T

Abstract

see formulation.

FormalPara tablet

see formulation.

FormalPara tablet excipients

In addition to the active drug, medicinal products often contain a number of other substances, e.g. for improving bioavailability such as disintegrants (e.g. starch), for taste masking and lubrication to ease swallowing (e.g. coats of sugar, cellulose, polymers in film-coated tablets), or simply substances which facilitate production such as binders (e.g. cellulose derivatives), glidants (colloidal silica) or diluents (lactose, crystalline cellulose); see also formulation.

FormalPara tablet splitting

syn. Tablet scoring; splitting a (high dosage) tablet into two or four equal parts along breakmarks; the FDA has proposed measures in order to avoid problems related to dose such as: (1) the dosage amount meant to be achieved after splitting the tablet should not be below the minimum therapeutic dose indicated on the approved labelling; (2) the split tablet should be safe to handle and not pose risk of unintended drug exposure; (3) the split tablet , when stored in the dispensing container should demonstrate adequate stability for a period of 90 days at 25 °C (+/−2°) and 60% relative humidity (+/−5% RH); (4) the split tablet portions should meet the same finished-product testing requirements as for a whole-tablet product with equivalent strength; (5) modified-release products for which the control of drug release could be compromised by splitting, should not have a scoring feature; breaklines must be fully functional (“functional score”) also for the respective on generic drug; see formulation.

FormalPara tachyphylaxis

Decreasing response to a drug with repeated doses; this develops, in contrast to tolerance, within a very short time (minutes or hours) as e.g. for histamine.

FormalPara telomerase

an RNA-containing enzyme (a reverse transcriptase) that extends chromosome ends (telomers) by copying its RNA sequence repeatedly into chromosomal DNA. This extension enables DNA replication of the chromosome ends and compensates for the loss of DNA that occurs with replication.

FormalPara telomere

Repetitive nucleotide sequences at the end of a chromosome protecting the chromosome from damages resp. modifications and cells from senescence; as each cell division necessarily needs chromosome replication this protecting region progressively shortens with each cell division; without this protection apopotosis occurs; telomers can however be lengthened by an enzymes called telomerase, thus allowing cells to become potentially immortal as in cancer; telomerase seems to be involved also in chromosome repair; see advanced therapy, aging, apoptosis, longevity, Peto’s paradox.

FormalPara temperature monitoring

see cold chain products.

FormalPara temporality

Exposure to a cause must precede the effect of the exposure.

FormalPara teratogenicity

Capability to cause developmental malformations (embryo, foetus) and therefore birth defects.

FormalPara termination visit

syn. close out visit; last visit of a monitor or clinical research associate to a centre in order to collect all remaining case report forms (CRF), drug samples, unused CRFs or consent forms and usually also the investigator’s brochure; at this occasion also financial and analysis/reporting aspects may be discussed with the trialist and her/his staff.

FormalPara terminator

A DNA-site which, upon being bound by a terminator protein, causes arrest (or pausing) of a replication fork when it approaches from one side of the complex, but not the other. (2) Signal sequence that halts formation of an RNA transcript and allows for addition of a poly(A) tail.

FormalPara terminus region

A restricted and defined-segment of the chromosome in which replication forks meet and fuse.

FormalPara test article

Any substance or device for human use which is subject to premarket approval; although regulations differ between countries most of them exclude e.g. cosmetics from national drug regulations.

FormalPara test article accountability

(TAA) American term for drug accountability.

FormalPara test-retest

Use of the same or questionnaire in the same patient at different periods of time to assess validity of measurement of exposure; see also forward-backward translation, validation.

FormalPara therapeutic equivalent

Dosage form exhibiting the same efficacy (toxicity) when administered in the same appropriate dosage regimen; EC: “A medicinal product is therapeutically equivalent with another product if it contains the same active substance or therapeutic moiety and clinically shows the same efficacy and safety as that product, whose efficacy and safety has been established”; see also biologic equivalent, essentially similar product, pharmaceutical equivalent.

FormalPara therapeutic index

syn. protective index; ratio of the the toxic dose (LD50) to the therapeutic dose (ED50) [LD50/ED50] or ratio of the dose at which there is no more than 5% toxicity to the dose at which there are at least 95% cures [TD05 / ED95] (the larger this index, the safer the drug); see also therapeutic window, toxicity tests, margin of safety.

FormalPara therapeutic potential

Some health authorities provide accelerated approval programs for new drugs, depending on their therapeutic or innovative potential; for the FDA classification as “P” (priority) or “S” (standard) does exist; the therapeutic potential may be also important for price negotiations and reimbursement; see also accelerated approval program.

FormalPara therapeutic supplement products

see food supplement.

FormalPara therapeutic window

syn. safety margin; margin between the effective (and safe) dose of a medication and the dose causing adverse reactions (range between ED50 and TD50); this term is also used for the relatively short time window within which therapeutic measures are helpful, e.g., thrombolysis must be induced a.s.a.p. but within 3–6 h; see also therapeutic index, margin of safety.

FormalPara therapy management

see disease management.

FormalPara three-way crossover design

see crossover, design.

FormalPara threshold limits

Percentage of the total daily intake (TDI) of an impurity or, in absolute terms, the total amount allowed whichever is lower; different thresholds exist (ICH-Q3A): for a maximum dose not exceeding 2 g/day, the reporting th. is defined as the level that must be reported to regulatory agencies to inform them on the presence of a specified impurity (0.05%); it is generally higher or equal to the quantitation limit; the identification th. is defined as the level that requires analytical identification of a specified impurity (generally 0.10%, for degradation products 0.20%); the qualification th. is defined as the level where the specified impurity must be subject of non-clinical toxicological testing to demonstrate safety (generally 0.15%, for degradation products 0.20%; ICH-Q3B); see also limit of detection, limit of quantification, maximum residue level, minimal risk level.

FormalPara Threshold of Toxicological Concern

(TTC) A general human exposure threshold value for chemicals below which no appreciable risk to human health is assumed despite the absence of chemical-specific toxicity data; currently set for toxic substance such as carcinogenic or mutagenic agents at 1.5 μg/person/day; a more elaborated approach includes the total duration of exposure for the recommended limits for daily intake of mutagenic impurities: 120 mcg – < 1 month, 20 mcg – >1–12 months, 10 mcg – >1–10 years, <1.5 mcg – >10 years to life time (ICH M7); see also acceptable daily intake, allowed daily dose, impurity, permitted daily exposure, residual solvents, tolerable daily intake, tolerable upper intake level, toxic dose level, toxicity.

FormalPara time-event schedule

see flow chart.

FormalPara time trade-off

(TTO) Technique for measuring utility or quality of life; patients are asked about the number of years in their present health state they would be willing to trade for a shorter life span in full health.

FormalPara time-treatment interaction

see carry-over effect.

FormalPara time window

see therapeutic window.

FormalPara tincture

Usually an alcoholic extract (mostly 25–60%) of herbal or animal material; less common is vinegar or glycerine; see also extraction, herbal substance, phytochemical, refined extract.

FormalPara tissue engineered product

see advanced therapy.

FormalPara TNM-staging

Stands for tumour-node-metastasis; widely used classification system of the Unio Internationalis Contra Cancrum, UICC (Union International contre le Cancer, Unio Internationalis Contra Cancrum) which is based on the size of the primary tumour T (To–no evidence of primary tumour, T4-tumour invades adjacent organs and vessels, TIS, Tx), degree of local spread to lymphnodes N (No–N3, N4 if applicable, Nx) and distant spread of metastases M (Mo–M1, Mx); histopathologic grading is also of prognostic importance (Histopathologic Grade G: Gx – grade cannot be assessed; G1 – well differentiated; G2 – moderately differentiated; G3 – poorly differentiated; G4 – undifferentiated); see also tumour staging.

AJCC / UICC				Dukes
Stage 0	Tis	N0	M0
Stage I	T1	N0	M0	A
	T2	N0	M0
Stage II	T3	N0	M0	B
	T4	N0	M0
Stage III	any T	N1	M0
	any T	N2	M0	C
	any T	N3	M0
Stage IV	any T	any N	M1	D

1. Dukes B, C is composed of better and worse prognostic groups

FormalPara tolerable daily intake

(TDI) – describes the permitted exposure level to a potentially harmful, toxic (chemical) contaminant that should not be exceeded considering a lifelong ingestion (e.g., 150 mcg/kg b.w. of formaldehyde) in contrast to acceptable daily intake (ADI) which term is used for substances not considered as harmful; the newer term permitted daily exposure, is generally preferred;TDI levels are derived from the No Observed Adverse Effect Level (NOAEL) or (if not known) from the Lowest Observed Adverse Effect Level (LOAEL); TDI or maximum tolerable daily intake are terms used by the International Program on Chemical Safety. The biological half-life must be taken into consideration as some of the substances have a very long biological half-life or are bio-accumulative resp. Examples: acrylamide (TDI): 40 / 2.6 mcg/kg bw (for neurotoxicity / cancer); bisphenol A (TDI): 5–50 mcg/kg bw (T1/2 ~43 h); deoxynivalenol (an aflatoxin): 1 mcg/kg bw (EFSA); lead 25 mcg/kg/week (T1/2 ~10 years); inorganic mercury (TWI): 4 mcg/kg bw/week (JECFA; T1/2 ~60 days); methyl-mercury: 1.3 mcg/kg bw/week (EFSA; T1/2 ~70 days); D9-tetrahydrocannabinol (TDI): 0.4 mcg/kg bw (EFSA; T1/2 ~5 h to >24 h, biphasic); see also alimentary risks, tolerable upper intake level, defined daily dose, impurity, residual solvents, threshold limits, threshold of toxicological concern.

FormalPara tolerable upper intake level

(UL) Highest amount of a nutrient that can be taken daily and life-long by a healthy adult without risks (example: 300 mg / about 450 IE for vitamin E, < http://www.efsa.eu.int>); overlapping with acceptable daily intake; see also defined daily dose, dietary reference intake, dietary allowance, recommended daily allowances, threshold of toxicological concern.

FormalPara tolerable weekly intake

(TWI) see tolerable daily intake, acceptable daily intake, defined daily dose, impurity, permitted daily exposure, residual solvents, threshold of toxicological concern.

FormalPara tolerance

Reduction in the response of a drug treatment in a particular patient, e.g. by induction of enzymes as in the case of barbiturates; see also tachyphylaxis.

FormalPara total organ carbon

(TOC) Analysis of the Total Organ Carbon is a method used to test pure water and to validate it’s quality or cleaning procedures; see also alimentary risks.

FormalPara total quality management

(TQM) In clinical research, TQM is ensured by strict adherence to “GXP” (GCP, GLP, GMP,…) including various additional standards such as e.g. ISO 9000 and EN 45000; see also qality assurance.

FormalPara toxic dose level

(TDL) Lowest dose that produces haematological, chemical or other drug induced changes in the animal such that doubling the dose is not lethal; see also allowed daily dose, noel, threshold of toxicological concern.

FormalPara toxic equivalent

(TEQ) The TEQ scheme weighs the toxicity of the less toxic compounds as fractions of the toxicity of the most toxic tetrachlordibenzodioxin (TCDD); each compound is attributed a specific toxic equivalency factor (TEF); this factor indicates the degree of toxicity compared to 2,3,7,8-TCDD (the most toxic form of dioxin), which is given a reference value of 1.

FormalPara toxicity index

(T) T = (number of deaths associated with drug X) / (number of prescriptions for drug X); T is often closely related to the corresponding fatal toxicity in animals (LD50), and to physicochemical factors which are known to be correlated with other measures of human drug toxicity. In general, T is a measure of the probability of a fatal outcome following the use of a particular drug.

FormalPara toxicity tests

Single dose t. (acute tests) are used to establish the lethal dose of a compound in at least two different species by at least two different routes of administration (incl. usually intravenously and route planned for application in man); increasing doses are administered till an end-point, usually death, is reached; test animals are observed usually for a period of 14 but not less than 7 days; in repeat-dose t. (sub-acute t./less than 1 months duration, subchronic t. 1–3 months, chronic t./>3 months) the top dose is chosen so that it produces some minimal adverse effect (e.g. reduction in rate of body-weight gain) and dose/response relationship can be examined (2 species of mammals, one of which must be a non-rodent); for products to be administered once only to humans, a test lasting 2–4 weeks shall be performed; reproductive toxicity t. investigate potential adverse effects during production and fertilization of gametes; embryo/foetal and perinatal t. investigates effects of a drug administered to the female during pregnancy or embryogenesis resp. (“fetal toxicity” or “teratology”) or during birth and subsequent development; mutagenicity t. reveal changes in the genetic material of individuals or cells; carcinogenicity t. are normally required for substances likely to be applied in man longer than 3 months; intensive toxicity tests are especially important for products likely to be administered regularly over a prolonged time of a patient’s life; as example for the correlation between planned duration of human treatment and necessary toxicity testing the following overview can be given:

Human treatment	Toxicity studies (in two species, one non-rodent)
One/several doses, 1 day	2 weeks
Repeated doses up to 14 days	4 weeks
Repeated doses up to 1 month	1 month
Up to 3 months	3 months
>3 months up to 6 months	6 months
Above 6 months	6 months

the FDA still requests 12 months chronic toxicity tests for drugs intended to be used for longer than 6 months; a complete toxicity program costs about 5 to 10 million US$ and may use up to about 5000 animals; see also aneugen, animal welfare rules, carcinogenicity tests, cosmetics, double-strand breaks, ecotoxicity, genotoxicity, immunotoxicity, ld-10, maximum tolerated dose, minimal toxic dose, Mutagenicity test, no-toxic-effect-level, old substance, therapeutic index, threshold of toxicological concern; see also in vitro toxicity testing, Registry of Toxic Effects of Chemical Substances, stem cells.

FormalPara toxicokinetic

Relates body drug concentrations and their kinetics to toxicological findings; see also idiosyncratic reaction.

FormalPara TOXNET

Toxnet is the United States of America’s National Library of Medicine’s toxicology data network. It gives access to databases on toxicology, hazardous chemicals, environmental health, and toxic releases (http://toxnet.nlm.nih.gov/index.html); see also eChemPortal, Registry of Toxic Effects of Chemical Substances (RTECS), ATSDR http://www.atsdr.cdc.gov/toxicsubstances.html. For terms used in toxicology see also IUPAC, International Union of Pure and Applied Chemistry http://sis.nlm.nih.gov/enviro/iupacglossary/frontmatter.html, https://chem.sis.nlm.nih.gov/chemidplus/.

FormalPara toxtree

Open source application to estimate toxic hazard by a decision tree approach (http://toxtree.sourceforge.net/download.html); see also toxnet.

FormalPara traceability records

see gene therapy.

FormalPara trademark

syn. proprietary name, brand name, adopted name, invented name; may be the name of the manufacturer (opp. international non-proprietary name, generic name); a tm includes any word, name, symbol, device, or any combination, used, or intended to be used, in commerce to identify and distinguish the goods of one manufacturer or seller from goods manufactured or sold by others, and to indicate the source of the goods; relates to a finished product and identifies the manufacturer; for a commercially available medicinal product; within the EC it is recommended to use the same t.m. throughout the Community, unless a justification to do otherwise is given; in most countries the t.m. is liable to revocation after 3–5 years of non-use. EMA states “if there is a minimum of 3 distinguishing letters, it is unlikely that it will be considered that there is a risk of confusion in writing” (“3-letter rule”).

FormalPara trade name

Name used together with a trade mark; see trademark.

FormalPara traditional herbal medicinal product

EU: Medicinal product of herbal origin that has been in medicinal use throughout a period of at least 30 years preceding the date of application, including at least 15 years within the European Community; it has to be a non-prescription (OTC) medicine, i.e. claimed indications must be appropriate without the supervision of a medical practitioner and refer to the use “after exclusion of serious conditions by a medical doctor”; see also functional food, herbal drug, herbal medicinal Product, herbal substance, over-the-counter, phytomedicines, self medication, well-established medicinal use.

FormalPara traditional medicine

Medicinal use of products where their use is based solely on long lasting experience and ethnological evidence but usually not on conventional scientific standards; similar regulatory requirements apply as for traditional herbal medicinal products; see alternative medicine, ayurvedic medicine, natural health products, phytomedicine.

FormalPara traditional use registration

For products intended to be used as non-prescription drug (OTC); (i) No clinical tests and trials on safety and efficacy are required as long as sufficient safety data and plausible efficacy are demonstrated; (ii) Involves assessment of mostly bibliographic safety and efficacy data; (iii) Must have been used for at least 30 years, including at least 15 years within the EU; (iv) Are intended to be used without the supervision of a medical practitioner and are not administered by injection (Dir 2001/83/EC); similar regulatory requirements apply as for traditional herbal medicinal products; see well-established use,.

FormalPara transcript

An RNA molecule produced by transcription (transcriptase DNA-dependent RNA polymerase); an RNA polymerase that catalyses the formation of RNA on a DNA template.

FormalPara transcription

The synthesis of RNA molecules using DNA as the template to determine the sequence of bases in the RNA product. The synthesis of RNA is catalysed by the enzyme RNA polymerase.

FormalPara transcription factor

A regulatory protein required to initiate, upregulate or repress transcription. The term originally referred especially to those factors involved in the precise binding of RNA polymerases to promoters on the DNA and the initiation of transcription, but is now widely used for any gene regulatory protein. Examples for t.f.: nuclear factor kappa B (NF-kB), which regulates the expression of a range of signalling molecules that trigger inflammation a/o carcinogenesis; peroxisome proliferator-activated receptor gamma (PPARg) which is activated by ligands such as (endo-)cannabinoids or quercetin and alters the transcription of genes involved in glucose & lipid metabolism; activation of PPARg is antiproliferative (anticancer effects) and inhibits NFkB activation; it reduces insulin resistance, blood glucose levels and promotes neuronal differentiation.

FormalPara transcription–coupled nucleotide excision repair

A DNA repair process by which nucleotide-excision repair occurs preferentially on the transcribed strand on a transcriptionally active gene, presumably by the coupling of repair and transcription.

FormalPara trans–encoded antisense RNA

An RNA encoded by a gene that is not linked to its target gene. Target and trans-encoded antisense transcripts are not completely complementary and form imperfect RNA–RNA duplexes.

FormalPara transcriptome

The full complement of RNA species transcribed by a cell.

FormalPara transcriptome-sequencing

Also referred as RNAseq or whole-transcriptome shotgun sequencing. The sequencing of cDNA generated from total RNA. Transcriptome sequencing can provide data on gene expression, alternatively spliced transcripts, non-coding RNA and gene fusions or rearrangements.

FormalPara transdermal delivery system

(TDDS) syn.: transdermal delivery device (TDD); see transdermal patch, drug delivery, formulation, niosomes.

FormalPara transdermal patch

Special formulation where the drug is absorbed through the skin, e.g. nitroglycerin, nicotin a.s.o.; in passive patches, the drug diffuses into the skin as a result of a gradient in either the drug concentration or solubility; in active patches, external forces are used; transdermal delivery is limited by the size of the drug (upper limit around 500 Dalton), the water and lipid solubility and the pharmacologically effective dose to be delivered; potential irritation/sensitisation of the drug towards the skin must be excluded; hair follicles can act also as an entry portal for both antigens and DNA to the skin; see also controlled release, drug delivery, ethosomes.

FormalPara transduction

Introducing foreign genetic material into cells using viral vectors; see gene therapy.

FormalPara trans fats

Fatty acids that contain “unsaturated” bonds between carbon atoms with ligands in “trans”-position (both ligands point in the opposite direction in contrast to the large majority of naturally occurring fatty acids with ligands in “cis”-position); the large majority of t.f. are of industrial origin; they are found in some margarines and “refined” (partially hydrogenated) oils but also in commercially baked products (e.g., biscuits, cakes, popcorn) and deep fried fast food and are a major health concern; t.f. are known since 1911 (first patent for hydrogenated cotton seed oil); t.f. of food are incorporated into cell membranes affecting cell functions, and have been linked with many diseases such as coronary heart diseases, breast cancer (mortality rate in Western Europe ~175 per million) and diabetes (prevalence ~200,000 per million); in 1994, before restricting the content of t.f. in food by the FDA, it was estimated that t.f. caused 20,000 deaths from heart diseases annually; many countries recommend a maximum limit of 2 g/100 g total fat/day, the WHO defined a population goal of less than 1% of t.f. of overall energy intake; see also alimentary risks, allowed daily dose, junk food, maximum residue limit, pharmacovigilance.

FormalPara transfection

Transfer of (foreign) DNA to a cell by non-viral methods; a transfection product incorporates in one molecule of (human) DNA, an inserted segment of DNA from another species; see also gene therapy.

FormalPara transferosomes

Ultra-deformable vesicles that transport substances across the skin, driven by the osmotic gradient, (non-occlusive application); see also ethosomes, liposome, niosomes.

FormalPara transfer RNA

(tRNA) A family of small RNA molecules that act as “adaptors” in the process of translating the sequence of a messenger RNA into protein. Each tRNA molecule carries an amino acid that matches its anticodon (which will match to the appropriate codon in mRNA); tRNAs are small (75–100 nucleotide) elbow-shaped RNA molecules that carry a three- base sequence (‘anticodon’) on the long arm and an amino acid on the short arm.

FormalPara transformation

Genetic alteration of a cell through incorporation of exogenous DNA which causes transient or stable genetic changes; see gene therapy.

FormalPara transgenic animal

An animal which has grown from a fertilized oocyte where a foreign DNA construct was introduced (usually via microinjection); all cells of the experimental animal will contain the foreign DNA, which can also be passed on to the progeny of the animal; an important model to study the in-vivo function of mutated genes (for example oncogenes etc) in carcinogenesis; in contrast to knock out animals, transgenic mice are particularly suitable to study effects of dominant rather than recessive mutations in genes (gain of function disease).

FormalPara transgenic drug

Drug (usually a protein) which is manufactured from transgenic animals (e.g. by introducing a human gene such as for antithrombin III in a cow which then excretes the drug with the milk); see biotechnology, gene therapy.

FormalPara transition matrix

Frequently used format for presentation of e.g. laboratory data (example given for a total of 170 subjects, x-axis: number of subjects with observations as specified after treatment, y-axis: number of observations before treatment); see also shift table.

Before	After
	Lowered	Normal	Raised	Total
Lowered	9	5	0	14
Normal	27	29	14	70
Raised	0	45	41	86
Total	36	79	55	170

FormalPara translation

The process whereby the nucleotide sequence of a messenger RNA is read out and used to make a polypeptide chain. It takes place on the ribosomes. The process is called translation because the alphabet of nucleic acids (AT/UGC) is converted into sequences of amino acids; see also messenger RNA (mRNA), nucleotides, RNA interference, siRNA.

FormalPara translational control

Regulation of protein synthesis at the translational stage.

FormalPara translational operator

Sequence in mRNA, generally encompassing the translation initiation region, to which translational repressor proteins bind.

FormalPara translational repressor

Protein which binds to an mRNA, usually near the translation start, blocking access of ribosomes and inhibiting protein synthesis.

FormalPara transmucosal delivery

Drug delivery through across mucosal membranes such as in the mouth, nose, rectal or (rarely) vaginal wall; see also transdermal patch, drug delivery.

FormalPara transplantation

Over 28.000 human-to-human organ transplants were carried out in 2006 in the U.S (1994: 18.200); over 1 million people worldwide has received allograft organs and some of them have already survived more than 25 years; 5-years survival rates for most organ transplant programmes are around 70%; the increasing demand for organs outstrips supply; in the EC, the number of organs transplanted increased from 26,340 in 2004 to 31,165 in 2013; (all 28 Member States troughout the period) see also allogenic, biological medicinal product, biopharmaceutical, biotechnology, immunotherapy, xenotransplantation, http://www.irodat.org/, http://www.who.int/transplantation/en/. .

FormalPara transposable element

A DNA sequence that is able to move itself, or a copy of itself, to a new location in the genome (the process of transposition). Such movements often cause mutations.

FormalPara treatment emergent signs and symptoms

(TESS) ICH: Signs and symptoms not seen at baseline (i.e. before starting a new treatment or a clinical trial) and that worsened even if present at baseline; see also adverse drug reaction.

FormalPara treatment IND

syn. treatment use, named patient use; FDA: “A t.IND is a special case of an IND (investigational new drug) where the only protocol under the IND is the treatment protocol. … A treatment protocol allows use … of a promising new agent directed primarily at patient care by physicians who agree to follow the protocol.” t.IND criteria: treatment of a serious or immediately life-threatening disease, no satisfactory alternative treatment available, the drug is under investigation in a controlled clinical trial under an IND, sponsor is actively pursuing marketing approval; in contrast to a compassionate use a t.IND is based on at least enough data to provide a reasonable expectation that the drug may be useful and will not be unduly harmful; the t. protocol or t.IND covers an unspecified number of patients (anyone meeting the entry criteria) which would not be the case with other protocols under an IND; see also expanded-access program.

FormalPara treatment schedule

Frequency with which a specific drug should be taken by patients, e.g. weekly, once daily to several times daily; this depends on how long the desired effect lasts which is very much depending on the half life of the substance but also organ functions and the duration of the biological effect; see also loading dose, maintenance dose, pharmacokinetic.

FormalPara treatment use

see treatment ind.

FormalPara trial

see clinical trial.

FormalPara trial design

see design.

FormalPara trialist

see investigator.

FormalPara trial management organisation

see clinical research organisation, site management organisation.

FormalPara trial master file

(TMF) syn. clinical trial manual, project book note, study file; hard copy of all the documentation relating to a clinical trial; includes e.g. also audit certificates and reports, data on adverse events; a similar, widely overlapping file is held at the investigational site (Investigator’s Site File-ISF); see also archiving.

FormalPara true copy

Exact (and verified/confirmed) copy of an original record.

FormalPara truncating variant

A DNA sequence variant that results in the formation of a premature stop codon and therefore a truncated protein.

FormalPara tumour staging

Classification systems used to describe size of a tumour and extent of disease; classification systems which are widely used are e.g. according Dukes, or the TNM- (UICC-, AJCC-) staging, FIGO-staging; see TMN-staging, classification of recurrence, Disease free interval.

FormalPara tumour suppressor (gene)

A recessive gene normally involved in normal control of cell growth and division, preventing excessive cell proliferation, which, when eliminated at both alleles, allows uncontrolled proliferation.

FormalPara turbo-haler

see powder inhaler.

FormalPara two-stage design

see gehan’s design.

FormalPara two-tailed test

syn. two-sided t.; opposite: one-tailed t.; used to detect differences in either of two directions (e.g. experimental treatment is either superior or worse than control treatment); a two-tailed t. is most appropriate when the two treatments are roughly equivalent (e.g. in terms of risks or costs); two-tailed t. require larger sample sizes.

FormalPara two-way crossover design

see crossover, design.

FormalPara type I error

see alpha error.

FormalPara type IA variation

(type IA notification); variation to a marketing authorisation which has only a minimal impact, or no impact at all, on the quality, safety or efficacy of the medicinal product concerned (“do and tell”; e.g., typographical changes which are otherwise non-consequential to the main change; “administrative changes”; contact details of the MA holder; up to 10-fold increase/decrease of batch size; tightening of in-process limits); variations can be grouped whereby the further process is depending on the change(s) with the highest impact; changes can be grouped and submitted within 12 months, including the date of implementation of each variation; there are also Type IA variations with immediate notification (“Type IAin”) e.g., change of the QPPV or address of MA holder, manufacturer, switch to the “Summary of the PV Sytem + PV Master File” (replacing the “Detailed Description of the PV System”, DDPS); see also extension application, changes being effected.

FormalPara type IB variation

variation to a marketing authorisation which neither IA nor II nor an extension (“tell, wait 30 days, and do”), e.g., more than 10-fold increase compared to the currently approved batch size; addition or replacement of a specification parameter as a result of a safety or quality issue; harmonisation of the patient information leaflet (PIL) across all member states for a MR product is also a Type IB variation; the applicant must include a detailed justification to his submission why he considers the variation as Type IB; if within 30 days following the acknowledgement of receipt of a valid notification, the competent authority of the reference Member State has not sent the holder an unfavourable opinion, the notification shall be deemed accepted by all relevant authorities; see also extension application.

FormalPara type II error

see beta error.

FormalPara type II variation

variation to a marketing authorisation not deemed to be minor (type IA and IB), e.g. a new pharmacovigilance system, new indication, modification of the SPC on safety / efficacy information, new manufacturer of the API or other substantial changes to the manufacturing process a/o specification; in case of an urgent safety restriction (USR), a “Safety Variation Application” must be submitted within 15 days after the initiation of the USR; for fees see European Medicines Agency; see also extension application, urgent safety restriction.

FormalPara type III error

see gamma error.

FormalPara type of reaction

see adverse reaction.