CVM Guidance for Industry #282 - Informed Consent Forms for

#282

Informed Consent Forms for Studies

that Enroll Client-Owned Companion

Animals

Guidance for Industry

Draft Guidance

This guidance document is being distributed for comment purposes only.

Submit comments on this draft guidance by the dated provided in the Federal Register notice

announcing the availability of the draft guidance. Submit electronic comments to

https://www.regulations.gov. Submit written comments to the Dockets Management Staff

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD

20852. All comments should be identified with docket number FDA-2023-D-2654.

For further information regarding this document, contact Steven Fleischer, Center for Veterinary

Medicine (HFV-110), Food and Drug Administration, 7500 Standish Place, Rockville MD

20855, 240-402-0809, email: [email protected].

Additional copies of this draft guidance document may be requested from the Policy and

Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration,

7500 Standish Place, Rockville MD 20855, and may be viewed on the Internet at

https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-

guidance-documents, or http://www.regulations.gov.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Veterinary Medicine (CVM)

September 2023

Contains Nonbinding Recommendations

Draft — Not for Implementation

Table of Contents

I. Introduction .......................................................................................................................... 1

II. Background .......................................................................................................................... 1

III. Scope...................................................................................................................................... 2

IV. Terminology.......................................................................................................................... 2

V. General Considerations ....................................................................................................... 3

A. Use of plain language ..................................................................................................... 3

B. Coercion and undue influence ...................................................................................... 4

C. Exculpatory language .................................................................................................... 5

VI. Basic Elements of an Informed Consent Form ................................................................. 5

A. Description of the clinical investigation ....................................................................... 5

B. Description of benefits and compensation ................................................................... 8

C. Statements regarding voluntary participation, involuntary termination of

owner’s participation, and consequences of owner’s decision to withdraw ............. 8

D. Description of procedures, treatments, and potential discomforts ........................... 9

E. Description of the risks associated with participation in the study ........................... 9

F. Providing significant new findings to owners ............................................................ 11

G. Statements on confidentiality ...................................................................................... 11

H. Signature on the Informed Consent Form ................................................................. 11

I. List of contacts.............................................................................................................. 12

VII. Informed Consent Form discussions with CVM ............................................................. 12

Contains Nonbinding Recommendations

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Informed Consent Forms for Studies that Enroll Client-Owned

Companion Animals

Draft Guidance for Industry

This draft guidance, when finalized, will represent the current thinking of the Food and Drug

Administration (FDA or Agency) on this topic. It does not establish any rights for any person

and is not binding on FDA or the public. You can use an alternative approach if it satisfies the

requirements of the applicable statutes and regulations. To discuss an alternative approach,

contact the FDA staff responsible for this guidance as listed on the title page.

I. Introduction

The FDA’s Center for Veterinary Medicine (CVM) is issuing this guidance to provide

recommendations on informed consent forms (ICF) used for studies that enroll client-owned

companion animals (dogs, cats, and horses). CVM recommends all studies conducted with

client-owned companion animals use an ICF and be conducted in accordance with Good Clinical

Practice (GCP) guidelines.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

as recommendations, unless specific regulatory or statutory requirements are cited. The use of

the word should in Agency guidances means that something is suggested or recommended, but

not required.

II. Background

As defined in Guidance for Industry (GFI) #85 (VICH

GL9), “Good Clinical Practice”

and for

the purposes of this guidance, informed consent is a documented process by which an owner or

owner’s agent voluntarily confirms the owner’s willingness to allow their animal(s) to participate

in a particular study, after having been informed of all aspects of the study that may be relevant

to the owner’s decision to participate. The sponsor or investigator should ensure the owner is

provided with adequate information and time to allow for an informed decision about voluntary

participation in a clinical investigation. CVM recommends an investigator, whenever possible,

provide an owner with a copy of the ICF at least 12-24 hours prior to enrollment in the study (for

example, at the time of screening) to allow sufficient time for the owner to review the

information, formulate any questions, and consider whether to participate.

International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal

Products

https://www.fda.gov/media/70333/download

Contains Nonbinding Recommendations

Draft — Not for Implementation

CVM recommends animal drug sponsors consider the components of the ICF as described in this

ICF guidance early during the development of their drug. Discussions regarding the ICF may be

particularly important for novel drug classes, novel dosage forms of new animal drugs, or

previously unapproved uses or new conditions of use of an approved animal drug (for example,

novel routes of administration or target animal species). Additional discussions may be

warranted as new information pertaining to safety or effectiveness becomes available during

product development. Sponsors are encouraged to contact CVM to discuss the ICF or any

questions they may have about the ICF.

III. Scope

The purpose of this guidance is to provide recommendations on informed consent forms used in

studies that enroll client-owned companion animals. This guidance is not applicable to studies

conducted in food-producing animals. This guidance is directed at individuals who develop ICFs

and conduct studies in client-owned companion animals.

The guidance provides recommendations regarding the following items:

• The use of plain language.

• The avoidance of coercive, unduly influential, or exculpatory language.

• The basic elements of an ICF, including:

o A description of the clinical investigation.

o A description of benefits and compensation.

o Statements regarding participation, termination, and withdrawal.

o A description of procedures, treatments, and potential discomforts.

o A description of risks associated with participation in the study.

o Providing significant new findings to owners.

o Statements on confidentiality.

o Signature(s).

o Contacts.

• Informed consent form discussion with CVM.

IV. Terminology

Investigator: The investigator is an individual, qualified by training and experience, responsible

for all aspects of the conduct of the study. These responsibilities may include: the dispensing

and administration of the investigational and control veterinary product(s), the implementation of

the study protocol, the collection and reporting of the study data, and the protection of the health

and welfare of the personnel involved in the study and the animals during the study.

Study animal: An animal participating in a clinical study.

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V. General Considerations

A. Use of plain language

The U.S. Department of Health and Human Services (HHS) defines health literacy

follows:

• Personal health literacy: the degree to which individuals have the ability to

find, understand, and use information and services to inform health-related

decisions and actions for themselves and others.

• Organizational health literacy: the degree to which organizations equitably

enable individuals to find, understand, and use information and services to

inform health-related decisions and actions for themselves and others.

Health literacy incorporates a range of abilities: reading, comprehension, and analyzing

information; decoding instructions, symbols, charts, diagrams; weighing risks and

benefits; and, ultimately, making decisions and taking actions. Everyone, no matter

how educated, is at risk for misunderstanding health information if the topic is

emotionally charged or complex.

These general concepts are applicable to

investigational new animal drug studies that enroll client-owned companion animals.

CVM recommends the ICFs use language understandable to owners (i.e., plain

language) of potential study animals. The ICF should incorporate all the information

into a single document to avoid the possibility that an owner does not receive all the

relevant information. The ICF should be in the owner’s primary language. If an owner

is not fluent in English, a translated document, in plain language, is preferred over ad

hoc translation.

Documents should avoid the use of technical, scientific, or medical terminology. When

such terms are necessary or unavoidable, the document should explain them in context

and/or provide a definition using plain language. All complex concepts, including risks

and benefits, should be explained in plain language. The owner should have the

opportunity to ask questions and have those questions answered.

The Agency for Healthcare Research and Quality

makes some the following

recommendations regarding ICFs for human subjects enrolled in research studies and

they are generally applicable to the owner or agent of client-owned companion animals

enrolled in investigational new animal drug studies:

https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/clear-

communication/health-literacy

https://www.nih.gov/institutes-nih/nih-office-director/office-communications-public-liaison/clear-

communication/health-literacy

https://www.ahrq.gov/sites/default/files/publications2/files/ictoolkit.pdf

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• Keep the reading grade level low. It is recommended, where possible, for

documents to be written at the 5th or 6th grade level.

• Do not use medical jargon.

• Use the active voice.

• Use short sentences with simple sentence structure.

• Use easily legible fonts and font size.

• Do not use all capital letters or italics.

• Use wide margins and avoid fully justified alignment of text. For example, a

line length of 50 characters and spaces or fewer may be easier to read.

• Break up text into manageable sections using headings and subheadings.

• Documents that use large fonts, short lines, white space, bulleted lists, and

headings to break the text into manageable pieces are easier to read than short,

dense documents.

Charts, tables, or graphics that outline what happens at each visit may simplify the ICF

and assist owners in understanding what participation in the clinical investigation may

entail.

Although there are no Federal laws that regulate the informed consent process for

investigational new animal drug studies that enroll client-owned companion animals,

for similar information on informed consent for studies that enroll human subjects,

review 21 CFR 50.20, as well as FDA guidances, “Informed Consent: Guidance for

Institutional Review Boards, Clinical Investigators, and Sponsors,”

and “A Guide to

Informed Consent.”

These documents describe the law surrounding informed consent

for human subjects and the FDA’s interpretation of these laws.

B. Coercion and undue influence

Coercion and undue influence are the use of pressure, either by promises of benefits or

threats of harm, whether explicit or implied, to persuade the owner or agent of a

potential study animal to participate in the study. All efforts should be made to

eliminate or minimize the possibility for undue influence or coercion, intentional or

inadvertent, to play a role in the owner’s decision. It is important to compose the ICF

to avoid the possibility that the owner will feel coerced or unduly influenced, whether

or not actually intended, because a valid consent depends on the owner’s ability to

freely decide on their own whether or not to allow their animal to participate in the

https://www.ahrq.gov/health-literacy/improve/precautions/tool11.html

https://www.fda.gov/media/88915/download

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guide-informed-consent

Contains Nonbinding Recommendations

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study. The ICF should provide factual, relevant information and avoid persuasive

language.

The ICF should avoid statements that:

• Could be false or misleading;

• May cause owners to believe the investigation has the FDA’s endorsement; or

• Could give rise to overly optimistic expectations as to risks, prognosis,

outcome, safety, effectiveness, or any matter that might influence the owner to

participate.

To help ensure the integrity of the study, CVM recommends avoiding the enrollment of

animals owned by investigators, employees or relatives of investigators or the sponsor,

or any person with any direct or indirect interest in the outcome of the study. For

example, an employee of an entity with an interest in a study may be vulnerable to

influence or coercion. Consider including a statement for signature that the owner does

not have a direct or indirect interest in the study.

The ICF should make clear that clients may remove their animals from the study at any

time without penalty or loss of benefits to which the client is entitled. The ICF should

not pressure the owner to continue participation in the study by suggesting, implicitly

or explicitly, that leaving the study would cause harm to the animal. The ICF should be

consistent with any oral information given to the owner.

C. Exculpatory language

The ICF should not incorporate any language that waives or appears to waive any of the

owner’s legal rights or releases the investigator, sponsor, institution, or other entity or

its agents from any legal liability it may have or come to have.

The ICF should not require the owner to affirm that they “understand” the information

provided. The owner should also not be asked or required to affirm that the ICF

provides all relevant information. Any language intended to limit the study

investigator’s responsibilities or duty of care is inappropriate. A signed statement by

the client confirming receipt of the written information is more appropriate, as further

discussed below.

VI. Basic Elements of an Informed Consent Form

A. Description of the clinical investigation

1. Identifying the clinical investigation as investigational. The ICF should contain a

brief introductory paragraph that:

a. States the product is investigational, and safety and effectiveness have not

been demonstrated or evaluated for the indicated investigational use. If the

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product has been approved for other uses under a new animal drug

application (NADA), the ICF should include that information.

b. States the purpose of the study is for the investigational use of the veterinary

product rather than to provide medical treatment to the study participants.

c. Describes the objective of the clinical investigation (for example, to evaluate

the safety and effectiveness of the test article or to evaluate a different dose

or route of administration of an approved drug).

If the ICF contains multiple pages or sections, repeating this information in other

parts of the ICF may aid the owner in understanding the nature of the clinical

investigation.

The ICF should not include statements that suggest the investigational veterinary

product (IVP) is “safe” or “effective” under the proposed conditions of use. The

ICF may incorporate factual information that accurately reflects data from

completed studies.

2. Identify the treatment groups and number of study animals. The ICF should include

the following:

a. The approximate number of study animals intended to be enrolled in the

study.

b. A description of the treatment groups, including control groups (placebo,

active control, or no treatment), presented in plain language.

c. The likelihood of the animal being assigned to a control group versus a

treatment group (for example, the animals have a 33% chance of being

enrolled in the control group in a field study with a 2:1 treated:control

enrollment ratio).

3. Alternative procedures or treatments:

The ICF should include information about appropriate alternatives, if any, to

entering the study that may be advantageous to the study animal. The ICF should

identify:

a. Procedures or treatments, if any, that animals with the condition(s) would

likely receive if they choose not to participate in the study, including

alternatives such as approved drugs (for example, an approved oncology

drug) for the study animal’s condition, or other forms of therapy (for

example, surgery). This should include identifying any procedures and

treatments that will not be performed or allowed during the study (for

example, a requirement to not receive insulin during a study investigating a

novel drug to treat diabetes mellitus). CVM recommends the ICF briefly

describe these procedures or treatments, if any, first and then provide the

Contains Nonbinding Recommendations

Draft — Not for Implementation

information about the study. This sequence allows the owner to understand

how the study differs from the care their animal might otherwise receive.

b. Potential consequences of these differences in care, if known (for example,

a worsening of the disease or clinical condition than would be expected with

an approved drug).

4. Owner’s responsibilities to comply with the protocol:

The ICF should state the owner’s responsibilities while participating in the clinical

investigation. Examples of responsibilities include, but are not limited to, the

following:

a. To maintain masking, only discuss treatment information with pre-specified

study personnel involved in the conduct of the investigational study.

Depending on treatment, masking, and other study requirements and

circumstances, do not disclose treatment information to investigators, staff,

other owners, or others.

b. Complete an owner diary, questionnaire, or other means of recording events

and data. Owners should be provided with the means to use sound

documentation practices that are attributable, legible, contemporaneous,

original, and accurate (ALCOA).

c. Comply with medical, dietary, or other restrictions for the animal during the

study.

d. Know when to contact the Investigator regarding any clinical concerns (for

example, whether to contact the Investigator regarding any vomiting,

diarrhea, anorexia, or clinical concerns prior to the next scheduled visit).

e. Know when to return for study visits. If the study is complex or the

duration is long, consider including a study schedule or calendar.

If a detailed description of every responsibility would make the ICF too lengthy,

CVM recommends generally listing the responsibilities and describing additional

details of all owner responsibilities in an addendum.

Charts, tables, or graphics that outline what happens at each visit may simplify the

ICF and assist owners in understanding what participation in the clinical

investigation will involve.

5. Additional costs to the owners:

The ICF should include the following:

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a. Whether owners will be responsible for the cost of any treatments or

diagnostics that may be necessary for the health of the animal should any

adverse events occur as a result of the investigational study.

b. Other potential costs to the owner.

c. Where further information regarding costs may be obtained.

B. Description of benefits and compensation

The ICF should include:

1. Reasonably expected benefits to the animal derived from reliable information. The

ICF can provide a clear and balanced description of potential benefits not only to

the individual animal, but also to “others.” For example, the animal’s participation

in the study may not benefit the animal but may benefit future patients with the

same disease or condition.

2. A statement that a beneficial outcome for the study animal cannot be guaranteed.

3. A clear statement when there is no intended clinical benefit to the study animal.

4. A clear statement that, because the purpose of the study may be to determine the

safety and/or effectiveness of the drug compared to a control or placebo, it is not yet

known whether the drug may or may not provide a benefit and the study animal

may be in a control or placebo group.

5. Avoidance of overly optimistic statements of the clinical investigation that may be

misleading or represent the new animal drug as safe or effective for the purpose for

which it is under investigation, which would violate FDA regulation (21 CFR

511.1(b)(8)(iv)).

6. A statement of whether any compensation will or will not be provided to the owner.

7. A description of any compensation, which may include, but is not limited to, things

such as medical care, procedures, reduction of costs (for example, no charge for

physical examinations), or cash payments. CVM considers payment to owners for

participation in clinical investigations to be compensation for expenses and

inconveniences, not a benefit of participation in the study. If payments are

provided, the consent process should not identify them as benefits; however, the

requirements to qualify for payments should be clearly delineated in the ICF.

Compensation should not be contingent on completion of the study.

C. Statements regarding voluntary participation, involuntary termination of owner’s

participation, and consequences of owner’s decision to withdraw

The ICF should include:

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1. A clear statement that study animal participation is voluntary and that refusal to

participate, or the owner’s decision to terminate participation at any time, will not

impact the care of the animal or involve a penalty or loss of benefits to which the

owner is otherwise entitled.

2. A statement indicating the study animal may be removed from the study at the

discretion of the investigator with or without the owner’s consent. For example, the

investigator may remove the animal from the study if the owner is unable to comply

with procedures required by the protocol, if the animal no longer meets eligibility

criteria for continuing in the study, or if the site at which the animal is enrolled

withdraws from the study.

3. A description of any special procedures for study animal withdrawal from the study,

including an explanation of any withdrawal procedures or follow-up care that are

recommended to ensure the animal’s safety.

4. A statement informing the owner of the requirement for study animal medical

record retention when their animal is withdrawn from the study.

5. The potential consequences resulting from an owner’s decision to withdraw from

the study. For example, potential side effects, additional costs not compensated, or

loss of veterinary medical oversight provided by participation in the study.

D. Description of procedures, treatments, and potential discomforts

The ICF should briefly discuss, in plain language, the procedures, treatments, and

potential discomforts the study animal may experience, for example, imaging

(radiographs, ultrasound, etc.), blood and/or urine sample collection, injections, and

drug administration or application. The ICF should identify study procedures and tests

that would not be part of their animal’s care (for example, drawing blood samples for

pharmacokinetic data).

E. Description of the risks associated with participation in the study

The ICF should briefly discuss of the following:

1. Potential risks or side effects of the use of the IVP or active pharmaceutical

ingredient(s) (API) to study animals. These risks may include any safety

information or relevant findings identified in pilot data, the target animal safety

technical section, published literature, or publicly available reports (for example,

European Medicines Agency reports). If safety information about the IVP is

limited, the ICF may include safety information about the API(s), drugs in the same

drug class, approved drugs containing the same API(s), or other relevant

information.

2. Potential risks of the study procedures to study animals (for example, anesthesia,

sedation, or surgery).

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3. Potential risks of any active control products to study animals. Client Information

Sheets for FDA-approved products used as an active control product are acceptable

to provide to owners. Providing the owner with a copy of the package insert as the

sole description of potential risks or side effects is not appropriate, as the package

insert is not written in plain language.

4. Human User Safety:

Human user safety should be considered a component of the ICF, and should

include the following:

a. A clear description of how to handle and dispose of the IVP, active control

product, and any associated delivery devices, as well as any procedures to

mitigate the risk to owners, if applicable.

b. Risks from exposure before and during the administration of the test

article(s), if known.

c. A clear description of how to handle and dispose of animal bodily fluids,

particularly if the IVP is to be administered at home or if special mitigations

are necessary (for example, use of gloves, disposing of vomitus or waste in

plastic bags). This may be especially applicable to oncology drugs, or other

IVPs that maintain a high-risk profile after administration.

d. Information regarding no contact or petting times for treated animals, if

applicable. Contact between treated animals and humans or other animals is

a common potential risk for dermal or topically applied products.

e. Risks to household members from accidental exposure.

f. A clear description of the occupational and residential risks to humans,

including children and pregnant or nursing women, if applicable.

g. Risks to human users as a result of IVP lack of effectiveness, including any

zoonotic concerns (for example, ascariasis should an anti-parasiticide

demonstrate a lack of effectiveness).

h. Procedures following accidental human exposure, including directions on

medical assistance, for removing the product from the eyes or skin (for

example, wash contacted skin or rinse eyes), or counteragent (for example,

naloxone).

i. A statement that any reported accidental human exposure is required to be

reported to the FDA by the sponsor (as defined in 21 CFR 511.1(8)(ii)).

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For more information regarding Human User Safety, see draft GFI #278, “Human

User Safety in New and Abbreviated New Animal Drug Applications.”

F. Providing significant new findings to owners

The ICF should state that significant new findings will be provided to the owner in a

timely manner. It is particularly important to include this information for investigations

that are complex or involve significant risk and when knowledge of potential risks is

limited (for example, studies using novel therapies and new molecular entities).

Examples of significant new findings that should be provided to the owner include, but

are not limited to, the following:

1. New risk information that may relate to the study animal’s continued

participation in the study.

2. Unexpected adverse events.

3. Adverse events occurring at greater frequency or severity than previously stated

in the consent process.

4. Lack of effectiveness when it may impact the survival or well-being of the study

animal.

G. Statements on confidentiality

Confidentiality is a critical element of any ICF. The ICF should clearly describe:

1. The extent, if any, to which confidentiality of records identifying the owner and

animal will be maintained.

2. That there is a possibility that the FDA may inspect the records.

3. How the data generated from the study will be used by the sponsor/investigator

(for example, published, reported to the FDA, etc.).

4. That the confidentiality provisions described will not be affected by the owner’s

decision to remove their animal from the study or by any other action, save by

operation of law.

H. Signature on the Informed Consent Form

Each owner participating in the study should be required to sign an ICF. The space for

the owner’s signature should be preceded by an explanation in plain language of what

https://www.fda.gov/media/166696/download (April 2023). When final, this guidance will represent FDA’s

current thinking on this topic.

Contains Nonbinding Recommendations

Draft — Not for Implementation

the owner’s signature represents.

The ICF should describe the signature as an acknowledgement that the owner has been

provided the information discussed in the form. It may describe the signature as

affirming the investigator has explained that:

1. Participation in the study does not guarantee that the study animal will

experience any improvement in health.

2. The drug product being studied is not FDA-approved for the use under

investigation.

3. The owner wishes to participate in the study and that such participation is

undertaken voluntarily.

4. A confirmation that the owner is the owner of the study animal. In cases of

authorized agents, the agent’s identity and scope of authority should be set forth

in writing, signed by the owner, and attached to the ICF upon the agent’s

signing on behalf of the owner.

Consider having a neutral witness present for the signing of the ICF by the owner or

their agent. Consider providing a space for the witness to sign, confirming that they

witnessed the owner signing the ICF.

I. List of contacts

The ICF should provide an explanation to the owner of whom to contact:

1. For answers to general questions or concerns.

2. With concerns regarding clinical signs their study animal may be experiencing.

3. In the event of a study-related injury to a study animal or owner.

4. For further explanation of the owner’s rights.

VII. Informed Consent Form discussions with CVM

Informed consent may be discussed with CVM at any point in the development process, although

ideally, conversations would occur before studies are conducted using an informed consent form.

The sponsor’s decision regarding when to start the conversation with CVM may be affected by

where the project is in the development process and the information available, among other

factors. CVM recommends the sponsor consider any concerns regarding animal and/or human

user safety or conditions of use that may impact the ICF as early in the drug approval process as

possible. CVM recommends sponsors use the initial presubmission conference process to

discuss plans to address unique aspects of the new animal drug or conditions of use that may

impact the ICF.

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If the sponsor is seeking review and concurrence on an ICF, the ICF should be submitted at the

time the applicable study protocol is submitted for review (E-submission). To allow CVM to

review the ICF and provide appropriate feedback, if necessary, CVM recommends the sponsor

assess the ICF for inclusion of the recommendations discussed in this GFI, as applicable, prior to

submission.

CVM’s Office of New Animal Drug Evaluation (ONADE) project managers (PMs) serve as a

central point of contact for pioneer drug sponsors and can provide information about the new

animal drug review process and ONADE’s regulatory procedures. If sponsors have questions

and do not have an ONADE PM assigned to their company, sponsors can contact the PMs

through the CVM mailbox CVM.ONADE.PM@fda.hhs.gov.