Legal Sidebari
Testing, Testing, (Phase) 1-2-3:
Legal Considerations for Clinical Trials
of Potential COVID-19 Vaccines
June 2, 2020
In the race to develop a Coronavirus Disease 2019 (COVID-19) vaccine, several pharmaceutical
companies, governments, and educational institutions around the world have begun testing their potential
COVID-19 vaccines in clinical trials. Clinical trials are used to assess whether a new pharmaceutical
product, such as a vaccine, is safe for humans and effective in achieving its intended purpose. Companies
must general y test new pharmaceutical products on humans through clinical trials to obtain U.S. Food
and Drug Administration (FDA) approval to market the product. But using human subjects to test these
novel products exposes them to unknown health and safety risks, raising ethical considerations for FDA
and for the sponsors and Institutional Review Boards (IRBs) overseeing the investigations. These
stakeholders—sponsors, IRBs, and FDA—aim to balance the need to ensure that the product is safe and
effective against the desire to bring the product to market quickly, tensions that are heightened during a
worldwide pandemic. Existing law requires FDA and IRBs to weigh these considerations when evaluating
proposed clinical trial designs for COVID-19 vaccines.
This Sidebar describes the legal and regulatory framework that governs clinical trials for pharmaceutical
products, such as vaccines, and some avenues researchers and Congress may consider for accelerating
that process during the COVID-19 pandemic. (For ease of reference, this Sidebar uses the term drugs
includes both traditional drugs and biological products, including vaccines.)
Clinical Trials of Investigational New Drugs
Sponsors use clinical trials to generate the data needed to obtain FDA approval to market their products.
Because clinical trials expose human subjects to unapproved pharmaceutical products, they risk causing
unanticipated serious adverse side effects in the participants. To manage these risks, the Federal Food,
Drug, and Cosmetic Act (FD&C Act) and FDA regulations have imposed procedural requirements on
clinical trials, such as advance and ongoing scientific and ethical review, to help protect the participants
by minimizing risks, requiring informed consent, and ensuring that the studies col ect the data needed to
determine whether to approve the product.
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Using Clinical Trials to Collect Substantial Evidence
Sponsors must submit “substantial evidence” to FDA that their products are safe and effective (or safe,
potent, and pure) to obtain FDA approval. Section 505(d) of the FD&C Act defines substantial evidence
to mean adequately and wel -controlled investigations on the basis of which qualified scientific experts
could fairly and responsible conclude that the product has the purported effect. FDA assesses both the
quality and quantity of the data provided when determining whether a product meets this standard.
Quality refers to the strength of the evidence and the amount of certainty it provides as to the product’s
safety and effectiveness—i.e., whether the investigation is “adequate” and “wel -controlled.” The quality
of the evidence depends on how the clinical trial is designed and how the study is conducted. Under FDA
regulations, the design must al ow for a valid comparison of the product to a control, such as a placebo, an
existing therapy, or no treatment. FDA also evaluates whether the study’s method for selecting
participants and assigning them to groups is adequate to ensure that meaningful data are collected. The
methodology must also include a wel -defined and reliable means of assessing the participants’ responses
and explain the analytical and statistical methods used to assess the results. Final y, sponsors must provide
a clear statement of the investigation’s objectives and take adequate measures to minimize bias in the
study. FDA may, however, waive any of these criteria for a specific investigation if the sponsor can show
that the criteria is not reasonably applicable to the study and an alternative approach yields substantial
evidence of effectiveness. FDA guidance further clarifies how sponsors should select their clinical trial
design, endpoints, and statistical methods.
As for quantity, FDA general y requires that sponsors complete two “adequate and wel -controlled clinical
investigations” to meet the substantial evidence standard. FDA notes in its guidance that two studies,
particularly those that are designed and conducted differently, reduces the likelihood of a design flaw,
bias, or other issue or anomaly that could result in erroneous conclusions. However, under the Food and
Drug Modernization Act of 1997, FDA may al ow sponsors to rely on one large multi-center adequate and
wel -controlled clinical investigation supported by another form of additional data, such as data regarding
the effectiveness of other drugs in the same pharmacological class. In deciding whether to al ow a sponsor
to rely on a single study, FDA states that it considers, among other factors, the seriousness of the disease,
whether there is an unmet medical need, and whether additional trials would be ethical and practicable.
Given the flexibility afforded sponsors in designing and conducting their clinical trials, FDA uses written
guidance and individual meetings to help sponsors ensure that their investigations wil generate the
substantial evidence needed for approval. Sponsors that obtain fast track product or breakthrough therapy
designation for their products are entitled to additional assistance from and communication with FDA
staff to craft efficient and effective clinical trial designs.
Submitting an Investigational New Drug Application to FDA
New drugs and biological products that are being tested in clinical trials are referred to as investigational
new drugs. Section 505(i) of the FD&C Act, Section 351(a)(3) of the Public Health Service Act, and their
implementing regulations al ow investigational new drugs to be used for research before they are
approved. To conduct clinical trials of investigational new drugs, the company developing the product
(i.e., sponsor) must general y receive FDA approval for the investigation and comply with regulatory
requirements for human subjects research.
Sponsors obtain FDA approval to test an investigational new drug on human subjects through an
investigational new drug application (IND). The IND gives FDA an opportunity to ensure that the study
wil protect the safety and rights of its human subjects and gather scientific data that adequately shows the
product’s safety and effectiveness. The sponsor may begin its clinical trials 30 days after submitting an
IND unless FDA notifies the sponsor that it is either (1) authorizing the IND and the study can begin

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immediately or (2) imposing a clinical hold due to concerns about the study. If FDA imposes a clinical
hold, the study cannot begin (or resume, for ongoing investigations) pending further notification.
FDA regulations prescribe the information that sponsors must include in an IND. The IND must contain
information about the product, such as the substance and formulation; existing data on use in animals or
humans if available; and anticipated risks and side effects. The IND also contains a general
investigational plan, which explains why the sponsor is undertaking the study and includes, among other
things, the indications being studied, the sponsor’s approach to evaluating the product, the kinds of
clinical trials being conducted, the anticipated number of participants, and any anticipated risks. Along
with the general investigational plan, the IND must include specific protocols for each clinical trial phase.
The sponsor must also general y certify that an institutional review board (IRB) wil provide initial and
continuing review of each study, including the proposed protocols and any subsequent changes to the
study. FDA may, however, waive any IRB requirements, including the requirement of IRB review itself.
Institutional Review Board Review and Approval
An IRB is a group convened by an institution to review and approve biomedical research involving
humans. IRBs evaluate the initial clinical study design and protocols, along with any changes
implemented during the investigation, in an effort to ensure that the rights and wel -being of the human
subjects are protected. To that end, IRBs assess whether risks to the participants are minimized and
reasonable in relation to the anticipated benefits, both to the participants directly and from the knowledge
expected to be gained through the study. IRBs also aim to ensure that the researchers wil obtain adequate
informed consent from al participants (unless an exemption applies) and that selection of the participants
wil be equitable. IRBs may also require (as appropriate) that the research plan provide for monitoring of
the collected data to protect the participants’ safety and privacy. To the extent the study may include
participants from populations that may be vulnerable to coercion or undue influence (e.g., children,
prisoners), IRBs must ensure that sufficient safeguards are in place to protect these populations in
participant selection and during the clinical trials.
IRBs review clinical trial plans and protocols from various standpoints, including ensuring that the study
complies with legal, ethical, and professional standards; is scientifical y sound; and is free from il icit
discrimination. Accordingly, to ensure adequate and independent review, IRBs must have at least five
members from multiple backgrounds, including at least one member with a scientific background and at
least one with a nonscientific background. At least one member must be independent from the institution
running the clinical trials, and the IRB members cannot have any financial or other conflicting interests in
the project. IRB review must comply with any other requirements relating to IRBs and human subject
research found in Parts 50 and 56 of Chapter 21 of the Code of Federal Regulation.
Clinical Trial Phases
Clinical trials for a new pharmaceutical product general y proceed in three phases, transitioning from
smal er trials focused on initial safety early on to larger trials assessing safety and effectiveness to inform
approval and labeling. The size, duration, and specific purpose of each clinical trial phase varies from
product to product depending on such factors as the type of product (e.g., a vaccine, treatment, or
preventative medication), how the product works, and the relevant underlying patient population.
However, as defined by FDA regulations, a clinical investigation general y proceeds as follows:
 Phase 1 Trials. Phase 1 trials are the first time the product is introduced in human
subjects. These carefully controlled trials typical y involve 20 to 80 patients or volunteer
subjects, though the exact numbers may vary depending on the product. Phase 1 trials
general y assess how the product acts in the body and evaluate initial safety (i.e., side
effects). They may also be used to determine the dosing levels to use in phase 2 (e.g., the

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maximum safe dose or what dose is required to have an effect). Depending on the
product, phase 1 trials may also provide some initial indication as to whether the product
may be effective. In the case of vaccines specifical y, phase 1 trials also assess their
ability to provoke an immune response in the body (i.e., immunogenicity).
 Phase 2 Trials. Phase 2 trials continue to assess safety but also evaluate the product’s
effectiveness and common short-term side effects or other risks associated with the
product. Phase 2 trials are also used to determine the optimal dose of the product. For
vaccines, phase 2 assesses how much of the vaccine to administer and on what dosing
schedule (e.g., whether a boost is needed to maximize its effectiveness or whether the
vaccine must be administered on a regular schedule to maintain immunity). As with phase
1 studies, phase 2 studies are carefully controlled. However, phase 2 involves a larger
(though stil relatively limited) number of volunteer subjects—general y no more than a
few hundred participants.
 Phase 3 Trials. Phase 3 trials involve an expanded number of participants—from several
hundred to thousands—and are used to assess the product’s safety and effectiveness
across a wide range of patient categories through controlled and uncontrolled studies.
These trials are intended to present a clearer picture of expected risks and benefits under
real-world conditions. The information obtained from phase 3 trials also forms the basis
for the product’s labeling.
Sponsors must general y complete al three phases to obtain FDA approval unless they obtain accelerated
approval, in which case FDA requires post-approval trials to confirm the expected clinical benefit. FDA
may also require, at its discretion, additional clinical trials after approval (i.e., phase 4 trials) for any
approved product to continue assessing the product’s safety and effectiveness once on the market.
Considerations for Congress
The current legal framework seeks to balance various competing interests, which may be amplified in the
current crisis. The FD&C Act and implementing regulations provide standards and factors to consider but
otherwise give FDA and IRBs discretion to evaluate investigational plans and clinical trial protocols for
investigational new drugs. FDA may also waive requirements relating to IRB review and clinical trial
design. To the extent Congress may seek to direct how FDA and IRBs exercise that discretion with
respect to any potential COVID-19 vaccine, Congress could consider implementing legislation that
provides more specific direction on how to approach clinical trials either specifical y for the current
COVID-19 pandemic or in epidemic, pandemic, or other emergency situations more general y. For
example, courts have determined that Congress can cabin FDA’s discretion by imposing mandatory (e.g.,
“shal ”) rather than permissive (e.g., “may”) language in a statute.
In light of the multiple companies involved in developing potential COVID-19 vaccines, Congress could
also consider facilitating the coordination of any clinical trials or appointing a neutral scientific body to
consider the ethical and scientific considerations and generate guidelines or a master protocol. The World
Health Organization (WHO) employed this approach to facilitate development of an Ebola vaccine
following the 2014 to 2016 Ebola epidemic. Congress could also direct or fund increased global
collaboration between regulators to promote information sharing, which could potential y result in more
streamlined clinical investigations with fewer participants being exposed to investigational vaccines.
Congress could also consider providing additional funding or other resources to facilitate the clinical trials
themselves or any research directed toward understanding the SARS-CoV-2 virus or COVID-19 disease
to al ow for improved risk minimization in future clinical trials.

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Author Information

Erin H. Ward

Legislative Attorney




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