|NIH Guidance on Informed Consent
For Gene Transfer Research
NIH GUIDELINES: "How will the major points covered in Appendix M-II, Description of Proposal, be disclosed to potential participants and/or their parents or guardians in a language that is understandable to them?"
The requirements of Appendix M were always intended to be complementary to and are consistent with other requirements, regulations, and guidance documents, including 45 CFR 46, 21 CFR 50, and 21 CFR 56, and other guidance from the Office for Human Research Protections and the Food and Drug Administration. However, even after the promulgation of Appendix M-III and M-IV, NIH has continued to seek ways to assist investigators and others involved in the consent process for gene transfer trials.
In 2002, the NIH Office of Biotechnology Activities (NIH OBA) formed a RAC Informed Consent Working Group - composed of members of the RAC, outside experts, and representatives of the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) - to assist the in the development of a comprehensive, web-based guidance document to supplement Appendix M. After an extensive development process, the guidance document was endorsed by the RAC in December 2003.
The guidance provided here is intended to serve as a resource and learning tool for individuals involved in gene transfer studies and others with an interest in this field.
Intended Audience: This guidance is intended to be useful to a variety of audiences:
How to Access the Guidance: The guidance can be viewed on this website or downloaded and printed in its entirety as a pdf document. To view the guidance on the website, you may either start at the beginning and go through the guidance page by page by clicking on the navigational arrow, or click on the headers in the navigational menu on the left of the page to be directed to the specific section that you want to read more about.
How to Maximize Utility of the Web-based Guidance: Each page of the guidance is devoted to a particular section of Appendix M. In general, each page has five components:
This guidance was designed to be interactive when used on the Web. You can scroll over and click on any underlined words to access further information on that item, particularly in the Tools & Background Materials and Sample Language boxes.
Communication about the Study to Potential Participants
The purpose of the consent process is to:
The consent form serves as a record of the information conveyed to the potential participant about participation in the study. The signing of the consent form provides documentation that the individual has agreed to participate in the study.
Improving Understanding and Voluntariness: A crucial outcome of the consent process is that potential participants understand pertinent information about the research. Another important outcome is that potential participants understand that the choice to participate is theirs and that refusal to participate will not jeopardize their clinical care. A number of techniques have been shown to increase understanding and voluntariness, including:
A number of concepts that are crucial to improving understanding and voluntariness are discussed more fully in the Voluntary Participation, Time for Decision-Making, Consent Form, and Comprehensibility sections.
Conflicts of Interest
NIH GUIDELINES: "Which members of the research group and/or institution will be responsible for contacting potential participants and for describing the study to them? What procedures will be used to avoid possible conflicts of interest if the investigator is also providing medical care to potential subjects?"
Non-financial Conflicts of Interest: All researchers can be viewed as having non-financial conflicts of interest because they benefit from publications and grants, which are generally facilitated by positive research results. The resulting pressure to complete a study and publish impressive results could compromise the integrity of the research and the rights and safety of participants in various ways. Investigators need to be aware of the pervasive and subtle nature of such conflicts.
If an investigator is also the personal health provider of the potential research participant, there may be an additional conflict of interest. A physician's duty is to honor the best interests of the patient. An investigator must do what is best for the study. These two objectives are not always consonant. Further, potential participants may be reluctant to question the advice of a health provider on whom they depend for care.
Many participants in gene transfer research first learn of the study from an investigator as part of a therapeutic encounter. Therapeutic relationships may develop before, during or after the study. Such relationships may influence both participants' and researchers' understanding of the goals of the study. Researchers should address this nonfinancial conflict of interest both before and during the conduct of a trial in order to ensure that differences between research and treatment are understood.
Financial Conflicts of Interest: Investigators may have equity, patent and other commercial interests in the products they research and develop, thus creating a financial conflict of interest that could influence their communication with potential research participants and the conduct of the study.
Potential participants should be told who is sponsoring the research study, whether the investigators are receiving compensation from the sponsor to conduct the research, and whether there are any potential conflicts of interest. Investigators should be required to disclose possible financial conflicts of interest to their institutions and to potential participants. Investigators should consult their institutions' IRB to determine how much information should be provided regarding the existence, nature, and management of those conflicts. Institutions should have procedures in place to mitigate the influence that such conflicts have on the study and consent process.
Financial conflicts of interests can be addressed and managed by various means, such as divestiture and wider disclosure (e.g., to scholarly journals). Some professional organizations have made specific recommendations about managing and disclosing possible financial interests. These statements may prove helpful to investigators and institutional review boards. The National Institutes of Health (NIH) has issued guidance clarifying its regulations regarding possible financial conflicts of interest that apply to all NIH-funded research.
To address concerns about both financial and non-financial conflicts of interest, it may be useful to have a person who is not the health provider discuss the research study with the potential participant. A decision-monitoring plan may also be considered. Potential participants should always be told that they are free to participate in the study or not, and that a decision about study participation will not affect their clinical care.
Sample 1 - Non-financial Conflict of Interest
Your physician is a researcher in this study. As a researcher in this study, he/she is interested not only in your health and well being, but also in the results of this study. It is possible that sometimes these two goals may conflict with one another. Researchers protect the rights and interests of participants by carefully following the rules of the study.
You do not have to be in any research study offered to you by your health provider. When you are deciding if you should join the study, you may want to talk with someone not part of the study about your questions and feelings about joining. This could be s a family member, friend, or another health provider.
Sample 2 - Financial Conflict of Interest (adapt for specific circumstances)
The investigator of this study, [name], is an officer in the company that makes the gene transfer agent you will get if you join the study. The investigator also holds stock and options in the company. This means the investigator may make more money if the study shows that the gene transfer agent is helpful. Although the investigator is not supposed to let his/her financial interests affect the study, this may not be always possible.
Sample 3 - Financial Conflict of Interest Disclaimer
This research is sponsored by [name of sponsoring company, agency, or group]. This means that [name of sponsoring company, agency, or group] is paying the research team for the costs of doing the study. The researchers do not have a financial stake in the results of the study.
NIH GUIDELINES: "How will the major points covered in Appendix M-II, Description of Proposal, be disclosed to potential participants and/or their parents or guardians in a language that is understandable to them?"
Improving Comprehensibility of the Consent Form: Comprehensibility of the consent form is promoted by:
The text of the consent form can then provide detailed information about the particular study, and may repeat some of the summarized issues in the context of the particular study.
Sometimes, "research" and "treatment" terms are used interchangeably in consent forms. Consistent use of terms is preferred, however, to help minimize the potential for confusion. For example, one term should be used to describe the experimental gene transfer intervention, instead of calling it, at various places, study injection, delivery of a modified virus vector, or gene shot. One term should be used to refer to the investigator (instead of using, for example, both "researcher" and "study doctor"), and one term should refer to participants (instead of using, for example, both "patients" and "subjects" to refer to those enrolled in the study).
Furthermore, consent forms should be written in the second person rather than the first person. Telling potential subjects, "This is what will happen to you if you are in this study" conveys information more clearly than "I have been told that if I join this study, this will happen to me" - a construction that can be awkward and confusing.
In addition, the use of emphatic and directive language should be avoided. A common example is "You understand that....". This construction should never be used in consent forms because it conveys a presumption about what the participants comprehend and detracts from the consent form's proper educational focus on providing information and explanations to potential participants.
Various tools exist to gauge the comprehensibility of the consent form before it is used with potential participants. Such tools include:
Improving Comprehensibility of the Consent Process: In some studies that are especially complicated or risky, or that propose to enroll especially vulnerable participants, it may be desirable to develop a communication evaluation plan to ensure that study personnel have clearly and thoroughly explained key information and that potential participants understand key issues. Such evaluation can take many forms, including:
Communicating with Non-English Speakers: Federal regulations require that consent be provided in a language understood by the potential participant. For potential participants who do not understand English, it may be advisable for the consent form and any supplementary materials to be professionally translated and for the translation to be checked for scientific accuracy so that important nuances are properly conveyed. In addition, investigators, institutional review boards, institutional biosafety committees, and institutions should have appropriate plans in place for use of interpreters experienced with the translation of medical information in all verbal communication during the consent process and throughout the study.
Time for Decision Making
NIH GUIDELINES: "What is the length of time that potential participants will have to make a decision about their participation in the study?"
Many institutional review boards provide guidance to investigators on this issue, including recommendations that potential participants take the consent form home to discuss it with family members or primary care providers before making an enrollment decision.
Investigators and IRBs should consider the following:
SAMPLE LANGUAGE FOR CONSENT PROCESS
Process Sample 1
You may have already thought a lot about participating in this study. You may even have already made a decision about whether to be in the study. Even if this is true for you, it is important that we provide you with this information and talk about it before we start you in the study. Some information may be new or different. Some could even change your mind. It is always okay to change your mind about being in the study. And even if you don't change your mind, the information can help you understand the study better.
NIH GUIDELINES: "If the study involves children or persons with impaired decision-making capacity, how will the assent of each person be obtained?"
Permission from Legally Authorized Representatives: For potential participants who cannot give consent, investigators must obtain permission from a legally authorized representative of the potential participant. For children, this is usually the parent. For adults, it may be someone designated as health care proxy. The permission process should include instruction to the parents and/or legally authorized representatives regarding the difference between permission for treatment and permission for research participation. Legal counsel should be consulted to determine who is permitted to act as a legally authorized representative for research enrollment in the state(s) in which participants will be enrolled. It should be noted that authority for treatment decision-making does not always extend to decision-making about research participation.
Cognitively Impaired: If a potential participant is cognitively impaired and judged to be incapable of giving consent, the potential participant must still be asked and agree to participate in the study even though he or she may not fully understand its purpose, benefits, and risks - unless the impairment completely precludes any meaningful communication. The investigator should follow institutional guidelines for obtaining assent and addressing dissent from cognitively impaired individuals.
Minors: Investigators should follow Federal regulations, namely, 45 CFR 46 Subpart D and FDA guidance on assent of children for enrolling minors (generally children under age 18) in research. Investigators should obtain parental permission, and the assent of the minor when appropriate. In addition, investigators should plan how dissent from minors should be addressed - a determination that is specific both to the age of the child and the design and purpose of the study. Information should be appropriate for the developmental age of the child. It is generally a good idea to approach individuals who assented to participate in research as a minor once they reach the age of majority for either continued participation in the study or continuation of long-term follow-up.
"Submission of a human gene transfer experiment to NIH OBA must include a copy of the proposed informed
consent document. A separate informed consent document should be used for the gene transfer portion of a
research project when gene transfer is used as an adjunct in the study of another technique, e.g., when a
gene is used as a "marker" or to enhance the power of immunotherapy for cancer.
If a separate consent form for the gene transfer component of the study is not possible, the single consent form should describe the gene transfer component separately whenever possible, in order to give adequate attention to gene transfer's unique features. For example, separate sections or subsections addressing gene transfer aspects of the study may be placed throughout the consent form in such a way as to enable potential research participants to distinguish among the various components of the study.
The NIH Office of Biotechnology Activities (OBA), which staffs the Recombinant DNA Advisory Committee (RAC) and administers the NIH Guidelines, can be a resource for development and review of gene transfer research consent forms. Among the valuable resources available on the OBA website are a number of sources of information, data, and descriptions applicable to different gene transfer interventions, vectors, diseases and conditions, including:
NIH GUIDELINES: "The subjects should be provided with a detailed explanation in non-technical language of the purpose of the study and the procedures associated with the conduct of the proposed study, including a description of the gene transfer component."
The greatest challenges to investigators in describing the purpose of the study include:
Placing emphasis on the research nature of the intervention and appropriately qualifying any statements or claims about anticipated outcomes and potential benefits of the current study are as important when describing the purpose as when describing or disclaiming any potential benefits. The purpose section of the consent form should be compared with the potential benefits section to avoid discrepancies and minimize possible confusion.
Study Phase: The purpose description should reflect the phase of the trial and should be based on pre-clinical and other clinical evidence. A brief description of classic study phases, reflecting the design and purpose of each, is included below as a reference. These descriptions could also be modified and adapted to use when informing potential participants.
Phase I studies are small studies of an experimental intervention and are usually the first time the intervention has been tried in humans. Their primary purpose is to test for safety, to see how the intervention affects the body, to test for harms and discomforts, and to see how the side effects change at different doses. Many phase I studies employ dose escalation designs.
Some, but not all, Phase I trials also attempt to reveal whether or not the intervention has any beneficial effects. Any Phase I trials with this additional purpose should be designed and powered appropriately. The hope for therapeutic benefit is not a sufficient basis for identifying efficacy testing as a secondary purpose.
Phase II studies are mid-sized studies of the experimental intervention and are designed to begin a more complete evaluation of the effectiveness of the intervention. The purpose of Phase II studies is to see if the intervention has any beneficial effects at a dose level thought to be safe based on earlier studies. Phase II studies also continue to test for harms, discomforts, and side effects resulting from the intervention.
Phase III studies are large studies of the experimental intervention for the purpose of gathering data on a larger group of participants in order to prove or disprove the safety and effectiveness of the intervention that has been tested in earlier studies. Phase III studies also reconfirm optimal doses and routes of administration. Phase III studies also provide an opportunity for investigators to recognize less-common side effects in a larger number of participants. The experimental intervention in Phase III studies may be compared to a standard treatment or to a placebo.
Relevant aspects of study design linked to phase - such as dose escalation in Phase I trials, and use of placebo groups, control groups, and comparison group designs in Phase III trials - should be briefly mentioned in the purpose section, and then explained in appropriate and relevant detail in the procedures section of the consent form.
Phase I/II Studies: Because investigators should build upon the knowledge gained in Phase I of their study, and so that potential participants considering enrollment in Phase II can benefit from knowing the outcomes of Phase I, it is important that Phase I and Phase II not be combined unnecessarily. The NIH Recombinant DNA Advisory Committee (RAC) reviews many Phase I/II studies and sometimes questions the appropriateness of a combined design. In the event that Phase I and Phase II must be combined, one consent form should be used for the Phase I portion of the trial and a second should be used for the Phase II portion of the trial to allow the different goals of the Phase I and Phase II components to be properly understood. If two separate consent forms are not possible, investigators should consider how potential participants are best informed of the differences between Phase I and Phase II and about the phase to which they will be assigned.
Describing Gene Transfer: A brief description of the gene transfer intervention should be provided to the potential participant. If the investigator's institutional review board approves, it may be desirable to create a scientific appendix to the consent form that briefly explains the scientific theory behind gene transfer and how that theory is to be applied in the current study.
The process of gene transfer is likely to be unfamiliar to most potential participants. Therefore, it is especially important that the investigator clearly and simply explain the gene transfer methodology used in the given study. Sample descriptions of different gene transfer methods are provided in this guidance. It is also important to use terms like "genes" and "DNA", especially if the gene transfer intervention is otherwise described by an acronym or other term that does not itself make an obvious connection to the introduction of new genes or new DNA into the body. Background material about basic genetics and the science of gene transfer research may be beneficial to some potential participants.
Describing Vectors: Most gene transfer requires a vector, often described as a transportation system to deliver the gene. Many descriptions use vivid analogies that compare the vector to a car and the gene to the passenger. For studies using a vector, descriptions of this sort may be helpful to lay readers. For those few studies not using a traditional vector (e.g., naked plasmid DNA), the description should discuss the method of delivery in plain language.
Sample vector descriptions for potential participants are included in this guidance. Investigators should pay particular attention to how adenoviruses are described since they are not just a common cold. Adenovirus can be better described this way: "Adenovirus is a common virus found in human respiratory systems. In its normal state, it can reproduce and cause a respiratory infection. Respiratory illnesses caused by adenovirus infections range from the common cold to pneumonia, croup and bronchitis."
2 Although use of healthy volunteers is uncommon in gene transfer research, it is not unknown. Healthy volunteers may be an appropriate population in selected studies.
Sample 1 - Healthy Volunteer
You have been asked to join this study as a healthy volunteer. This means that the investigators think that they can learn about a certain disease or condition that other people have from participation of healthy people like you.
Sample 2 - Patient-Subject Volunteer
You were asked to be in this study to help the investigators learn more about the type of disease you have. The investigators will try to keep the risks of harm to you from being in the study as low as possible. They believe that being in the study will not keep you from getting any treatments you may need for your disease.
This study will enroll people with your disease [CHOOSE WHICHEVER APPLIES]
Sample 3 - Phase I
This study is experimental. It is meant to investigate the safety, possible harms, and side effects of injecting your cancer with an experimental gene transfer agent called [X]. This is the first time that this gene transfer agent will be used in humans with your disease.
Sample 4 - Phase I
The investigator's goal is to find out the highest dose of the gene transfer agent that is safe. This is the first step in studying whether it can be used to treat others with your disease in the future.
Sample 5 - Phase II
The purpose of this study to find out if repeated doses of the gene transfer agent, [xx,] are safe for research participants with your disease, and to see if any side effects cause problems for participants. This study is also being done to find out if giving [xx] can help lung disease in CF by making normal genes in the lung cells.
Sample 6 - Phase III
The purpose of this study is:
We will also continue to check the safety of the gene transfer agent.
You have been invited to participate in this study because your disease has progressed despite standard treatment.
You are eligible to participate in this study because there is no effective treatment for your disease.
Comments: For early-phase studies, these statements, standing alone, may foster the perception that research participants are likely to benefit from study participation, simply because nothing else has worked for them. In order to avoid creating this impression, descriptions of the targeted study population should focus on how risks can be minimized in and knowledge can be gained from the population, as illustrated in Sample 2 above.
SAMPLE GENE TRANSFER DESCRIPTIONS
SAMPLE VECTOR DESCRIPTIONS
NIH GUIDELINES: "The subjects should be provided with a detailed explanation in non-technical language of the purpose of the study and the procedures associated with the conduct of the proposed study, including a description of the gene transfer component."
Whenever applicable, the consent form and process should attempt to make clear to potential participants how research participation differs from being treated for health problems outside of the context of the study. This topic is also addressed in the Alternatives section.
Organization of Procedures Section: It is especially important in early-phase research, such as most gene transfer studies, to distinguish standard treatments from investigational interventions, and tests and measurements provided as part of clinical care from those related to the research study. Institutional review boards (IRBs) and institutional biosafety committees (IBCs) can provide guidance on how to differentiate between these activities. Using separate consent forms, or separate consent form sections, for the research component and standard treatment component is one reasonable way to distinguish between the two.
Avoiding Improper Language: Because gene transfer interventions, like other investigational interventions in early-phase trials, are unproven and have not yet been studied for efficacy, they should not be referred to as treatments.
Some examples of improper language are:
Alternative language reinforcing the experimental character of gene transfer should be chosen appropriately for a given protocol. Possible alternatives to the above examples might be:
Dosing Group Designs and Cohort Assignments: Many Phase I studies utilize dose escalation to determine a safe gene transfer agent dosage amount. If the study involves dose escalation, the investigator should explicitly state to which dosage cohort the potential participant will be assigned, the dose level to be received, and any potential risk-benefit balance for that particular cohort. In providing this information, the investigator should describe and explain dose escalation designs for the following reasons:
Other Study Designs: Many Phase III studies involve such features as randomization, inclusion of control groups, use of placebos, and blinding. All of these features should be explained simply and clearly in the consent form and process. Double-blind design explanations should include the information that the blind may be broken if necessary to protect the participant's health and welfare. IRBs and IBCs can provide guidance and sample language on blinding and randomization.
Procedures Language: In order to simplify consent forms, researchers are encouraged to consult resources like the Simplification Guide to Medical Terms that suggest replacements for terms that are difficult to understand and, thus, require explanation or substitution. In addition, dosage information should be as precise as possible; terms like low, medium, or high dose should be quantified in terms that are most informative to potential participants.
Sample 1 - Dose Escalation Design
We do not know the highest dose of the gene transfer agent that is safe. To find out we will give the gene transfer agent to [number] participants at one dose level. If that is safe we will raise the dose given to the next group of participants. The dose you will get will depend on how many participants get the agent before you and how they react. The investigator will tell you this information. This will help you think about possible harms and benefits. Since the gene transfer intervention is experimental, what is likely to happen at any dose is not known.
Sample 2 - Randomization to Experimental or Control Arm
It is not clear whether experimental gene transfer will be more effective than standard treatment. For this reason, you will be randomly assigned (like the flip of a coin) to one of two groups: the experimental group (gene transfer) or control group (standard treatment). You will have a 50% chance of being assigned to either group.
NIH GUIDELINES: "The Informed Consent document should indicate the availability of therapies and the possibility of other investigational interventions and approaches."
Disease-appropriate alternatives include:
There may be no alternatives that have been shown to have significant success in individuals with certain diseases or conditions. Researchers should discuss this situation with potential participants, as appropriate.
In the consent process, investigators should recognize that some potential participants may consider themselves to have no real choice other than to participate in research. Investigators should take extra care in explaining and discussing alternatives with these potential participants. In contrast, very ill potential participants, whom investigators may be tempted to characterize as having no options, may view themselves as having a range of choices. Investigators should be sure to give these potential participants complete information about alternatives to participation.
Sample 1 - Standard Treatment Alternatives
Instead of being in this study, you may choose to have treatment with one or more standard chemotherapy drugs, alone or in combination. Some individuals have responded to standard treatments. The drugs used for your type of cancer include: [drug listing]. Or you may choose to have radiation treatment to control symptoms of your disease
Sample 2 - Experimental alternatives
It is not known whether any of the other experimental agents being studied are effective in your disease. If you decide not to be in this study, you can still join other studies, here or at other medical centers, if you wish.
Sample 3 - Palliative care alternatives
You may decline life-prolonging interventions for your disease. If you did, you would receive palliative care. This is supportive care that will not help you live longer, but will make you as comfortable as possible for as long as you live.
Sample 4 - Combination of alternatives
You do not have to participate in this study. You may want to be in a different study. You can choose not to participate in this study and continue to be cared for regularly here at [hospital]. You may choose at any time to stop being in this study and maintain all other aspects of your care by your doctors at [hospital]. [INCLUDE WHEN APPLICABLE: Getting the gene transfer in this study should not prevent future treatment with standard therapy. Getting the gene transfer in this study should not make you ineligible for participation in other studies either.]
Sample 5 - Combination of alternatives
You may choose not to participate in this study. If you choose not to, your decision will not affect your care at [study site]. Alternatives to being in this study include:
You can receive these treatments during and after the study. Since this study will not directly treat your [disease], a decision not to participate will not affect your health.
Sample 6 - Randomization to Experimental or Control Arm
Standard treatment cannot cure your disease. You may be in other studies that may improve your quality of life and help you live longer even though they will not cure your cancer. A variety of research studies for your cancer are going on in medical centers around the world. The effectiveness of these approaches is unknown. [New treatment X] has recently shown longer survival in some patients. Other treatments may also be available. You can also decline further life-prolonging treatment for your disease, and receive palliative care to manage your symptoms. If you decide not to participate in this research study, we will discuss all appropriate treatments with you and help you decide what to do next.
NIH GUIDELINES: "The subjects should be informed that participation in the study is voluntary and that failure to participate in the study or withdrawal of consent will not result in any penalty or loss of benefits to which the subjects are otherwise entitled."
Withdrawal: Participants have the right to withdraw from the study at any time, including during follow-up. The implications and consequences of withdrawal (from the intervention only or from the entire study) should be discussed as part of the consent process. Potential issues to consider include:
Investigators may emphasize that withdrawal may deprive the research of important data, and they may request (but not require) that participants who do not want to complete a full course of the experimental intervention or long-term follow-up nonetheless remain in the study and complete all study visits.
Study Discontinuation: Potential participants should be informed that the investigator or the study sponsor may terminate their participation in the study at any time without their consent if it is believed to be in their best interest, if they do not comply with study requirements, or if the study is discontinued. The investigator should explain the reason for terminating participants' involvement in the study and what arrangements will be made for continued care.
You do not have to be in this study. You can say no. If you join the study, you can leave it at any time. If you choose not to participate, there will be no penalties, and no bad effects on any benefits or medical care that you are entitled to get from this hospital or from your health care providers. If you leave the study, please tell the investigator or research coordinator. Then we will ask you to come back to the clinic for a final assessment and discussion of future treatment options.
Being in this study is completely voluntary. You may withdraw at any time without penalty, without loss of benefits to which you are entitled, and without affecting the medical care you get at our hospital. However, once you receive the gene transfer, there may be some effects that cannot be reversed.
The investigators may stop your participation at any time. This could be because you have had an unexpected reaction or because the whole study has been stopped.
NIH GUIDELINES: "The subjects should be provided with an accurate description of the possible benefits, if any, of participating in the proposed study. For studies that are not reasonably expected to provide a therapeutic benefit to subjects, the Informed Consent document should clearly state that no direct clinical benefit to subjects is expected to occur as a result of participation in the study, although knowledge may be gained that may benefit others."
Generic benefits discussions are commonly found in gene transfer research consent forms, but they should be avoided. Simple potential benefit statements, such as "You may or may not benefit from being in this study," or "Personal benefit cannot be predicted or guaranteed," do not provide sufficient meaningful information for potential participants in gene transfer research, particularly in early-phase studies. Such statements should be avoided whenever it is possible to provide more specific information about the nature and likelihood of potential benefits, if any, and their limitations, as described in the text of Appendix M-III-B-1-d and throughout this guidance section.
Vague statements like "Getting the gene transfer in this study may or may not improve your health, reduce your symptoms, or make you feel better" should also be replaced by appropriate discussion of specific disease aspects, since the meaning of "reduce symptoms", "improve health", and "feel better" may be interpreted differently by different potential participants.
Detailed discussion of potential benefits may assist potential participants in understanding the differences between receiving medical treatment and participating in research. An explicit statement of differences between treatment and research may also be helpful. In addition, investigators should distinguish between the ultimate goal of the line of research, the endpoints of the current study, and potential benefits to participants from the gene transfer. Without careful differentiation, the consent form could inappropriately convey the impression that the long-term goal of curing disease with gene transfer is identical to the potential benefit offered in a Phase I trial.
Societal Benefit: Many gene transfer consent forms fail to mention benefit to society. However, potential participants should always be informed that early phase studies are designed for scientific purposes and that those who participate in these studies may extend benefit to future patients by helping to advance scientific and medical knowledge. The investigator should distinguish between these benefits to society and potential benefits, if any, to participants.
Reducing Therapeutic Misconception: Characterizing an experimental study as treatment may be misleading to potential participants because it incorrectly implies that the experimental intervention is in fact a treatment -- or at least that it would not be tried unless there was some realistic expectation of its success for that potential participant. However, in a research context, benefits may not be anticipated with such confidence. This is especially true in early-phase trials, in new fields like gene transfer research, and when participants are seriously ill. Correcting inappropriate "treatment" language may help not only participants but also study personnel and oversight bodies avoid developing unrealistic expectations of clinical improvement from the gene transfer intervention.
Some examples of misleading language are:
Examples of misleading terms that may imply medical benefit include therapy, treatment, and patient. These terms should be replaced with terms such as gene transfer or gene transfer agent, and research participant, respectively.
Describing Potential Benefit for Different Phases and Designs: What is known about the potential benefits, if any, of a gene transfer intervention in a given study depend on the design and phase of the study and available evidence. Potential benefits discussions should be phase-specific. For combined Phase I/II studies, it is important to distinguish between the potential benefits of each phase.
Investigators should consider how to present information about prior experience and its limitations in the consent form so as to best inform potential participants. Previous experiences related to benefits in animal studies, and possibly even in vitro experience, may be relevant when the meaning and limitations of the findings are carefully described. Previous human experience is usually relevant, but should nonetheless be described carefully and its limitations addressed.
Uncertainty about the likelihood of the occurrence of direct personal benefit from the gene transfer intervention should always be mentioned. Especially in Phase I and II trials, it is appropriate to say that the primary purpose of the study is to produce benefits to society - that is, contributions to scientific knowledge and medical progress, and perhaps benefits to future patients.
Surrogate Endpoints: In gene transfer research, investigators most often seek to measure surrogate endpoints. However, these surrogate endpoints may not directly relate to any benefits that participants may clinically experience. Surrogate endpoints should not be described as benefits to participants unless there is a well-established, direct link to a clear health benefit. The challenge of discussing potential benefits lies in explaining the relationship, or lack thereof, between what the investigators seek to measure and what participants might experience. Whenever appropriate, investigators are encouraged to discuss explicitly and specifically the nature and extent of clear clinical benefits that potential participants may be expecting, in order to explain what expectations are reasonable and why, and what expectations are not reasonable and why.
Sample 1 - Societal Benefit
This study is meant to answer scientific questions about gene transfer for your disease. The results may give investigators information to use in future research, even if the gene transfer does not work. Some people find potential societal benefits like these a good reason to participate in this study. Please consider whether you think that as well.
Sample 2 - Phase I
The gene transfer you get in this study is not likely to change the natural course of your disease. This study is not meant to be a treatment for your disease. Instead, the investigators hope that the information learned from this study can benefit patients with [condition] in the future.
Sample 3 - Phase I
The purpose of this study is to test the safety of this gene transfer and to see if we can successfully put the gene into cells of people with [condition]. Treating your disease is not the purpose of this study. It is very unlikely that getting the gene transfer in this study will improve your health or [specific symptoms].
Sample 4 - Phase I
This study is not intended to benefit you directly. Investigators simply want an understanding of gene transfer for [condition]. Information about the amount of DNA needed and the effects of the gene transfer agent will be critical for further studies in the future. Getting the gene transfer in this study will not improve your health or [specific symptoms].
Sample 5 - Phase I
The reason for doing this study is to test the safety of different doses of gene transfer given to participants with [condition]. Although there is some evidence that the gene transfer injections could help [achieve surrogate endpoint] in some participants, we do not know if that will happen to you. Even if it does, the good effect would probably be small and not last long. However, it is very unlikely that this will happen. Benefit to you is not the goal of this study. Instead, we want to see if the study injections are safe. We also want to provide a foundation for future studies of these injections. We hope to benefit future patients with [condition].
Sample 6 - Phase II
Earlier studies support the safety of the gene transfer, but it is far too early to say whether it will help you at all. Even if it does, it is far too soon to know how much it may help and how long any benefit might last.
Sample 7 - Phase II
This is a Phase II study. It is the first systematic attempt to find out if this gene transfer will help individuals like you. You should not enroll in this study with any expectation that you will personally benefit.
Sample 8 - Phase III
Earlier research shows that this intervention may help individuals like you. However, we are not sure there will be any helpful effects. If there are any, we do not know how great those effects might be, or how long they might last. You should keep this uncertainty in mind as you decide whether you want to participate in this research.
Sample 9 - Phase III
This is a Phase III trial. It is an attempt to identify the extent and duration of benefit of this intervention. Any hope you have of gaining a meaningful personal benefit should be just a hope and not an expectation.
Sample 10 - Phase III
We cannot predict if you will gain any personal benefit from getting this gene transfer. Earlier studies show that the experimental gene transfer agent may shrink some tumors. This could decrease cancer-associated symptoms or prolong life for a time. However, the gene transfer may have no good effects on your disease at all. If your disease becomes worse, or if the side effects from the gene transfer become too great, or if there is any other reason to think that participation in this research is not in your best interest, we will stop your participation so that you can be treated with standard therapy.
Sample 11 - Surrogate Endpoints
In this study we are measuring [surrogate endpoint-SE]. We hope that a change in this measure will have [beneficial clinical effect] on this disease. But because this study is short, we do not know if changes in [SE] will change how participants in this study feel. We also do not know if [SE] will last for longer than a short time. It is also possible that for participants whose disease is very severe, a beneficial effect might not be felt very much or at all.
Possible Risks, Discomforts, and Side Effects
NIH GUIDELINES: "There should be clear itemization in the Informed Consent document of types of adverse experiences, their relative severity, and their expected frequencies. For consistency, the following definitions are suggested: side effects that are listed as mild should be ones which do not require a therapeutic intervention; moderate side effects require an intervention; and severe side effects are potentially fatal or life-threatening, disabling, or require prolonged hospitalization. If verbal descriptors (e.g. 'rare,' 'uncommon,' or 'frequent') are used to express quantitative information regarding risk, these terms should be explained. The Informed Consent document should provide information regarding the approximate number of people who have previously received the genetic material under study. It is necessary to warn potential subjects that, for genetic materials previously used in relatively few or no humans, unforeseen risks are possible, including ones that could be severe. The Informed Consent document should indicate any possible adverse medical consequences that may occur if the subjects withdraw from the study once the study has started."
Bulleted lists of clearly defined items with a brief explanation of what the risk or side effect may entail may be helpful way to present the risks of harm in the consent form.
Since some risks of harm cannot be known with certainty, it is always helpful to discuss what is uncertain and unknown.
Differences in Risk of Harm for Phase I, II, III Studies: The available evidence about risks of harm and potential discomforts of a gene transfer intervention differ according to the phase of the study. Risk discussions should be phase-specific. For combined phase I/II studies, it is especially important to distinguish (preferably in separate consent forms) between the risks for harm of each phase.
Sample 1 - Risks Associated with a Study Agent
The vector, which carries the gene into your cells, is considered harmless in humans. However, it is possible that the virus could grow and/or make the cells cancerous. There is a risk that the vector may enter the normal tissue surrounding the tumor, or other sites in the body. Another risk is that the vector might stay in your body and cause cancer or other diseases. Your immune system is expected to reject (kill) the vector in [time amount]. Thus, the vector should not be able to survive and grow in your body. The risk of causing a new cancer is probably very small. Although some vectors have caused cancers, no cancers have yet been found in any of the experiments in which genes have been transferred into monkeys and humans using this vector.
Sample 2 - Risk of Cancer Caused by Gene Transfer
Researchers have wondered whether a transferred gene might sometimes land in a place in a cell where it can cause harm. This happened to two children in another study. After getting the gene transfer, they developed leukemia (a type of blood cell cancer). A group of experts looked at all the test results. They found that gene transfer caused the leukemia by making some cells grow out of control. The children appear to be responding to treatment of the leukemia, but their long-term health is unknown at this time.
There is a risk of unknown size of your child developing cancer, such as leukemia, should you volunteer your child to enter into this experimental study. This is a serious risk because cancers of the blood can lead to death.
Problematic Sample 1
[Gene transfer agent] may cause pain at the injection site. It may also cause some heart toxicity. Patients may also have shortness of breath and/or allergic reactions, including hives, skin rash, difficulty breathing, and/or fever. There may be damage to the liver and kidneys. These reactions could result in death. Having a tumor biopsy may cause air in the chest and/or bleeding to occur. Air in the chest is treated with the insertion of a small tube. A bronchoscopic biopsy (sample of very tiny piece of the mucosa inside the lung) may cause coughing up of blood. This is usually temporary. Severe bleeding requiring emergency treatment such as intubation and thoracotomy could also occur. This clinical research study may involve risks to the participants that are unknown at this time.
Comments: The risks of harm would be clearer if they were ranked according to likelihood and severity. Risks of harm particular to the gene transfer should be included. Also, medical terms like "intubation" and "thoracotomy" need to be described in lay terms.
NIH GUIDELINES: "The subjects should be provided with specific information about any financial costs associated with their participation in the protocol and in the long-term follow-up to the protocol that are not covered by the investigators or the institution involved. Subjects should be provided an explanation about the extent to which they will be responsible for any costs for medical treatment required as a result of research-related injury."
Participant Costs: Costs associated with participation in the study and long-term follow-up that will be the responsibility of the participant should be enumerated. Such costs may include:
Bulleted lists of the costs that will be incurred may be helpful to potential participants, including:
Research-Related Injury: Institutions and sponsors are not required to compensate or provide free treatment to participants for research-related injuries. However, institutions and sponsors may adopt individual policies regarding compensation and provision of treatment for research-related injuries. Investigators should consult with their sponsors, Institutional Review Board and Institutional Biosafety Committee for their policy and model language. Investigators should provide information about the study's policy on research-related injuries, including whom to contact if a research-related injury should occur, regardless of whether compensation or treatment will be provided.
Financial Counseling: An increasing number of institutions make financial counseling available to potential research participants. Such counseling can help determine what is likely to be covered by the participant's health insurance and can help identify sources of supplemental support, such as uncompensated care funds, special arrangements and discounts from institutions and sponsors, subsidization for travel and living expenses for participants and families, and the like. Financial information and counseling may be particularly helpful for gene transfer trial participants. Although insurance coverage for participation in clinical trials has broadened considerably in recent years, coverage for early-phase trials, like most gene transfer, is far from certain because of the low likelihood of direct benefit from the experimental intervention. The investigator should provide information about financial counseling available to potential study participants.
The following items will not be charged to you or to your insurance company:
Health care costs not related to this study are billed to your health insurance company. Because this is a research study, insurance companies or government health care programs may not pay for the experimental interventions, research-related tests, or treatment of research-related injuries. You must pay all charges related to the medical care you receive for treatment of your disease except for those listed above. This includes charges your insurance company refuses to pay because of the connection with an experimental procedure. You will not be paid for being in this study.
There will be no costs to you for any research-related laboratory tests, investigator's time, or the [gene transfer agent]. You or your insurance company will be billed for tests and treatments that are considered standard care. Medical treatment for physical injuries directly resulting from research procedures that are not covered by your insurance will be provided free of charge at [study site] by the [study sponsor].
Comments: Although this sample language is common, it is insufficiently helpful. It does not allow potential participants to reasonably foresee the costs they will be expected to pay as a result of their participation in the study, since these are merely described as "standard care".
NIH GUIDELINES: "To avoid the possibility that any of the reagents employed in the gene transfer research could cause harm to a fetus/child, subjects should be given information concerning possible risks and the need for contraception by males and females during the active phase of the study. The period of time for the use of contraception should be specified. The inclusion of pregnant or lactating women should be addressed."
Discussion of the risk of reproductive harm should always be study-specific. Study-specific factors include, but are not limited to, frequency of pregnancy testing and the possibility of inadvertent germline effects, which could be teratogenic.
Reproductive considerations may be unique to one gender or may need to be discussed differently for men and women. It may be worthwhile to have separate sections in the consent form for issues especially pertinent to men or to women.
Avoiding Risk of Reproductive Harm: To avoid the possibility of causing harm or abnormalities to an unborn child, participants and their sexual partners should be encouraged to practice abstinence for an appropriate length of time or, at minimum, to use certain methods of contraception. The short- and long-term advantages and disadvantages of each method should be explained. In some studies, it may be advisable for investigators to discuss sperm and ova banking, which may involve an additional cost to the participant.
The risk of horizontal transmission of the vector-transgene combination to sexual partners should be addressed separately in the consent form. Here, too, the advantages and disadvantages of typical contraceptive methods should be discussed.
Under some circumstances, pregnant or nursing women may not be eligible to participate in gene transfer trials that pose risks of reproductive harm. When such exclusions are justified, investigators should inform potential participants that they will be tested to rule out pregnancy. In some gene transfer studies, women who are breast-feeding may not be eligible for participation or may be asked to stop breast-feeding during and for a specified period after the study completion.
In addition to discussing possible reproductive harms relevant to both sexes, investigators should also discuss with potential participants what will happen if a study participant or the partner of a participant becomes pregnant. This should include information about reporting pregnancies to the investigators, so that risks of harm may be individually assessed and counseling may be offered. It may also include requests for long-term monitoring of offspring.
Sample 1 - Men and Women
Risks of harm from this study include the possibility that the genes in some of your sperm (men) or eggs (women) may be permanently changed. Some of these changes could lead to miscarriage or birth defects in your future children. Other changes may have no apparent effects but could still be passed on to future generations. The likelihood of such outcomes is currently unknown.
Sample 2 - Men and Women
It is not known if DNA injected into your muscles can become part of the DNA of your reproductive cells (eggs or sperm). If this happens, it may cause fetal death or birth defects in future pregnancies of participants and their partners. It is also unknown whether or not the gene transfer vector will be present in body fluids (semen, vaginal secretions) and, if so, whether it will be transmitted to a sexual partner.
Sample 3 - Men and Women
You should not be in this study if you are planning a pregnancy soon. The risk of transmission of the gene transfer vector to a sexual partner or an embryo or fetus is unknown. It is possible that harmful side effects could occur to both the mother and unborn or breast-feeding children. You should not become pregnant during the study. The risks of harm from the gene transfer vector to an unborn or newborn child are unknown. If you become pregnant while in this study, you must tell your investigator at once. If you can give birth or father a child, you must use an adequate form of birth control. If you are able to become pregnant, you must have a negative pregnancy test within [time] before you get the first dose of the gene transfer. You may not take part in this study if you are pregnant or a nursing mother.
Sample 4 - Men and Women
You should not become pregnant or father a child while taking part in this study. Women who are pregnant or breast- feeding may not be in this study. If you are a female who can have children, you will take a pregnancy test and the results will be given to you. You must confirm that you do not plan to become pregnant while on this study. If you are capable of giving birth or fathering a child, you must use an acceptable form of birth control. For women, contraception should go on for [time period] after the last dose of the [gene transfer agent] to ensure that it has completely cleared from your body. For men, contraception should go on for [time period] after the last dose of the [gene transfer agent] to make sure that all sperm in the body during the trial have been replaced. If you or your partner becomes pregnant, or you suspect that you or your partner is pregnant while in this study, notify the investigator at once.
Sample 5 - Men Only
There is no information on whether the vector and gene can be transferred to sperm cells. Thus, the risk of gene transfer to germline cells (sperm cells) is unknown. Transfer of gene to germline cells could cause serious birth defects or fetal death. It could also lead to unknown health problems (such as cancer) in the child. If you may want to have children in the future, we recommend that you bank sperm before beginning the study, so that you have sperm available that has no DNA from the vector and gene. The investigators will provide you with information on sperm banking at [study site] or at your home institution. In addition to sperm banking, fertile men are encouraged to use barrier birth control devices (i.e., condoms). The investigators will notify you when it is safe to stop barrier methods of birth control.
Sample 6 - Men Only
One risk of this study is that [gene transfer agent] could have harmful effects on an unborn child. We do not know if the gene transfer you will get can become part of normal reproductive cells. If it can, it could cause harm to fetuses conceived after the gene transfer. These harms could include birth defects or death of the fetus, or of the child after birth. If you can father a child you should use precautions to prevent any sexual partner from becoming pregnant during this study.
Also, we do not know if the [gene transfer agent] may be present in body fluids. If it is, it could be transmitted to sexual partners. Condoms are essential for preventing transmission to a sexual partner.
Sample 7 - Randomization to Experimental or Control Arm
One risk of this study is that the [gene transfer agent] could have harmful effects on an unborn child. We do not know if the gene transfer you will get can become part of normal reproductive cells. If it can, it could case harm to fetuses conceived after the gene transfer. These harms could include birth defects or death of the fetus, or of the child after birth. If you are capable getting pregnant, you should use precautions to prevent becoming pregnant during this study.
If you become pregnant during the study or suspect that you may be pregnant, you should tell the investigator immediately. You also should not breastfeed during the study.
Also, we do not know if the [gene transfer agent] may be present in body fluids. If it is, it could be transmitted to sexual partners. Condoms are essential for preventing transmission to a sexual partner.
NIH GUIDELINES: "To permit evaluation of long-term safety and efficacy of gene transfer, the prospective participants should be asked to agree to long-term follow-up that extends beyond the active phase of the study. The informed consent document should include a list of persons who can be contacted in the event that questions arise during the follow-up period. The investigator should request that subjects continue to provide a current address and telephone number.
The subjects should be informed that any significant findings resulting from the study will be made known in a timely manner to them and/or their parent or guardian including new information about the experimental procedure, the harms and benefits experienced by other individuals involved in the study, and any long-term effects that have been observed."
Investigators need to inform prospective participants that they will be expected to participate in long-term follow-up that extends beyond the active phase of the study. Investigators should explain the rationale for long-term follow-up and describe the specific follow-up activities planned, including the desire to collect information about new cancers, blood disorders, autoimmune diseases, and neurologic disorders. Long-term follow-up may be viewed by participants as a benefit, a burden, or both. Potential participants need to understand what long-term follow-up activities will occur, how long follow-up will continue, and what, if any, procedures they will be asked to undergo.
Both the design and extent of long-term follow-up and its discussion in the consent form and process should always be tailored to the specific study design and vector used.
Although participants have the right to withdraw from research, they should be encouraged (but not required) to provide follow-up information even if they do not complete the gene transfer administration. Additional discussion about participants who withdraw from the study can be found in the Voluntariness section.
Facilitating Long-term Contact: To make long-term follow-up possible, participants should be asked to provide a current address and telephone number to the research staff, as well as the names and addresses of their current primary care provider and someone whom the research staff can contact to locate them. They should also be encouraged to contact the research staff when their contact information changes. Investigators may want to consider other ways to maintain current contact information, such as holiday cards or a newsletter, and inform participants of such efforts to maintain contact at the time of consent. The need to retain contact information for long-term follow-up raises privacy and confidentiality concerns, which are addressed in the Privacy section of this guidance.
Government Requirements: Gene transfer studies are subject to oversight by other Federal agencies, such as the Food and Drug Administration, which may have specific requirements for the duration of long-term follow-up. Investigators should know the current FDA policy regarding long-term follow-up, and the impact of these requirements on the participant should be discussed.
Significant Findings: If significant information is generated during or after the study that may be pertinent to a potential participant's decision to enroll or a current participant's continued involvement in a study, the investigator should consult the Institutional Review Board to determine whether the new findings are significant enough to:
Sample 1 - Long-term Follow-up
Long-term follow-up in gene transfer research allows for the collection of important information on the long-term safety and effects of the gene transfer intervention used in this study. The long-term follow-up planned for this study will occur [frequency] for [length of time]. It includes [study-specific information, as available; e.g., drawing a small amount of blood once a year; completing a health history questionnaire every year; having a biopsy of the injection site every five years; etc.]. The investigators will try to make it easier for you to participate in long-term follow-up by [study-specific information as available, e.g., using mail and telephone to collect some information; arranging with your local doctor to collect blood or biopsy specimens and send them to investigators; etc.].
Sample 2 - Long-term Follow-up
At the end of the experimental phase of the study you will be asked to participate in the long-term follow-up phase for the rest of your life. Once a year you will be asked to have your blood drawn (~[amount]) and answer questions about your general health and medical condition. The investigators may ask you to report any recent hospitalizations, new medications, or the development of conditions or illness that were not present when you enrolled in the study and may request that physical exams and/or laboratory tests be performed if necessary. We will also ask you to participate in the long-term follow-up phase if you leave the study early.
Sample 3 - Significant Findings
We will give you any new information we learn during this study that might affect your willingness to stay in the study. This includes new information about the procedures used, the [gene transfer intervention], or side effects other participants in the study may have had.
Request for Autopsy
NIH GUIDELINES: "To obtain vital information about the safety and efficacy of gene transfer, subjects should be informed that at the time of death, no matter what the cause, permission for an autopsy will be requested of their families. Subjects should be asked to advise their families of the request and of its scientific and medical importance."
Potential participants should be informed that at the time of their death, regardless of cause, an autopsy will be requested. The investigator should explain that they are not being asked at this time to consent to autopsy nor is it required for study participation. However, participants should be encouraged to express their wishes about an autopsy to their families so that families are prepared to take those wishes into account at the time of the participant's death.
When possible and appropriate, investigators may wish to further specify the nature and extent of postmortem testing that is likely to be of greatest interest for a particular study or whether a "partial autopsy" would be of value. If such a limited postmortem examination would be of scientific value, granting permission for specific testing only may be a desirable option for some participants and, at the time of the participant's death, for their families.
When you die, no matter what the cause, investigators will ask your family if they can do an autopsy. An autopsy will help the investigators learn more about the safety and efficacy of gene transfer. Please advise your family about your wishes regarding autopsy.
Because you are a study participant, investigators will ask your family for permission to do an autopsy when you die, even though this may be years after the study. This may help investigators learn about the effects of gene transfer. By signing this consent form, you are not forcing your family to agree to this. You should talk about this request with your family and advise them of your wishes.
Your investigator will ask your family for permission to perform an autopsy when you die, no matter what the cause. The evaluation of your organs after your death is a very valuable method to learn more about the good and bad effects of gene transfer. A "partial autopsy," in which needles are used to take samples of specific organs, may also be helpful. This type of autopsy does not require surgical incisions. You should talk about the possibility of autopsy with your family and health provider, and advise them of your wishes. The investigator may be able to tell you or your family what kind of autopsy information will be most helpful for this study. The study sponsor will pay all costs of the autopsy.
Interest of the Media and Others
NIH GUIDELINES: "To alert subjects that others may have an interest in the innovative character of the protocol and in the status of the treated subjects, the subjects should be informed of the following:
NIH GUIDELINES: "Indicate what measures will be taken to protect the privacy of subjects and their families as well as maintain the confidentiality of research data. These measures should help protect the confidentiality of information that could directly or indirectly identify study participants.
Appendix M-IV-A. What provisions will be made to honor the wishes of individual human subjects (and the parents or guardians of pediatric or mentally handicapped subjects) as to whether, when, or how the identity of a subject is publicly disclosed.
Appendix M-IV-B. What provisions will be made to maintain the confidentiality of research data, at least in cases where data could be linked to individual subjects?"
In particular, investigators should address potential participants' concerns about protection of their identities against undesired intrusions by the media and others (privacy) and about limiting access to study information that might identify them (confidentiality).
Maintaining Contact Information: Long-term follow-up of gene transfer research participants and the desire for autopsy information may require keeping basic contact information for participants as well as preserving links between names, contact information, and study results for many years. The consent form should alert potential participants that long-term follow-up will require the investigator to keep contact information, sometimes for long periods.
Stored Data and Specimens: Sometimes data or specimens collected as part of the gene transfer study may be stored for use in other research. In such cases, the investigator should:
IRBs and IBCs can provide guidance for investigators about the uses of stored specimens, including model consent language.
Reporting Requirements: While every effort should be made to keep confidential any information that identifies the participant, certain groups or individuals may inspect and/or copy participant research records for quality assurance and data analysis. The potential participant should be informed that information obtained in connection with the study may be disclosed to:
Public Discussion: An additional concern arises in gene transfer studies with regard to the privacy of participants after an adverse event. Gene transfer safety information must be reported to the NIH Office of Biotechnology Activities. These reporting requirements have been developed to keep gene transfer research as safe as possible for all research participants. Potential participants should be told before they enter a gene transfer study that adverse events and other safety information derived from their research experience could be discussed at a public session of the NIH Recombinant DNA Advisory Committee. Although individually identifiable information is not released or discussed at these meetings, they often draw public and media attention.
Media Interest: Because of the high degree of public interest in gene transfer research, the local or national media may seek information on or interviews with study participants. Investigators must be sensitive to the needs and interests of participants, both when public interest arises from positive information and when it arises from adverse events. Potential participants should be informed that every effort will be made to keep personal information confidential, but it is unwise to imply that the media will never discover or report the identity of individuals. Moreover, sometimes research participants may choose to permit disclosure of their identities, and even to participate in media coverage. Therefore, investigators should discuss the circumstances in which information would be provided to the media. The investigator should also acknowledge that sometimes disclosure of only a small amount of information might lead to the identification of the participant.
Publication of Research Data: Research results are often published in medical literature or used for teaching purposes. Potential participants should be informed that a publication will not individually identify them and that any potentially identifying information, including family pedigrees, photographs, and audiotapes or videotapes, will be used only with their explicit permission.
We will try to keep your identity and other information collected in this study confidential. There may be some exceptions when the law requires disclosure. Representatives of [study site], and/or the Food and Drug Administration, and/or the National Institutes of Health, or other regulatory agencies outside [study site] may ask to review the data collected from this study. These groups can have access to your name and medical records.
It is possible that the media may want to find out about you because you took part in this study. We will take every precaution to protect your privacy and that of your family. We will also maintain the confidentiality of the research data. To lower the chance that your identity will be made public, all requests for information will be directed to the [study site] Public Relations Office. Despite these efforts, reporters may try to find out who you are without the approval of the [study site]. If the media succeed, they might ask to interview you and your privacy may be invaded. Every effort will be made to protect your privacy but it may not be possible to do so.
If you become part of this study, investigators and their assistants can look at your medical records as necessary for the purposes of this study. The U.S. Department of Health and Human Services, employees of the study sponsor, the sponsor's monitor, contractors, and auditors, may do so as well.
The media may be interested in this study. You can talk to reporters about being in the study if you want to. The investigators will not talk about the results of the study until study information has been published in a scientific journal. Investigators will not give away your identity to news reporters at any time.
Because this study involves gene transfer, safety information must be reported to the Recombinant DNA Advisory Committee of the National Institutes of Health. This information is available to the public. However, no information by which participants can be identified will be reported with the safety information.
The media (TV, newspapers, radio, Internet, etc.) may also want to know about this study. We will try our best to protect your privacy. However, because we have to share safety information, it is always possible that the media could find out who has been in the study.
In addition to the resources within this guidance, the following resource materials may be valuable. Some of these materials are specific to human gene transfer research. Others deal with informed consent and other research ethics issues that are particularly salient in these trials (e.g., therapeutic misconception).
These materials were selected because they provide additional information on the topics discussed in the guidance that may assist investigators, institutional review boards, and institutional biosafety committees in developing consent forms or aiding the consent process for gene transfer. Materials that report the results of empirical research without providing such assistance have not been included. This list is not exhaustive and will be periodically updated.
The author asserts that current human subjects research protections are in need of reform. Changes should focus on using informed consent as an educational process. Issues are raised that relate specifically to educating potential study participants about genetic research.
This publication offers ethical commentary regarding the authors' research on therapeutic misconception. The authors suggest ways to improve the informed consent process, including the use of a trained, neutral educator to guide the consent process. This third party would focus discussion on information regarding the subject's personal care, dispel the therapeutic misconception, and better explain the purposes of the study, randomization, and use of placebos.
The author discusses the ethics of experiments that do not confer direct benefit on participants themselves. Several case studies are analyzed with respect to shared difficulties with informed consent. Suggestions are made which may help researchers provide a more thorough and effective consent process.
The author considers informed consent for study participants who are desperately ill and for whom a clinical trial may falsely offer a "last hope." To protect this vulnerable population from coercion, a decision to participate in a clinical trial must be based on a careful weighing of risks and benefits.
The author asserts that informed consent must strike a compromise between promoting moral values and ensuring risk management. This can be accomplished by using the informed consent process to encourage autonomous decision-making. A study participant's intentionality, voluntariness, and understanding are essential to this approach.
The authors suggest that, given the rapid pace of research in this area, human protocols for in utero gene transfer research may be seriously considered in the foreseeable future. Federal guidelines for fetal research rely on minimizing risk and informed consent to protect the "rights and welfare" of both the fetus and pregnant woman. However, in utero gene transfer research poses special challenges to informed consent. An expectant parents' comprehension of, and voluntariness for participation in, research may be easily undermined, leaving the fetus unprotected from undue research risks. To compensate for this limitation, a greater emphasis should be placed on the benefit/harm assessment.
An empirical study that explores the kinds of potential benefits IRBs look for when reviewing a study and how they prioritize particular benefits. The authors conclude that there is a great deal of heterogeneity in how IRBs consider benefits in research and that standards and common tools for assessment would be helpful in defining and clarifying the critical assessment elements.
After the release of the Belmont Report, the volume of information disclosed to potential study participants increased substantially. To make sure this information is conveyed thoroughly, researchers should approach this task with a commitment to open communication and collaborative decision-making.
Daugherty C, et al. A feasibility study of informed consent and medical decision-making: Employing an interactive patient choice design in phase I trials. Presented at the 1996 Annual Meeting of the American Society of Clinical Oncology 1996.
A report on a study in which participants chose from a range of predetermined dose levels after extensive information regarding risks and potential toxicities of drugs was provided. Participants were then surveyed after giving consent. Results show that allowing participants to choose their dosage level is feasible and does not interfere with the overall informed consent process. Authors assert it may even provide participants with an additional sense of control, empowerment or self-worth, and could facilitate rapid dose escalation n some Phase I studies.
A study revealed that most patients who participate in Phase I trials are strongly motivated by the hope of therapeutic benefit. Accordingly, only a minority of participants appears to have an adequate understanding of the purpose of Phase I trials as dose-escalation/dose-determination studies. The implications of these results are discussed.
The meaning and historical development of informed consent are analyzed from the standpoint of Phase I clinical trials for cancer. The author reviews empirical studies of informed consent in these Phase I trials, and calls for further research on the intricacies of communication between investigators and research participants.
Ethical issues associated with informed consent are reviewed on the basis of personal experience and reviews of current research. The ethical underpinnings of informed consent are discussed and the inadequacies of some informed consent documents are highlighted. Suggestions for future research are made which may help investigators and study participants maximize the educational value of informed consent.
The authors discuss the possibility that the current system for informed consent places a researcher's need for impartiality in direct conflict with his or her fiduciary obligation to a sick patient. The roles of the FDA and the NIH in resolving these conflicts are discussed, as is the importance of adverse event reporting.
This article proposes a framework for reviewing human gene therapy protocols for clinical trials. The author provides a description of gene transfer techniques along with a checklist of issues commonly faced by IRBs. Major points of controversy regarding gene therapy are discussed as well, including national and local review, risks to society and individuals, and the ethical quandaries raised by the prospect of germ line intervention.
To avoid the therapeutic misconception, researchers and IRBs should make sure that study participants who enroll based on potential benefits stand a reasonable chance of obtaining them. Throughout this process, researchers and IRBs must carefully distinguish between the different types of benefit and, in doing so, must discuss the nature of the potential benefit, its potential magnitude and the likelihood that it will occur, while acknowledging any uncertainty.
Investigators preparing to engage in human gene transfer research must use the NIH guidance document, "The Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into the Genome of One or More Human Subjects," written by the Recombinant DNA Advisory Committee, to prepare for the submission of a research protocol. Several corrections in the terminology (like using "gene transfer" instead of "gene therapy" and "subject" instead of "patient") employed by this guidance document could help to avoid misconceptions about gene transfer research and clarify both the promise and the limits of the research enterprise for investigators and subjects.
This article emphasizes the importance of follow up for participants in gene transfer trials. Each investigator is responsible for ensuring that participants receive proper long-term follow-up. This is especially important for gene transfer, a cutting edge technology for which public support is often tenuous. Also, the merits of a system for participant tracking are evaluated.
This article explores what happens when a physician assumes the role of researcher. In these cases, a physician's fiduciary duty to individual patients competes with a new obligation to contribute to generalizable knowledge. When conflict arises, individual IRBs can choose to introduce a third party to educate the potential study participant regarding possible risks and the expectation of benefit.
The author suggests that nonfinancial conflicts of interest are intrinsic to human subjects research. Institutions must emphasize proper behavior. IRBs should conduct widespread audits of ongoing research so that conflicts are exposed before they become problematic.
A look at some of the questions raised by minor modifications in medical practice. Focusing on the example of a change in the administration of chemotherapy for ovarian cancer, the author considers whether such innovations should be considered research and whether they should undergo review by an IRB.
This source suggests that physicians receive training in both research techniques and ethics in before they assume the role of investigator. Furthermore, when a potential participant is also the physician's patient, the physician should enlist a third party to assist in the informed consent process. Also, any financial compensation must be commensurate with the tasks performed by the physician-investigator and disclosed to the public.
NIH Recombinant DNA Advisory Committee. Assessment of adenoviral vector safety and toxicity: report of the National Institute of Health Recombinant DNA Advisory Committee. Human Gene Therapy 2002. 13(1): 3-13.
This source focuses on the gene transfer community's response to the death of Jesse Gelsinger. Particular areas of focus include adverse event reporting and information sharing as means of increasing the safety of vector use.
Sorscher EJ, et al. Informed consent to participate in a research study - gene therapy for cystic fibrosis using cationic liposome mediated gene transfer: a phase I trial of safety and efficacy in the nasal airway. Human Gene Therapy 1994. 5(10): 1271-7.
The authors provide an example of an informed consent document used in a gene transfer trial for cystic fibrosis. It may be of more general interest as a model, since the document covers the major topics raised by Appendix M for all gene transfer studies, such as the purpose of the study, procedures, follow-up, risks and discomforts, benefits, confidentiality, alternatives, and the right to withdraw from the study.
Issued by the Kennedy Institute of Ethics, this web site compiles gene transfer bibliographies on topics ranging from general information to philosophical and religious perspectives. "Quick Bib" search engine provides the most recent literature on this topic.
Some of the most recent articles about informed consent in clinical studies are referenced.
Berg JW, et al. Informed Consent: Legal Theory and Clinical Practice. Oxford University Press, 2001.
An overview of informed consent, emphasizing the practical issues facing both physicians and investigators. The historical and ethical underpinnings of informed consent are discussed, along with the challenges faced when applying current legal theory in the clinical setting.
Brody BA. The Ethics of Biomedical Research: An International Perspective. Oxford University Press, 1998.
This book analyzes the major issues of research ethics, including human subjects research protections, via a review of official policies from throughout the world.
Faden RR and Beauchamp TL with King NMP. History and Theory of Informed Consent. Oxford University Press, 1990.
Current ways of thinking about informed consent are explained from a historical perspective. Philosophical and legal frameworks are used to explore informed consent as it pertains to clinical medicine, federal policy and research involving human subjects. Autonomy is considered the foundation of current informed consent theory.
Fletcher JC. The Evolution of the Ethics of Informed Consent. In: Research Ethics. New York: Alan R. Liss, Inc., 1983, pp. 187-228.
This book addresses the philosophical, historical, and societal touchstones of informed consent. It begins with the biological and social basis for altruism (which is at the core of human concern for ethics and others), applies those concepts to the notion of consent in the practice of medicine, reviews the abominable practices of Nazi physicians at Nuremberg and the outcome of the Nuremberg trials, and closes with the more recent development of Public Health Service policy.
Getz K and Borfitz D. Informed Consent: The Consumer's Guide to the Risks and Benefits of Volunteering for Clinical Trials.
This guidebook provides the information that may help potential participants and their advocates make well-informed decisions about participating in clinical trials. Participants' rights and reasonable expectations are illustrated. Special focus is attributed to various ways participants can seek recourse if an adverse event occurs.
Katz J. Experimentation with Human Beings: The Authority of the Investigator, Subject, Professions and the State in the Human Experimentation Process. New York: Russell Sage Foundation, 1972.
This publication explores the rights and responsibilities of the various participants in clinical research. The roles of investigators, subjects, medical professionals and the state are portrayed through a case-based analysis of legal precedent.
Levine, RJ. Ethics and Regulation of Clinical Research. 2nd ed. Baltimore: Urban and Schwarzenberg, 1988.
This resource presents an overview of the medical, ethical and regulatory underpinnings of clinical research. Fundamental concepts like balancing harms and benefits are discussed, along with proper methods for selecting participants and protecting their privacy. The responsibilities of IRBs are illuminated through a case study based on Yale-New Haven Medical Center.
Veatch RM. The Patient as Partner: A Theory of Human Experimentation Ethics. Bloomington: Indiana University Press, 1987.
A review of the general ethics of experimentation and the federal regulations governing research with human subjects. Ethical dilemmas in research design and recruitment are examined, along with potential ethical problems inherent in investigations involving particular risks or patient populations. The author calls for participants to be regarded as partners in research who are well informed regarding purposes, methods, and alternatives.
The National Institute of Health Office of Biotechnology Activities compiled this brochure as a way to educate potential study participants' about what gene transfer is and how it is performed. It also includes a list of questions potential participants may want to ask when deciding whether or not to enroll in a gene transfer clinical trial.
Assembled by the National Hemophilia Foundation, this brochure discusses both positive and negative aspects of enrolling in gene transfer trials. The need for potential study participants to gather a significant amount of information prior to making their decisions is stressed.
A guide to understanding the process of informed consent through which potential study participants can learn about possible risks and benefits as well as their rights and responsibilities. Contains some sample forms and templates.
This patient reference guide, published by the American Association of Health Plans, highlights key issues for adult patients who are thinking about enrolling in a clinical trial.
This pamphlet provides important questions that potential study participants should ask before participating in a clinical trial.
This site provides a glossary pertinent to rare diseases and conditions that was compiled by the NIH Office of Rare Diseases. It also provides links to other sources of information about clinical trials more generally.
The University of Michigan IRB compiled definitions of scientific terms that frequently appear in informed consent documents but may be unfamiliar to potential study participants. In addition to helping potential study participants, this is a useful tool for researchers and IRB members as they write and evaluate informed consent documents.
The National Human Genome Research Institute (NHGRI) created this database to help potential study participants better understand the terms and concepts used in genetic research. One click on the term of interest reveals information ranging from term's pronunciation, audio information, images and additional links to related terms.
Government Guidelines and Regulations
Subpart A provides the basic federal policy for the protection of human subjects. Subparts B, C, and D, respectively, set forth additional protection for research, development and related activities involving fetuses, pregnant women, and in vitro fertilization; research involving prisoners; and research involving children.
Part 50 sets forth the Food and Drug Administration's requirements for informed consent, while Part 56 outlines the agency's provisions for IRBs. Though largely similar, the FDA regulations differ in several key respects from the "Common Rule" (45 CFR Part 46) adopted by other agencies and administered by the Department of Health and Human Services. For research falling under the purview of both HHS and FDA, the requirements of both sets of regulations must be met.
This document represents the FDA's current guidance on protection of human subjects involved in clinical research. While this document is not intended create or confer any rights and does not operate to bind the FDA or the public, it is meant to serve as an aid to IRBs as in effectively protecting human research subjects.
This document recommends ways to attain higher levels of harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines. The objective of such harmonization is a more economical use of human, animal and material resources, and the elimination of unnecessary delay in the global development and availability of new medicines while maintaining safeguards on quality, safety and efficacy, and regulatory obligations to protect public health.
IRBs confront many complex issues. Familiarizing oneself with the pertinent regulations is a challenge, and understanding the concepts involved, how they relate to human subject research, and how they should be applied can be equally difficult. This document offers an explanation of the legal and ethical constructs that form the basis for human subjects research regulations which researchers and IRB members may find helpful.