This guidance provides to you, sponsors of gene therapy studies, recommendations regarding the design of studies to include the collection of data on delayed adverse events in subjects who have been exposed to. Guidance for Industry: Gene Therapy Clinical Trials. Criteria to Assess Potential Delayed Risks of Gene Therapy. We generally will not require long- term follow- up observations following exposure to gene transfer technology when the risk of delayed adverse events is low. To assess the risk related to your product, we recommend that you use available preclinical and clinical evidence. To assess the risks of delayed adverse events, you may use current information about your product and similar products based on studies that you and others have performed. As more data accumulates, it is important to reassess the risk to your subjects and, if appropriate, revise your protocol as it relates to long- term follow- up observations. We consider the assessment of risks to be a continuous process. New information may support the need for long- term follow- up observations or the revision of an existing study. For example, if recently reported evidence suggests a newly identified risk associated with your product or similar products, long- term follow- up observations may be necessary to mitigate long- term risks to subjects receiving these vectors. Similarly, if sufficient data accumulate to suggest that your product is not associated with delayed risks, it may be appropriate to reduce or eliminate provisions for long- term follow- up observations. Pertinent previous preclinical and clinical experience with your product or similar products is highly relevant in the assessment of delayed adverse events. JOURNAL OF PERSONALlTY ASSESSMENT. 1994.63(3), 534-553 Copyright O 1994. Lawrence Erlbaum Associates, Inc. Form C of the MHLC Scales: A Condition-Specific Measure of Locus of Control Kenneth A. ASSESSING SOCIAL SUPPORT 129 of satisfaction with the available support. These two factors in social support may vary in their relation to one another, depending on the individual's personality. Some people may think that only. Self-control, an aspect of inhibitory control, is the ability to control one's emotions and behavior in the face of temptations and impulses. As an executive function, self-control is a cognitive process that is necessary for.Experience with products in the same vector class, administered by a similar route, and given for the same clinical indication may contribute helpful information. We recommend you refer to the series of questions in Figure 1, “Framework to Assess the Risk of Gene Therapy- Related Delayed Adverse Events” to help you assess the level of risk. When the risk of delayed adverse events is low based on your answers to these questions, a plan for long- term follow- up observations may not be necessary to mitigate risks to subjects. Evidence from preclinical studies will help you answer questions 1 – 3. Rotter's Locus of Control Scale For each question select the statement that you agree with the most 1. Children get into trouble because their patents punish them too much. The trouble with most children nowadays is that. Rotter's Locus of Control Scale This is a questionnaire to find out the way in which certain important events in our society affect different people. Each item consists of a pair of alternatives lettered a or b. Multivariate logistic regression analysis was used to test the three hypotheses as to the effect of culture on the likelihood of (1) an internal locus of control orientation, (2) an innovative orientation, or (3) a combined. Include all of the primary data relevant to the assessment of the risk of delayed events when you submit your IND to FDA (see 2. CFR 3. 12. 2. 3(a)(8), (1. We suggest you use the framework in Figure 1 by answering the questions in sequence as follows: Question 1: “Is your gene therapy product used only for ex vivo modification of cells?”If the answer is “no,” go to Question 2. If the answer is “yes,” go to Questions 3 and 4. Question 2: “Do preclinical study results show persistence of vector sequences?”If the answer is “no,” the risk of gene therapy- related delayed adverse events is low, and long- term follow- up observations may not be needed. If the answer is “yes,” go to questions 3 and 4. If it is unknown whether your vector persists, for the purpose of assessing risk, we recommend that you either assume that it does persist, or perform a preclinical study to assay for vector persistence in a relevant animal species. Please refer to Section IV. B, “Considerations for Preclinical Study Design to Assess Vector Biodistribution and Persistence,” for help with preclinical trial design and details on the use and expected sensitivity of polymerase chain reaction (PCR) assay for biodistribution studies. In assays performed after the final administration of vector, persistence is indicated by detectable levels of vector sequences above the threshold level in the PCR assay and absence of an apparent downward trend over several time points. In contrast, persistence is unlikely if you cannot detect vector sequences with a sensitive PCR assay or if the assay for vector sequences demonstrates a downward trend over time. We encourage you to consult with OCTGT, CBER for specific advice about determination of persistence and biodistribution in your test system. Question 3: “Are vector sequences integrated?”. If the answer is “no,” go to question 4. If the answer is “yes,” we would require that clinical protocols with the product include clinical long- term follow- up observations. Question 4: “Does the vector have potential for latency and reactivation?”. If the answer is “no,” the risk is low that exposure to your gene transfer technology will be followed by gene therapy- related delayed adverse events. Long- term follow- up observations may not be needed. If the answer is “yes,” we would require that all your clinical protocols with the product include clinical long- term follow- up observations. Laboratory and preclinical evidence of the low risk of delayed adverse events following exposure to a similar product may show that long- term follow- up observations are not needed. If you provide data from a similar product, we can assess the relevance to your product if you provide a clear explanation. We provide the following two examples: Your product is a plasmid and the similar product is also a plasmid, but has different coding sequences for the proposed therapeutic gene product. The similar product has been used in preclinical and clinical studies, administered by an identical route and in an identical final formulation to that proposed in the prospective studies. Reference to a published study demonstrating lack of persistence of the vector for the similar product may adequately address concerns regarding the persistence of the proposed vector. Your proposed product and the similar product differ only with respect to route of administration. The similar product was administered into tumors (intratumorally). The proposed product is to be given intravenously. There is a published study demonstrating the lack of persistence of the vector when administered intratumorally. The data from the studies with the similar product are not sufficiently relevant, since there was no intended systemic exposure to the product. Thus, there is insufficient similarity to conclude that long- term follow- up observations are not necessary to mitigate long- term risks to subjects. In the absence of relevant data from a study involving a similar product, we recommend that you assess the risk of vector persistence in a preclinical study with the proposed product administered by the intravenous route. If you believe you have evidence from studies on a similar product that is adequate to support conclusions that the vector is unlikely to persist in human hosts and that the vector’s DNA does not integrate into the human genome, you may decide to submit a clinical protocol that does not provide for long- term follow- up observations. We will review such submissions and, if we disagree based upon our review of your submission or other additional information, we may conclude that long- term follow- up observations for delayed adverse events are necessary to mitigate long- term risks, and that without long- term follow- up observations, the study presents an unreasonable and significant risk to study subjects (2. CFR 3. 12. 4. 2(b)(1)(i) and (b)(2)(i)). We provide the following examples of evidence that might cause us to require you to perform long- term follow- up observations for delayed adverse events: A preclinical toxicology study indicates that expression of the transgene is associated with delayed toxicity. The transgene provides functional replacement of a host gene; the transgene product is potentially immunogenic. Data collected in your short- term clinical study indicate vector persistence, even though data from your preclinical studies suggested that the vector did not persist. Figure 1. Framework to Assess the Risk of Gene Therapy- Related Delayed Adverse Events. If you have evidence that suggests that the vector may integrate or if the vector was intentionally designed to facilitate integration (please refer to Table 1, Section IV. C), the answer is “yes.” If you have no evidence regarding integration, we recommend that you include preclinical study in your development plan to address this question. If you or others identify an increased risk of delayed adverse events from persistent gene expression or from exposure to your product based on additional information reported after your protocol is accepted, you should plan to perform long- term follow- up observations even if the answer to these questions is “No”. See Section IV. A of the text for examples. See Section V of the text for recommendations on how to perform clinical long- term follow- up observations. Return to Table of Contents. Considerations for Preclinical Study Design to Assess Vector Biodistribution and Persistence. As discussed in Section IV. A, vector persistence heightens the risk of delayed adverse events following exposure to gene transfer technology. Indeed, the longer the vector persists, the greater the duration and degree of risk of delayed adverse events. We recommend that you perform preclinical biodistribution studies using methods that are shown to be sensitive and quantitative to detect vector sequences. Such studies would be designed to determine the distribution of your vector in nontarget tissues and the persistence of the vector in both nontarget and target tissues following direct in vivo administration of the vector product. If possible and applicable, we recommend that the studies employ an animal species that permits vector transduction and/or vector replication and that the animal species be biologically responsive to the specific transgene of interest (Ref. The duration of the preclinical studies will vary, depending on the animal model employed. Projections of delayed adverse reactions in human subjects may be derived from assessment of data from appropriate long- term observational studies in animals, when possible. A biodistribution study in animals can be performed either as a separate study or as a component of a toxicology study. Consider the following points in your animal study design to permit evaluation of vector localization and persistence (Ref. Animal Study Design.
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