Off-label prescription of anti- cancer drugs in Italy: what responsibilities? Jacopo Giuliani 1 , Valentina Maiolli 2 , and Andrea Bonetti 1 1 Department of Oncology, Mater Salutis Hospital, ASL 21, Regione Veneto, Legnago (Verona); 2 Specialist in legal profession, Legal assistant at G Dainese’s law firm, Rovigo, Italy Any new drug is labelled with indications, dose and administration by drug approval authorities and is called an on-label drug. A drug use outside the terms of its official labelling is referred to as off-label 1 . This is dif- ferent from the case of an ‘unlicensed’ drug. In the latter case, the drug is not accessible on the market and, in principle, can only be used for clinical studies, or for a compassionate/expanded access setting, generally pro- vided for free by the pharmaceutical company 2 . The use of off-label drugs in oncology has been esti- mated to reach 50%, or even more 3 . Some authors have estimated that the use of off-label antineoplastic drugs (patients submitted to chemotherapy in 15 Italian on- cology centers were evaluated for two non-consecutive days in a two-week period) accounts for less than 20% of prescriptions, and most of them are based on scientific evidence of efficacy 4,5 . From a legal point of view, the doctor’s responsibility arising from off-label drug prescription is a question poorly addressed by doctrine and jurisprudence. Cur- rently, use of off-label drugs represents an important opportunity for the cure of certain cases, especially seri- ous ones. However, the lack of scientific evidence on the subject raises issues of liability that may arise from the prescription of such drugs. Off-label drug use presup- poses the existence of specific requirements set out in Article 3 of Law 1998/94 a , related to clinical trials in on- cology. According to the aforementioned norm, off-la- bel drug use depends on the existence of documented data, lack of alternatives and on the fact that the use is known and in accord with papers that have appeared in scientific publications of international relevance. It is the same Finance Act of 2008 b to provide that un- der no circumstances is the doctor allowed to prescribe a drug, the trading of which is not authorized, when not even favorable data of phase II clinical trials on the pro- posed use of the medicine are available. However, the duty of disclosure, the obligation to obtain the patient’s prior consent, and the duty to control and monitor the effects of the prescribed drug remain in the hands of the doctor. The off-label treatment choice is therefore a sort of extrema ratio, and it can be used in cases specifically indicated and circumscribed by law. The lack or non-observance of even one of these re- quirements is relevant in terms of professional miscon- duct. In case of existence of the above requirements, the doctor may decide to prescribe an off-label drug, but he takes direct responsibility. In agreement with recent law, medical malpractice is based on a “social contact” with the patient, which has a contractual nature, and on the contract stipulated with the hospital. The hospital and the doctor’s liability are therefore based on a contractu- al liability, under Article 1218 c of the Civil Code, which is characterized by a presumption of guilt of the debtor who is in default, i.e., the doctor. Therefore, it rests with the doctor to overcome that presumption and, in case of summons of the doctor by the injured patient, to prove the exact fulfilment of the performance with the dili- gence required by the qualified nature of the existence of conditions required by ‘Article 3 Law 1998/94’ and that the failure was caused by impossibility of perform- ance resulting from causes not attributable to him. It is important to highlight that the practitioner must first obtain his patient’s consent to off-label drug treat- ment. He must also provide the patient with the correct information about the drug, explain the possible effica- cy of an off-label treatment and, at the same time, he should reveal any risk that the patient may encounter. When the doctor is faced with cases involving the reso- lution of technical problems that are particularly diffi- cult or not yet sufficiently studied by medical science as is often the case in oncology, from a legal point of view it is good to keep in mind the provisions laid down by Article 2236 d of the Civil Code, which limit the liability of the person undertaking the activity to cases of wilful misconduct or gross negligence. In any case, this limita- tion only applies to inexperience and not to impru- dence and negligence. Consequently, if during the exe- cution of a medical treatment the doctor causes damage by omission of care or inadequate preparation, he will also respond to simple negligence. If the damage is due to non-observance or lack of diligence, negligence or malpractice, the doctor who prescribes an off-label therapy may incur criminal liability for such negligence. In fact, in the health field, there are often cases of cul- pable liability. In contrast, the type of liability caused by intentional, conscious and voluntary transgressions is rare. In summary, the practitioner who prescribes an off-label treatment is responsible for any injury caused to the patient and directly related to the therapy. Med- ical malpractice is mainly due to the lack of prior as- sessment of the risk/benefit resulting from administra- tion of an experimental treatment. The medical profes- sion deals with legally authorized activity, as it is social- ly useful although by its nature risky. Thus, the practi- tioner will respond by way of guilt only for those dam- ages that were foreseeable by the observance of the due diligence required by the nature of the activity. He is not liable for unpredictable damage, as which may occur despite faithful observance of the legis artis. Therefore, Tumori, 99: e190-e192, 2013