Quality Assurance for Clinical Research

The Quality Assurance Plan (QA Plan) is designed to ensure that clinical studies conducted at Children's Hospital Los Angeles adhere to their respective research protocols, applicable federal and state regulations, the ICH-GCP guidelines and all relevant Children's Hospital Los Angeles policies and procedures. The QA Plan consists of two major components – the Education Plan the Audit Plan.

Education Plan

The education plan will consist of:

  • Study Initiation Visits,
  • Training – both in service and scheduled classes,
  • CCI Quality Assurance web site section, and
  • Consultation services.
  • Study Initiation Visits
  • Training
  • Nuremberg Code
  • Declaration of Helsinki
  • The Belmont Report
  • ICH GCP Guidelines
  • CIOMS GCP Guidelines
  • PhRMA GCP Guidelines
  • Title 21 Parts 56 and 50
  • Title 21 Part 50
  • Title 45 Part 46

For all investigator-initiated, greater than minimal risk studies, the QA and Education Specialist (Specialist) will visit with the research team prior to the initiation of study activities.  Industry sponsored and multicenter funded studies will be included as time permits. At the Study Initiation Visit, the Specialist will acquaint the research team with the basic principles of the ICH-GCP guidelines. The main focus of the visit will be on the record keeping requirements for the clinical trial.

  • The Specialist will take a practical and directional approach at the Site Initiation Visit by presenting the research team with two pre-tabbed binders in which to organize the most important clinical trial documentation. The purpose of these binders is to standardize record keeping for clinical studies and to increase compliance with the ICH- GCP guidelines.
  • One binder, the study binder, will store the documents pertinent to the research study (including the protocol, investigator’s brochure, CCI approval letter, informed consent document, sponsor contracts, SAE reporting plan, the delegation of authority form, the shipping related documents, normal values for lab ranges, and the pre-monitoring and site initiation visit reports from the external or internal monitors or investigator meeting attendance records).
  • The second binder will store the essential logs which will have to be updated during the course of the clinical study (including logs for patient screening, patient enrollment, patient eligibility assessment, source documentation, SAEs, site monitoring reports, IRB and sponsor related correspondence, and drug accountability forms).

In service training and classes will be administered to research staff on an as-needed and scheduled basis and will consist of presentations on ICH- GCP guidelines and pertinent FDA regulations and Children's Hospital Los Angeles policies and procedures.

Study Initiation Visit

  • In an attempt to improve the practice of clinical research at Children's Hospital Los Angeles, the CCI is pleased to introduce a Quality Assurance and Education program. Our goal is to conduct study initiation visits with the research team prior to the start of all greater than minimal risk studies. At the study initiation visit, the Specialist will review ICH-GCP guidelines with the research team, primarily focusing on clinical trial record-keeping requirements.
  • The study initiation visit will take approximately one hour. We will make every effort to schedule these visits at a time when all members of the research team responsible for clinical trial execution and record keeping can attend. For studies receiving GCRC support, the study initiation visit will be incorporated into the GCRC study initiation/implementation meeting. During this visit, the Specialist will furnish the research team with customized binders, pre-tabbed for the collection of the necessary clinical trial documentation. The Specialist will review with the research team the study documentation that must be completed prior to subject enrollment, together with the logs required to collect information during the course of the trial.
  • We believe that these study initiation visits will help to standardize our clinical trial record keeping practices and align them with ICH GCP guidelines. This will position us well for external audits and contribute to better clinical trial management.
  • The topics discussed during the study initiation visits – site initiation documents and logs for clinical trials.

“The modern story of human subjects protection begins with the Nuremberg Code, developed by Nuremberg Military Tribunal as standards by which to judge the human experimentation conducted by the Nazis. The code captures many of what are now taken to be the basic principles governing the ethical conduct of research involving human subjects. The first provision of the Code states that “the voluntary consent of the human subject is absolutely essential. Freely given consent to participation in research is the cornerstone of ethical experimentation involving human subjects. The Code goes on to provide the details implied by such a requirement: capacity to consent, freedom from coercion, and comprehension of the risks and benefits involved. Other provisions require the minimization of risk and harm, a favorable risk/benefit ratio, qualified investigators using appropriate research designs, and freedom for the subjects to withdraw at any time.”

(Institutional Review Board Guidebook)

“The World Medical Association developed a code of ethics for research on human subjects in 1964, which came to be called the Declaration of Helsinki. The Declaration of Helsinki is divided into three primary sections: basic principles, medical research combined with clinical care (clinical research) and non-therapeutic biomedical research involving human subjects (non-clinical biomedical research). Provisions of the Declaration provide guidance on the following topics:

  • Study design and experimental protocols
  • Research conformity with institutional guidelines and local and national laws
  • Risk assessments and risk/benefit comparisons
  • Consideration and protection of test subjects
  • Hazard avoidance
  • Informed consent of legally competent and legally incompetent test subjects
  • Volunteer status of research subjects
  • Discontinuation of research that proves harmful to test subjects.”

(R.J. Rohrich, in Ethical approval of clinical studies - plastic and reconstructive surgery, 119, 2307 – 2309)

“On September 30, 1978 the National Commission for the protection of Human Subjects of Biomedical and Behavioral Research submitted its report entitled “The Belmont Report: Ethical Principles and Guidelines for the protection of Human Subjects of Research.” The Report, named after the Belmont Conference Center at the Smithsonian Institution, where the discussions which resulted in its formulation were begun, sets forth the basic ethical principles underlying the acceptable conduct of research involving human subjects. Those principles, respect for persons, beneficence, and justice, are now accepted as the three quintessential requirements for the ethical conduct of research involving human subjects.

  • Respect for persons involves a recognition of the personal dignity and autonomy of individuals, and special protection of those subjects with diminished autonomy.
  • Beneficence entails an obligation to protect persons from harm by maximizing anticipated benefits and minimizing possible risks of harm.
  • Justice requires that the benefits and burdens of research be distributed fairly.”

(Institutional Review Board Guidebook)

In the United States, guidelines and regulations on ethics in clinical trials emerged from the Belmont Report, published in 1979, and the Code of Federal Regulations, Titles 21 and 45. Although these guidelines are recognized by many countries outside the United States, there was a need for a more international perspective.

  • In 1997, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use published the “Good Clinical Practice Consolidated Guideline” to provide a unified standard for the EU, Japan and the U.S. to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.
  • These guidelines now form the cornerstone of clinical trial management internationally and are followed by most industrial sponsors of clinical trials.

The main points addressed by these guidelines include:

  • Responsibilities of the IRB
  • Responsibilities of the Principal Investigator
  • Responsibilities of the Sponsor
  • Clinical Trial Protocol and Protocol Amendments
  • Investigator’s brochure
  • Essential Documents for the Conduct of the Clinical Trials.

Of the many topics covered by these guidelines the ones pertinent to quality assurance include:

  • Monitoring of Clinical Trials
  • Auditing of Clinical Trials
  • Quality Control and Quality Assurance Procedures
  • Record keeping for the site initiation, site maintenance and site close-out of clinical trials.

The Council for International Organizations and Medical Sciences (CIOMS) was formed in 1949 jointly by the WHO and UNESCO. The International Ethical Guidelines for Biomedical Research involving Human Subjects, developed in conjunction with WHO, were published in 1993 and updated in 2002. The guidelines acknowledge their historical foundations in the Declaration of Helsinki and set out how these principles might be applied in clinical practice.

The main points addressed in these guidelines include the following:

  • Ethical justification and scientific validity of research
  • Requirements for ethical review and informed consent
  • Consideration of vulnerability of individuals and populations
  • Equity regarding burdens and benefits
  • Choice of controls in clinical trials
  • Confidentiality
  • Compensation for injury
  • Strengthening of national or local capacity for ethical review
  • Obligation of sponsors to provide health care services.

(D.J.Macrae, Proc. Am.Thorac.Soc. 4, 176 – 179, 2007)

The Pharmaceutical Research and Manufacturers of  America (PhRMA) represents research-based pharmaceutical and biotechnology companies.

PhRMA acknowledges the principles set forth for the conduct of research in the Declaration of Helsinki, the ICH–GCP guidelines and regulations enforced by the FDA.

In addition to these, PhRMA adopted a set of voluntary principles to clarify its members’ relationships with other individuals and entities involved in the clinical research process.
The key issues addressed include:

  • Protecting Research Participants
  • Conduct of Clinical Trials
  • Ensuring Objectivity in Research
  • Disclosure of Clinical Trial Results.

This part of the code of Federal Regulations describes the requirements for an Institutional Review Board and is extensively used by institutions in formulating and implementing IRBs.

  • Subpart A describes the circumstances in which IRB review is required and include features for exemptions and waivers from IRB requirements.
  • Subpart B is devoted to describing the criteria for IRB membership.
  • Subpart C describes IRB functions and operations as well as the criteria for expedited review.
  • Subpart D describes the requirements for IRB recordkeeping.
  • Subpart E describes the administrative actions for non-compliance including criteria for the disqualification of an IRB or an institution.

This part of the code of Federal Regulations describes the requirements for the protection of human subjects.

  • Subpart A describes the general provisions for protection of human subjects.
  • Subpart B describes in some detail the requirements for an informed consent of human subjects and exceptions from the general requirements.
  • Subpart D describes the duties of an IRB and further details the gradation of risk in categorizing human research.

These categories include:

  • Clinical investigations not involving greater than minimal risk. (50.51)
  • Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects. (50.52)
  • Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or conditions. (50.53)

These classifications are extensively used by the CCI in classifying risk of research proposals at Children's Hospital Los Angeles.

This part of the code of federal regulations contains the basic guidelines for the protection of human subjects and is extensively used by Institutional Review Boards in their decision-making.

It is comprised of four parts which are briefly summarized below.

  • Subpart A:  Basic HHS policy for Protection of Human Subjects research.
    • This part contains the key guidelines for IRB membership, IRB functions and operations, IRB review of research, criteria for IRB approval of research and IRB records.
  • Subpart B:  Additional protections for Pregnant Women, Human Fetuses and neonates involved in research.
    • As the title suggests this part relates to the duties of the IRB in connection with research involving pregnant women, fetuses, and neonates.
  • Subpart C: Additional protections pertaining to biomedical and behavioral research involving prisoners as subjects.
    • As the title suggests this part defines the role of the IRB , its composition, duties and permitted research involving prisoners.
  • Subpart D: Additional protections for children involved as subjects in research.
    • This part of the regulations provides the IRB with guidance on research involving children – it describes different levels of risk in such research.
  • Research not involving greater than minimal risk (46.404)
  • Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (46.405)
  • Research involving greater than minimal risk and no prospect of direct benefit to individual subjects but likely to yield generalizable knowledge about the subject’s disorder or condition. (46.406)

This categorization of research is extensively used by the CCI in assessing research protocols at Children's Hospital Los Angeles.