UAMS Human Research Advisory Committee
July 31, 2002
Drug trials provide the transition from promising basic or
laboratory research to helpful therapeutic or diagnostic procedures for
patients. New drugs that offer the hope of some beneficial response in afflicted
patients are first tested in animal models. But animal trials do not necessarily
demonstrate what the physiological, pharmacological, or toxicological effects of
a new drug will be in human beings. Only by careful testing in human subjects
can the safety and effectiveness of a new drug be evaluated. The Food and Drug
Administration (FDA) is responsible for monitoring the testing of new drugs in
humans, for determining whether a new drug can be marketed, and for observing
drugs after marketing to be sure that they are safe, effective, and properly
labeled (21CFR312 and 21CFR314;
Clinical Trial: A
controlled study involving human subjects, designed to evaluate prospectively
the safety and effectiveness of new drugs or devices or of behavioral
Drug: Any chemical
compound that may be used on or administered to humans as an aid in the
diagnosis, treatment, cure, mitigation, or prevention of disease or other
Investigational New Drug or Device: A drug or device permitted by FDA to be tested in humans,
but not yet determined to be safe and effective for a particular use in the
general population, and not yet licensed for marketing.
Investigator: In clinical trials, an individual who actually conducts an investigation (21CFR312.3; 45 CFR).). Any interventions (e.g., drugs) involved in the study are administered to subjects under the immediate direction of the investigator.
Phase 1, 2, 3, 4 Drug Trials: Different stages of testing drugs in human, from first
application in humans (Phase 1) through limited and broad clinical tests (Phase
3), to post marketing studies (Phase 4).
Phase 1 Drug Trial:
Phase 1 trials
include the initial introduction of an investigational new drug into humans.
These studies are typically conducted with healthy volunteers; sometimes, where
the drug is intended for use in patients with a particular disease, however,
such patients may participate as subjects. Phase 1 trials are designed to
determine the metabolic and pharmacological actions of the drug in humans, the
side effects associated with increasing doses (to establish a safe dose range),
and, if possible, to gain early evidence of effectiveness; they are typically
closely monitored. The ultimate goal of Phase 1 trials is to obtain sufficient
information about the drug's pharmacokinetics and pharmacological effects to
permit the design of well-controlled, sufficiently valid Phase 2 studies. Other
examples of Phase 1 studies include studies of drug metabolism,
structure-activity relationships, and mechanisms of actions in humans, as well
as studies in which investigational drugs are used as research tools to explore
biological phenomena or disease processes. The total number of subjects involved
in Phase 1 investigations is generally in the range of 20-80.
Phase 2 Drug
Trial: Phase 2 trials include controlled
clinical studies conducted to evaluate the drug's effectiveness for a particular
indication in patients with the disease or condition under study, and to
determine the common short-term side effects and risks associated with the drug.
These studies are typically well-controlled, closely monitored, and conducted
with a relatively small number of patients, usually involving no more than
several hundred subjects.
Phase 3 Drug
Trial: Phase 3 trials involve the
administration of a new drug to a larger number of patients in different
clinical settings to determine its safety, effectiveness, and appropriate
dosage. They are performed after preliminary evidence of effectiveness has been
obtained, and are intended to gather necessary additional information about
effectiveness and safety for evaluating the overall benefit-risk relationship of
the drug, and to provide an adequate basis for physician labeling. In Phase 3
studies, the drug is used the way it would be administered when marketed. When
these studies are completed and the sponsor believes that the drug is safe and
effective under specific conditions, the sponsor applies to FDA for approval to
market the drug. Phase 3 trials usually involve several hundred to several
Phase 4 Drug
Trial: Concurrent with marketing approval,
FDA may seek agreement from the sponsor to conduct certain post marketing (Phase
4) studies to delineate additional information about the drug's risks, benefits,
and optimal use. These studies could include, but would not be limited to,
studying different doses or schedules of administration than were used in Phase
2 studies, use of the drug in other patient populations or other stages of the
disease, or use of the drug over a longer period of time (21
Principal Investigator: The scientist or scholar with primary responsibility for the design and conduct of a research project.
Sponsor: A person or entity that initiates a clinical
investigation of a drug — usually the drug manufacturer or research institution
that developed the drug. The sponsor does not actually conduct the investigation
but rather distributes the new drug to investigators and physicians for clinical
trials. The drug is administered to subjects under the immediate direction of an
investigator who is not also a sponsor. A clinical investigator may, however,
serve as a sponsor-investigator. The sponsor assumes responsibility for
investigating the new drug, including responsibility for compliance with
applicable laws and regulations. The sponsor, for example, is responsible for
obtaining FDA approval to conduct a trial and for reporting the results of the
trial to the FDA.
Sponsor-Investigator: An individual who both initiates
and actually conducts, alone or with others, a clinical investigation.
Corporations, agencies or other institutions do not qualify as
Once a chemical (drug) is identified as having a potential effect on a disease state, it is subjected to testing in animals. Initial animal tests are designed to see whether the chemical has any desired drug effects, what dosage levels are poisonous, what the safe dosage range might be in humans, and whether there is a reason to test the chemical in humans. Additional animal tests may be required as human tests progress. If initial animal tests indicate that the drug can be safely tested in humans and that the chemical may be therapeutically useful, the drug sponsor will submit an Investigational New Drug Application (IND) to the FDA.
In the IND, the sponsor must describe the complete
composition of the drug, its source, and how it is made. In addition, the
sponsor must submit the results of all animal studies that support the drug's
potential usefulness in humans and that define its toxicity in animals. The data
should indicate that no human subject will be exposed to an unreasonable risk.
The IND must also include a protocol describing the plan for testing in humans.
To permit the FDA to review the materials and make sure subjects will not be
exposed to unreasonable risks, the sponsor may not begin clinical tests for 30
days after submitting the IND. At the end of that period, the sponsor may begin
the proposed clinical trial unless the FDA has asked for a delay because of a
potential safety problem involving use of the drug.
Clinical trials are conducted by clinical
investigators (usually physicians) who have entered into an agreement with a
sponsor to conduct the study. All physicians administering an investigational
drug agree to conditions regarding the conduct of the study outlined by FDA
regulations. Clinical investigators agree to these conditions by signing an FDA
form that certifies that the investigator has obtained HRAC review and approval
prior to conducting the study.
Investigational new drugs may be available outside of a clinical trial, through a treatment protocol, to patients with life-threatening or other serious diseases for which no satisfactory alternative drug or other therapy exists. Established by the FDA in 1987, the Treatment Investigational New Drug exemption (Treatment IND) is a treatment protocol that is added to an existing IND. The Treatment IND allows physicians to treat qualifying patients according to the protocol.
In reviewing proposed drug research, HRACs
must first consider whether the protocol is scientifically sound. Since this
decision is not the HRAC's primary concern, however, an HRAC may rely on the
FDA, institutions, scientific review committees, funding agencies (e.g.,
NIH), or others for this determination. Evaluating the risks and benefits of
drug trials requires HRACs to consider many aspects of the study design, paying
special attention to the study population, the trial phase, and mechanisms for
data analysis and surveillance. Risk/benefit analysis and review of the
procedure for obtaining informed consent must be performed in all HRAC reviews.
In addition, subjects participating in studies involving investigational drugs
must be told that the FDA may have access to their medical records as they
pertain to the study.
The obligation of HRACs and investigators to assure that subjects understand the purposes, methods, and possible hazards of the research is more difficult to fulfill when prospective subjects are seriously ill and in need of therapy. The consent process may require additional efforts and attention for research involving particularly vulnerable subjects such as the seriously ill.
Phase 1 trials are historically safest because
they usually involve administering a single dose to healthy volunteers. However,
Phase 1 trials may pose the highest level of unknown risk because they involve
the drug's first administration to humans. (With highly toxic drugs such as
cancer chemotherapies, Phase 1 trials are usually conducted with cancer patients
as subjects.) Insofar as possible, risks should be identified from previous
laboratory experiments and animal trials. The FDA, which reviews Phase 1 trials
submitted in the initial IND application, may have valuable information and
recommendations on particular protocols.
Subjects in Phase 2 trials are usually patients with the condition that the new drug is intended to detect or treat. HRACs should recognize that although Phase 2 testing is preceded by earlier clinical trials, the physiological responses of healthy volunteers to a therapeutic drug may not be reliable indicators of how safe the drug is for persons who are ill, taking other medication, or have immunodeficiencies. Since the primary purpose of a Phase 2 trial is to test the drug's effectiveness in achieving its purpose, the responses of subjects receiving the drug are usually compared with those of subjects who are not receiving the drug (control subjects). Whether control subjects receive some existing therapy or a placebo is a research design issue with serious ethical implications. Where an alternate safe and effective drug is available for a serious condition being studied, it should generally be given to the control subjects; however, existing therapies may be inadequate because they are of limited effectiveness against the disease, they have relatively high levels of toxicity, or because they are inconvenient to administer. When determining the acceptability of a proposed research design, HRACs must examine the risks and effectiveness of existing therapies, as well as the risks associated with providing no therapy (or a placebo).
While most drug trials involve agents that the
FDA has not yet approved for marketing, some drugs may be the subject of further
testing concurrent with or following FDA approval. Post-marketing
investigations, also called Phase 4 trials, are conducted to develop further
information about the article's safety or effectiveness. Such studies might, for
example, seek to establish the safety or effectiveness of using the drug for a
new indication, with a new dosage level or a new route of administration (21
Phase 4 studies should be distinguished from use of a marketed product by a physician for an indication not in the approved labeling as part of the "practice of medicine." Investigational use of a marketed product differs from such uses by physicians in that the principal intent of the investigational use of a test article is to develop information about its safety or efficacy; the submission of an IND or IDE may therefore be required.
Throughout drug trials, the distinction
between therapy and research must be maintained. A physician who participates in
research by administering a new drug to consenting patients must ensure that the
patients understand and remember that the drug is experimental, and that its
benefits for the condition under study are unproven. Furthermore, whereas the
principal investigator's primary allegiance is to the protocol, the physician's
allegiance is to the patient. Where an individual is both an investigator and
the subject's treating physician, these two allegiances may conflict. The
subject must recognize that the person with whom he or she is dealing may have
such conflicting interests. The HRAC should be aware of the need to inform the
patient of the potential conflict.
If the trial is to collect accurate and timely
data concerning the drug's safety and effectiveness, procedures for identifying
positive and negative responses to the drug should be in place, and all
participating physicians should be well integrated into a reporting system. The
principal investigator is responsible for keeping all subjects informed of
material changes in the design and conduct of the research, and must communicate
new information that might affect their willingness to continue as subjects (38
CFR16.116). The HRAC may assist the investigator in deciding when
information from accumulating data should be disclosed to participating or
prospective subjects. The disclosure of information gained during the conduct of
the trial is especially important with patients entering a study when it is
As part of their determination of the
appropriate methods for conducting continuing reviews of ongoing studies, HRACs
should be aware of the arrangements made for monitoring the study results. In
FDA-regulated clinical investigations, arrangements for data monitoring are the
sponsor's responsibility. The sponsor may designate an independent person or
group (often called a data and safety monitoring board) to assume this
responsibility. An HRAC may function in such a capacity; however, most HRACs do
not have the necessary expertise. Independent monitoring is most appropriate
when the study is double-masked (i.e., neither the subjects nor the
investigators know which drug a subject is receiving) or if the trial is
multicentered. Ongoing monitoring of drug trials includes review of data on
therapeutic effects, side effects and the effects of any changes in the study
design. Sponsors must notify the FDA and all participating investigators of any
adverse experiences associated with the use of an investigational new drug that
is both serious and unexpected (21 CFR312.32; 45 CFR).).
Occasionally, hazards are discovered after a
trial is concluded. If the drug has since been marketed, the FDA and the drug
manufacturer are usually responsible for notifying users and physicians.