- Email: [email protected]
Recommendations proposed for adenovirus gene therapy trials in the UK
Letter
MOLECULAR MEDICINE TODAY, DECEMBER 2000 (VOL. 6)
Recommendations proposed for adenovirus gene therapy trials in the UK The adenovirus-related death of 18-year-old Jesse Gelsinger, on 17 September 1999, in a phase I gene therapy trial to correct an ornithine transcarbamylase (OTC) deficiency, raised concerns about the safety of gene therapy, particularly adenovirus-related adverse reactions. The UK Gene Therapy Advisory Committee (GTAC) had initiated a review of serious adverse events (SAEs) in gene therapy trials early in 1999. With the reported death in the USA, the UK review focused on the adenoviral gene therapy trials, of which there were 11, involving a total of 69 patients, all with advanced cancer. Although no major lifethreatening toxicity had occurred with the use of adenoviral vectors, it was decided to set up a working group with membership from GTAC, other regulatory bodies and the research community, with the remit to review UK practice in adenoviral gene therapy trials, including the reporting of SAEs and to develop recommendations for the guidance of researchers who use adenoviral vectors. The report of the working group* makes recommendations for the clinical monitoring and surveillance of patients, route of administration of the vector, standardization of viral dose, appropriateness of patient groups, procedure for reporting SAEs and serious adverse reactions (SARs), and for increasing the availability of information to researchers and the public. The level of clinical monitoring recommended depends on the route of administration and, in particular, reflects concerns related to risks associated with systemic exposure to the vector. It is recommended that routine monitoring should be more frequent in the first 48–72 hours and should include additional investigations, such as pre- and postdosing anti-adenoviral antibody levels and pretreatment assessment of T-cell populations (CD3, CD4) at suitable intervals. The storage of preadministration samples to enable retrospective analysis in the event of SARs is strongly encouraged. Intravascular administration of adenovirus raises
a particular problem with theoretically greater risk than for the intra-tumoural route. The report enumerates the investigations that should be monitored in the first three to four days posttreatment and for a longer period if any of the investigations are abnormal. Researchers proposing to use the intra-hepatic route for the delivery of the adenovirus should monitor the recipient on an in-patient basis. The lack of accurate standardization of adenoviral dose and the need for reference standards for use as controls in assays of vector potency was recognized. It was recommended that investigators should set the initial dose of adenovirus at two logs lower at least than the maximum safety dose predicted by clinical evaluation. In dose escalation studies, early signs of toxicity might indicate that the dose levels are approaching a maximum tolerated dose and that future dose increments should be reduced. With some adenovirus trials, GTAC might require a case-by-case assessment before permitting the investigators to proceed to a higher dose. In deciding the suitability of patients, GTAC will consider carefully the balance of potential risks against the possible benefits. It is recommended that only patients with severe and life-threatening diseases should be recruited into dose escalation studies. All SARs must be reported by law to the Medicine Control Agency. In addition, SAEs, whether deemed to be related to the study or not,
should be reported within 14 days (seven days for death) to the appropriate Local Research Ethical Committee in accordance with their requirements and also to GTAC. Investigators are encouraged to include in their reports to GTAC, any data which might be suggestive of a dose-related toxicity, but which does not result in a clinical SAE. GTAC would value notification of SAEs in trials conducted outside the UK, which might have relevance for safety of subjects enrolled in UK studies. The report also recommends that any information that might be relevant to the safety of patients should be made available to all UK investigators involved in adenoviral gene therapy trials. The sharing of data will be by agreement with the submitting investigator but would have all proprietary and confidential references erased. Norman C. Nevin MD*, FFPHM, FRCPath, FRCPEd, FRCP Professor and Chairman Jayne Spink PhD GTAC Secretariat Gene Therapy Advisory Committee Belfast City Hospital Trust, Belfast, UK BT9 7AB. Tel: 144 28 9026 3873 Fax: 144 28 9023 6911 *e-mail: [email protected]
MEETINGS Are you organizing a meeting that would interest readers of Molecular Medicine Today? If so, we would like to hear from you. We are happy to publish details of relevant meetings in the Diary section of the journal (see page vii of this issue) Please send meeting details (including meeting name, dates, location and contact details) to the Editor at:
*Gene Therapy Advisory Committee, Report of the GTAC Adenovirus Working Party, June 2000, Departments of Health,
[email protected]
United Kingdom
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
461
MOLECULAR MEDICINE TODAY, DECEMBER 2000 (VOL. 6)
Recommendations proposed for adenovirus gene therapy trials in the UK The adenovirus-related death of 18-year-old Jesse Gelsinger, on 17 September 1999, in a phase I gene therapy trial to correct an ornithine transcarbamylase (OTC) deficiency, raised concerns about the safety of gene therapy, particularly adenovirus-related adverse reactions. The UK Gene Therapy Advisory Committee (GTAC) had initiated a review of serious adverse events (SAEs) in gene therapy trials early in 1999. With the reported death in the USA, the UK review focused on the adenoviral gene therapy trials, of which there were 11, involving a total of 69 patients, all with advanced cancer. Although no major lifethreatening toxicity had occurred with the use of adenoviral vectors, it was decided to set up a working group with membership from GTAC, other regulatory bodies and the research community, with the remit to review UK practice in adenoviral gene therapy trials, including the reporting of SAEs and to develop recommendations for the guidance of researchers who use adenoviral vectors. The report of the working group* makes recommendations for the clinical monitoring and surveillance of patients, route of administration of the vector, standardization of viral dose, appropriateness of patient groups, procedure for reporting SAEs and serious adverse reactions (SARs), and for increasing the availability of information to researchers and the public. The level of clinical monitoring recommended depends on the route of administration and, in particular, reflects concerns related to risks associated with systemic exposure to the vector. It is recommended that routine monitoring should be more frequent in the first 48–72 hours and should include additional investigations, such as pre- and postdosing anti-adenoviral antibody levels and pretreatment assessment of T-cell populations (CD3, CD4) at suitable intervals. The storage of preadministration samples to enable retrospective analysis in the event of SARs is strongly encouraged. Intravascular administration of adenovirus raises
a particular problem with theoretically greater risk than for the intra-tumoural route. The report enumerates the investigations that should be monitored in the first three to four days posttreatment and for a longer period if any of the investigations are abnormal. Researchers proposing to use the intra-hepatic route for the delivery of the adenovirus should monitor the recipient on an in-patient basis. The lack of accurate standardization of adenoviral dose and the need for reference standards for use as controls in assays of vector potency was recognized. It was recommended that investigators should set the initial dose of adenovirus at two logs lower at least than the maximum safety dose predicted by clinical evaluation. In dose escalation studies, early signs of toxicity might indicate that the dose levels are approaching a maximum tolerated dose and that future dose increments should be reduced. With some adenovirus trials, GTAC might require a case-by-case assessment before permitting the investigators to proceed to a higher dose. In deciding the suitability of patients, GTAC will consider carefully the balance of potential risks against the possible benefits. It is recommended that only patients with severe and life-threatening diseases should be recruited into dose escalation studies. All SARs must be reported by law to the Medicine Control Agency. In addition, SAEs, whether deemed to be related to the study or not,
should be reported within 14 days (seven days for death) to the appropriate Local Research Ethical Committee in accordance with their requirements and also to GTAC. Investigators are encouraged to include in their reports to GTAC, any data which might be suggestive of a dose-related toxicity, but which does not result in a clinical SAE. GTAC would value notification of SAEs in trials conducted outside the UK, which might have relevance for safety of subjects enrolled in UK studies. The report also recommends that any information that might be relevant to the safety of patients should be made available to all UK investigators involved in adenoviral gene therapy trials. The sharing of data will be by agreement with the submitting investigator but would have all proprietary and confidential references erased. Norman C. Nevin MD*, FFPHM, FRCPath, FRCPEd, FRCP Professor and Chairman Jayne Spink PhD GTAC Secretariat Gene Therapy Advisory Committee Belfast City Hospital Trust, Belfast, UK BT9 7AB. Tel: 144 28 9026 3873 Fax: 144 28 9023 6911 *e-mail: [email protected]
MEETINGS Are you organizing a meeting that would interest readers of Molecular Medicine Today? If so, we would like to hear from you. We are happy to publish details of relevant meetings in the Diary section of the journal (see page vii of this issue) Please send meeting details (including meeting name, dates, location and contact details) to the Editor at:
*Gene Therapy Advisory Committee, Report of the GTAC Adenovirus Working Party, June 2000, Departments of Health,
[email protected]
United Kingdom
1357-4310/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
461