Glossary

In the medicines development process, this is the compound among several (compounds), which meets criteria in efficacy and safety in order to be used in clinical trials with humans. Broad information on the mechanism of action and pharmacology has to be available for a candidate drug.

A candidate gene is any DNA sequence (gene) in a chromosome considered likely to cause a disease. The gene may be a candidate because it is located in a particular chromosome region involved in the disease, or its protein product is suspected to be the cause of the disease. Candidate genes have been used to identify genetic risk factors for complex disorders such as alcoholism.

These studies, called the candidate gene approach, test the effects of variants of a candidate gene in members of an affected family, or in unrelated cases and controls. The candidate gene approach is useful for quickly determining the association of a genetic variant with a disorder. However, this approach is limited by how much is known about the biology of the disease being investigated.

Studies that use animal models to evaluate the carcinogenic potential of pharmaceuticals. They are also used to test chemicals and food additives. The objectives of carcinogenicity studies are to identify a tumorigenic potential in animals and to assess the relevant risk in humans. Any cause for concern derived from laboratory investigations, animal toxicology studies, and data in humans may lead to a need for carcinogenicity studies. The fundamental considerations in assessing the need for carcinogenicity studies are the maximum duration of patient treatment and any perceived cause for concern arising from other investigations.

A case control study is one that compares two groups retrospectively.

For example, people who developed a disease might be compared with a group of people who have not. The researcher will look at whether there is any difference in the two groups in their previous exposure to possible risk factors. This kind of study is useful when studying risk factors for rare diseases, and is often used to create new hypotheses which can then be tested.

For example, there are fewer than 300 confirmed cases of new-variant Creutzfeldt-Jakob disease (CJD). A cohort study that follows healthy people over time to see what risk factors might lead to the development of the disease would need to recruit a huge number of people in order for just one to develop symptoms (around 200,000). It would also take a very long time, because the period between infection and the appearance of symptoms is thought to be between 10 and 30 years. A much better approach in this case is to carry out a case control study, beginning with people who have already been diagnosed with new-variant CJD, and comparing their past exposure to possible risk factors with a group of people who do not have the disease.

A case report form is a paper or electronic data entry form used in clinical trials. It is used by sites taking part in clinical trials (such as hospitals) to collect data about each trial participant. All the data on each individual taking part in a clinical trial, including information on adverse events, are held in the case report form.

A case report form is developed specifically for each clinical trial so that all the data needed to answer the research question is captured. The organisation running the trial is responsible for designing a case report form in line with the protocol of the trial. They must also monitor and audit the data that is collected to ensure it is complete and accurate.

Personal data such as, the patients' names, medical record numbers, and any other identifying information are usually not disclosed in the CRF's. Each patient is instead given a unique identifier.

Is the relation between an event (the cause) and a second event (the effect), where the effect is a direct consequence of the cause.

The relationship between an event or situation and a possible reason or cause.

Centre within the US FDA that regulates biological products for human use. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/"

The centralised procedure is a process for obtaining marketing authorisation for a medicine in the EU. The European Medicines Agency (EMA) oversees the centralised authorisation procedure for human and veterinary medicines. This procedure results in a single marketing authorisation, granted by the European Commission, which allows a medicine to be marketed in all EEA (European Economic Area) countries (EU member states and the three EEA EFTA States: Iceland, Liechtenstein, and Norway).

Division of the Canadian Cardiology Institute of Montreal that promotes personalised medicine. http://www.cepmed.com/"

Chemistry, Manufacturing, and Control

Chemotherapy is a type of cancer treatment that uses medicines to destroy cancer cells. Chemotherapy is used along with surgery, radiation therapy, or biological therapy. It works by stopping or slowing the rapidly growing cancer cells. However, chemotherapy can also harm healthy cells that divide quickly, such as those that line the mouth and intestines. Due to the effect these medicines have on healthy cells, serious or severe side effects are common.

A chronic condition is a long-lasting disease that can be controlled but not cured. The term chronic is usually applied when the course of the disease lasts for more than three months.

Common chronic diseases include asthma, chronic obstructive pulmonary disease (COPD), cancer, and diabetes. In certain diseases or conditions, prevention is effective in reducing the possible development of the condition or its effect. Early diagnosis and timely treatment can help to reduce serious effects of the condition.

Class effect refers to the similar outcomes, therapeutic effects and similar adverse effects of two or more medicines. All products within a class are assumed to be closely related in three concepts: a similar chemical structure, mechanism of action, and pharmacological effects.

In the EU there are two classifications of medicinal products for human use:

1. medicinal products subject to medical prescription
   
2. medicinal products not subject to medical prescription
   

Further subcategories may exist on a national level.

Clearance is a term in pharmacokinetics which describes the volume of plasma that is completely cleared of a substance per unit time. The usual units are mL/min. The total body clearance will be equal to the renal (kidney) clearance + hepatic (liver) clearance + lung clearance although for many medicines the clearance is simply considered as the renal excretion ability.

Clinical development is one step in the process of bringing new medicines or treatments to the market. Based on non-clinical research (microorganisms/animals), it refers to clinical trials, which are done in people. They follow different phases designated as Phase I, II, III (and IV after marketing authorisation).

As a component of a dossier submitted for HTA assessment, clinical effectiveness is a measure of how well a particular treatment works in the practice of medicine. It depends on the application of the best knowledge derived from research, clinical experience, and patient preferences.

In medicine, clinical efficacy indicates a positive therapeutic effect. If efficacy is established, an intervention is likely to be at least as good as other available interventions to which it will have been compared. When talking in terms of efficacy versus effectiveness, efficacy measures how well a treatment works in clinical trials or laboratory studies. Effectiveness, on the other hand, relates to how well a treatment works in the practice of medicine.

In relation to clinical development, pharmacology deals with the effects of compounds (medicines in development) in healthy volunteers and in patients. It usually includes pharmacodynamics and pharmacokinetics. In the evaluation process the action and adverse effects of compounds can be measured and compared.

The clinical phase of medicines development is the one involving humans, and is different from the 'non-clinical' or 'pre-clinical phase' in which studies are performed in labs or in animals (such as for pharmacology/toxicology analysis). Clinical studies are conducted in four steps, called 'phases' - each designed to answer separate research questions:

Clinical practice is the treatment and management of patients by healthcare professionals supported by clinical-based evidence. There are clinical practice guidelines that have been designed to assist health professionals and patients in decisions about appropriate health care for specific circumstances.

Clinical Practice Research Datalink (CPRD) https://www.cprd.com"

Clinical Research Associate

A clinical study is a scientific investigation in which participants receive a health-related intervention, such as a medicine, in order to learn about (discover or verify) how it works and interacts with the body (clinical, pharmacological, pharmacodynamic, and pharmacokinetic effects), or to identify any adverse reaction in order to understand the safety of and/or how well the medicine works (efficacy).
Previously, the terms clinical study and clinical trial were used synonymously. Refer to Regulation 2014/536 for more information.

A clinical study report is a document containing extensive detail about the plan, methods and conduct of the study so that it is clear how the study was carried out. This report should provide a clear explanation of how the design features of the study were chosen and include results of the trial. A clinical study report should also provide enough individual patient data, to allow the key analyses of data to be repeated, should the regulatory authorities wish to do so. It is a central part of any application for a new medicine to receive marketing authorisation, and it must meet the requirements of the regulatory authority that has to assess the application.

A clinical trial is a clinical study in which participants are assigned according to a pre-defined therapeutic strategy or plan (protocol) to receive a health-related intervention, such as a medicine, in order to investigate its effects on health outcomes, usually compared to another (or sometimes no) treatment.
Clinical trials are used to evaluate clinical practices that do not fall within the current practices of a country, or to evaluate a new medicine (investigational medicinal product).
Clinical trials are used to generate data on the safety and efficacy of the intervention. Clinical trials are conducted only after a regulatory authority approval and ethics committee review. Clinical trials are often characterised in Phases from I (first-in-human), II (exploratory), III (confirmatory) to IV (post approval).
Previously, the terms clinical study and clinical trial were used synonymously. Refer to Regulation 2014/536 for more information.

Clinical Trial Application

Before a clinical trial can start, the sponsor must apply for and be given clinical trial authorisation (CTA). Each European country has its own regulatory authority that assesses applications for clinical trial authorisations. For clinical trials that will take place in more than one European country, there is a ˜Voluntary Harmonisation Procedure™ which allows one application to be submitted to the authorities in all the relevant countries.

As well as clinical trial authorisation, a positive opinion from an ethics committee (or institutional review board) is needed before a clinical trial can go ahead.

ClinicalTrials.gov is an online resource that provides information about clinical studies on a wide range of diseases. It includes information on whether the studies are recruiting patients, and a summary of the results of studies once they have finished.

The resource can be found at https://clinicaltrials.gov (address correct November, 2015).

Studies can be searched for by disease or by country. Although it is funded by the US government, it includes studies based around the world. The resource is aimed at patients and their families, healthcare professionals, researchers and the public. The website is maintained by the National Library of Medicine (NLM) at the National Institutes of Health (NIH).

A type of outcome assessment determined by a trained health-care professional after observation of a patient™s health condition.

Cohort studies are used to study how common diseases are, their causes, and their prognoses. Cohorts are groups of people who are selected on the basis of certain characteristics. For example, if exposure to a risk factor such as cigarette smoke is suspected to cause a disease, a cohort can be selected in which one group has been exposed and another group has not. Both groups are then studied for signs or symptoms of disease.

Cohort studies can be prospective (cohorts are identified before any signs of disease and are followed up over time) or retrospective (data is used that has already been collected, possibly over a long period of time).

Cohort studies are a kind 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, deliberately exposing people to cigarette smoke or asbestos would be unethical and therefore cannot be done.

An uninterrupted series of production, storage, and distribution activities, along with associated equipment and logistics, which maintain a desired low temperature range. It is necessary to maintain the quality and efficacy of certain medicines and vaccines.

Dutch National Competent Authority (English: MEB). http://www.cbg-meb.nl/"

Combined advanced-therapy medicines are medical products based on the combination of genes (gene therapy), cell therapy (cell therapy) or tissues (tissue engineering) with one or more medical devices as an integral part of the medicine.

Belgian Health Technology Assessment body. http://www.riziv.fgov.be/nl/riziv/organen/Paginas/commissie-tegemoetkoming-geneesmiddelen.aspx#.V1rMphM4ViQ"

Belgian commission for reimbursement of medicines. http://www.inami.fgov.be/fr/inami/organes/Pages/commission-remboursement-m%C3%A9dicaments.aspx#.V16FmNKLRD8"

French Health Technology Assessment body. http://www.has-sante.fr/portail/jcms/c_419565/fr/commission-evaluation-economique-et-de-sante-publique"

Committee for Advanced Therapies (CAT) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000266.jsp"

Committee for Medicinal Products for Human Use (CHMP) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000094.jsp"

Committee for Orphan Medicinal Products (COMP) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000263.jsp"

Committee for Proprietary Medicinal Products (CPMP) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000094.jsp"

Committee at the European Medicines Agency. http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000262.jsp"

Committee on Herbal Medicinal Products (HMPC) http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000264.jsp"

Common European Submission Platform (CESP) http://cesp.hma.eu"

The Common Technical Document (CTD) is an internationally agreed format for the preparation of marketing applications to regulatory authorities for new medicines approval. The CTD is divided into five modules, where modules 2 to 5 constitute the actual CTD and module 1 differs according to the region. The modules are:

1. Administrative and prescribing information (these contents might differ based on national requirements),
   
2. Overview and summary of modules 3 to 5,
   
3. Quality (pharmaceutical documentation),
   
4. Non-clinical study reports (pharmacology/toxicology),
   
5. Clinical study reports“ efficacy and safety (clinical trials).
   

Community Advisory Board

Method of providing an unlicensed medicine prior to final approval by a regulatory (competent) authority for use in humans. This procedure is used with very sick individuals who have no other treatment options. Often, case-by-case approval must be obtained for compassionate use of a medicine or therapy.

Complementary DNA

Two or more elements or molecules which are chemically bound to each other. The term ˜compound™ is often used to refer to a medicine which is being developed.

Computer Tomography

Something that exists or occurs at the same time as something else. It can be a natural event, but in medicine is used when referring to:

• Concomitant medication: two or more medicines are given at the same time when treating diseases, or
  
• Concomitant disease: a second disease (or more) is present at the same time as the primary disease (or secondary symptoms occur with a main symptom).
  

A confidence interval is an estimated range of values in which all data (results) are likely to lie. For a given treatment effect measured in a trial on a sample of a population, the confidence interval can be calculated to give a 'best estimate' range of the treatment effect that will be seen in the whole population.

The likelihood that the confidence interval will contain the value is called the confidence level. Traditionally, confidence levels are set at 95% or 99%. This means that researchers are 95% (or 99%) certain that the measured effect lies within the true range.

For example, instead of estimating the mean age of a population as 15 years, researchers say that the mean age is between 14 and 16. This confidence interval contains the true value being estimated.

These are studies conducted in Phase III of the clinical development of a medicine. They aim to confirm the efficacy and safety in a large patient population. They can involve thousands of patients, can be run in many countries, require a huge amount of expertise to be run effectively, and are therefore resource intense and very time consuming. They are the largest, most complicated, and most expensive part of the development of a medicine.

A confounding variable is something, other than the treatment being studied, that can affect the measured outcome of a trial . For example, imagine that a medicine to prevent the common cold is tested by administering it to 1,000 men, while a placebo is administered to a group of 1,000 women. The trial results show that far fewer men caught a cold during the trial period. It would not, however, be possible to conclude that the medicine had an effect because all of the placebo group were women, and therefore gender is a confounding factor. The trial results could have a plausible alternative explanation - for example, that women are more susceptible to the cold viruses circulating at the time of the study.

Well-designed trials take account of potential confounding variables and allow the elimination of plausible alternative explanations for study findings. In the example given above, men and women could be randomly assigned to the intervention and placebo groups to remove gender as a confounding variable.

A measurement, often expressed in numbers, collected in a clinical trial that represents a specific variable. Unlike binary endpoints which are expressed by ˜yes™ or ˜no™ (e.g. ˜survived™ against ˜dead™), continuous endpoints are expressed by measurement on a continuum of possible values over time (e.g. blood pressure or months of survival).

A contract research organisation (CRO) is an independent organisation that provides support into the medicines development process. Typically, a CRO will organise and conduct clinical trials to test an investigational medicinal product in humans.

Coordination Group for Mutual Recognition and Decentralised procedures – human (CMDh) http://www.hma.eu/cmdh.html"

In the context of pharmacoeconomics, cost effectiveness is studied by looking at the results of different interventions by measuring a single outcome, usually in 'natural' units (for example, life-years gained, deaths avoided, heart attacks avoided, or cases detected).

Alternative interventions are then compared in terms of cost per (natural) unit of effectiveness in order to assess how it provides value for money. This economic evaluation helps decision-makers to determine where to allocate limited healthcare resources.

Cost effectiveness, however, is only one of a number of criteria that should be used to determine whether or not interventions are made available. Other issues, such as equity, needs, and priorities should also be part of the decision-making process.

Council for International Organisations of Medical Sciences (CIOMS) http://www.cioms.ch/"

Council of Health Ministers (CDSP) http://www.coe.int/t/dg3/health/CDSP_en.asp"

Compounds under investigation as potential new medicines must meet certain criteria, at each stage of development, in order to progress further. These criteria need to be agreed upon by the medicines developers. A ˜go™ decision means that the compound meets the criteria, and will be advanced to the next development step. Failure to meet the criteria will lead to a ˜no-go™ decision and the medicine development will stop.

A cross-sectional study is one type of observational study, in which the researcher does not perform any intervention (such as administering a medicine).

Cross-sectional studies are primarily used to find out how many cases of a disease are present in a population at a given point in time (called 'prevalence'). They are used to assess the health needs of a population and are useful in planning and allocating health resources. Cross-sectional studies are generally performed by survey/questionnaire or interview.