People with dementia often lack mental capacity and subsequently need assistance in their decision making. Research involving individuals with compromised mental ability can be ethically challenging as the lack of capacity may limit their ability to give free and informed consent.
The need to adopt special cautions in research involving individuals with compromised capacity has been highlighted by the most relevant declarations on research ethics, like the Nuremberg Code and the Declaration of Helsinki.
The Nuremberg Code of 1947 
, adopted a restrictive approach towards participation of incompetent patients in research, stating that: “The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent” (point 1).
In the 1964 version of the Declaration of Helsinki 
the possibility of “surrogate” or “proxy” consent overcame the “preclusion” from participation in research of incompetent patients: “In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation” (point 11).
Thereafter, following the first version of the Declaration of Helsinki, other relevant declarations on research ethics have confirmed the acceptability of surrogate or proxy consent thus sanctioning the ethical acceptability of participation of incompetent adults in research, provided that more protections be offered to these subjects.
The 2008 version of the Declaration of Helsinki states that potential research subjects who are incompetent “must not be included in a research study that has no likelihood of benefit for them unless it is intended to promote the health of the population represented by the potential subject, the research cannot instead be performed with competent persons, and the research entails only minimal risk and minimal burden” (point 27).
Moreover, “When a potential research subject who is deemed incompetent is able to give assent to decisions about participation in research, the physician must seek that assent in addition to the consent of the legally authorized representative. The potential subject's dissent should be respected” (point 28).
These principles have been adopted by all national legislation in western countries.
However, while the protection afforded to potential research participants who lack capacity has received recognition through legislation and ethical debate, the practical aspect of recruiting and retaining such participants in research presents a number of challenges.
One main problem in dementia research is the evaluation of the patient's capacity and, when the individual is deemed competent, the requirement that he or she expresses a valid consent to participate. To give valid consent the potential participant should understand and retain relevant information, weigh the information, make a decision and communicate the decision 
. In the context of clinical trials the information should include the purpose of the trial, the trial procedures, the risks and benefits of participation. Potential participants should understand the concept of equipoise which provides the ethical basis for the conduction of a clinical trial, placebo (if used), and randomization.
According to some authors if participants were required to understand all of this information, dementia research would become “harder to conduct” 
or it would cease entirely, restricting the continuing development of a much needed area of research 
As indicated by the Declaration of Helsinki, one possible way to meet the ethical requirements of informed consent is to safeguard the potential participants interests through the use of proxy consent in the recruitment process. At present, the majority of Alzheimer's Disease (AD) research is conducted with “double consent”, that is, by obtaining consent from both the patient and a proxy who is typically a family caregiver.
The practice of obtaining surrogate consent however can vary according to differences in national legislation. In particular, in some countries, including Italy, the system of proxy is determined by the courts - a procedure which is not necessarily required for the recognition of a proxy in other countries.
In the European Union (EU) a common legal framework for the inclusion and protection in research of adults who lack capacity is set up by the Directive 2001/20/EC 
, also known as the “Clinical Trials Directive” (hereinafter the Directive).
To ensure legal protection to incapacitated participants in research the Directive requires the written consent of the participant's legal representative.
However, according to the Directive “The notion of legal representative refers back to existing national law and consequently may include natural or legal persons, an authority and/or a body provided for by national law”(introduction, point 5).
National implementation of the Directive hence raises distinct issues which reflect the legal, cultural, political and socio-economic background within each member state.
To compare the national legal framework of some EU member states regarding the inclusion and protection in research of incapacitated participants we retrieved national laws using the European Forum for Good Clinical Practice (EFGCP) Report on “The Procedure for the Ethical Review of Protocols for Clinical Research Projects in the European Union” 
In particular, we analysed the national laws on clinical trials which are written in English, French or Spanish or for which an English translation is available.
Some countries have legislation that is specific to an incapacitated participant's involvement in research while in other countries the proxy provision falls from legislation on health and welfare more broadly.
Several legislation provide that an individual is able to appoint a representative prior to the onset of incapacity (e.g. Belgium, France, Italy, U.K. and Germany).
In all of the analysed legislation: Belgium 
, Denmark 
, Finland 
, France 
, Germany 
, Ireland 
, Italy 
, the Netherlands 
, Spain 
and the UK 
a relative is allowed to take on the role of proxy.
However, only in Germany and Italy the system of proxy is determined by the courts - a procedure which is not necessarily required for the recognition of a proxy in other member states.
In Belgium, the Netherlands, Finland and Spain a more pragmatic procedure has been adopted for proxy consent in research. This system describes a cascade of measures aimed to legitimately arrive at a consent that reflects the individual's presumed will, going from the authorised legal representative to a hierarchy of family members.
In France a similar system for legal agency is in place. However, if according to the ethics committee the research imposes serious risks to the participant's private life or bodily integrity, authorisation to participation must be given by the tutelary judge.
In Ireland an incapacitated person may only participate in a clinical trial if written and signed consent is given by a person, independent from the trial, who in the opinion of the ethics committee is able to give a decision on such a participation.
In Denmark, if an adult is permanently incapacitated consent must be given by the nearest relative (or legal representative) and the person's general practitioner (GP).
Also in the UK, if it is not reasonably practicable to contact an adult's legal representative then the doctor primarily responsible for the medical treatment of the individual, or a person nominated by the relevant health care provider, can act as legal representative, providing they have no connection with the conduct of the clinical trial 
The different ways of obtaining surrogate consent for subject's participation in research in the EU countries may have an impact on countries “attractiveness” for dementia research.
For example, one may suppose that countries where courts are not involved in the appointment of a patient's proxy are more attractive for dementia research, as courts involvement may slow down the process of appointment of the proxy and hence of obtainment of the informed consent. However the available data, even if they are quite limited, do not confirm this hypothesis. According to clinicaltrials.gov many clinical trials on dementia are being conducted in Europe ().
It is to note that in Germany, where the patient's legal proxy must be appointed by the courts, the number of clinical trials involving patients with dementia is high.
Recently in Germany a law was published, amending the Civil Code, regulating sensitive issues like the value of advanced directives and surrogate consent in the care of incompetent patients. The law specifies the value and the limits of the decisions of the “authorised representatives” in the care of the incompetent patient, but does not describe the process of appointment of the authorised representative 
Unluckily we did not retrieve detailed information on the German system for legal agency of persons with compromised capacity, which apparently allows a good level of participation in research of the patients with dementia.
This is not the case for Italy.
In Italy relatives are not “legally authorized representatives” and cannot give informed consent in clinical practice nor in medical research. Legal agency is mediated by the courts but at present very few patients have appointed a legal representative. This may be due to the fact that, until recently, legal agency for incompetent persons was synonymous of debarment.
In 2004 a law has changed the civil code, and in place of the traditional institutions of guardianship and tutelage, which completely deprived persons of their legal rights, legal agency is now focused on care and assistance 
. The new legal entity is a “carer” (in Italian: “amministratore di sostegno”) and is appointed by the tutelary judge, found in every magistrate's court. The law provides for a hierarchy of family members who can be appointed as legal proxy going from the beneficiary's spouse to his or her partner, father or mother, son or daughter, brother or sister, and other persons who are close to the patient. Nomination is inexpensive, the patient can directly apply for it and he/she can indicate his or her legal proxy prior to the onset of incapacity. Also relatives, neighbours and healthcare professionals can apply for appointment. Persons working in the healthcare or social services who are directly involved in the care of the person, when needed, must invite the tutelary judge to appoint a legal proxy for the patient. However, they themselves cannot be appointed if they are involved directly in the care of the patient.
The legal proxy must warrant the patient's desires in treatment decisions.
In the act of appointment, the judge must specify all actions that the legal proxy will be able to do for the person, which may include the care of his or her health and the right to give informed consent, as well as the management of his or her financial affairs.
The kind and number of powers and duties assigned to the legal proxy do not determine the length of the process of appointment which, according to the law, should be completed in 60 days.
However, in very urgent cases the tutelary judge may intervene with an accelerated procedure.
Theoretically, the law is easily applicable. The patient or his or her relatives do not need a lawyer's assistance to enforce it, they do not have to pay any money (apart from a € 8 revenue stamp) but must present several documents to the tutelary judge among which a medical certificate and a birth certificate which can only be obtained in the patient's common of birth.
Since the publication of the law 6/2004 many Italian courts have experienced an exponential increase in demand of appointment of the legal proxies for the persons who need it 
For this reason we hypothesise that the requirement that informed consent for an incapacitated subject's participation to a research be given by a legal representative appointed by the courts slows down the recruitment process in research thus complicating the conduction of dementia research in Italy.
In this study we want to verify how does the Italian law 6/2004 work and more precisely:
- Evaluate the timing and procedure for the appointment of a patient's legal proxy according to the law 6/2004;
- Identify the predictive variables of the appointment of the legal proxy according to the law 6/2004.