The term may be applied to any form of planned experiment which involves patients and is designed to elucidate the most appropriate treatment of future patients with a given medical condition. The essential characteristic of a clinical trial is that the results based on a limited sample of patients are used to make inferences about how treatment should be conducted in the general population of patients who will require treatment in the future.

Animal studies do not come within this definition and experiments on healthy human volunteers are somewhat borderline in that they provide only indirect evidence of effects on patients. However, such volunteer studies (often termed phase I trials) are an important first step in human exposure to potential new treatment and are included in the definition of a clinical trial when appropriate.

Field trials of vaccines and primary prevention trials for subject with presymptomatic condition, (e.g. high serum cholesterol) involve many of the same scientific and ethical issues as in the treatment of patients who are clearly diseased.

An individual case study, where one patient’s pattern of treatment and response is reported as an interesting occurrence, does not really constitute a clinical trial.

Retrospective surveys examine the outcomes of past patients treated in a variety of ways. These unplanned observational studies contain serious potential biases so that they can rarely make a convincing contribution to the evaluation of alternative therapies. Such studies will not be considered as clinical trials.

Classifying trials by type of treatment. The great majority of clinical trials are concerned with the evaluation of drug therapy more often than not with pharmaceutical company interest and financial backing. However, clinical trials may also be concerned with other forms of treatment which may be evaluated by clinical trials, e.g., surgical procedures, radiotherapy, medical advice (diet and exercise policy), and alternative approaches to patient management (home care or hospital care).

Clinical trials can be rigorously defined. A clinical trial is an experiment testing medical treatments on human subjects. An experiment is a series of observations made under conditions controlled by the scientist.

In addition to being true experiments, clinical trials possess important general characteristics of the scientific method. These include:
- instrumentalizing perception or measurement, which enhances repeatability and quantification;
- externalizing plans and memory in a written record, to facilitate reference and defense;
- control of extraneous factors as part of the study design; and
- submitting completed work to external recognition, verification, or disproof.

Sometimes investigations that superficially appear to be clinical trials are not. Examples are so-called "seeding trials", occasionally conducted by pharmaceutical companies as marketing tools, because they encourage physicians to prescribe a new drug. The distinction between such efforts and true clinical trials can be made by examining the purposes and design of the study. Warning signs for seeding trials include:

1. a design that cannot support the research goals,
2. investigators are recruited because of their prescribing habits rather than scientific expertise,
3. the sponsor provides unrealistically high reimbursements for participation,
4. minimal data or those of little scientific interest are collected,
5. the study is conducted through the sponsor’s marketing program rather than the research division,
6. the agent being tested is similar to numerous therapeutic alternatives.

Clinical experiments do not originate and reveal their finding in isolation. Trials co-exist with clinical and pre-clinical research of all types. The following characterization of clinical research, adapted from Ahrens (1992) shows how designed experiments fit within the spectrum of clinical research. Based on scientific objectives, sponsor funding, and technical skills and training of investigators, clinical research can be divided into seven areas:

1. Studies of disease mechanisms. These studies may be either descriptive or analytic but require laboratory methods and clinical observations under controlled conditions. Examples are metabolic and pharmacologic studies.
2. Studies of disease management. These studies involve evaluations of developing treatments, modalities or preventive measures and have outcomes with direct clinical relevance. Often, internal controls and true experimental designs will be used. Most clinical trials fit within this category.
3. In vitro studies on material of human origin.
4. Models of human health and disease processes.
5. Field surveys. These are descriptive or analytic studies of risk factors or disease correlates in populations. Examples include epidemiologic and genetic studies.
6. Technology development. Includes development and mechanistic testing of new diagnostic and therapeutic methods.
7. Health care delivery. These studies focus on economic and social effects of health care practice and delivery.

Any one or several of these types of clinical research studies can relate directly to clinical trials. For example, they may be precursor, follow-up, or parallel studies essential to the design and interpretation of a clinical trial.

Information taken from Clinical Trials, A Methodological Perspective, Steven Piantadosi, 1997.

Clinical trials should be designed, conducted and analyzed according to sound scientific and ethical principles to achieve their objectives and should be reported appropriately. The essence of rational drug development is to ask important questions and answer them with appropriate studies. The primary objective of any study should be clear and explicitly stated.

Clinical studies can be classified according to when the study occurs during clinical development or by their objectives.

An Approach to Classifying Clinical Studies According to Objective

Nonclinical Studies
Important considerations for determining the nature of nonclinical studies and their timing with respect to clinical trials include:
- Duration and total exposure proposed in individual patients.
- Characteristics of the drug (e.g., long half life, biotechnology products).
- Disease or condition targeted for treatment.
- Use in special populations (e.g., women of childbearing potential).
- Route of administration

Safety Studies
For the first studies in humans, the dose that is administered should be determined by careful examination of the prerequisite nonclinical pharmacokinetic, pharmacological and toxicological evaluations. Early nonclinical studies should provide sufficient information to support selection of the initial human dose and rationale for dose escalation and safe duration of exposure, and to provide information about physiological and toxicological effects of a new drug.

Pharmacological and pharmacokinetic studies
The basis and direction of the clinical exploration and development rests on the nonclinical pharmacokinetic and pharmacology profile, which includes information such as:

- Pharmacological basis of principal effects (mechanism of action).
- Dose-response or concentration -response relationships and duration of action.
- Study of the potential clinical routes of administration.
- Systemic general pharmacology, including pharmacological effects on major organ systems, and physiological responses.
- Studies of absorption, distribution, metabolism, and excretion.

Quality of Investigational Medicinal Products
Formulations used in clinical trials should be well characterized, including information on bioavailability wherever feasible. The formulation should be appropriate for the stage of drug development. Ideally, the supply of a formulation will be adequate to allow testing in a series of studies that examine a range of doses. During drug development, different formulations of a drug may be tested. Links between formulations, established by bioequivalence studies or by other means, are important in interpreting clinical study results across the development program.

Phases of Clinical Development
Clinical drug development is often described as consisting of four temporal phases (Phases I-IV). It is important to recognize that the phase of development provides an inadequate basis for classification of clinical trials because one type of trial may occur in several phases. A classification system using study objectives is preferable.

Some clinical trials may be subject to income taxation. This section will help investigators and MUSC administration determine whether the research warrants tax exempt status.

Unrelated Business Income Tax (UBIT) is imposed upon organizations otherwise exempt from federal income tax and was implemented to prevent unfair competition with taxable (commercial) businesses. Specifically, tax-exempt organizations are liable for income generated from any regularly performed trade or business which is not substantially related to the performance of the entity’s tax exempt purposes. In order to comply, the Medical University of South Carolina must define and differentiate research and testing procedures to identify those activities which generate unrelated business income.

3.2 Key Phrases

Trade or Business: includes activities carried on for the production of income from the sale of goods or the performance of services.

An activity is Substantially Related if a material causal relationship exists to the achievement of exempt purposes. The activity maybe substantially related to the accomplishment of the organization’s purposes if the activity leads to the advancement of education, advancement of science, and/or the promotion of health. Research which includes the provision of health care to patients, scientific research in the public interest, or testing for the safety of the general public would not be subject to UBIT. To the extent research activities contribute importantly to the education of graduate students and/or medical residents or constitutes care of patients (as opposed to volunteers), the research is substantially related to a college, university, or hospital’s tax-exempt purpose.

Public Interest: Scientific research is in the public’s interest if the results of such research are made available to the general public - not a limited segment. Public interest also is met if the research is performed for:

• The national, state, or local government;
• Directed to the benefitting public through aiding scientific education at the college or university level;
• Obtaining scientific information which is published;
• Discovering a cure for disease; or
• Aiding a community or geographic area with economic development.

Exemptions: Research exemptions of UBIT are applicable if the research is performed for the United States government, its agencies, instrumentalities, or any state or political subdivision, performed by a college, university, or hospital, or performed by an organization operated primarily to carry on fundamental research, the results of which are freely available to the general public. In order to take advantage of these exemptions, the activity must meet the definition of scientific research inclusive of furtherance of a scientific purpose and in the public’s interest.

Scientific Research does not include activities of a type ordinarily carried on as incidental to commercial or industrial operations. Testing performed for commercial entities of products for pre-market clearing or safety or for quality standards does not meet the exemption; however, testing performed to validate a scientific hypothesis would be exempt. Scientific Research must have three key components:

• Design and supervision of a project must be accomplished by professional researchers; i.e., expertise in a particular technological field which in not ordinarily available in commercial or industrial enterprises is required.

• Researcher must design the project to solve a problem thorough a search for demonstrable truths. Uniqueness and originality should be inherent in the concept. Intellectual questions must be posed. Activities should not be routine or repetitive.

• The Scientific Method (Observation, Experimentation, and Reasoning) is used by the researcher to form a hypothesis, design and conduct the test, to gather data, and analyze data for its effect on the verity or falsity of the hypothesis. Research goal must be demonstrable truth and provision of knowledge which is novel and important to be discovered.

Clinical Trials: Some Clinical Trials represent activities ordinarily carried on as an incidental to a pharmaceutical company’s commercial operations and may not meet the definition of scientific research per UBIT regulations. These clinical trials may be considered service performed for a manufacturer and may principally serve the private interest of the manufacturer rather than the public interest.

If the Principal Investigator (PI) considers that the clinical trial is solely for the benefit of the manufacturer, the PI must notify the Director of the Office of Research and Sponsored Programs. The Director will then determine if the clinical trial qualifies for the UBIT exemption. If it does not qualify, the Director will indicate in the "Remarks" section of the Grant and Contract Acceptance Form.

The MUSC Internal Review Board (I.R.B.) forms were evaluated by the CAS Clinical Trials Working Group and the consultants from PricewaterhouseCoopers and determined appropriate for CAS considerations. The detailed policies and procedures of the I.R.B. are developed and maintained by the Office of Research Integrity.

Each sponsored project must have a budget. A budget is essential to determine the projected costs of a study, to provide information for negotiating an acceptable agreement with a sponsor and to provide a guide for managing (accounting, planning, reporting, decision-making) finances for a clinical study. Budgets related to corporate sponsored trials are for internal management purposes only. MUSC considers corporate trials as fixed price awards unless the sponsor requires a proposal consisting of a detailed cost breakdown.

Budget proposals are to be prepared in accordance with MUSC ORSP policies and procedures. A standardized budget template which is adequate to accommodate all clinical trial studies at the University has been developed. See Exhibit A for template. Faculty with MUSC appointments, but who are full time UMA employees, could use the same budget template, and must have their studies administered through the MUSC department in which they hold their primary appointment. These studies would then receive the benefit of MUSC’s administrative infrastructure for research administration.

Clinical Trial balances can earn interest provided the sponsor agrees to include this as a condition of the agreement. Redistribution of budget across budget categories is allowable at the discretion of the Principal Investigator (PI) with approval of the department chairperson, based on changes in protocol and/or support resources required for the study conducted. The redistribution of budget is also subject to MUSC regulatory guidelines and sponsor contract conditions. The initial budget must have the approval by the departmental chairperson.

Federally funded clinical trial grants will be budgeted and charged at the current negotiated F&A rate applied to modified total direct costs (MTDC). F&A costs cannot be recovered on Patient Care expenses provided from internal sources.

Corporate funded clinical trial grants will be budgeted and charged at an F&A rate of 23 percent of total direct costs (TDC). F&A costs can be recovered on patient care expenses.

All requests for reduced or waived F&A costs must be made to the Director, Office of Research and Sponsored Programs.

7.0 Appropriate Distribution of Funds

• There are two methods to distribute the funds received from clinical trial projects.

1) Cash driven accounts - Under this method, the budget is increased as the revenue is received from the sponsor
2) Line of credit that reduces as revenue is received - Under this method a line of credit can be established and as revenue is received, it will be posted to the line of credit first.

• A line of credit will not be granted at the beginning of a project that equals 100 percent of the project budget. An appropriate percentage of the budget to be granted at the beginning should be determined by the Principal Investigator and the Department Chairperson.

• Expenditures must reflect the initial budget and all approved revisions.

• Redistribution of budget across budget categories would be allowable at the discretion of the Principal Investigator, with approval of the Department Chairperson, based on changes in protocol and/or support resources needed for study conduct.  The redistribution is subject to MUSC regulatory guidelines and sponsor contract conditions.

• Pre-award expenses (expenses incurred after a signed contract is in hand but before receipt of first payment of approved funding) is considered allowable on all clinical trials.

• A bimonthly review by the Principal Investigator and MUSC Grants and Contracts Accounting Office of lines of credit for assessment of amount of credit at risk will be performed.

8.0 Distribution of Residual Funding from Clinical Trials

The characteristics of clinical trials that meet the definition of research and are exempt from UBIT have been defined previously in the guidelines. In contrast to most other forms of sponsored research, the funding for the performance of the non-federal clinical trials may result in residual funds that can be retained by the University. The generation of residual funds by this mechanism is legitimate and consistent with the mission of the University provided that these funds are spent in support of the mission of the University. These residual funds are recognized as an important source of research support for the clinical faculty of the University. As such, the guidelines of the University are designed to assure that appropriate Facilities and Administrative (indirect) costs are recovered from both the direct clinical trial funding and from any residual funds while preserving the incentive for faculty to attract clinical trials funding by maximizing the benefit to the Principal Investigator.

• Residual funds are those funds remaining after all costs incurred in conducting the study, including Facilities and Administrative (indirect) costs, have been paid. Clinical trial funds cannot be designated as residual funds until the full Facilities and Administrative (indirect) costs (23 percent on corporate trials and 44 percent on federal trials) have been paid on the award.  For example: If a reduced or waived F&A rate was granted at the onset of the trial and at the completion of the trial there are funds remaining, these funds cannot be designated as residual until the reduced or waived portion of the F&A costs have been paid. 

• On the recommendation of the Principal Investigator and Department Chairperson, the Office of Research and Sponsored Programs will establish an account in the name of the investigator(s) of record to receive clinical trial residual funds. These funds shall be considered extramural research support to the investigator(s) of record. Disbursement of these funds is at the discretion of the investigator(s) subject to oversight by and accountability to the administration of the University.

• The intended use of the residual funds will be declared at the time the funds are transferred to the "residual account". The Facilities and Administrative (indirect) cost rate applied to residual funds will not be less than the clinical trials rate; however, it will be appropriate to the use of the money (e.g. Facilities and Administrative [indirect] costs initially charged at a clinical trials rate may be subject to an additional F&A costs charge to residual funds that are use for laboratory research).

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                                                                                                                                   EXHIBIT A

  Budget Template

Medical University of South Carolina
Clinical Trials Budget Template
Name of Trial:
Sponsor:
Study Dates:
Year:
Estimated Enrollment:

Category

Clinical Trials Working Group

Patrick Mauldin - Team Leader
Patricia Arford
Ed Conradi
Julia Foxworth
Gerry Garza
Velma Graham
Tom Higerd
Sandi Finanger-Larson
Dillard Marshall
Robert Merenbloom
Janet Scarborough
Maurice Snook
Pam Thompson
Marie Townsend
Ron Turner
Ken Roozen
Marilee Rose
Randy Sallee
David Welch

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