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The condition of being protected against consequences of failure, error or any other event which could be considered non-desirable. The safety of a medical product concerns the medical risk to the patient, usually assessed in a clinical trial by laboratory tests, vital signs, adverse events and other special safety tests.
Safety pharmacology studies predict whether a medicine is likely to be found unsafe when administered to human populations within the therapeutic range. Safety pharmacology studies aim to prevent the use of unsafe medicines.
Normally, results from previous safety pharmacology studies and effects related to the therapeutic effects of the medicine are considered. Safety pharmacology uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform benefit-risk assessments. Safety pharmacology includes a regulatory requirement to predict the risk of rare lethal events. The vigilant post-marketing surveillance (PMS) efforts of regulatory authorities are necessary to detect the existence of a rare adverse event occurrence after approval for human use.
The safety specification of a medicinal product is a summary of the important identified risks of a medicinal product, important potential risks, and important missing information. It should also address the populations potentially at risk, and any outstanding safety questions which may benefit from further investigation to refine understanding of the benefit risk profile during the post-authorisation period. In the RMP, the safety specification will form the basis of the pharmacovigilance plan, and the risk minimisation plan. It is one of the three pillars of the risk management plan.
In a clinical trial, the sample size is the number of patients or observations made. There must be enough patients or observations so that differences between groups within the trial can be detected. An estimate of sample size is required and must be specified in the study protocol before recruitment starts. It is also necessary to control the probability with which a real effect can be identified as statistically significant. Too few patients or observations will mean that real effects might not be detected, or they will be detected but at a level that is statistically insignificant (a Type II error, which is directly proportional to sample size). It is just as true that it is unjustified for a medicine to be tested on too many patients.
In pharmaceutical development, scale-up refers to the transition of a manufacturing process from lab scale (typically milligrams/grams) to plant-scale or commercial scale (typically kilograms/tonnes).
Scientific Advice Working Party
The Scientific Advice Working Party (SAWP) within the European Medicines Agency (EMA) provides scientific advice and protocol assistance to companies developing medicines. The SAWP was established by the EMA™s Committee for Medicinal Products for Human Use (CHMP).
It is a multi-disciplinary group with expertise in non-clinical safety, pharmacokinetics, methodology and statistics, and in therapeutic fields for which there are frequent requests or other specific fields such as cardiology, oncology, diabetes, neurodegenerative disorders and infectious diseases including human-immunodeficiency-virus (HIV) infection. Membership includes representatives from the Committee for Orphan Medicinal Products (COMP), the Paediatric Committee (PDCO), and the Committee for Advanced Therapies (CAT).
The SAWP develops integrated views on quality relating to the development of medicines non-clinical and clinical safety and efficacy relating to the development of medicines
Scientific Advisory Group
Scientific advisory groups (SAG) at the European Medicines Agency (EMA) provide independent recommendations on scientific /technical matters related to medicinal products under evaluation at the EMA, or any other relevant scientific issue. Scientific advisory groups are created by the EMA™s Committee for Medicinal Products for Human Use (CHMP). They consist of experts selected according to the particular expertise required.
Selection bias occurs when there are systematic differences between the comparison groups in a study. For example, differences in clinical signs between the groups might lead to different disease progression or response to treatment between groups, rather than the intervention itself. Proper randomisation and/or blinding have not been achieved, which can affect the statistical analysis and internal validity of the study.
Selection bias is sometimes used to refer to an error in the selection of studies for reviews. Publication bias is a type of selection bias. Confusingly, selection bias is also sometimes used to refer to systematic differences between the study group and the general population. This leads to problems with external validity.
Selective reporting is the reporting of results from only a selection of studies. Selective reporting can lead to publication bias. For example, if a greater proportion of studies with a positive outcome are reported than those with a negative outcome, a review of publications will be biased toward a positive result.
Selective reporting can arise if, for example, an investigator, journal editor, or trial sponsor thinks that negative results (where no effect of a new medicine is found) are uninteresting or unimportant. However, the reporting of negative results adds valuable information to the body of evidence available, and can prevent new unnecessary trials being set up.
Sensitivity (of an assay or test) is the ability of an experiment or trial to detect a difference “ for instance, between two groups of participants receiving different medicines in a clinical trial.
Serious Adverse Event
An adverse event (AE) is called serious if it:
Other events such as those requiring emergency intervention to prevent one of the serious outcomes described above might also be reported as a serious adverse event.
Serious Adverse Reaction
An adverse drug reaction (ADR) is called serious if at any dose it:
Seventh Framework Programme for Research and Technological Development (European Commission)
Seventh Framework Programme for Research and Technological Development (European Commission)
A side effect, or adverse reaction, is an unintended response to a medication. Side effects are generally regarded as being harmful, and may occur after a single dose or prolonged administration. They might result from the normal use of a medicine, or from the use of a medicine in a way unintended by the marketing authorisation holder (MAH) “ such as taking an overdose or from the combination of two or more medicines being taken at once.
A symptom is a manifestation of disease apparent to the patient himself, while a sign is a manifestation of disease that the physician perceives. The sign is objective evidence of disease; a symptom, subjective. (source: https://jamanetwork.com/jornals/jama/article-abstract/341611)
In a clinical trial, the significance is a description of how meaningful (valid) a trial result is. When evaluating the validity of a study, one must consider both the clinical and statistical significance of the findings. A study that claims clinical relevance may lack sufficient statistical significance to make a meaningful statement. Conversely, a study that shows a statistically significant difference in two treatment options may lack clinical relevance (if, for instance, an observed effect is very small but highly consistent).
The significance level (or О± level) is a threshold that determines whether a study result can be considered statistically significant after performing the planned statistical tests. The significance level is most often set to 5% (or 0.05), although other levels may be used depending on the study. This represents the probability of rejecting the null hypothesis when it is true. For example, a significance level of 0.05 indicates a 5% risk of concluding that a difference between the study results and the null hypothesis exists when there is no actual difference.
The significance level must be stated in the trial protocol as part of the statistics section. The probability of a result being due to chance rather than due to a medicine or other intervention being studied, if the null hypothesis is true (that is, if there is really no true difference), is known as the p-value™. A result is then said to be statistically significant if it yields a p-value equal to or less than the significance level and thus will not be considered a chance occurrence. This is generally written as p ‰ 0.05.
Silencing refers to the ability of a cell to prevent the expression of a certain gene. Methods used to silence genes are increasingly being used in the laboratory to produce therapies against diseases, such as cancers, infectious diseases, and neurodegenerative disorders by selectively turning off specific genes in diseased tissues.
Single ascending dose study
A single ascending dose study (SAD study) is a type of Phase I trial. Single ascending dose studies are usually conducted in a small number of healthy volunteers (although some trials recruit patients). The aim is to find out the safe dose range, and to look for any side effects. The initial dose given will be very small and increased gradually (in a new group of volunteers) if no or only mild side effects are seen. Researchers will also take measurements to determine how the medicine is processed in the body.
Small Interfering RNA
Small Interfering RNA
The endpoint in a clinical trial is an event such as occurrence of a disease, or symptom, or a particular laboratory result. Once someone reaches the endpoint, they are generally excluded from further research in the trial.
A soft endpoint is a subjective measure. For example, it is common to measure quality of life as an endpoint in Phase III trials, with patients asked specific questions about the impact of their disease and/or treatment.
In contrast, a hard endpoint is an endpoint that is well defined and can be measured objectively. For example in cancer research, the endpoint in a trial might be related to response to treatment (such as shrinkage of a tumour).
The endpoints used in a trial must be defined and documented as part of the trial design.
The ability of a substance (solute) to permanently dissolve in liquid to form a homogeneous solution.
The term somatic is often used in biology to refer to the cells of the body, in contrast to the germ-line cells which usually give rise to the eggs or sperm. In medicine, it is a term that means (more generally) relating to the body. Somatic mutations are changes to the genes which are not passed on to the offspring. In cancer genetics, somatic mutations specifically refer to mutations arising in tumours (which are not present in healthy tissue). Such mutations are often responsible for driving the growth of tumours.
Somatic Cell Nuclear Transfer
In genetics and developmental biology, somatic cell nuclear transfer (SCNT) is a laboratory technique for creating an embryo from a body cell and an egg cell. The technique consists of taking an egg cell lacking the nucleus and implanting a donor nucleus from a body cell. It is used in both therapeutic and reproductive cloning.
Somatic-cell therapy medicine
A somatic-cell therapy medicine contains cells or tissues that have been manipulated to change their biological characteristics, and subsequently reintroduced into patients. These cells or tissues can be of autologous, allogeneic, or xenogeneic origin (cells obtained from a donor of a different species). The aim with somatic-cell therapy is to cure, diagnose, or prevent diseases.
Specificity (of an assay or test) is the ability of an experiment or trial to correctly detect only the particular effect being studied “ for instance, a difference in symptoms between two groups of participants receiving different medicines in a clinical trial. If a trial is not specific enough, it will give a false positive result (Type I error).
The sponsor is the individual, company, institution or organisation which takes responsibility for the initiation and management of a clinical trial. The financing of a clinical trial may come from the sponsor, but can also come from a third-party. The organisation of a clinical trial is particularly complex because important aspects of the trial are not under the direct control of the sponsor.
Stability is the ability of a substance to remain unchanged. Changes may occur due to the environment that the substance is in, e.g. being exposed to sunlight or water, or being in the body. Changes may also occur due to chemical and biological processes found inside the substance.
The standard deviation is a measure of the amount of variation within a data set. If all values in a data set are very close together, the standard deviation will be close to zero. In such cases, the data points will all lie close to the mean (average). A high standard deviation indicates that the values are much more spread out.
The standard deviation is normally included when clinical trial results are reported because it provides a (rough) guide to statistical significance. Take, for example, a clinical trial in which the observed symptom reduction is greater than one would expect if the medicine had no effect. The difference (between the observed result and what one would expect if the medicine had no effect) would generally have to be greater than two times the standard deviation to be regarded as statistically significant.
Standard Operating Procedure
Standard Operating Procedure
Standardised Mortality Ratio
Standardised Mortality Ratio
Statistical analysis plan
A statistical analysis plan (SAP) describes the planned analysis for a clinical trial. It contains the necessary details so that is can be followed and reproduced, providing clear and complete templates for each analysis.
Statistical inference is the process of drawing conclusions about a population through statistical analysis from a sample of that population.
For example: In clinical trials, hypothesis testing is a means of drawing conclusions on the effect of the medicines under study on the population that the sample of trial participants was drawn from. For instance, the null hypothesis would state that the medicine being studied does not affect symptom reduction while the alternate hypothesis would state the opposite. Statistical inference from the trial data will allow researchers to reject the null hypothesis if the analysis indicates a statistically significant effect.
Statistical significance is a fundamental aspect of hypothesis testing. In any experiment using a sample from a population (for instance, a sample of patients with a particular disease) there is the possibility that an observed effect may be due to differences between the sample and the whole population (sampling error) rather than the medicine under study. A test result is called statistically significant if it has been predicted as unlikely to have occurred by sampling error alone, according to a threshold probability: the significance level.
Statistical significance does not imply importance or practical significance. For example, the term clinical significance refers to the practical importance of a treatment effect. Researchers focusing solely on whether their results are statistically significant might report findings that are not relevant in practice. It is always prudent to report an effect size along with p-values. An effect size measure quantifies the strength of an effect, and makes it easier to draw conclusions on the practical implications.
Statistics are a mathematical methods of describing and drawing conclusions from data. Statistics are an essential part of the medicines development process at multiple stages.
Státní ústav pro kontrolu léčiv
Štátny ústav pre kontrolu liečiv
Stem Cell Therapy
Stem cell therapy, also known as regenerative medicine, is the use of stem cells to treat or prevent a disease or condition. Stem cells grown in a lab are manipulated to specialise into specific types of cells, such as heart muscle cells, blood cells or nerve cells. The specialised cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the damaged heart muscle. The healthy transplanted heart cells could then contribute to repairing defective heart muscle.
Stem cells are undifferentiated (unspecialised) cells that can transform into specialised cells and can divide to produce more stem cells. They have the potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as an internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. There are two types of stem cells: Embryonic stem cells, found in the early stage of embryonic development, can differentiate into all the specialised cells of the body, such as muscle cells, red blood cells, and nerve cells. Adult stem cells, which are found in some adult tissues, can act as a repair system for the body.
In medicine, a stent is an artificial tube inserted into a vessel or duct to keep the passageway open. Often it is used to treat narrow or weak arteries.
In clinical trials, stratification is the separation of patients or the analysis of results based on something other than the treatment given.
Stratification has two different meanings. In its first meaning, it describes the natural distribution of patients into subgroups. For instance, patients may be stratified by age, disease severity, or biomarkers.
In its second meaning, stratification controls the random allocation of people to the different groups in a trial. Stratified randomisation is used to ensure that equal numbers of participants with a characteristic thought to affect response to the intervention will be allocated to each group in the trial.
Stratified medicine is based on the identification of subgroups of patients that differ in their mechanisms of disease, their susceptibility to a particular disease, or in their response to a medicine. The aim of stratified medicine is to offer the treatment that is most likely to give benefit, or to avoid an adverse reaction. Personalised medicine takes this approach a step further by using targeted medicines and also taking information such as the patient's genotype and lifestyle into account when deciding on the best treatment.
This is the administration of a medicine into the layer of skin directly below the dermis and epidermis (the top layers of skin). Subcutaneous tissue has few blood vessels and so medicines administered here are for slow, sustained rates of absorption. An example is a local anaesthetic injected before suturing.
A route of medicine administration in which the medicine is placed under the tongue. These medications can come in the form of tablets, films, or sprays. It is an extremely fast pharmacological route of absorption, as medicines diffuse rapidly into the blood through tissues under the tongue. This is especially effective in an emergency when the medication needs to work immediately like during a heart attack. Another advantage is that the medicine does not go through the digestive system, so it is not metabolised through the liver, and thus a lower dose can be used.
In order to market a medicine, a submission (an application) must be made to the relevant regulatory authority, for example the European Medicines Agency (EMA). Submissions provide comprehensive information about the medicine, its formulation, the trials it has undergone, its intended use, and its risks and benefits.
Subpopulations are groups within a population. The population might be defined by, for example, the presence of a certain disease of interest to researchers. A subpopulation within that will have additional traits, such as disease severity, or failure of previous treatments, or specific genetic traits, or belonging to a certain age group that are also of interest. Subpopulations are identified in this way to allow statistical analysis with respect to the additional traits of interest.
Summary of Product Characteristics
The Summary of Product Characteristics (SmPC) is a document approved as part of the marketing authorisation of each medicine. It is aimed at healthcare professionals and includes information such as:
Danish Health Authority. https://sundhedsstyrelsen.dk"
The endpoint in a clinical trial is an event such as the occurrence of a disease, or symptom, or a particular laboratory result. Once someone reaches the endpoint, they are generally excluded from further research in the trial.
A surrogate endpoint (or marker) is a measure which in itself is not the outcome that the study treatment aims to elicit. For example, blood pressure is used as a surrogate endpoint in trials because it is a risk factor for heart attacks and strokes “ even though in itself blood pressure might not be important for patients.
Surrogate endpoints are useful if it would take a very long time for clinical endpoints to appear. Surrogate endpoints must be proven to be valid markers of clinical endpoints when they are used in clinical trials.
Suspected Unexpected Serious Adverse Reaction
A Suspected Unexpected Serious Adverse Reaction (SUSAR), is a serious adverse reaction (SAR) for which a reasonable causal relationship with the medicine use is suspected but not confirmed. Unexpected in this context means not consistent with the applicable product information (e.g. investigator's brochure for an unapproved investigational product or summary of product characteristics (SmPC) for an authorised product).
Swiss Agency for Therapeutic Products
A symptom is a manifestation of disease
apparent to the patient himself, while a sign is a manifestation of
disease that the physician perceives. The sign is objective evidence of
disease; a symptom, subjective. (source: https://jamanetwork.com/jornals/jama/article-abstract/341611)
This refers to toxic effects caused as a result of absorption and distribution of a substance that affects the whole body rather than a specific (local) area, i.e. to an area distant from its entry point. Most chemicals that produce systemic toxicity do not cause a similar degree of toxicity in all organs, but usually cause major toxicity to one or two organs. These are referred to as the target organs of toxicity for that chemical.