The definition of dementia is based on diagnostic criteria3 that, in AD, are exclusively clinical.4,5 The progress in genetics, biochemistry, cell biology and neurosciences in the last 3 decades has changed the way we understand AD.6 At present, AD is understood as a “continuous” process, from neurodegenerative changes in asymptomatic (preclinical phase) to the onset of cognitive impairment (prodromal phase) and the subsequent clinical condition of dementia.7,8 The knowledge acquired from biomarkers (neuroimaging and amyloid-β [Aβ], tau and phosphorylated tau proteins in cerebrospinal fluid [CSF]) play a key role.9 The earliest finding (preclinical phase) is the presence of amyloidosis in the brain (with retention of specific amyloid tracers for positron emission tomography [PET]) or in the CSF (with changes in the concentrations of Aβ, tau and phosphorylated tau proteins),7,8 which may last more than 15 years before the onset of symptoms.10 The use of biomarkers that reveal the state of the Aβ protein in an asymptomatic individual with AD is only considered in the framework of a research project.7,8 It is this way because, without validation of the diagnostic criteria and their clinical predictive value in the preclinical phase,11 individuals who are in this phase might not progress to AD over the course of their lives.7

The Alzheimer's and Families study (ALFA) is a longitudinal, long-term cohort study sponsored by and Pasqual Maragall Foundation. The study includes cognitively healthy (at baseline) children of patients with sporadic AD. Every 3 years, the participants perform various tests and procedures, including the PET determination of Aβ deposits in the brain. At the baseline visit, a lumbar puncture is performed to extract CSF. Using an Aβ PET, the volunteers are categorized as individuals with negative PET or positive PET (in the preclinical phase).8 In this study, PET revealed whether the (asymptomatic) participant was accumulating Aβ in the brain. The function of PET is, therefore, physiological and is performed using an intravenous injection of a radiotracer.12,13

Spanish legislation considers PET radiopharmaceuticals to be drugs for human use.14,15 Since 2004, the criterion of AEMPS has been to consider that “the administration of a radiopharmaceutical cannot be performed on a patient in the framework of a biomedical research project without the compliance of said project with legislation applicable to CTs”.16 Nuclear medicine professionals, researchers, sponsors and clinical research Ethics Committees (ECs) accepted this criterion without evaluating in each case whether the study in question was or was not a CT that should be regulated by the specific legislation.2 In any case, it is clear that studies using PET radiopharmaceuticals do not meet any of the characteristics required by the definition of a CT, nor does the radiotracer meet the characteristics of a “research drug” (Table 1).2

In 2008, AEMPS published a document of clarifications to the legislation on CTs.17 The first issue was establishing whether a study was “a CT with drugs”. The document provided an algorithm that showed that the ALFA study could not be considered a CT (Appendix Banexo 1). In addition, the European Union published a document18 years ago clarifying the regulation of CTs.19The document established that “if the objective of the study is only a physiological characterization, in which PET is only used to study this, that is, there is no medicinal product that is the objective of the study, then the study is not a CT”. These studies are not regulated by the European Union; it is the responsibility of each member state to decide whether and how to regulate them.19 Therefore, any PET study, such as that envisaged by the ALFA study, cannot be considered a “CT with drugs”. Moreover, the European Union does not distinguish between marketed and nonmarketed radiotracers in these types of physiological studies. The Spanish legislation that applies to the ALFA study is BRA,1 which specifies the following: “Biomedical research that this Law refers to includes basic and clinical research, with the exception in the latter case of CTs with drugs and healthcare products, which shall be governed by their specific legislation”.1

Malaria is the most common parasitical disease in the world and is caused by the Plasmodium parasite and transmitted by the Anopheles mosquito. Recently, the “Research Agenda for the eradication of malaria” initiative was conducted. Its objective is the development of a roadmap that will indicate the gaps in research and the tools that need to be developed to progress in the eradication of the disease.20

Given that there are no appropriate in vitro or animal models, the only possible model for studying future drugs and vaccines in this case is the so-called “experimental challenge”. This consists of the induction of a controlled infection of malaria by P. falciparum in human volunteers. Controlled infection with microorganisms in volunteers has made an exceptional contribution to our understanding of the pathogenesis, immune response, treatment and prevention of numerous infectious diseases.21Plasmodium is a particularly appropriate parasite for “experimental challenge” studies, given that it has a relatively short, asymptomatic incubation period, there is a well-established diagnostic laboratory method (thick smear microscopy) and there are very effective treatments. Moreover, if the volunteer receives proper treatment, the infection is completely eliminated, with no sequelae. Therefore, the induction of a controlled malaria infection has become a key tool for the study of the efficacy of new drugs and vaccines.

Since the end of the 1980s, the number of institutions that conduct induction of controlled malaria infections with P. falciparum has not stopped growing; between 1985 and 2009, 1343 volunteers have participated in experimental challenges.22 There are currently 2 strategies. In the first, the experimental infection by sporozoites is conducted using the controlled biting of infected mosquitoes.23 In the second, the experimental infection is produced by the inoculation of aseptic, purified and cryopreserved (CHMI) P. falciparum sporozoites (PfSPZ). The PfSPZ are developed based on an NF54 laboratory strain of P. falciparum that is sensitive to chloroquine. An international consortium has recently been assembled whose objective is to standardize the CHMI through experimental challenge with PfSPZ. To date, experimental challenge studies have been conducted with PfSPZ in 4 countries. The Barcelona Centre for International Health Research (CRESIB) and the Hospital Clínic (Barcelona), along with 2 institutes from Tanzania and Switzerland, will complete the international consortium.

The aim of the BACHMI-01 study is to establish the administration route, the method and the dosage of sporozoite that induces a 100% infection in nonimmune volunteers, with a period of induction between the administration and the onset of the parasite in blood of approximately 11 days, imitating as much as possible the process that occurs in nature. This study, along with others conducted in centers that form the consortium, seeks to describe a standardized method for studying in vivo the efficacy and immunogenicity of potential vaccines and drugs for malaria.

The applicable Spanish legislation indicates that the study proposed should not be considered a “CT with drugs”.2 In fact, the definition of drug (Table 1) seems to remove any doubt about how to consider PfSPZ in the proposed study. When the previously mentioned decision algorithm (Appendix Banexo 1) is used, we can see that the first question (“Is it a substance that is said to have properties for treating or preventing diseases in humans?”) could receive a positive or negative response, depending on the perspective taken. Therefore, the “experimental” administration of PfSPZ can be understood as causing an immune response in a number of subjects, which could protect them from a “natural” case of malaria by subsequent contact with P. falciparum. Understood this way, the response may be positive. However, those who consider this potential hypothetical effect as a secondary, unintended effect of the administration of PfSPZ would reply to this question in the negative. To remove all doubt, we continue with the algorithm and obtain a negative answer to the question in column B. Therefore, the study should not be considered as a “CT with drugs” and, hence, not subject to the regulation of CTs.2 By reaching this point, it seems clear once again that the applicable regulations would be the BRA.1