After the Ethical Reassessment Continuation of Clinical Gene Therapy Studies Recommended

As a result of a meeting which took place on 19th November 2002, the Paul-Ehrlich-Institut and the German Medical Association recommend that certain clinical studies using live retrovirally modified cells be continued. This decision was possible after study protocols were changed on the basis of an ethical reassessment. Among other things, it was made compulsory for the principal investigators in Germany to include the description of a case of leukaemia in France and its assumed connection with the induction of retroviral vectors into the genome of human cells into the patients' information leaflets.

After an expert meeting on 17th September 2002, the Paul-Ehrlich-Institut and the Commission of Somatic Gene Therapy (Kommission Somatische Gentherapie (KSG)) of the Scientific Council of the German Medical Association recommended to put all clinical gene therapy studies in Germany on hold after the occurrence of a case of leukaemia in France during a study with retroviral gene transfer (see "Letter of Information Issued by the Paul-Ehrlich-Institut and the German Medical Association" of 23rd October 2002 and "Joint Press release by the Paul-Ehrlich-Institut and the German Medical Association" of 30th September 2002. At the expert meeting, a possible connection was discussed between the case of leukaemia which occurred in France and the treatment of the affected child with retrovirally modified blood stem cells. At first, a connection was not ruled out and can be assumed in accordance with the present state of the art. During the observation period of three years, the treatment had brought about a cure of the congenital immune deficiency disorder SCID-X1.

The principal investigators had to submit an amendment of the study protocol in preparation of the meeting of 19th November in which a recommendation on the continuation of their clinical study was to be discussed. This amendment was to comprise a now risk / benefit analysis of the study, statements regarding a possibly required adaptation of the inclusion and exclusion criteria of the patients, and a change in the patients' information leaflets. Three affected principal investigators out of sixteen followed this request, while two submitted a new application. Eleven clinical studies were already completed or will not be started.

The result of the meeting was that the KSG has now demanded further amendments of the patients' information leaflet and the written risk / benefit analysis for the three remaining clinical studies. After receipt of the amendments, the KSG will recommend a positive vote on the studies to the competent ethics commissions which were form in compliance with the law of the appropriate Bundesland (state). The Paul-Ehrlich-Institut, with whom this vote has been agreed upon, will forward this recommendation to the competent land authorities. The studies which may be continued after the appropriate amendment include the so-called CGD study ('Chronic Granumatous Disease', a congenital immune deficiency disorder) and two so-called GvHD studies ('graft versus host disease', - a life-threatening extreme immune reaction of foreign donor lymphocytes against organs and tissues of the patient treated; for more information, see studies in the appendix).

According to Klaus Cichutek, chairman of the Commission of Somatic Gene Therapy and Vice President of the Paul-Ehrlich-Institut, "both the commission and the Paul-Ehrlich-Institut supported the principal investigators in their advisory function and the patients who had to face a decision on a participation in the studies. The decision was to be made after the case of leukaemia in France." Mr. Cichutek also expressed the view that with the improvement of gene therapeutic treatments, first successes but also serious side effects became apparent. Therefore, the use of each gene therapy was to be assessed against the background of the disease to be treated. "Taking a risk such as the development of leukaemia is only acceptable in the event of a life-threatening disease and in expectation of a future successful treatment", as Mr. Cichutek expressed it. "Each patient had to decide on the participation in such a study by himself. Therefore, the patient would have to be informed extensively on the benefit and the risk", as Mr. Cichutek went on, "and would have to be informed that other methods, which could replace the use of live, retrovirally modified cells within the clinical studies affected were currently not available."

All three clinical Phase I/II studies for which a continuation has been recommended are primarily aimed at testing the safety and tolerability of the use of the genetically modified cells in patients with life-threatening conditions. Two submitted new applications for studies using retrovirally modified cells will be decided upon in normal procedures. For these studies, an ethical evaluation in view of the assumed risk of leukaemia by using retroviral vectors has already been taken into consideration in formulating the application. The two new applications concern studies on the gene therapy in HIV infections and rheumatoid arthritis.

Prof. Dr. Klaus Cichutek

Vice President of the Paul-Ehrlich-Institut

Chairman of the 'Commission of Somatic Gene Therapy'

Background Information:

Since 1994, the following clinical studies using live retrovirally modified cells have been registered (application at the Commission for Somatic Gene Therapy (Kommission Somatische Gentherapie (KSG) and/or submission in conformity with Section 40 German Drug Law at the Paul-Ehrlich-Institut or the Federal Agency for Medicinal Products and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)).

1. Gene therapy of a monogenic hereditary disorder:

For the treatment of the life-threatening monogenic hereditary disorder CGD ("Chronic Granulomatous Disease"), autologous blood stem cells are transplanted the gene defect of which was corrected by retroviral transfer of a functionally intact gene. This serves to alleviate, or even cure, the congenital immune deficiency.

Status: 1 registered study;

this study is recommended to be continued after being on hold.

2. GvHD-treatment by 'suicide gene' transfer and administration of Ganciclovir:

Suppression of graft-versus-host disease during the treatment of leukaemia by transplantation of foreign (allogeneic) blood stem cells and lymphocytes. The transfer of allogeneic donor lymphocytes is a conventional therapy which, after prior chemotherapy and allogeneic stem cell transplantation, leads to suppression of leukaemia (donor-versus-leukaemia effect). However, a strong immunological reaction (graft-versus-host disease; GvHD) caused by the transplanted lymphocytes can occur and may cause possibly life-threatening complications. If allogeneic donor lymphocytes are used into which a drug-inducible cell-killing gene ("suicide gene"; thymidin kinase gene of the Herpes simplex virus) was transferred by a retroviral vector, these cells can be killed in vivo by administration of the specific drug Ganciclovir in the event of a severe GvHD. This treatment therefore helps to avoid life-threatening complications.

Status: 4 registered studies; on hold,

two of these studies will be recommended for continuation

after the changes in the protocol have been made

3. HIV-gene therapy:

The transfer of lymphocytes which bear an HIV inhibiting gene serves to suppress HIV replication in the body.

Status: 1 registered study, not started and permanently put on hold;

1 new application, to be decided upon in a normal procedure

4. Use of an indicator gene to analyse haematopoetic reconstitution:

Gene marked cells are transferred as part of the transplantation of blood stem cells indicated in leukaemia treatment. During haematopoetic reconstitution, the amount and type of emerging blood cells are analysed.

Status: 3 registered studies; permanently put on hold

5. Local gene therapy of rheumatoid arthritis:

(Synovial) cells are removed from the joints affected by arthritis. After transfer of a gene (IRAP, "interleukin receptor antagonist"), the product of which can block factors contributing to the inflammation of the joint (cytokines), the modified cells are re-transferred to the joint.

Status: 1 registered study, on hold;

A decision on a new application for continuation of this study is to be made in a normal procedure

6. Transfer of drug-resistence-gene modified blood stem cells during high-dose chemotherapy of malignant tumours:

The efficiency of cancer therapy is intended to be improved by high-dose chemotherapy. Since, above all, blood cells may be damaged by chemotherapy, these cells are intended to be protected by a gene which confers resistance against several drugs (mdr = "multiple drug resistance gene"). The mdr gene is transferred to the blood stem cells before stem cell transplantation.

Status: 2 registered studies; completed.

1 registered study negative appraisal, therefore not started.

7. Brain tumour treatment by injection of mouse cells producing a suicide vector, followed by administration of Ganciclovir:

In patients with progressive disease, live murine vector packaging cells are transferred during brain surgery. The cells release retroviral vectors transferred to residual tumour cells. The vectors transfer a suicide gene to the tumour cells which makes the tumour cells susceptible for the cell-damaging effect of Ganciclovir. After Ganciclovir administration, these tumour cells and the vector packaging cells should be killed in the body.

Status: 4 registered studies; completed

top