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.

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.

European regulatory perspectives for innovative therapies.

The current regulatory requirements offer accelerated assessment of innovative therapies in Europe. Future perspectives include the need for increased interaction between stakeholders in pharmaceutical development. Development of new, high quality, effective and safe medicines in Europe is the common goal of academia, pharmaceutical industry and regulatory authorities. To achieve this, it is important that regulatory requirements do not hinder innovation and vice versa, innovation cannot be allowed to proceed without concerns for public health. Interaction between stakeholders in pharmaceutical development is of the utmost importance. A dialogue has begun and in the future it will be the responsibility of all stakeholders to ensure continuous exchanges in an environment that is characterised by new scientific advances and global development programmes.

Total joint replacement of hip or knee as an outcome measure for structure modifying trials in osteoarthritis.

OBJECTIVE: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working group to assess the value of time to joint surgery as a potential therapeutic failure outcome criterion for osteoarthritis (OA) of the hip or knee in the assessment of potential structure modifying agents. METHODS: PubMed was searched for manuscripts from 1976 to 2004. Relevant studies were discussed at a 1-day meeting. RESULTS: There are no accepted guidelines for 'time to' and 'indications for' joint replacement surgery. A limited number of trials have examined joint replacement surgery within the study population. Several parameters, particularly joint space narrowing (interbone distance), correlate with surgical intervention. However, at the level of the knee, none of the parameters have positive predictive value for joint replacement surgery better than 30%. In contrast, lack of significant joint space narrowing has a strong negative predictive value for joint replacement surgery (>90%), that remains after controlling for OA pain severity. CONCLUSION: At this time, GREES cannot recommend time to joint surgery as a primary endpoint of failure for structure modifying trials of hip or knee OA-as the parameter has sensitivity but lacks specificity. In contrast, in existing trials, a lack of progression of joint space narrowing has predictive value of >90% for not having surgery. GREES suggests utilizing joint space narrowing (e.g., >0.3-0.7 mm) combined with a lack of clinically relevant improvement in symptoms (e.g., >/=20-25%) for 'failure' of a secondary outcome in structure modifying trials of the hip and knee.

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.

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.

Uncertain future of trials in osteoporosis.

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 since proven treatments are available. In this review we argue that, if new agents are to be developed, there is still a place for the placebo-controlled trial. A move to studies of equivalence or non-inferiority raises more problems than it resolves.

The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis.

Registration of new agents for the treatment of postmenopausal osteoporosis has been based over the past few years on placebo-controlled phase III trials with the incidence of patients with new vertebral/nonvertebral fractures as the most usual primary endpoint. The use of a placebo in diseases where an active treatment is available has been a matter of debate following the update of the Declaration of Helsinki by the World Medical Association which questioned this trial design. Current regulatory recommendations within the European Union suggest that placebo-controlled trials are still the best option when assessing the efficacy and safety of new drugs intended for the treatment of postmenopausal osteoporosis. This suggestion seems to be in apparent contradiction with the current content of the Declaration of Helsinki. This paper addresses the ethics and feasibility of placebo-controlled trials in the treatment of postmenopausal osteoporosis, in the light of available therapeutic options, and discusses possible alternative approaches in those patients where placebo treatment could be deemed to be unethical. It is concluded that placebo-controlled trials remain the most efficient design to establish the efficacy and safety of a new agent for the treatment of postmenopausal osteoporosis. Such trials are feasible and ethically acceptable in patients with osteoporosis but without prevalent vertebral fractures. Conversely, in patients with prevalent vertebral fractures, placebo-controlled trials are ethically questionable and non-inferiority trials are more appropriate. A relative margin of non-inferiority of 20-30% is suggested, to be discussed on a case by case basis.

Background for studies on the treatment of male osteoporosis: state of the art.

Male osteoporosis represents an important, although long underestimated, public health problem. Both in men and in women aging is accompanied by continuous bone loss and by an exponential increase in the incidence of osteoporotic fracture, with a female to male incidence ratio of about 2 to 3 to 1 in the elderly for hip and vertebral fractures. Morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. To date, no single treatment has been proved to be effective and safe in published prospective studies. The present report, based on a systematic search of the literature on male osteoporosis, summarises the state of the art on the clinical consequences of male osteoporosis and its risk factors, in relation to the present state of knowledge about female osteoporosis. This constitutes the background for the design of rational clinical development strategies for therapeutic interventions in male osteoporosis. From this review of the literature it is apparent that notwithstanding the existing sex differences in pathophysiology of osteoporosis and the difference in age-specific incidence of osteoporotic fractures, there are also important similarities between osteoporosis in women and men. The higher incidence of fracture in women than in men results from quantitative differences in risk factors rather than from different risk factors. Even though there are sex differences in bone geometry, incidence of fracture seems to be similar in men and women for a same absolute areal bone mineral density. However, the lack of data on the changes in fracture rates in men resulting from pharmacological intervention, leading to changes in bone mineral density or bone turnover, remains the main limitation for extrapolation of established treatment outcomes from women to men.

Vascular dementia: European perspectives.

Vascular dementia (VaD) is the second most frequent cause of organic acquired cognitive dysfunction in the Western world and is probably the first cause in some Asian countries. Therefore, it represents an important target for drug trials in dementia. This report puts in perspective methodological issues in VaD trials, as opposed to Alzheimer disease (AD), and reproduces in extenso the European Medicinal Products Evaluation Agency (EMEA) guidelines for trials of symptomatic treatments of dementia, particularly in AD. There are no explicit guidelines for VaD trials, but many of the recommendations for AD are already applicable to VaD for drugs aiming at alleviating symptoms of dementia. However, VaD can be viewed as being one of the many possible consequences of cerebrovascular diseases, so that there is more to expect from secondary prevention strategies for VaD than for AD (in which both the etiology and the pathophysiological mechanisms are largely unknown). So it seems logical to put more emphasis on the stabilization of the symptoms of VaD, by preventing progression or recurrence insofar as the vascular risk factors for VaD can often be identified and controlled, than in attempting to improve the existing clinical manifestations of established vascular brain damage. Even if purely symptomatic drugs are developed to improve the symptoms of VaD, they will have to be studied in the context of a tight control of existing vascular risk factors. For secondary prevention, trials of at least 1 year seem advisable.

[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 and when to create a pediatric file for authorization to market a new drug. A proposal of the SNIP clinical group (National Syndicate of Pharmaceutical Industry)]. / Comment et quand bâtir un dossier pédiatrique pour l'Autorisation de Mise sur le Marché d'un nouveau médicament. Une proposition du groupe clinique du SNIP.

In order to recommend the pediatric use of a new drug, the registration file should include several types of studies. Existing data on toxicological and pharmacological studies in animal and human have to be thoroughly examined. In addition, the splitting potential of single doses to be adapted to the child should be studied, according to the galenic formula. In all cases, the clinical file should have one pharmacokinetic study on acute intake of one or several doses in the specific age bracket. When the efficacy of a drug has been demonstrated in adults for the same disease, and if the results are extrapolated to children, the file should include one or several open studies designs in order to assess the tolerability. On the contrary, for example when the disease is different in or specific for children, one or several double blind randomized studies against reference treatment are necessary. All those studies should show the therapeutical value of the drug, and should allow precise recommendations for the dosages, depending on the body weight and/or the body surface compatible with the galenic formula.

[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.

Vascular and insulinotropic effects of YC 170, a calcium agonist, on isolated perfused rat pancreas.

To explore simultaneously the effects on insulin secretion and on vascular tone of YC 170, a new dihydropyridine derivative calcium agonist, isolated perfused rat pancreases were studied for insulin output and for duodenopancreatic resistances before, during and after exposure to YC 170 10(-4) M (n = 15) or its solvent (n = 10). Although insulin was stimulated transiently during the five first minutes following addition of YC 170 (p less than 0.01) the integrated insulin output measured during the whole experiments was not different with YC 170 from that observed with solvent. Conversely, the initial duodenopancreatic resistances (22 +/- 4 mmHg.ml-1.min-1) rose progressively with YC 170 up to maximal values at the end of experiments (104 +/- 28 mmHg.ml-1.min-1; p less than 0.01); no significant variation occurred with solvent. Vascular and insulinotropic effects of YC 170 can be dissociated, suggesting variable abilities to promote calcium transport across membranes of smooth muscle cells and of pancreatic B-cells.

[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.

[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.