HOW TO PRINT To print this page, use your browser's print button. To print the entire document, download the PDF or click here and use your browser's print button. SAMPLE LANGUAGE Sample 1 - Risks Associated with Study Agent Sample 2 - Risk of Cancer Caused by Gene Transfer Problematic Sample 1 TOOLS & BACKGROUND MATERIALS Kimmelman J.  Recent developments in gene transfer: risk and ethics. British Medical Journal 2005.
MAIN POINTS The purpose statement should: Not overstate the goals of the study Reflect the study phase Include an understandable explanation of gene transfer

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."

DISCUSSION
Gene transfer is a deliberate intervention with potential risk. Potential participants should be given information about all reasonably foreseeable risks of harm, discomforts, and potential side effects associated with the procedures and agent as outlined in the study. Such information should include the seriousness, likelihood of occurrence, timing (short- or long-term), and reversibility of the possible harm.

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.

• Phase I Study: Phase I trials involve the greatest uncertainty about risks of harm, since existing evidence is limited to animal or laboratory studies or to results of the gene transfer intervention in a separate disease. All the expected and remote risks of harm that may foreseeably be associated with participation in the study should be listed and explained.
  
  Previous experiences with the same or similar vector, or even a different transgene, should be included in the risks section, particularly in phase I studies. Experience with animal studies may be relevant, as well as other human experience, and possibly even in vitro experience, when the meaning and limitations of the findings are carefully described. A general statement that humans and animals respond very differently, and a statement about the relationship between the dose levels used in animals and humans would be appropriate. Uncertainty about the likelihood of the occurrence of most risks of harm from the gene transfer intervention at this early stage of research should be acknowledged.
• Phase II Study: The risks of harm from the intervention are better defined for a Phase II study. The consent form should include descriptions of risks of harm that were discovered in Phase I, such as reactions to the maximum-tolerated dose. It should be acknowledged that the extent of experience is still limited and that unanticipated harms may develop.
• Phase III Study: The risk statement of a Phase III trial should reflect the results of earlier trials. It should also acknowledge that with a greater number of enrolled participants, less-common side effects are likely to be recognized at this stage.

• Risks associated with the study procedures: If the study includes non-research procedures as well as study procedures, the risks of harm from medical procedures that are not being conducted for research purposes are better addressed in a treatment consent form separate from the consent form for the gene transfer experiment. If it is essential to include risks of harm from medical procedures that are not being conducted for research purposes in the research consent form, such risk statements should be distinguished from the risks of harm from the research procedures, and the latter should remain the primary focus of the risk section.
• Risks of harm associated with the study agent: Potential participants should be informed of the specific risks of harm from the vector and transgene used in the given study. The following risks of harm from gene transfer should be included whenever appropriate:
  • The added vector and/or gene could create changes in cells that could lead to cancer
  • The added vector and/or gene could create permanent changes in cells that could be passed on to children conceived and born during or after study participation
  • The added vector and gene could go to unexpected cells or tissues in the body
  • The added vector could become able to reproduce itself, and the added vector and gene could be passed on to close contacts like an infection

SAMPLE LANGUAGE

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 LANGUAGE

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.