Table of contents :

• genotype therapy (a.k.a. gene therapy)
• phenotype therapy
• physical therapy / physiotherapy
• emergency medicine : basic life support (BLS)
• surgical operations (net addition or removal of parenchyma)
• radiation therapy (radiotherapy) (aspecific or targeted cell killing by ionizing radiations)
• electrotherapy
• mechanotherapy
• chemotherapy / drug therapy / pharmacotherapy (administration of molecules)
• immunotherapy
• biological therapy (administration of living organisms)
• biotherapy
• probiotic therapy
• phage therapy
• virotherapy : replication-selective (or conditionally replicating) lytic viruses
• psychotherapy

Physiatry refers to all non-surgical approaches.
More therapeutical approaches can be combined ...

• ... in a strategy (e.g. radioimmunotherapy, immuno-gene therapy, ...)
• ... in a therapeutical protocol (e.g. radiotherapy + suicide gene therapy).

• preventive (see prevention)
• aetiological : it removes the cause(s)
• pathogenetic : it impairs the pathogenetic mechanism(s)
• symptomatic : it doesn't remove cause(s), but just symptom(s) and/or sign(s)
• monotherapy : treatment of a condition by means of a single drug.

• placebo effect : the sum total of all nonspecific effects, both good and adverse, of medical treatment, primarily psychological and psychophysiological effects associated with the physician-patient relationship and the patient's expectations and apprehensions concerning the treatment. In 1978, scientists demonstrated that an opioid blocker called naloxone could abolish the placebo effect in a pain experiment^ref. The simple interaction between patient and practitioner has measurable effects in the brain : "open" injections of analgesics (patient-witnessed) were significantly more effective and less variable than "hidden" injections (patients were ignorant of injections). Furthermore, they showed that by blocking the opioids, naloxone greatly reduces this open-injection placebo effect, suggesting that the therapist-patient interaction activates the endogenous opioid systems^ref. Placebo and opioid analgesia may have a common neural mechanism in activation of the rostral anterior cingulate cortex (rAAC) for both treatments, though analgesic provide more pain relief^ref :


Both severely depressed men given either placebo or fluoxetine exhibit increased activity in the cortex and decreased activity in limbic regions, but only patients given fluoxetine experienced changes in brain stem, striatum, and hippocampus^ref. The release of dopamine, may be triggered by the placebo effect in patients with Parkinson disease^ref. To uncover regions of the brain that show decreased activity during the placebo effect, in one trial, researchers told subjects that they were administering a powerful analgesic cream. In another, the subjects received the same cream but were told it has no effect. When subjects were experiencing the placebo effect, a subset of known pain-sensitive brain regions showed a signal reduction of 20% to 25%^ref. In a subsequent study, patterns of neuronal firing, not visible via neuroimaging, corresponding to the previous findings were observed performing single-neuron recording via deep brain stimulation of subthalamic nuclei in patients with Parkinson disease who had been administered a sham treatment^ref. The brain areas involved in anticipation of pain relief have significant overlap with those involving empathy^ref. Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, the activity of the endogenous opioid system on µ-opioid receptors was directly examined in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of µ-opioid receptor-mediated neurotransmission was observed in both higher-order and sub-cortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of µ-opioid receptor signaling in the human brain^ref.
Placebo responses are often larger in studies of alternative therapies^{ref1, ref2}. This may, in part, be due to elevated expectations of patients.
The nocebo effect is the phenomenon whereby a patient who believes that a harmless substance cause harm actually experiences adverse effects due to negative expectations or the psychological condition of the patient.
Web resources : The science of the placebo: Toward an interdisciplinary research agenda
• + pharmacological effect

• 
• empiric or focused screening => optimization via chemistry
• preclinical testing according to good laboratory practice (GLP) and standard operating procedure (SOP)

 (1-5 years : average 2.6 years) :
• studies in vitro to define binding properties
• testing on model organisms with experimental diseases (rare for psychiatric disorders, except anxiety)
• short-term preclinical animal studies
• acute (single dose) toxicity testing in several species using route of administration for clinical use
• subacute or subchronic toxicity studies ranging from 1 week to 3 months
• mutagenicity/gene tox : short term tests (in vitro or in vivo) which may predict carcinogenic potential
• initiation of reproduction study (segment I)
• long-term preclinical animal studies
• chronic toxicity (6-12 months) for kidney, liver, nervous system and blood
• reproductive/teratology studies are typically conducted into 3 phases or segments:
• segment I - fertility and general reproductive performance
• study of fertility and general reproductive performance, e.g., mating behavior, gonadal function, conception, and early gestation
• required to initiate short term trials in females
• species studied include male and female rats
• segment II
• measure the embryo toxic (embryo lethality) and/or teratogenic (external visceral and skeletal defects) effects caused by administration of new drug to pregnant females during organogenesis
• 2 species are studied, the rat and rabbit (mouse and primate are also studied  if indicated)
• segment III - perinatal and postnatal study
• study of perinatal and postnatal effects, e.g., on late stage fetal development, labor, delivery, lactation, viability, and growth of the newborn
• assessments include observations of labor; deliver; lactation; viability, growth, development, and weaning of newborn
• species studied include the rat (mouse or primate if indicated)
• carcinogenicity
• pre-IND meeting
• investigational new drug (IND) : the notification of data relating to a new drug, which must be made to the FDA or local bioethic committee, which then review its safety before it may be administered to man (30 days). Chemistry, manufacturing and control (CMC) data are the chemical and pharmaceutical data which are included in an IND or an NDA. The clinical protocol must include :
• background and rationale
• objectives
• patient selection criteria
• study design and treatment
• expected toxicities and dose a
• clinical and lab monitoring
• criteria to evaluate endpoints
• statistical considerations
• references
• informed consent
• data form
• investigators
• clinical testing in human beings (2-10 years : average 5.6 years)

Principles of drug testing prior to trials in humans :
• exact composition of drug should be known; if not, method of preparation
• acute toxicity studies in animals of different species
• chronic toxicity experiments at varying doses in different species for cumulative effects
• careful and frequent observations of animals, to develop a composite picture of clinical effects
• careful pathological examinations of tissues with appropriate stains
• effects of drugs on excretory or detoxifying organs, expecially kidney and liver
• rate of absorption and elimination, path and manner of excretion, concentration in blood and tissues at varying times
• possible influence of other drugs and foodstuffs
• careful examination for any idiosyncrasies or untoward reactions
The Nuremberg Code^ref :
• the voluntary consent of the human subject is absolutely essential
• the experiment should be such a sto yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature
• the experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment
• the experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury
• no experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects
• the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment
• proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death
• the experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment
• during the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible
• during the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgement required of him, that a continuation of the experiment is likely to result in injury, disability or death to the experimental project.
Kind of trials :
• n of 1 trial : a specific therapy of uncertain efficacy can be compared with a placebo or alternative therapy in a double-blind design with well-defined endpoints for a patient with stable clinical symptomatology
• clinical trials
• phase I clinical testing is lead by clinical pharmacologists

Objectives : test drug interactions, pharmacokinetics (drug absorption, distribution, metabolism, and elimination (ADME)), and safe dosage range appropriate for use in phase II trials (maximum tolerated dose (MTD) and recommended dose (RD)
Patient selection criteria : 50-100 closely monitored healthy volunteers or special populations (e.g. patients with renal and hepatic impairment, advanced cancer resistant to standard therapies but with "normal" organ function, HIV-infected patients)
Starting dose : for INDs, 1/10 of LD₁₀ in the most sensitive species.
Study design : the initial types of phase I studies include :
• phase Ia
• single dose
• ascending dose tolerance : cohorts of 3-6 pts for each dose level up to dose-limiting toxicities (DLT) in 33% of pts (the so-called maximum tolerated dose (MTD)) (Fibonacci's scheme). When 1 out of 3 patients experience DLT, other 3 patients are tested, and only if none experiences DLT the upper dose can be tested in the next group.
• accelerated titration design (intra-patient dose escalation)
• multiple dose
• 7 day ascending dose tolerance
• 28 day tolerance of highest dose
• phase Ib : relation between dose and biological effect
Main of issues of concern to be included in a risk analysis of a new compound. This analysis assumes acceptable and stable pharmaceutical and chemical quality :

• phase II clinical testing is led by clinical pharmacologists and investigators to correlate blood levels with pharmacologic activity (a surrogate endpoint, i.e., ability to induce those pharmacodynamic modifications by which it is presumed clnical benefit can arise) and adverse events.

Patient selection criteria : same disease, histology, stage and previous therapies, normal organ function; if IND, resistance to (or not available) standard therapies is required
• phase IIa : studies in a small number (100-200) of patients to make a preliminary determination of safety and first signs of efficacy of a new drug to provide proof of the concept.
• phase IIb : studies in a larger number of patients to determine the range of doses to be used in the phase III clinical trials, establish dose and overall efficacy/safety properties, and the initial risk/benefit ratio
If pharmacological activity is enormously higher than for currently available therapies, a phase III trial may become unethical and an NDA can be directly submitted (e.g. what occurred for imatinib mesylate)
• phase III / pivotal studies clinical testing is led by clinical investigators who test effectiveness (ie. ability to induce clinical benefits), monitor effects from long term use, establish labeling requirements, and determine overall risk/benefit ratio on several hundred to several  thousand (inversely related to the width of the clinical benefit you aim to demonstrate, usually + 5-10% with respect to previously available therapies) of selected patients prior to seeking marketing approval and change guidelines for clinical practice. Lack of correlation with activity may be due to side effects or post-therapeutical rebound.
• requirements
• specific outcomes
• well-defined clinical end-point(s) should be used rather than an intermediate end-point / "surrogate" marker (i.e. a clinical sign or laboratory test that correlates with the clinical outcome of a disease). E.g. :
• quality of life (QOL) :
• pain relief
• visual analogic scale (VAS)
• analgesic consumption
• health-related quality of life (HRQOL)
• symptoms :
• freedom from progression (FFP) / freedom from disease progression (FFDP) / freedom from treatment failure (FFTF)
• local freedom from progression (LFFP)
• no evidence of disease (NED)
• symptom-free day (SFD)
• minimum clinically important differences (MCID)
• response :
• clinical response or remission
• histologic response or remission
• continuous complete histologic remission (CCR)
• haematological response or remission
• complete hematological response (CHR)
• cytogenetic response or remission
• major cytogenetic response (MCR)
• complete cytogenetic response (CCR)
• partial cytogenetic response
• minimal cytogenetic response (mCR)
• molecular response or remission
• complete response or remission (CR)
• near-complete response or remission (nCR)
• partial response or remission (PR)
• very good partial response or remission (VGPR)
• stable disease (SD)
• progressive disease (PD)
• survival :
• overall survival (OS) : death from any cause since entry onto trial
• cause-specific survival
• cause-specific mortality : death related to disease
• disease-free survival (DFS) / time to relapse (TTR) / freedom from recurrence (FFR) / time to progression (TTP) / response duration / duration of response (DR) : time to relapse or progression since first documentation of response
• disease-specific survival (DSS)
• event-free survival (EFS) / time-to-treatment failure (TTF) : failure or death from any cause since entry onto trial
• failure-free survival (FFS)
• relapse-free survival (RFS)
• progression-free survival (PFS) : disease progression or death from disease since entry onto trial
• time to next treatment : time when new treatment is needed since entry onto trial
• metameter is the measurement or transformation of the measurement used in evaluating biological tests.
• examples of metameters of dose include "milligrams," "moles," "log milligrams," "log milligrams per kilogram of body weight," etc.
• examples of metameters of response include "increase in blood pressure, in mmHg," "maximum blood pressure achieved, in mmHg," and "percent increase in blood pressure."
Metameters are frequently and erroneously chosen only to facilitate statistical summary and analysis of data; the metameter used may also obscure or influence the biological interpretation of the data in a manner not intended or expected by the investigator. For example, implicit in the calculation of "percent change in blood pressure" is the statement that the final state of the system is a function of the initial state which may or may not be true.
• accuracy of diagnosis and the severity of the disease must be comparable inn the groups being contrasted. This is a particular issue in developing therapies for syndromes whose aetiology and/or pathogenesis is poorly understood.
• dosages must be chose in a manner that allows relative efficicacy to be compared at equivalent toxicities or allows relative toxicities to be compared at equivalent efficacies
• randomized controlled trials (RCTs)
• randomized grouping
• cross-over experiment : each subject receives the test preparation at least once, and every test preparation is administered to every subject. At successive experimental sessions each preparation is "crossed-over" from one subject to another. The purpose of the cross-over experiment is to permit the effects of every preparation to be studied in every subject, and to permit the data for each preparation to be similarly and equally affected by the peculiarities of each subject. In a well-designed cross-over experiment, if it is at all possible, the sequence in which the test preparations are administered is not the same for all subjects, in order to avoid bias in the experiment as a result of changes in the behavior of the subjects that are a function of time rather than of drug administration, or a function of drug interactions. At least, the cross-over design permits detecting such biases when they occur. The preparations under test in a cross-over experiment may - ideally, should - include :
• one or more doses, of an experimental or "unknown" drug
• one or more doses of a dummy or placebo medication (negative control drugs)
• placebo control : a medicine or preparation with no inherent pertinent pharmacologic activity which is effective only by virtue of the factor of suggestion attendant upon its administration
• dummy control : a form of placebo mimicking in every way (dosage form, route of administration, etc.) the purportedly active ingredient upon which the effectiveness of the active treatment is expected to depend
In therapeutic trials involving life-threatening diseases for which there already is an effective therapy, the use of a placebo is unethical, and new treatments must be compared with current therapies.
• one or more doses of a "standard" drug, the actions of which are expected to be similar to those of the "unknown" (positive control drug).
• open experiment : pertaining to a clinical trial or other experiment in which both the subjects and the persons administering the test are aware of which treatment is administered to which subject.
• single-blind experiment : 1 participant - usually the subject - is left uninformed
• double-blind experiment / randomized double-blind controlled trial (RDBCT) : 2 participants - usually the subject and observer - are uninformed
• triple-blind experiment : pertaining to a clinical trial or other experiment in which neither the subject nor the person administering treatment nor the person evaluating the response to treatment knows which treatment any particular subject is receiving. The term triple mask is sometimes preferred to avoid confusion associated with the use of the term ?blind.?
• subjects compliance with the experimental regimens. Adherence to (or compliance with) a medication regimen is generally defined as the extent to which patients take medications as prescribed by their health care providers. The word "adherence" is preferred by many health care providers, because "compliance" suggests that the patient is passively following the doctor's orders and that the treatment plan is not based on a therapeutic alliance or contract established between the patient and the physician. Both terms are imperfect and uninformative descriptions of medication-taking behavior^ref.
• sample size enough to find statistically significant differences
• number needed to treat (NNT)
• number needed to harm (NNH)
• limitations
• patients for experimental trials often are selected to eliminate coexisting diseases and concomitant therapy
• trials usually assess the effect of only 1 or 2 drugs, not the many that might be given to or taken by the same patient under the care of a physician
• limited periods of time
• compliance may be better controlled than it can be in practice
• small numbers of patients => undetected rare side effects
• most medications have not been evaluated in women, children or elderlies
Cumulative analysis of many phase III trials with same endpoints (metaanalysis) is required if results are unconclusive.
During advanced clinical trials, neither doctors nor patients know whether they are using the drug or the placebo. But this is often not the case in earlier stages of trials, so patients could draw conclusions about the success of a prototype drug from their own response to it. Patients in clinical trials might be using information about the drug they are taking to trade illegally in pharmaceutical stocks : some patients, who pick up confidential information about the success of the drug they are taking, use this inside knowledge to trade in biotech or pharmaceutical company stocks. This may be illegal under trading rules. So far, there is only anecdotal evidence that this actually occurs, but the practice could be common among patients whose friends or family routinely invest in the market. If pervasive, steps might be introduced to prevent it, such as asking patients to sign forms that forbid them to release information or trade in any relevant stock during the trial. But any information patients might have is of little use to investors, because it could be overturned once all the data are analysed^ref
Evidence-based medicine (EBM)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9, ref10, ref11, ref12, ref13, ref14, ref15, ref16, ref17, ref18, ref19, ref20} (based on US Agency for Health Care Policy and Research (AHCPR) 1992) :
• level of evidence :
• the AHCPR classification is most appropriate for questions of causal relationships, and is usually used to assign studies, dealing with causal relationships, to levels of evidence.
• level I : intervention is useful and effective (should be administered unless contraindicated)
• level Ia : evidence obtained from meta-analysis of randomized controlled trials (RCT)
• level Ib : evidence obtained from at least one properly designed randomised controlled trial
• level IIa : weight of evidence/opinion is in favor of usefulness/efficacy; evidence obtained from at least one well designed controlled study without randomisation
• level IIb : usefulness/efficacy is less well established by evidence/opinion; evidence obtained from at least one other type of well designed quasi-experimental study
• level III : intervention is not useful/effective and may be harmful (should not be administered); evidence obtained from well designed non experimental descriptive studies, such as comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group, correlation studies and case studies
• level IV : evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities on case-series, either post-test, or pre-test and post-test
This classification however is proving to be increasingly problematic in guideline development that considers issues beyond intervention, and more specifically pharmacological interventions, and is also increasingly inadequate for assigning levels of evidence even to pharmacological intervention evidence. For example, there is no specific evidence level for systematic reviews (rather than meta-analysis). In terms of randomised controlled trials (RCTs) there is no recognition of whether the trial is considered adequately powered, or other indicators of quality. In non-pharmacological intervention evidence the problems are considerable. RCTs may contain other information that is useful. For example, in this guideline valuable epidemiological data was available from a large RCT (the UKPDS). But it is not obvious how the evidence classification deals with this. (In this guideline we have given a level III to the epidemiological evidence from the UKPDS, and level Ia or Ib to intervention evidence). The classification of studies that are concerned for example with screening for a condition/disease are not well served by this classification. None of the screening studies could achieve a level of evidence higher than III using this system, no matter how good the screening study. Similarly differentiation between high quality and lower quality screening studies are obscured by giving all screening studies level III as this system requires. Although other taxonomies for classifying and assigning evidence levels to other types of study (with different research questions as their starting point) have been developed they are not yet widely used (e.g. evidence levels for studies concerned with diagnosis and prognosis are detailed in Canadian Medical Association, 1998, S3).
• NHMRC system^ref :
• E1 / level I : evidence obtained from a systematic review of all relevant randomised controlled trials.
• E2 / level II : evidence obtained from at least one properly designed randomised controlled trial.
• E3₁ / level III-1 : evidence obtained from well-designed pseudo-randomised controlled trials (alternate allocation or some other method).
• E3₂ / level III-2 : evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a parallel control group.
• E3₃ / level III-3 : evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series without a parallel control group.
• E4 / level IV : evidence obtained from case-series, either post-test, or pre-test and post-test.
• US Preventive Services Task Force Rating System of Quality of Scientific Evidence (US Preventive Services Task Force. Appendix A: task force ratings. In: Guide to Clinical Preventive Services. 2nd ed. Alexandria, VA: International Medical Publishing; 1996:861 ?865)
• I : evidence obtained from at least 1 properly designed, randomized, controlled trial
• II-1 : evidence obtained from well-designed controlled trials without randomization
• II-2 : evidence obtained from well-designed cohort or case-control analytic studies, preferentially from >1 center or group
• II-3 : evidence obtained from multiple time series with or without the intervention or dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s)
• III : opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees
•  grading of recommendations :
• grade A : directly based on category I evidence
• grade B : directly based on category II evidence, or extrapolated recommendation from category I evidence
• grade C : directly based on category III evidence, or extrapolated recommendation from category I or II evidence
• grade D : directly based on category IV evidence, or extrapolated recommendation from category I, II or III
• generalizability index :
• 1 : very likely that results generalize to women
• 2 : somewhat likely that results generalize to women
• 3 : unlikely that results generalize to women
• 0 : unable to project whether results generalize to women
The arguments in favor of the registration of clinical trials are now familiar^{ref1, ref2, ref3, ref4}. Chief among these addresses the practice of selective reporting, whereby negative or detrimental studies are not brought into the public domain, which experts on the subject of clinical trials consider an important form of scientific misconduct^ref. This practice, as illustrated in a number of high-profile examples, have increased the demand for the mandatory public registration of clinical trials. Registration of trials should improve the completeness, reliability, and quality of the interpretation of clinical research. This need for registration prompts the question of where trials should be registered. It seems obvious that, to avoid conflicts of interest and to increase the public trust, the entities that establish and manage registries should meet certain requirements. One set of such requirements, as established by the International Committee of Medical Journal Editors (ICMJE) on September 2005^ref, requires that registries be owned and operated by not-for-profit entities, that they contain a minimal, clinically directive data set^ref, and that they be electronically searchable, without charge, by any interested party.  In October, the US Senate and Congress introduced legislation seeking mandatory registration of clinical trials.
• Through the European Clinical Trials Directive (Directive 2001/20/EC), the European Union introduced legislation requiring the registration of "clinical trials on medicinal products for human use" in a European database. Since 1 May 2004, all clinical trials conducted in member states of the European Union had to be registered in the EudraCT database, supervised by the European Medicines Agency (EMEA). This registry is confidential and open only to regulatory agencies and organizations that provide funding for research.
• The United Kingdom?based Current Controlled Trials' metaRegister of Clinical Trials (mRCT) is an example of a registry that may compile the data from smaller registries. The World Health Organization (WHO) is working together with the ISRCTN and ClinicalTrials.gov to develop a common scheme to reduce duplicate registrations and publications and to establish the unambiguous identification of trials with the use of a unique numbering system^ref. This is an important standard that must be met if registries are to be maximally effective. But the WHO does not have the last word on this subject. For example, the Ottawa statement^ref on trial registration goes much further than the WHO minimal data set. Its principles are to disclose the protocol details up front, to disclose amendments along the way, and to post the results at the end. The principles underlying this statement have been endorsed by > 100 persons and organizations on all 5 continents, but not by a single pharmaceutical company. This strategy is more than wishful thinking. The ultimate goal should be to make trial protocols publicly available in their entirety, including any financial arrangements and agreements with regard to publication, so that patients can be sure that the results will become available. At the same time, it is the responsibility of those who set the rules and establish the registries to make them practical to use and understandable for all kinds of research groups, both small and large. Only then will the use of registries become sufficiently comprehensive. The widespread use of trial registries will not prevent negative trial results or unwelcome outcomes from remaining unpublished. The current demand for the public registration of all clinical trials at their inception must therefore be followed by a demand for the addition of all results after each trial is complete and a certain amount of time has elapsed, to allow the researchers to publish in a journal^ref.
• the International Standard Randomised Controlled Trial Number (ISRCTN) Register scheme was launched on a pilot basis in 2000 and formally began operations in May 2003. The goal of this system is to simplify the identification of trials and provide a unique number that can be used to track all publications and reports resulting from each trial. This registry charges a minimal fee to registrants but is free to all who search its contents. This past September, ownership of the database was transferred to a not-for-profit entity, and it now meets all the ICMJE registration requirements. In addition to EudraCT and ISRCTN, publicly accessible national registries of clinical trials have been established in several European countries, Japan, and Australia. There has also been a proliferation of registries based on trials involving specific diseases. In addition to public registration, the confidential registration of most clinical trials already exists in France, Italy, Spain, UK (National Clinical Research Network) and the Netherlands. If these databases were open to the public, a wealth of information would be unearthed. Although the desire for regional and specialized registries may be understandable, it is important for all such registries to contain uniform data elements and to be linked electronically ? and even better, to share data ? so that a search for trials that meet certain criteria would automatically cover all trial registries.
• ClinicalTrials.gov, a public registry that was set up to fulfill the legislative requirement mandating the registration of U.S. clinical trials involving patients with serious and life-threatening diseases, was the first to met these requirements. At first, this database was limited to clinical trials sanctioned by a U.S. entity, but as of the fall of 2004, it began including clinical trials from anywhere in the world. Even so, many European researchers were reluctant to use ClinicalTrials.gov as a locus for trial registration. Sponsors, principal investigators, or other persons or organizations with primary responsibility for a given clinical trial (called "data providers") can register with ClinicalTrials.gov through a Web-based system^ref. In some instances, "intermediary trial registries," such as that of the National Cancer Institute, provide trial data. The database uses both open-ended responses and menu-based options, and terms from the National Library of Medicine Unified Medical Language System^{ref1, ref2} are used to facilitate subsequent information retrieval. Trials with the same protocol that are conducted at multiple sites are considered one trial in the registry. The complete entry in the registry for a given trial is referred to as a record in the database. ClinicalTrials.gov includes both mandatory and optional data elements. Trials cannot be registered without the completion of all mandatory data elements, which include both FDAMA 113 and registry-imposed requirements. In addition, the ICMJE requires completion of some of the optional data elements. Members of the National Library of Medicine staff manage the quality of information in the registry by rejecting records that do not have all required fields completed, reviewing entries for appropriate content and internal consistency, ensuring that links are active and relevant, checking contact information for recruiting studies, and confirming that approval from an institutional review board has been obtained. In addition, sponsoring organizations must electronically sign off on all entries (and subsequent revisions) before they are made available on the Web site^ref. Many investigators already register their trials in national or European databases, but unfortunately, no pan-European agreement has been struck with regard to how to move forward with public registration of clinical trials^ref.
• International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Clinical Trials Portal
One measure of medical progress is new treatments. The discovery of a novel therapy takes time and money, but more important, it requires the mutual effort of groups that, while they share the common goal of improved treatment, often have fundamentally competing interests. These interests intersect at the clinical trial. Patients who are looking for more effective and safer treatment agree to take part in a clinical trial in the hope that they will benefit from such treatment or that others with similar conditions will benefit later. The company developing the new therapy shares the hope that the trial will be successful, because it wants to market the tested therapy exclusively and profitably for as long as possible before its competitors can launch a similar therapy into the marketplace. These goals, though overlapping, are inevitably in conflict and will generate tension. Such tension has been thrown into sharp relief over the past 15 months by the push for clinical trial registration. The academic establishment and patients have argued that when patients, motivated by altruism, participate (or even consider participating) in a clinical trial, they are entitled to understand fully all the options available to them in the various trials that are currently recruiting subjects. In addition, their participation in a clinical trial should result in generalizable knowledge that will be available to future patients and investigators to improve patient care. This can happen only when appropriate details of the clinical trial are made available to the public in a timely fashion. The Internet and public registries have made this possible. Some in industry have argued that to open their portfolio of clinical trials to public scrutiny, particularly the scrutiny of other drug companies, would put them at such a competitive disadvantage that they would be unable to bring new products to market. Congress, however, decided to encourage openness by enacting on November 21, 1997, Section 113 of the Food and Drug Administration Modernization Act (FDAMA 113) (Public Health Service Act, 42 U.S.C.  282(j).). Section 113 ultimately created ClinicalTrials.gov as an Internet-based public resource for information on studies of drugs, including biologic drug products, that are conducted under the FDA's investigational-new-drug regulations (Investigational New Drug Application, 21 C.F.R. 312) and involve the treatment of serious or life-threatening diseases and conditions. In September 2004, the International Committee of Medical Journal Editors (ICMJE) announced that its journals would not publish the results of any ongoing trial that had not been appropriately registered in ClinicalTrials.gov or another qualified public registry by September 13, 2005^{ref1, ref2}. In this issue of the Journal, Zarin et al.5 provide a report card on compliance with these legislative and ICMJE requirements and the quality of the reporting that occurred before and after the ICMJE deadline for clinical trial registration. This report card examines whether the data fields required by FDAMA 113 have been completed in a meaningful fashion, with details about the drug or other intervention being studied and the prespecified measure of the trial's primary outcome. Without such critical data, registration becomes meaningless. Zarin et al. show that there was a dramatic change in the number of trials registered during the summer of 2005. There can be no doubt that this spike was related to the ICMJE statement and deadline, because the rate of registration fell (though to a rate higher than that before the statement) after the deadline for registration passed. In addition, they show that the Intervention Name field was universally completed in a meaningful fashion when the trials were sponsored by academic institutions or the National Institutes of Health. In contrast, among trials registered by commercial sponsors, compliance with this field was variable. Here the message is more nuanced. The vast majority of commercial entities provided meaningful data in most of their entries before the ICMJE statement and continued to do so during the summer of 2005. However, in the spring, some companies, such as Merck, GlaxoSmithKline, and Pfizer, provided meaningful entries in the Intervention Name field in an astonishingly low number of registrations. During the summer, Merck amended most of its meaningless entries to include clinically useful information in this field; by October they were in compliance in > 99% of their registrations. GlaxoSmithKline and Pfizer are still using meaningless entries in the Intervention Name field in 21% and 11% of entries, respectively. This is puzzling, since most other companies are able to comply fully with the requirements of FDAMA 113. The second critical measure examined by Zarin et al. was the number of records with the Primary Outcome field.  Here the data are less reassuring, and the performance of some companies remains abysmal. Of note, by October 2005, Novartis had completed this field only 3% of the time, and Merck only 20% of the time. Again, many of their competitors were in virtually full compliance, undercutting any argument that this failure reflects a commercial imperative. The ICMJE requirement that clinical trials be registered if they are to be considered for publication has been a resounding success. But the report cards for some companies would read improved but could do better. We demand complete compliance, because trial registration makes moral sense. When patients put themselves at risk to participate in clinical trials, they do so with the tacit understanding that their risk is part of the public record, not merely the secret record of the sponsor. In our opinion, it is unacceptable for a trial sponsor not to register its trial in a complete, meaningful, and timely fashion. We call for all clinical investigators and patients to participate only in fully registered trials. This call has recently been echoed by the major organization representing academic medical centers in the USA ? the Association of American Medical Colleges^ref. If a company continues to register trials using meaningless data, with no respect for the registration process and the patients who participate in those trials, investigators and patients should refuse to participate. If a company realizes that secrecy and failure to register mean that it cannot meet its recruitment goals, it will quickly recognize that the consequence of that secrecy is commercial failure, not competitive success. We must monitor the companies that are currently noncompliant to ensure that all live up to the spirit of the law as reflected in meaningful clinical trial registration^ref
Society risked taking for granted the huge successes brought to us through randomised clinical trials. The vast bureaucracy that now governs clinical trials is creating a culture in which it is harder, not easier, to conduct research. The result is not good for patients. Although much of the over-regulation?in adjudication committees, complex monitoring arrangements, and demands for voluminous data by national agencies?is done in the name of patients' safety, few researchers dare to say that this absurd regulatory hypertrophy is killing more than scientific curiosity. If investigators are dissuaded from doing experimental human research, the plain fact is that patients will die unnecessarily thanks to a diminution in the rate at which our clinical knowledge advances. The public could be forgiven for thinking otherwise. Britain's two biggest selling daily newspapers ran frightening headlines in March this year when TeGenero's phase I trial of an antibody treatment in healthy volunteers at Northwick Park Hospital went badly wrong??We saw human guinea pigs explode? (Parker N, Wheeler V. . The Sun March 16 2006; 1) and ?Hell of human guinea pigs? (Seamark M, Hope J. . Daily Mail March 17 2006; 1). The idea that doctors and clinical scientists see patients as little more than guineapigs is seriously mistaken. Yet this message is transmitted almost with glee by some influential sections of the mass media when an unforeseen experimental adverse event takes place. Such a response will surely damage perceptions of scientific integrity. It is vital that scientists and policymakers do all they can to protect this integrity and to secure its fragile roots in our society. This flourishing of clinical research for the benefit of patients is the overarching objective of WHO's effort to gain agreement on a practicable way of registering all clinical trials, from the moment of their inception and for a minimum set of scientifically and ethically essential elements. 2 principles must underpin trial registration^ref : all interventional trials, including early-phase studies (such as TeGenero's), should be registered, and all elements of the 20-item minimum dataset^ref must be disclosed at the time of registration.

Moreover, registration of all trials can help countries better manage, understand, and monitor their clinical research activities?especially given the trend towards greater conduct of early trials in the developing world (Vince G. Drug trials enter a new phase. New Scientist 2006; 189: 56-59), where regulation and oversight can be inadequate. The potential in such countries for exploitation of vulnerable populations^ref and for not reporting unfavourable trial results is a cause for concern. Lastly, trials of new interventions, including early trials, are often terminated for economic reasons^ref. Registration of all trials will ensure that these results are not lost to the body of general medical knowledge. Arguably, the registration of early-phase trials (and not only late-phase trials) is particularly indicated, to ensure that information about the risks of new interventions will be publicly available^ref. Therefore the Registry Platform considers it a basic principle that all interventional trials, including early trials in patients or healthy volunteers, be registered.  These positions are consistent with the Declaration of Helsinki^ref requirement that ?the design of all studies should be publicly available?, as well as with the recognition by the Declaration of Helsinki and the Nuremburg Code that the rights of trial participants hold primacy over commercial and career interests.
These principles have been arrived at after extensive consultation with all interested parties, including the pharmaceutical industry. WHO's latest statement therefore sets an important global ethical standard to which all those involved in clinical research now have an obligation to adhere. It represents an important step forward in the move to register trials, efforts that have stumbled on many occasions in the past. Details of the registration process remain to be resolved. For example, how will national or disease-specific registers be quality assured? What criteria will be applied for participating registers to be recognised? How will results be linked to the original record in the trial register? How can the minimum dataset for trial registration be expanded to include further elements that many experts believe are important for the patient to understand fully the meaning and value of a study? These questions will be answered over the next 12 months. And WHO would welcome support and commitment to ensure the successful implementation of the registry platform. But for now, WHO must begin to build a wide coalition of support for its two principles. Such an alliance is critically important to the success of this initiative. Two especially important partners have been the US National Library of Medicine's ClinicalTrials.gov and the UK's Current Controlled Trials International Standard Randomised Controlled Trial Number (ISRCTN) register. The Australian Clinical Trials Registry (ACTR) has also become a vital contributor to this emerging movement. Most member states of WHO and many pharmaceutical companies back the agency's plans. Disappointingly, a few have signalled their opposition to WHO's strong endorsement of transparency surrounding clinical trials. The Director-General, J W Lee, has successfully resisted this pressure so far. But he needs the continuing support of patients' groups and clinical researchers to convert sound principles into real practice. Journal editors can help. Just as the editors of general medical journals played a part in raising the profile of trial registration^ref, so editors could again help to move the current debate beyond merely an aspiration and towards a necessity. Results disclosure will be the next major step on the road to full transparency of all relevant information about a particular trial. Editors could drive that disclosure process by insisting that trialists and sponsors deposit key results information into a publicly accessible database, akin to GenBank. But, as GlaxoSmithKline's Frank Rockhold and Ronald Krall point out in this issue^ref, some editors are operating policies that inhibit rapid disclosure of trial data. Editors have been tough on pharmaceutical companies resistant to registering their trials. They have urged companies, such as GlaxoSmithKline, to put public interest before commercial interest. Yet journals now find themselves in a similar position to industry, but with respect to results disclosure. They?we?have a self-interested motivation to delay full disclosure of results until publication of a final paper?the Ingelfinger rule. In the past, editors have sought to control access to research results by insisting on a journal's priority in releasing data in advance of any other venue. Happily, that rule has broken down in the face of multiple outlets for data?in particular, presentation at scientific conferences. Given the ever-widening flow of information, it would be only a small step to recognise posting of trials data on an independent results database as an ethical imperative (Sim I, Owens DK, Lavori DW, Rennels GD. Electronic trials banks: a complementary method for reporting randomised trials. Med Decision Making 2000; 20: 440-450). GenBank is the National Institute of Health's genetic sequence database. It contains an annotated collection of publicly available DNA sequences. Many journals now require authors to send their sequence data to GenBank before publication. In that way an accession number can be published in the final paper and linked electronically to the scientific record. This has become an ethical norm for genetic sequencing studies. The same principle could be envisaged for trials. A trials results bank could contain minimum data derived from a randomised study. Journals could require that information be submitted to the trials results bank before publication. Trials registers might seamlessly overlap with the trials bank. This mechanism would not compromise the publication process. It would only add to transparency?helping to secure trust and credibility in the global clinical trials enterprise, an objective vital to patient's interests.
The industry's share of total biomedical research increased from nearly a third in 1980 to nearly two-thirds in 2000. Nonetheless, a report documenting combined data from > 1,100 studies showed that industry-sponsored clinical trials are "significantly more likely to reach conclusions that were favorable to the sponsor than were non-industry studies", possibly because of publication bias or selection of an inappropriate comparator to the drug being evaluated^ref. Within academic institutions, for example, trials funded by industry but initiated by the investigators typically have 10?20% lower overhead costs. They tend to restrict industry sponsors to ensuring adherence to good clinical-practice guidelines and to checking data for serious adverse events, notation errors and omissions. Hence industry has very limited influence on the conduct of the trial. In contrast, trials that are both initiated and funded by industry within academic institutions have higher overhead costs, usually in the range of 30?40%, paid to the academic institution. Such trials allow greater involvement by the industry funder, for example in writing the protocol, training and assisting investigators, and helping in data collection and analysis.
Web resources :
• Medical Dictionary for Regulatory Activities (MedRA)
• WHO Anatomical Therapeutic Chemical Codes (ATC)
• Good Clinical Practice (GCP)
• at FDA
• at EMEA
• data sheet : a summary of the information about a drug that is provided to doctors and pharmacists to enable the drug to be prescribed appropriately. It contains the uses, doses, contraindications, warnings and precautions that must be taken into account.
• pre-NDA meeting
• new drug application (NDA) (for non-biologicals) or product license application (PLA) (for biologicals) review by Food and Drug Administration (FDA) or marketing authorisation application (MAA) by drug regulatory authority in Europe for approval to market the drug (average 12 months)
• supplemental NDA (sNDA) may be submitted for a variety of reasons such as labeling changes, a new or expanded clinical indication, or a new dosage form presentation
• product license applications (PLA)
• biologics license applications (BLA)
• phase IIIb : differentiation from other treatments, exploring use in additional patient populations, seeking new indications for the study, or exploring AEs.
• phase IV / marketing support trial : these are marketing oriented trials which may extend the recommended duration of treatment or they may be primarily instructive in nature to help familiarize a larger number of practitioners with the drug's efficacy and side effects (seeding studies)
• limited market release surveillance study (LMRSS)
• postmarketing surveillance (PMS)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9} : all physicians check adverse drug reactions (ADR), patterns of drug utilization, and additional indications discovered on patients given drug for therapy, often in comparison with other treatments. 3 spontaneous signalations are considered an alarm signal, and may require an observational study to verify, confirm and quantify the reaction. Unfortunately animal testing is poorly predictive and trials are conducted on a few selected patients (excluding babies, elderlies and pregnants) for a limited period, in conditions differing signaficatively from clinical practice and without concurrent drug interactions. PMS should be practiced at a district level to face pharmacogenomical issues. Number of signalations per million inhabitants range from 370 in Sweden to 80 in Italy in 2000, 94,000 in Ireland, 97,295 in UK, 97, 290 in France > Denmark > Germany > Norway > Switzerland > Spain > Finland > The Netherlands > Italy > Austria > Portugal > Greece). The last drugs in old classes should never be extensively used at the beginning of marketing. The strength of evidence for an ADR comes from :
• case reports and cases series (82%), including positive dechallenge and rechallenge
• observation studies (18%) : e.g. for oral contraceptives and thromboembolism, b-blockers and sudden death, stilbestrol and vaginal carcinoma, glophenin hypersensitivity, phenfluramine and interstitial pneumonia, chlormezanone and TEN
The ADR may be :
• type A : dose-dependent (e.g. NSAIDs and SSRIs and gastrointestinal bleeding, third-generation oral contraceptives and venous thromboembolism)
• type B : dose-independent (e.g. nifedipine and aplastic anemia, cisapride and torsade de pointes syndrome when associated with CYP3A4 inhibitors (e.g. macrolides, antiproteases, azoles), astemizole and ventricular arrhytmias, alendronate and gastroesophageal reflux (prevented by assumption with 180 ml of water and remaining upright for 30' to allow gastric emptying and prevent direct first contact with gastric mucosa), nimesulide and hepatotoxicity in Spain and Finland when associated with ethanol)
• prescription event monitoring (PEM)
Web resources :
• Uppsala Monitoring Center (UMC)
• Sermo Physician Community intended for physicians licensed in the USA
• Waxman-Hatch Act is a 1984 act of Congress that extends patent exclusivity in marketing a drug for the same number of years that the regulatory process required (3-4 years). Also defined bioequivalence of some generics and eliminated many obstacles to generic product introduction in the market.

Web resources

• National Guideline Clearinghouse
• Medical Dictionary for Regulatory Activities (MedDRA) by Maintenance and Support Services Organization (MSSO)
• USAN stem list
• International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)

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