Dr. Athanasios Tsianakas Department of Dermatology University of Münster Von-Esmarch-Straße 58 D-48149 Münster, Germany Tel.: +49-251-83-52945 Fax: +49-251-83-56549 E-mail: Athanasios.Tsianakas@ukmuenster.de
Metastasized melanoma has an unfavorable prognosis. Therefore there is strong need for new innovative therapies. In cases in which standard therapies have failed and inclusion in clinical studies is not possible due to diverse causes, the option of compassionate use now opens new therapeutic windows. Compassionate use describes the use of not (yet) approved drugs for humanitarian reasons. It was legally established in Germany through drug laws issued in 2006. We describe legal aspects of compassionate use are discussed, taking two of our cases as examples. Finally, examples for necessary documents to apply for compassionate use are provided.
The incidence of melanoma has been increasing for years [1, 2] with stage IV metastatic melanoma xxx still having a grim prognosis with mean survival of only 6–9 months . The only drugs licensed in Germany for drug therapy of melanoma are the alkylating agent dacarbazine (DTIC), the vinca alkaloid vindesine as well as the platinum derivative cisplatin. In most recently clinical studies there was a response rate of 5.5–12.1% to DTIC , in a study from 2001 one of 23%. Other monochemotherapies (vindesine, temozolomide, fotemustine) possess similarly low response rates. Polychemotherapies (including cisplatin) have higher response rates but no significant prolongation of total survival and significantly greater toxicity [6–9]. Thus, unfortunately, the treatment of melanoma in stage IV had not made significant progress in the past decades.
It is therefore recommended to include stage IV patients in clinical studies so that they have access to new therapeutic modalities and to identify as quickly as possible study drugs that might bring advantages in the treatment of stage IV disease . Many patients are prevented from participating in such studies due to strict in-/exclusion criteria (often no previous chemotherapy is a requirement). Other problems might also arise, such as a long travel distance to the nearest study center.
In such cases where existing studies give a basis for the hope that a new drug might be effective, the possibility of compassionate use opens. That expression means the allowed use of a drug before its licensing on humanitarian grounds. This is understood as the use of a possibly effective but not yet licensed drug in the individual cases of patients in life-threatening situations or with severe diseases who cannot be treated in another manner, taking into account the physician's obligation to treat and his/her free therapeutic choices.
On the basis of EU regulation 2001/83/EG compassionate use was included in the German Drug Law by the 14th Amendment to the Arzneimittelgesetz (AMG, Drug Law), as is already the case in numerous other EU states as well as the USA (already since 1987). The possibility now exists in carefully selected individual cases to employ drugs that are not yet licensed and are still undergoing clinical trials (phase 3 or the time period after completion of the licensing study and commercial availability) (in contrast to off-label use, where a drug is already licensed, but for another indication). The Federal Institute for Drugs and Medical Devices instructs that the following requirements must be fulfilled before performing compassionate use:
• Evidence that the patient has a disease that is life-threatening or leads to severe disability
• Evidence that no satisfactory alternative therapy option with a drug licensed in the EU is available
• Evidence that a licensing application has been made for the drug in question or that it has not yet completed clinical trials
• Taking the Guideline on Compassionate Use of Medical Products, Pursuant to Article 83 of Regulation (EC) No. 726/2004, EMEA 2007  into consideration
• Evidence of efficacy for the foreseen indication and safety of treatment – availability of suitable documents, e.g. current “investigator's brochure” with clinical and non-clinical data relevant for use (study data)
• Definition of in- and exclusion criteria and perhaps discontinuation criteria for the “compassionate use” program
• Measures of pharmacovigilance (reporting of unwanted drug reactions and drug monitoring) in the “compassionate use” program
We wanted to treat two patients with stage IV melanoma with disseminated metastases who had each failed two chemotherapy regimens (monotherapy with DTIC and polychemotherapy according to McClay [Dartmouth scheme][carmustine, cisplatin, DTIC]) with the antisense molecule oblimersen (Genasense®). In a phase 3 study in patients with normal or only slightly elevated LDH levels, the combination of oblimersen with DTIC was significantly superior to monotherapy with DTIC. Oblimersen blocks the translation of Bcl-2 mRNA and thus increases chemotherapy-induced apoptosis [12, 13]. In a stratification performed later the combination of DTIC and oblimersen led to prolonged progression-free survival (3.1 versus 1.6 months) and even prolonged overall survival (11.4 versus 9.7 months) in patients with an LDH < 1.1 ULN .
Before licensing, these results must be reproduced in an international phase 3 study which has begun (Protocol No. GM307, Genta International Inc., Berkeley Heights, NJ, USA) but was not yet initiated when the two patients presented.
We examined if the prerequisites for compassionate use were fulfilled. They were, because:
• A life-threatening disease was present
• There was no longer a satisfactory licensed alternative therapy
• Oblimersen is the subject of not yet completed trials
• Evidence of efficacy in the foreseen indication and safety of treatment was documented (investigator's brochure and study data)
• We had defined in- and exclusion criteria and discontinuation criteria for compassionate use
Further the manufacturer must be willing to make the product available for compassionate use. It is not obliged to do so, as side effects that occur might endanger planned licensing. In the case of oblimersen, the Genta company was willing. The price is set by the manufacturer (no set list price, as the drug is not yet licensed).
We prepared an information sheet for the patient, we applied for permission of the regional government (required by the pharmacy, as it is an unlicensed drug), applied for approval at the ethics commission of the Medical Association (for better legal protection) and applied to the patients’ health insurance for reimbursement of costs (Figure 1, 2, 3). In contrast to off-label use, health insurance funds are not legally obliged to automatically reimburse costs in compassionate use. We received a positive vote by the ethics commission, and approval of the regional government to treat both patients with the antisense molecule oblimersen in the framework of compassionate use. The health insurance funds of both patients also agreed to reimburse costs.
Course of therapy
Our first patient had LDH values in the upper normal range at the initiation of therapy, the second slightly elevated LDH values (< 1.1 ULN). Tw o complete cycles (day 1–21) of intravenous oblimersen (imported by IDIOS, London) 7 mg/kg t/24 hours continually for 120 hours (day 1–6) followed by DTIC (day 6 1000 mg/m2 body surface area i.v.) were administered to both patients. As a side effect only a mild temporary thrombocytopenia typical for oblimersen occurred. Technical staging before the planned third cycle showed disease progression in both cases, so that therapy had to be discontinued.
With this article we want to draw attention to the legal possibility of compassionate use and illustrate the requirements that must be fulfilled. Other oncology centers should be encouraged to consider compassionate use in select cases in order to broaden treatment options for patients with diseases such as stage IV melanoma that have low response rates to standard therapy schemes.
Conflicts of interest
Prof. Dr. Cord Sunderkötter has received reimbursement for clinical studies and a lecture.