Model framework for off label use of medicines

Background The drug licensing regulatory system ensures that marketed drugs to be used, meet the high standards and requirements for quality, efficacy and safety. Unfortunately, in practice, prescribers are often obliged to deviate from granted medicine marketing authorisation, due to the lack of availability of appropriate medicines for patient’s therapeutic needs and progress. This concept of medicines use not mentioned in the approved labelling (FDA Modernization Act) or outside of the terms of Summary of Product Characteristics regarding indication, age, dosage, pharmaceutical form and route of administration (British NHS Guideline) is defined as off-label use of licensed medicines. On the global level, many supportive evidence and health care needs confirm that off-label medicines use occurs in every country and each level or specialty area of healthcare (Conroy, 2003). Moreover, it is an integral part of Good Medical Practice and may provide the best available option or even the standard of care in a particular health condition (Dresser and Frader, 2009). In general, this concept is legal and may be appropriate, but it can be associated with safety, clinical and ethical concerns, emphasizing the increased incidence of adverse events associated with off-label medicines uses in particularly vulnerable patient groups (Gazarian and Kelly, 2006). A concerning issue is that the majority of all off-label uses have limited to no scientific support (Radley et al., 2006) and a considerable number of prescribers have no or limited knowledge about off-label medicine use or do not meet regulations regarding off-label use, if they exist. (Piñeiro Pérez et al., 2014). Experience shows that to ensure the quality of off-label use of medicines, there should be a formal mechanism to assess the feasibility, monitoring the safety and efficiency of medication used based on this concept.Thus, in continuum, the off-label use of medicines has been an essential part of the ethical and legal considerations as well as, many regulatory initiatives. The overall objective is to present a model regulatory framework setting out guidelines and recommendations for quality use of off-label medicines within the national profile of health care policy. A literature search was undertaken to identify the issues and challenges related to off-label medicines use including clinical, safety and ethical concerns. Recommendations for model framework Principles of good practice for off-label use of medicines should include the following elements: identifying the medical needs; compilation of a consensus list of accepted, scientific based off-label uses; creating an official expert group for the evaluation and approval of specific offlabel uses; and, providing a safe and effective supply. The main guiding principles and developed activities to support a responsible decision-making with regard to off-label medicines include: 1) the medical need- the best avail- S7 OP 290 608 Maced. pharm. bull., 62 (suppl) 607 - 608 (2016) Oral presentations Continuing professional development able treatment in cases of specific characteristics when authorized medicines cannot meet the patients’ need; 2) sufficient scientific basis and/or clinical practice experience to justify their action. Distinguish the routine off-label use, which is the use of these medicines based on “high quality” evidence and the use in specific exceptional circumstances; 3) information duty and a high degree of respect for patient rights, involving the patient/carer in decisionmaking process; 4) monitoring and reporting the outcomes, efficiency and adverse reactions; 5) considering self-monitoring of prescribing practices, liability and accountability. An additional special responsibility which among others falls on pharmacists should be to ensure that the prescriber is conscious for off-label prescribing and the reasons for that 6) production of compendia of certain medicines, enlisting those off-label uses judged to be legitimate.7) financial sustainability of an off-label use in medical practice. Before deciding to compound a patient-specific preparation, a step by step evaluation of alternatives should be made. These alternatives include a therapeutic alternative, dose rounding or manipulation of licensed dosage forms (splitting tablets, crushing tablets/opening capsules, dispersing their content in water or food, splitting suppositories, the use of a preparation designed for another route of administration). Conclusion Prescription, compounding, dispensing and administration of off label use of medicines should be regulated within the national profile of health care policy. The regulation regarding the practice of off-label medicine use differs between countries. Some countries have this practice regulated by law, while in others it is covered by good practice regulations or general professional recommendations and ethical standards. Assuming that there is no any general rule to regulate the “accurate” offlabel use of medicines it is of paramount importance for the countries to find a national solution to fulfil the ethical and legal demand, especially in the areas of pharmaceutical law and health insurance law. The common elements of these regulatory frameworks are the physicians’ freedom to prescribe off-label medicines if the scientific evidence exists and the need to inform patients when making this decision. Making policy efforts, by adopting appropriate guidelines for off-label medicines use, based on scientific evidence, with specifications of healthcare professionals’ responsibilities and a registry of off-label drug use in every day practice, would make possible a valuable approach towards ensuring a quality use of these medicines. Recommended solutions, as practiced in some countries, would support prescribes in more direct and active approach to handle the ethical and legal phenomenon associated with the off-label use of medicines

The best practices and risks assessment strategy for unlicensed and “off -label” use of medicines in pediatric population

Despite many global initiatives and efforts to improve the availability of marketing authorized dosage forms appropriate for pediatric population, there is still a supportive evidence and widespread need for the implementation of the concept of unlicensed (UL) and “off-label” (OL) medicines use as a common therapeutic strategy or as the only treatment option and standard of health care for this vulnerable population. As acknowledge, prescription, compounding, dispensing and administration of UL and OL use of medicines should be regulated within the national profile of health care policy. Bearing in mind that in our country there is no formal mechanism for management of OL drug prescribing and use that could lead to their quality use, this concept continues to be an important public health issue. For this underlining reason the purpose of our survey is to present the best practices and risk assessment strategy for UL and OU of medicines in pediatric population. First of all it is of paramount importance to establish national policies governing UL and OL prescribing and use along with ethical standard since prescribing by clinicians is an area of practice that is not regulated by drug regulatory authorities. Strategies for collaboration and the shared responsibilities among prescribers, clinicians, pharmacists and regulators with regard to the OL and UL medicines use should be developed and adopted on every level of pediatric health care. The process of determining the need for UL and OL medicines for pediatric population will serve for regulation of certain uses. Responsible OL and UL prescribing also require development of explicit guidance for pediatric clinicians to assess appropriateness, to evaluate safety and efficacy of OL and UL prescribing justified by high-quality evidence as well as in the cases where adequate evidence is lacking. Moreover, monitoring system for OL and UL medicines use by indication then, active collection of safety data and systematically monitoring of pediatric patient responses to OL use will decrease and prevent risky and ineffective OL prescribing. There is a need of policy reforms to promote care giver and public interest in evidence-based OL prescribing. Another issue that has to be regulated is the potential cost associated with this concept of use of medicines in paediatric drug therapy

Off-label and unlicensed use of medicines in Macedonian neonatal wards

Despite all efforts to improve the use of licensed on-label medicines, there is still high percentage of off-label and unlicensed use of medicines in neonatal therapy. Therefore, the aim of this study was to investigate, analyze and present the extent and manner of use of medicines that are either outside the terms of their product license (off label), or are not licensed (unlicensed) within the neonatal therapeutic areas. This study was designed as a pilot cohort study, prospectively conducted in, and involving all newborns admitted to the Department of Neonatology, Republic of Macedonia. The results have shown high percentage of off-label use in preterm newborns, compared with term newborns, especially use out of age and out of indication

Lactobacillus casei Loaded Alginate-Soy Protein Microparticles: acidification Kinetics and Survival of the Probiotic in Simulated Gastrointestinal Conditions

L. casei has already proven its health effects. However, its viability decreases after exposure to gastric juice and bile salts. The aim of this study was to protect the probiotic microorganism from the harsh environment of the GIT by microencapsulation in alginate-soy microparticles. Aqueous dispersion of alginate (2.5%w/w) and probiotic cells (ca12log CFU/g) was emulsified in olive oil containing 0.2% Tween 80 to obtain microparticles which were subsequently cross-linked (CaCl2, 3%w/w), coated with the protein (1:4-4:1 in respect to alginate), isolated, washed and stored (0.9% saline, 4oC). Negatively charged microparticles were obtained (d50 16-36um, Ca-content 5.56-9.38%), viability 9.11-11.25log CFU/g). Free and encapsulated cells were cultivated in MRS broth (37oC) to determine if they were still metabolically active. pH values and optical density at 600nm were measured every 4h. Viability tests of free and encapsulated cells were performed by exchanging simulated GI juices, after incubation. The enumeration of living cells was assayed by incubation on MRS agar (37oC, 48h). The time taken to decrease the initial pH of MRS broth to 4 was 20h for free cells and for encapsulated cells 32-56h. Initial decrease in cell survival was observed after 0.5h (70% for free, 20-35% for encapsulated cells). After 12 h, the viability of the encapsulate cells was 5.7-8.6 log CFU/g. In conclusion, encapsulated L. casei in alginate-soy protein microparticles showed significantly higher survival in simulated GIT compared to free cells. The use of protein increased the survival compared to alginate alone