EMEA revises guidelines for evaluation of drugs in the treatment of primary osteoporosis

Innovation in drug development for osteoporosis, combined with emerging new proposals to identify individual patients at high risk of fractures, prompts EMEA to release new guidelines

The last guidelines for approval of drugs to be used in post-menopausal osteoporosis endorsed by the European Agency for Evaluation of Medicines (EMEA) were dated January 2001. Since that time, several new chemical entities with original mechanisms of action have been approved for the treatment of osteoporosis (teriparatide, strontium ranelate, ibandronate) as have new and alternative formulations of previously approved drugs (alendronate and risedronate once weekly dosing formulations).

This environment of innovation in drug development for osteoporosis, combined with emerging new proposals to identify individual patients at high risk of fractures (World Health Organisation [WHO] initiative), has prompted the EMEA to release new guidelines which will come into effect on May 31, 2007. Many changes have occurred, notably on indication of new compounds, duration of clinical studies and studies to be performed for new routes of administration.

Adequacy of the former “prevention of osteoporosis indication”

New developments that only concern prevention of bone loss after menopause are no longer seen as a goal. Indication for “prevention of osteoporosis” or “post-menopausal bone loss” will not be specifically granted to new products.

Scientifically, it has become evident that the decision process for initiating treatment in women to prevent the occurrence of the first osteoporotic fracture should be based on the global assessment of specific clinical risk fractures, rather than relying on a bone mineral density (BMD) measurement only. Hence, the theoretical basis for differentiating an indication of osteoporosis “prevention” from “treatment” as defined in the previous guidelines no long appears to be substantiated.

New indication

From the regulatory viewpoint, the therapeutic indication will now generally be “the treatment of osteoporosis in post-menopausal women at increased risk of fracture”, or, secondarily, “the treatment of osteoporosis in men at increased risk of fracture”. Pharmaceutical companies will be requested to demonstrate the effect of the investigated medicinal product on both spinal and non-spinal fractures.


Duration of pivotal studies required for granting of indication

Previous guidelines recommended that Phase III trials designed to demonstrate the efficacy of new compounds on fracture reduction in osteoporotic patients should last three years. In the context of increasing concerns raised by the design of clinical trials in osteoporotic patients (ethical restrictions when patients at increased risk of fractures are exposed to long-term placebo use or practical limitations due to the sample size required to demonstrate non-inferiority in active comparator studies), it seems scientifically sound to consider shorter duration for studies designed to demonstrate the anti-fracture efficacy of new chemical entities, provided that sufficient safety data has been collected. The new guidelines, requesting duration of randomised treatment of at least two years, take these elements perfectly into account.


Treatment of osteoporosis in men at increased risk of fracture

Previous guidelines were specifically designed for the treatment of osteoporosis in women.

Whereas twofold to threefold lower than in women, the lifetime risk of fragility fracture in men is also widely considered as a major public health issue, as men and women have the same incidence of vertebral fracture, after BMD adjustment.


The new guidelines, issued by the EMEA’s Committee for Medicianl Products for Human Use (CHMP), recognise the importance of osteoporosis in males. Although the gold standard for being granted a marketing authorisation for the treatment of osteoporosis in men at increased risk of fracture remains the demonstration of anti-fracture efficacy in a 2-year minimum, placebo-controlled, prospective study, a separate bridging study can be considered in medication for which an initial marketing authorisation has been granted for the treatment of post-menopausal osteoporosis in women at high risk of fracture.


The new CHMP guidelines on the evaluation of medicinal products in the treatment of primary osteoporosis are the most advanced document produced by any regulatory agency in this particular field. It encompasses all the new scientific acquisitions? developments during the last decade. It is expected that these new guidelines will help to provide osteoporotic patients with medication that has been assessed for efficacy and safety in optimal conditions.


About EMEA

The EMEA’s Mission Statement is to protect and promote public and animal health by

  • developing efficient and transparent procedures to allow rapid access by users to safe and effective innovative medicines and to generic and non-prescription medicines through a single European marketing authorisation,
  • controlling the safety of medicines for humans and animals, in particular through a pharmacovigilance network and the establishment of safe limits for residues in food-producing animals,
  • facilitating innovation and stimulating research, hence contributing to the competitiveness of EU-based pharmaceutical industry, and
  • mobilising and coordinating scientific resources from throughout the EU to provide high-quality evaluation of medicinal products, to advise on research and development programmes, to perform inspections for ensuring fundamental GXP* provisions are consistently achieved, and to provide useful and clear information to users and healthcare professionals.

For further information about EMEA, and to download new guidelines visit [link http://www.emea.eu.int/index/indexh1.htm]www.emea.eu.int/index/indexh1.htm [/link]


About Clinical studies
Clinical trials are categorized as Phase I to IV trials.


Phase I (small number of healthy volunteers; in certain cases, i.e. virology/oncology, also patients)

Phase I studies are designed to allow scientists and medical doctors to understand what effects an investigational compound has in human subjects. The goal is to study what happens to the investigational compound in the body from the time it is swallowed or injected until it is excreted, when it is excreted and how the human body reacts to the new compound from a safety and tolerability point of view. Study participants are monitored for the occurrence and severity of any side effects that they may experience.

Phase II

Phase II studies are designed to evaluate the safety and efficacy of an investigational compound in patients with a specific disease or condition. Phase II trials are typically conducted in a group of patients who are usually selected based upon being at the same stage of a disease. The patients are given various doses of the compound and closely monitored to compare the effects and to determine the safest dosing regimen. In many instances, multiple Phase II studies are conducted to test the compound in a variety of patient populations or indications.

Phase III

Phase III studies are designed to confirm the safety and efficacy of an investigational compound and the dosage regimen chosen in large numbers of patients with a specific disease or condition. These studies, like the previous ones, may involve one or more ‘treatment arms’, which allow the investigational drug to be compared to other available treatments, or to be tested for effectiveness in combination with other therapies. The safety and efficacy of the new compound is compared to that of the currently accepted standard treatment. Information obtained from Phase III studies is used to determine how the compound is best prescribed to patients in the future. The complete information available on the new compound is submitted to Health Authorities.

Phase IV

Phase IV studies take place after the drug has been approved for marketing and are designed to provide broader experience in evaluating the safety and effectiveness of the new medicine in larger numbers of patients, subpopulations of patients, and to compare and/or combine it with other available treatments. These studies are designed to evaluate the long-term effects of the drug. Under these circumstances, less common adverse events may be detected.