Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies.

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

Study design in osteoporosis: a European perspective.

The advent of effective agents for the treatment of osteoporosis has led to the view that placebo-controlled trials to test new agents for efficacy are no longer appropriate. Rather, studies of superiority, equivalence, or non-inferiority have been recommended. Such studies require very large sample sizes, and the burden of osteoporotic fracture in a trial setting is substantially increased. Studies of equivalence cannot be unambiguously interpreted because the variance in effect of active comparator agents is too large in osteoporosis. If fracture studies are required by regulatory agencies, there is still a requirement for placebo-controlled studies, although perhaps of shorter duration than demanded at present.

Guidelines for clinical studies assessing the efficacy of drugs for the management of acute low back pain.

In this paper we propose guidelines for clinical trials aimed at assessing the efficacy of drugs for acute non-specific low back pain (LBP) with or without radicular pain, preliminary to their approval and registration. To this end, consensus statements were obtained from a group of experts in the fields of rheumatology, clinical medicine, public health and epidemiology. EBM resources were systematically used as references. Four diagnostic categories were defined: type 1--LBP with no radiation; type 2--LBP radiating no further than the knee; type 3--LBP radiating beyond the knee, but with no neurologic signs; and type 4--LBP radiating to a specific and entire leg dermatome, with or without neurologic signs. Studies should be designed on the basis of the claimed indications for the drug, but must be double-blinded whatever the indication. The duration of the study may be shorter for LBP type 1 or 2 (one week) than for LBP types 3 and 4 (up to one month), depending on the aim of the study and the indications for the drug. The comparator may be inactive (placebo) or active (for a superiority trial, e.g., versus paracetamol). Specific inclusion and exclusion criteria have been defined here for each category. An appropriate wash-out period for any drugs that could affect the pain status should be planned. Paracetamol may be allowed as rescue medication. The primary endpoint should be based on a validated pain assessment tool that may be either generic (type 1 or 2) or oriented (back and knee for types 3 and 4). Secondary endpoints could include the assessment of functional performance; the duration of any period of bed-rest; work limitation; a global assessment comprising pain at rest, standing and walking; the time elapsed before epidural injection, the prescription of other therapeutic agents, or surgery; and the use of rescue medication. Adverse events (AE) should be monitored systematically using a methodology that reflects the mode of action of the tested drug. With the application of these guidelines, LBP could serve as an appropriate disease for testing analgesic drugs. Rigorous evaluation may also help to improve the management of acute LBP.

Pharmacogenomics in cardiovascular clinical trials.

Genomics - having quickly emerged as the central discipline in basic science and biomedical research - is poised to take the center stage in clinical medicine as well over the next few decades. Although there is no specific regulatory guideline on the application of pharmacogenetics to drug development, some recommendations are already included in several published guidelines on drug development. The patients more likely to provide the most valuable information on the specific contribution of a given gene or its variant are those who fail to respond to a drug ('therapeutic failures') and those who develop toxicity to the drug. However, before drawing definite conclusions on subgroups following pharmacogenomic analyses, one must be aware of disease classification, data collection, and how much is known about the disease process. It seems reasonable to collect genomic DNA from all patients enrolled in clinical drug trials (along with appropriate consent to permit pharmacogenetic studies) for the purpose of post hoc analyses. One exception to post hoc genomic analysis is when patients with a specific genotype are excluded from randomization into a clinical trial. Physicians will need to understand the concept of genetic variability, its interactions with the environment (e.g. drug-drug or drug-disease interactions), and its implication for patient care.

[Economic aspects of pharmacovigilance in the pharmaceutical industry]. / Aspects économiques de la pharmacovigilance dans l'industrie pharmaceutique.

The economical aspects of pharmacovigilance in the pharmaceutical industry can be assessed by two ways. First the balance between cost of avoiding adverse drug reactions (ADR) and cost of ADR should be evaluated during the development. The company will have to take into account both efficacy and safety of its compound. However if it increases the costs of avoiding ADR it will reduce the costs of avoiding ADR occurring after commercialisation. On the other hand the cost of side effects of a marketed compound can also be appreciated. This assessment will always have to be comparative with an other drug and to take into account the benefit of both drugs, if their efficacy is not deemed identical.

[How to determine the optimal dosage of a drug]. / Comment déterminer la posologie optimale d'un médicament.

Determining the optimal dosage is an important step in the development of any drug, as it will provide a basis to demonstrate the effectiveness of that drug at different dosage levels. This determination is mainly attempted in phase II, notably by means of dose-response studies, but it is obvious that data obtained at every stage in the life of the drug will provide a better approach to dosage recommendations. Several examples are discussed.

[Quality assurance of clinical trials]. / Pour une assurance de qualité des essais cliniques.

A quality assurance system for clinical trials entails the definition, prior to the trial, of a number of procedures (the "good clinical practices") ensuring that it will be correctly conducted and the verification that these procedures have been respected. Setting up a clinical trial quality assurance system involving the manufacturer, university staff and public authorities should result in trials that are better performed. The role and responsibilities of each party are discussed, together with the consequences to be expected from the introduction of good clinical practices in France.

[Ethics and clinical trials]. / Ethique et essais cliniques.

Clinical research is indispensable for determining the safety and efficacy of drugs in human. It provides the scientific basis for rational drug usage. Methodology of clinical trials can raise some ethical issues. As an example the use of a placebo is described in this paper. Generally the ethical issues may be solved by the adequate information of every individual assigned to clinical investigation in agreement with the Declaration of Helsinki and the Huriet law. This information must be approved by an ethical committee. Finally an information about the general provisions of clinical trials must be destined to the general public.

[Coronary insufficiency in hypercholesterolemic xanthomatosis. Angiographic aspects]. / L'insuffisance coronaire de la xanthomatose hypercholestérolémique. Aspects angiographiques.

Coronary arteriography for severe coronary artery disease was carried out in 21 patients with hypercholesterolaemic xanthomatosis (group I) and in 42 patients with serum lipids (group II). Both groups were matched with regard to age, sex and cardiovascular risk factors (hypertension, smoking habits, diabetes). The films were examined by an observer unaware of the patients' clinical features; the severity of the lesions observed was assessed by means of a coronary score system. Group I patients had significantly more severe coronary artery lesions and a significantly higher incidence (52% versus 7%; p less than 0.001) of left main coronary artery stenosis carrying a high risk of sudden death. The percentages of affected vessels amenable to surgery and abnormalities in left ventricular function were similar in both groups. It therefore seems reasonable to envisage early coronary angiography followed, if necessary, by aorto-coronary bypass in patients with hypercholesterolaemic xanthomatosis who experience anginal attacks, show ECG abnormalities on exercise and have persistent pain after myocardial infarction.

[Prevalence of antinuclear antibodies in hypertensive diabetics treated with acebutolol]. / Prévalence des anticorps antinucléaires chez les diabétiques hypertendus traités par l'acébutolol.

Acebutolol may induce the development of antinuclear antibodies and, exceptionally, of a lupus-like syndrome. The purpose of this study was to evaluate the prevalence of antinuclear antibodies in hypertensive diabetics under long-term treatment with acebutolol. Seventy-eight normal subjects, 75 diabetics under antidiabetic therapy only, and 75 hypertensive diabetics who received acebutolol in mean doses of 478 +/- 242 mg/day for at least one year were investigated. The 3 groups were comparable with regard to age and sex. Antinuclear antibodies were detected in 18.6% of diabetics under acebutolol, as against 3.8% and 1.3% respectively of subjects in the other groups (p less than 0.01). There was no correlation between the levels of antinuclear antibodies and the dosage or duration of acebutolol treatment. None of the sera tested contained antinative DNA antibodies, and none of the hypertensive diabetics exhibited signs of lupus-like syndrome.

[Pathogenesis of tachycardia in hyperthyroidism. Value of Holter monitoring and the use of a beta-blocker]. / Pathogénie de la tachycardie de l'hyperthyroïdie. Intéret de l'enregistrement Holter et de l'utilisation d'un beta-bloqueur.

The mechanisms of tachycardia in hyperthyroidism were investigated by means of Holter recordings of heart rate in 45 patients, 33 of whom had sinus rhythm and were left untreated. In the remaining 12 patients, recordings were taken after 3 days of treatment with either propranolol (120 mg/day; 6 patients) or pindolol (15 mg/day; 6 patients). Propranolol is a beta-blocker devoid of intrinsic sympathetic activity whereas pindolol possesses such activity. Changes in heart rate under the influence of each of these drugs were compared with those observed in 96 controls similarly treated. The difference in baseline heart rare between day and night was significantly higher (p less than 0.01) in patients with hyperthyroidism (17 +/- 1 QRS/min) than in controls (13 +/- 1 QRS/min). Day and night heart rates were increased by pindolol, the increase in night heart rate being significantly greater (p less than 0.05) in patients with hyperthyroidism (23.4 +/- 4.9%) than in controls (11.6 +/- 2.6%). These results suggest that sinus tachycardia in hyperthyroidism is related to an increase in the number of myocardial beta-adrenoceptors. They also indicate that thyrotoxicosis should not be treated with beta-blockers possessing intrinsic sympathetic activity.

Adaptive licensing: taking the next step in the evolution of drug approval.

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.