Clinical Trials 101

Research & Clinical Trials

What is research?

Research is defined by the Department of health and Human Services as a systemic investigation, including research, development, testing and evaluation designed to develop and contribute to generalizable knowledge.

Generalizable

  • Hypothesis is tested
  • Research outcomes are shared
Systemic

  • Defined procedure for data collection process
  • Primary and secondary endpoints are defined prior to data analysis
  • Data is gathered and then analyzed

TYPES OF RESEARCH

Interventional

  • 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

Observational

  • 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)
Clinical Trials

Sponsor

  • 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.

Funder

  • Source of funding to support the conduct of the trial; funding may come from the sponsor or another source.

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.

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
  • The external sponsor takes responsibility for the initiation, management, reporting, and document preparation of the trial

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
  • NIH uses activity codes (e.g. R01, R43, etc.) to differentiate the wide variety of research-related programs they support
Primary Investigator

An individual who actually conducts a clinical investigation, i.e. under whose immediate direction the test article is administered

PI RESPONSIBILITIES

21 CRF 312.60
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

21 CRF 812.100
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.

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
    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.

NOT eligible to server as the PI

  • Postdoctoral fellows
  • Research assistants
  • Graduate students
  • Research associates
  • Undergraduate students

The Clinical Trial Process

Clinical Trials: From concept to Implementation
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
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

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

Essential Elements of a Protocol

Objectives
Objectives should be clearly stated as a hypothesis to be tested

Background
Sufficient background information should be included so that the rationale for the study is clear

Patient Eligibility Criteria
Inclusion and Exclusion criteria should be explicitly stated

Pharmaceutical Information
Information should include product description, storage requirements, stability, route of administration, and toxicity information

Managing Bias

Controlled Trials

  • Study Drug vs. Placebo
  • Similar Age and Weight
  • Same Stage of Disease

Randomization

  • Subjects are randomly assigned to a specific arm of the study
  • The investigator does not control randomization

Blinding

  • Single Blinding: the patients do not know whether they are receiving study drug or placebo
  • Double Blinding: the patients, investigators, study staff, and data analysts do not know whether they are receiving study drug or placebo

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 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.

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
  • ontinuous monitoring looks for negative or positive results
Investigational New Drug (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

When to Submit an IND

  • 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.

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

Phase 1
  • Determine Safe Dose Range
  • Toxicity Levels
  • Pharmacodynamics
  • Pharmacokinetics
  • Dose Limiting Toxicity (DLT)
  • Maximum Dose Tolerated (MDT)

OBJECTIVES

  • Determine Safe Dose Range
  • Toxicity Levels
  • Pharmacodynamics
  • Pharmacokinetics
  • Dose Limiting Toxicity (DLT)
  • Maximum Dose Tolerated (MDT)
Phase 2
  • Evaluation of safety and disease treatment effects
  • 100-300 subjects
  • Specific disease condition
  • Continued research regarding safety and less common side effects

OBJECTIVES

  • Determine disease response to study drug
  • Drug-drug interaction
  • Efficacy at various doses
  • Patient Safety
Phase 3
  • Treatment evaluation
  • Thousands of subjects
  • Multi-center design
  • Treatment vs. Placebo
  • Controlled
  • Study intervention compared to or combined with standard treatment

OBJECTIVES

  • 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
New Drug Application
  • 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
Phase 4
  • 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

The Impact of Research

Scientific Research has produced substantial social benefits. It has also posed some troubling ethical problems.

— Belmont Report, 1979

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

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.

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

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

PRINCIPALS 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.

Beneficence: Benefits in research should outweigh the risks

  • Do not harm the human subject.
  • Maximize possible benefits.
  • Minimize possible harm.

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
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 GUIDANCE

Institutional (IRB) versus Central IRB (usually selected by sponsor but can be WIRB, Quorum or others)

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.

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 theHuman Subjects Research (HSR) andGood Clinical Practice (GCP) ICH training.