Glossary

A p-value, which stands for probability value, is a statistical measure between 0 and 1. It is used for hypothesis testing. In clinical trials it is used to give an indication of whether a result observed may be due to chance, or not.

A significance level should be set before data collection begins, and is usually set to 5% (or 0.05), although other levels may be used depending on the study.

A result is then said to be statistically significant (and allows us to reject the null hypothesis) if it has a p-value equal to or less than the significance level. This is generally written as p ‰¤ 0.05.
In calculating the p-value, we first assume that there really is no true difference between the two tested treatments,e.g. new versus standard treatment (the null hypothesis). We then calculate the likelihood (probability) that the difference we have observed is just due to chance if our supposition is true (that is, if there is really no true difference). This is the p-value.

So, the p-value is the probability to observe effects as big as those seen in the study if there was really no difference between the treatments. If p is small, the findings are unlikely to have arisen by chance and we reject the idea that there is no difference between the two treatments (we reject the null hypothesis). If p is large, the observed difference is plausibly a chance finding and we do not reject the idea that there is no difference between the treatments.

The Package Insert (formerly prescribing information) in the United States (USPI), is a document included inside the external packaging of a prescription or over-the-counter medicine to provide information for patients. In Europe, the patient information in the pack is the Package Leaflet (PL) (formerly called the Patient Information Leaflet (PIL)).

The document is subject to detailed regulatory specifications, including approved chemical and proprietary names, descriptions, and classifications clinical pharmacology

In the EU, medicinal products must be accompanied by outer and/or immediate packaging information (labelling) and a Package Leaflet (PL). The PL should be written in language understandable by the patient and must undergo readability testing. It contains:

1. What medicine X is and what it is used for (identification of the medicinal product).
   
2. What you need to know before you take/use X (contraindications and warnings and precautions for use: in children and adolescents with other medicines

A folded leaflet that comes inside the package with the medicine.

A paediatric investigation plan (PIP) is a medicines development plan to support the authorisation of a medicine for children. It aims to ensure that the necessary data is obtained through studies in children, when it is safe to do so.

Pharmaceutical companies submit proposals for PIPs to the European Medicine Agency's (EMA) Paediatric Committee (PDCO). This Committee is responsible for agreeing to or refusing the plan.

The normal development of a medicine requires that various studies be performed to ensure its quality, safety, and efficacy. In addition to this, PIPs:

• 
  
• include a description of the studies and of the measures to adapt the medicine's formulation to make its use more acceptable in children, such as the use of a liquid formulation rather than large tablets
  
• cover the needs of all age groups of children, from birth to adolescence

Paediatric Research Equity Act

Paediatric Use Marketing Authorisation

Pan American Health Organisation (PAHO) http://www.paho.org/"

An outbreak of a disease affecting a large proportion of a population and occurring over a wide geographic area.

Medicines administered via any route other than the gastrointestinal tract (oesophagus, stomach, and small and large intestines). The most frequent are subcutaneous, intravenous and intramuscular injections, but medicines that are topically administered to the eye, ear, and skin or even inhaled may be broadly considered as parenteral.

Passive surveillance is the use of local healthcare services to collect data on disease incidence or adverse effects of medicines. It relies on staff and services, who are part of a reporting network, collecting data and generating reports. There is no active search for cases.

For example, passive surveillance is the most common method used to monitor the incidence of vaccine-preventable diseases so that national and international bodies can identify possible outbreaks and organise vaccine provisions.

A bacterium, virus, or other micro-organism that can cause disease.

Patient Information Leaflet

A patient registry is a collection of information about individuals, usually those with a specific diagnosis or with specific risk factors for a disease. Some patient registries seek people with varying health levels who may be willing to take part in research about a particular disease. Registries can be funded and/or managed by government agencies, non-profit organisations, clinics, or commercial organisations.

Patient registries have multiple uses. For example, registries for rare diseases can be used to establish the basic characteristics of the disease, how it is managed in clinics, and what outcomes people experience. Other uses include helping to measure clinical effectiveness of treatments in 'real world' settings, and investigating quality of patient care.

Clinical trial registries collect basic health information from people who agree to be contacted about taking part in future clinical trials. Volunteering for a registry does not mean a person has signed up for a clinical trial. Volunteering for a disease registry can sometimes become a first step toward taking part in a clinical trial, but registries and specific trials are not directly linked.

Patient selection can refer to how patients are matched with proposed treatments (in the clinic), or how patients are selected to take part in clinical trials.

For clinical trials, detailed inclusion and exclusion criteria are documented before recruitment of patients can begin. The inclusion and exclusion criteria are an important part of a trial protocol. If they are properly defined, inclusion and exclusion criteria will increase the chances of a trial producing reliable results. They also protect participants from harm and help avoid exploitation of vulnerable people (such as those without the ability to provide informed consent).

The patient year (or person year) statistic is used in many clinical studies and statistical assessments of risk.

Patient years are calculated as follows: If 15 patients participated in a study on heart attacks for 20 years, the study would have involved 300 patient years (15 x 20). This number can be divided by the number of patients who have been affected by a certain condition or event. For example, if six of the patients had heart attacks, that would be equal to one heart attack for every 50 patient years in the study (300 / 6 = 50).

Looking at data in this way can reveal trends and allows researchers to communicate levels of risk. Many studies on new medicines express their findings using patient years. For example, if one serious side effect is experienced for every 1,000 patient years of a study, this might be considered an acceptable level of risk.

A patient-reported outcome (PRO) is a measure of the experience or view of a participant in a clinical study. It is not a clinical measure, or an assessment made by anyone else involved in the study. PROs are commonly collected by asking patients to fill in questionnaires, or by interviewing patients. Questionnaires or interview guides used as part of clinical studies should undergo extensive testing to ensure they are reliable and valid.

PROs can be used to assess, for example, symptoms as experienced by the patient, disability, quality of life, and other health perceptions.

There are many published PRO questionnaires dealing with aspects of quality of life. some have been developed for specific conditions or treatments. Some are designed to be general, such as the 'EuroQoL' or 'EQ-5D', which has been translated into many languages and used extensively in clinical trials.

PRO is often used interchangeably with the term patient-reported outcome measure (PROM).

Patient Reported Outcomes (PROs) are data reported directly by a patient on his or her own health condition, without interpretation by a doctor or anyone else. They are based on a patient™s perception of a disease and its treatment. The findings or outcomes can be measured in absolute terms (e.g. severity of a symptom, sign, or state of a disease or condition) or as a change from a previous measure.

Patient-reported outcome measures (PROMs) are the tools used to measure and collect data on PROs. Generally, findings are measured by a well-defined and reliable patient-reported outcome (PRO) instrument. The use of a PRO instrument is advised when measuring an aspect of the disease or condition that is best known by the patient or is best measured from the patient perspective.

Patients’ and Consumers’ Working Party (PCWP) http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners_and_networks/general/general_content_000708.jsp&mid=WC0b01ac0580028d32"

German National Competent Authority. http://www.pei.de/"

Pediatric Committee (PDCO) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000265.jsp"

An analysis that is restricted to the participants who fulfil the protocol in terms of the eligibility, interventions, and outcome assessment. This analysis restricts the comparison of the treatments outcomes to the participants who adhered perfectly to the clinical trial instructions as stipulated in the protocol, i.e. completed the full treatment. If done alone, this analysis leads to bias because it does not consider participants who did not follow the protocol completely for any reason.

A performance-linked access system is a system used to minimise known safety risks of a medicine, once it is on the market. These systems guide prescribing, dispensing, and use of the medicine.

They are put in place when products have significant or unique benefits in a particular patient group or condition, but when unusual risks also exist, such as irreversible disability or death. These systems can include:

• 
  
• prescription only by specially certified healthcare practitioners,
  
• product dispensing limited to pharmacies or practitioners that are specially certified,
  
• product dispensing only after patients have, for example, undergone certain laboratory tests.
  

A period of exclusivity refers to a time after a medicine is authorised during which no other similar medicines with the same indications (intended uses) may be authorised. This protects the medicine from competition during the period of exclusivity. There can be several separate market exclusivities relating to designated conditions.

The period of market exclusivity is extended by two years for medicines that have also complied with an agreed paediatric investigation plan (PIP).

A Periodic Benefit Risk Evaluation Report is a format of safety report described by the ICH-E2C(R2) guideline which is used as a basis for the EU Periodic Safety Update Report (PSUR). The report is produced by the marketing authorisation holder (the individual or business that is granted authorisation to market a medicine) at defined time points after a medicine has been given marketing authorisation.

The purpose of the report is to provide comprehensive and up-to-date information about the safety of a medicine. The report should summarise any new evidence on safety, efficacy and effectiveness that might affect the balance of risks and benefits. The PSUR communicates risk to regulatory authorities and identifies where risk management initiatives may be required.

A Periodic Safety Update Report (PSUR) is EU terminology for a Periodic Benefit Risk Evaluation Report (PBRER). It is produced by the marketing authorisation holder (the individual or business that is granted authorisation to market a medicine) at defined time points after a medicine has been given marketing authorisation.

The purpose of the report is to provide comprehensive and up to date information about the safety of a medicine. The report should summarise any new evidence on safety, efficacy and effectiveness that might affect the balance of risks and benefits. The PSUR communicates about risk to regulatory authorities and identifies where risk management initiatives may be required.

Personalised medicine (PM) is a medical model that proposes to customise medical decisions, practices, and treatments for the individual patient. It uses targeted medicines aimed at specific molecules that are involved in the patient's disease and takes genetic, clinical, environmental, and lifestyle information about the patient into account. The aim is to select the best therapies for the individual patient to ensure the best outcome and reduce the risk of side effects.

Progress in understanding the link between genomics (and other molecular factors) and disease is an important part of the development of personalised medicine. Pharmaceutical companies are already producing some targeted medicines as a result.

Pharmaceutical form is the physical characteristics of the combination of active substance and excipients (non-active ingredients) forming a medicinal product (tablet, liquid, capsule, gel, cream, sprays, etc.).

Pharmaceutical Research and Manufacturers of America (PhRMA) http://www.phrma.org/"

Pharmacodynamics is the branch of pharmacology that studies what the medicine does to the body. Pharmacodynamics looks at the biological and physiological effects of a medicine, and their mechanisms of action at organ and cellular level.

Pharmacoeconomics

Pharmacoepidemiology is the study of the uses and effects of medicines in large numbers of people. It provides an estimate of the probability of beneficial effects of a medicine in a population and the probability of adverse effects. It involves continual monitoring of a population for unwanted effects and other safety concerns.

Pharmacogenetics is the study of individual genetic differences to understand how genes affect a person's response to medicines. Understanding how different genetics affect how a medicine is processed can help doctors to more accurately determine which medicine and which dose is best for each patient according to their response. Pharmacogenetics also helps doctors identify the medicine that best treats a disease and is least likely to cause side effects.

Pharmacogenomics is the study of entire genomes, across groups of individuals, to identify the genetic factors that influence responses to a medicine. Pharmacogenomics combines traditional pharmaceutical sciences, such as biochemistry, with an understanding of common DNA variations in the human genome.

A pharmacokinetic study is a study of how a medicine is handled by the body, usually measuring the concentration of the medicine in blood, urine, or tissues over time. Pharmacokinetic studies are used to characterise the absorption, distribution, metabolism, and excretion (ADME) of a compound, either in blood or in other locations, and are often employed at the discovery or candidate-selection stages of a medicine development program.

Pharmacokinetics is the study of what the body does to medicine. It studies the absorption, distribution, metabolism, and excretion of the medicine (ADME), as well as bioavailability.

These pharmacokinetic processes, often referred to as ADME, determine concentration of the medicine in the body, and the onset, duration, and intensity of a medicine's effect.

A pharmacologist investigates how medicines interact with biological systems, using in vitro (cells or animal tissues) or in vivo (live animals) research to predict what effect the medicine might have in humans. Pharmacologists aim to understand how medicines work and if they can be used effectively and safely in humans. They work closely with researchers to aid medicine discovery and development, and to determine questions of causation involving medications.

Pharmacology is the study of medicines, including their characteristics, interactions, and uses, and the biochemical or physiological effect they have on the cell, tissue, organ, or organism.

A pharmacopoeia is a collection of official standards for pharmaceutical substances and medicinal products. It includes directions for the quality control tests to be carried out on medicines and the raw materials used in production. It is a vital reference for individuals and organisations involved in research, development, manufacture, and quality control of medicines.

In most countries there is an official pharmacopoeia and all producers of medicines and/or substances for pharmaceutical use must comply with its quality/safety standards. In Europe, the European Pharmacopoeia provides the legal and scientific basis for quality control during development, production and marketing of medicines in European member states.

Pharmacotherapy is the treatment of diseases using conventional medicines (not biologic medicines).

Pharmacovigilance is the practice of detecting, assessing, understanding and preventing the adverse effects of medicines. Pharmacovigilance enhances patient safety and public health by providing reliable information on the risks and benefits of medicines.

Pharmacovigilance and Risk Assessment Committee (PRAC) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000537.jsp"

Phase 0 trials are conducted with sub-therapeutic doses to see if a medicine behaves in the body in the way that earlier laboratory studies (non-clinical trials) predicted.

Normally, the first studies in humans with a new medicine are Phase I trials.

Phase I trials are usually conducted in a small number of healthy volunteers (although some trials recruit patients). The aim of Phase I trials is to find out the safe dose range, and to look for any side effects. The initial dose given will be very small, and gradually increased if no or only mild side effects are observed. A new medicine has to meet certain pre-set requirements before it can continue to Phase II trials. Phase I, II, and III trials are commonly known together as 'clinical development'.

Phase II trials are generally the first studies with a new medicine in patients. They are usually conducted in a small number of patients who are monitored closely. These trials are often larger than Phase I trials.

Phase II studies are designed to find out if the medicine has a beneficial effect on the disease in question: They might compare the new medicine to an existing treatment or to a placebo. They also set out to determine the best dose range and how often the medicine should be given, and investigate the best way to manage any side effects.

A new medicine has to meet certain pre-set requirements before it can continue to Phase III trials. Phase I, II, and III trials are commonly known as 'clinical development'.

Phase III trials are generally large (comprising thousands of patients) and involve several study sites, sometimes in different countries. They compare the new medicine to existing treatments or a placebo, in order to show the safety and efficacy of the new medicine. Most Phase III trials are randomised.

Phase I, II, and III trials are commonly known as 'clinical development'. Phase III studies are critical to applications for marketing authorisation.

Phase IV trials are usually conducted after marketing authorisation is granted and the medicine is in general use.

Phase IV studies are also known as post-authorisation safety studies (PASS) and may be voluntary or imposed by the regulatory authorities. The possibility also exists of requesting the marketing authorisation holder to conduct post-authorisation efficacy studies (PAESs) in order to complement efficacy data that are available at the time of the initial authorisation. Phase IV studies collect additional information about side-effects and safety, long-term risks and benefits, and/or how well the medicine works when used widely.

Physical health is defined as the condition of your body, taking into consideration everything from the absence of disease to fitness level.

Physical health is critical for overall well-being, and can be affected by:

• Lifestyle: diet, level of physical activity, and behaviour (for instance, smoking)
  
• Human biology: a person™s genetics and physiology may make it easier or harder to achieve good physical health

A pivotal study is normally a Phase III study of a new intervention which is designed to provide the necessary data for a decision by a regulatory agency.

For example, the European Medicines Agency (EMA) requires specific safety and efficacy information about new medicines before it can issue a marketing authorisation. A pivotal study will be conducted to Good Clinical Practice standards. It will generally be randomised and controlled (an RCT). It will be of adequate size and, whenever possible, double-blind.

In clinical trials, a placebo is a medicine that contains no active ingredients. Placebos have no known medical effects.

The 'placebo effect' is a benefit or side effect perceived by patients taking a placebo, despite the fact that no medicine is involved.

A placebo-controlled trial is one in which a new medicine is tested against a placebo - a medicine that contains no active ingredients.

In placebo-controlled trials, people are assigned to a group (treatment arm) that receives the medicine, or a group that receives the placebo. This is one way to improve the chances that any benefit experienced by the treatment group receiving the medicine is due to the active ingredient in that medicine rather than some other factor.

Plasma is the fluid part of blood. It contains cells, gases, proteins, enzymes, etc. Unlike blood, plasma is yellow.

A population is a group of people who share a common trait. For example, they might have a certain disease of interest to researchers, have the same educational background or type of job, or they might live in a particular region.

Population pharmacokinetics is the study of variability in the Absorption, Distribution, Metabolism, and Excretion (ADME) of a medicine between individuals (healthy volunteers or patients). In order to understand how individuals from a population differ from one another, it is necessary to perform population pharmacokinetic analysis.

The branch of pharmacology and therapeutics concerned with dosage.

A post authorisation safety study is a study carried out after a medicine has been given a marketing authorisation. Its purpose is to obtain further safety information or to assess how well risk-management measures are working. The information from a post authorisation safety study is used in regulatory decision making.

A post authorisation safety study might be a clinical trial or a non-interventional study, and can be created voluntarily by the MAH, or can be required by the regulator (imposed™). The Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicines Agency (EMA) is responsible for assessing the protocols of imposed studies and for assessing the studies™ results. The EMA publishes the protocols and abstracts of the final study reports online.

Post marketing refers to the period after a medicine has been granted marketing authorisation and is available for general use.

A post-authorisation efficacy study (PAES) may be voluntary or imposed by regulatory authorities. Post-authorisation efficacy studies take place after marketing authorisation is granted and the medicine is in general use. They are Phase IV studies, intended to complement efficacy data that are available at the time of the initial authorisation, and gather long-term data about how well the medicine works when used widely.

A post-marketing surveillance study (PMS study), also known as a Phase IV study, may be voluntary or imposed by the regulatory authorities. They are conducted after marketing authorisation is granted and the medicine is in general use. Post-marketing surveillance studies collect additional information about side-effects and safety, long-term risks and benefits, and/or how well the medicine works when it is used widely.

"An unexpected event for which there is suspicion of an association with a medicinal product, but where this association has not been confirmed. Some examples are:

• toxicological findings seen in non-clinical safety studies which have not been observed in clinical studies
  
• adverse events observed in clinical trials or epidemiological studies for which the difference compared with the control group raises a suspicion of an association, but is not large enough to suggest a causal relationship"

A term often used in clinical research is statistical power. The power of a statistical test is the ability of the test to detect an effect, if the effect actually exists. In statistical terms, it is the probability that it will correctly lead to the rejection of a null hypothesis.

In some cases we may not be able to reject the null hypothesis, not because it is true, but because we do not have sufficient evidence against it. This might be because the experiment is not large enough to reject the null hypothesis. As such, the power of a test can be described as the probability of not making a Type II error (not rejecting the null hypothesis when in fact it is false).

A substance or cellular component from which another substance or cellular component is formed.

A predictive genetic test is a genetic test in a person without symptoms to predict future risk of disease. This testing allows early identification of individuals at risk of a specific condition, which can lead to reduced risk through targeted screening and prevention. For example, a woman who is found to have a BRCA1 or BRCA2 gene is at increased risk of breast cancer. She might be offered regular breast screening, or even preventative surgery, to help reduce her risk.

The value of a predictive test depends on the nature of the disease for which testing is being carried out, how effective treatment is, and the cost and efficacy of screening and surveillance measures.

Predictive medicine is a field of medicine that predicts the probability of disease. When an individual is predicted to have a high risk of a disease, preventive measures can be started in order to either prevent the disease altogether or significantly decrease its impact upon the patient. Preventive measures might be lifestyle modifications and/or increased monitoring by healthcare professionals.

Predictive medicine changes medicine from being reactive to being proactive, and has the potential to extend healthy lifetimes and to prevent disease. As yet it is not possible to predict with 100% certainty that a specific disease will occur. Predictive genetic testing is one of the key approaches in predictive medicine.

Someone who is predisposed to a disease is more likely than other people to develop the disease in the future.

For example, someone who is genetically predisposed to develop Alzheimer's has a genetic makeup that increases their risk of developing this disease. A predisposition will not in itself cause the disease, but the disease may eventually be triggered by particular environmental or lifestyle factors, such as tobacco smoking or diet. Genetic testing is able to identify individuals who are genetically predisposed to certain diseases.

Prevalence is the proportion of a population found to have a condition (typically a disease or a risk factor such as smoking). It is calculated by comparing the number of people found to have the condition with the total number of people studied, and is usually expressed as a fraction (for example, 1/3), as a percentage (%) or as the number of cases per 10,000 or 100,000 people.

Prevalence can be measured at a particular point in time (point prevalence), or over a specified period such as a year (period prevalence).

Probability is the measure of the likelihood that a particular event will occur.

Probability is quantified as a number between 0 and 1 (where 0 indicates impossibility and 1 indicates certainty). The higher the probability of an event, the more certain we are that the event will occur. A simple example is the toss of a fair (unbiased) coin. Since the two outcomes are equally probable, the probability of 'heads' is equal to the probability of 'tails'. Therefore, the probability of either 'heads' or 'tails' is 1/2 (or 50%).

A proof of concept (POC) trial is one type of trial carried out early in the clinical development phase of a medicine (in humans). Phase II trials usually begin with a proof of concept trial, which aims to show that the medicine interacts with its intended target and affects the disease in question.

A proof of mechanism (POM) study is normally done within Phase I Clinical Development in healthy volunteers. Such studies are designed to show that a new medicine reaches its target organ(s), interacts with its molecular target, and affects the biology of the target cells as intended.

Preventative (prophylactic) vaccines are substances that prepare the immune system to fight pathogens and provide immunity to a disease.

A part, share, or number considered in comparative relation to a whole, expressed as a fraction (ratio) or percentage. For example, in epidemiology, the number of people who have a disease compared with the total number of people studied.

In a prospective cohort study, groups of people are identified before they show any signs of disease and are followed up over time. Alternatively, in retrospective cohort studies, data is used that has already been collected (possibly over a long period of time) for other purposes.

Cohort studies are one type of observational study, in which the researcher does not perform any intervention (such as administering a medicine).

Cohort studies are useful when it would be unethical to carry out a randomised controlled trial (RCT). For example, it would be unethical to deliberately expose people to cigarette smoke or asbestos.

A prospective meta-analysis uses only trials that have been identified and selected before their results are known. This avoids some of the problems of meta-analyses.

Usually, meta-analyses are performed when individual trials have finished. However, collecting studies after their completion can lead to statistical problems. For example, if a meta-analysis is carried out because of knowledge of a particular positive trial result, this can influence how other studies are chosen for the meta-analysis and cause bias in the analysis. This is why prospective meta-analyses are performed.

The word 'proteome' is derived from 'Proteins expressed by a genome'. It refers to the entire set of proteins expressed and modified by a specific cell, tissue, or organism at a certain time, under defined conditions. The proteome changes constantly in response to intra- and extracellular environmental signals health or disease

A proteomic marker is one type of biological marker, or biomarker. The term is often used interchangeably with ˜protein marker™ and is a protein, or set of proteins, used as a biomarker.

Proteomics is a branch of biotechnology that applies the techniques of molecular biology, biochemistry, and genetics to study proteins, how they are modified, their structure, function, and interactions with one another. The goal of proteomics is to obtain a more global and integrated view of biology by studying all the proteins of a cell or tissue rather than each protein individually. Study methods include looking at protein-protein interaction, protein modifications, protein function, and protein localisation.

The protocol of a clinical trial is a document that contains:

• The objectives (aims) of the trial
• The trial design, including:
  • How participants will be selected
  • How many participants are needed;

  • What measurements and endpoints will be used; and

  • How bias will be minimised

Psychotropic substances affect brain function and alter mood, behaviour, consciousness or perception.

Public Health Genetics Foundation (PHGF) http://www.phgfoundation.org/"

An examination of how a health intervention (e.g. treatment, procedure, policy, etc.) might have broader implications for the health of a population. For example, a new therapy to treat HIV/AIDS may reduce the rate of HIV transmission within a community.

Publication bias occurs when one type of study result is more likely to be published than another.

For example, publishing results of studies that show a new treatment provides significant benefits, but not always publishing studies that show less or no benefit, will lead to publication bias. The effect is to exaggerate the benefit of the new treatment.

Methods exist to help address publication bias. For example, there are public databases where clinical trials can be registered before they begin. Thus, all the registered trials are known, including those that eventually demonstrate no significant benefit from the study treatment. Researchers are encouraged to register their trials because, for example, certain high-profile medical journals insist that they will only publish trials previously registered on a public database.