Nuremburg Code Regulations: 21CRF
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
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.
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
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.
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.
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
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.
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
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
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)
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.
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.
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
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).
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.
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)
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 (7th 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
