The medical product: Telithromycin is a semi-synthetic anti-bacterial agent synthesised from erythromycin, and belongs to a new family of antibiotics-Ketolides. It was advocated as an alternative treatment when conventional beta-lactam antibiotics are contra-indicated.

Indications for use: Telithromycin was indicated for treatment of following infections in 2001 (EU authorisation) :

In patients age 18 years or older:

• Community-acquired pneumonia, mild or moderate

• Acute exacerbation of chronic bronchitis

• Acute sinusitis

• Tonsillitis/pharyngitis cause by Group A beta streptococci, as an alternative when beta lactam antibiotics are not appropriate

In 2007 FDA restricted this to mild to moderate community-acquired pneumonia (CAP) and the updated label included a boxed warning and a contraindication stating that no one with myasthenia gravis should take telithromycin. In addition, warnings were strengthened for hepatotoxicity (liver injury), loss of consciousness, and visual disturbances. The new label narrows the usage for telithromycin by dropping two previously approved indications.

• Mild to moderate community-acquired pneumonia (CAP)

• Acute exacerbation of chronic bronchitis (AECB)

• Acute sinusitis (ABS)

• Tonsillitis/pharyngitis (TP) caused by Streptococcus pyogenes, as an alternative when beta-lactam antibiotics are not appropriate in countries/regions with a significant prevalence of macrolide resistant S. pyogenes, when mediated by ermTR or mefA

Introduction of a contraindication for patients with myasthenia gravis. This was previously introduced as a warning.

The therapeutic area and disease epidemiology: Telithromycin is indicated in the treatment of community acquired Respiratory Tract infections.

The unmet medical need: Beta-lactam agent and macrolides are commonly used for the treatment of community acquired RTI, but resistance against S. pneumoniae has reached significant levels in several European countries.

The decision problem: Do the benefits of telithromycin outweigh the risk using the drug for the four indications so that a market approval can be granted for one for more of the indications? If not, are there any risk minimisation measures which could be implemented, thus bringing the benefit risk balance to be positive, such as safety restrictions?

Considering post-marketing observations on QTc prolongation and acute liver injury, is the benefit risk profile still considered positive? Again, if not, could safety restrictions to the indications bring the benefit risk balance for telithromycin to be positive for one or more of the indications?

Frame the problem: Compared to other macrolides, telithromycin seems to be associated with a somewhat different risk profile, such as visual adverse events, syncope and acute liver failure, and also aggravation of myasthenia gravis. At the same time there is in some European countries a high S.pneumoniae resistance to antibiotics especially in Southern Europe. The main problem in connection to the telithromycin benefit risk assessment involves the different risk profile associated to telithromycin compared to other macrolides and the potential effect of risk minimisation measures.

Clinical efficacy data of telithromycin from 12 double-blind comparative trials and 4 open label non-comparative trials.

The adverse event (AE) profile of telithromycin has been examined in 4780 telithromycin-treated subjects (2702 from comparative studies and 2078 from open label studies) and 2139 comparator-treated subjects in Phases III pivotal efficacy and safety studies. In addition 12159 subjects in the telithromycin treatment group of study A3014 (Phase IV study) were evaluated for safety.

The aim: To evaluate the benefit-risk balance for telithromycin, with the use of safety and efficacy data obtained from clinical trials and cumulative post-marketing safety information from a regulators perspective. And to assess change in benefit-risk balance, which could give reason for recommending restriction to the authorisation. The benefit-risk evaluation will be done using BRAT, MCDA, SMAA, NNT/NNH, Impact numbers and PSM.

The criteria:

• Cure rate

The clinical response was categorised as cure or failure. Evaluation of efficacy is evaluated based on sixteen phase III studies (12 double-blind comparative trials and 4 open label non-comparative trials)

The primary analysis of efficacy was the per protocol analysis at post therapy/TOC (test of cure) of clinical outcome (PPc populations) in studies 3000, 3001, 3002, 3003, 3005, 3006, 3007 and 3009, and the per protocol analysis of bacteriological outcome (PP population ) in studies 3004 and 3008. One controlled phase IV study tested PERSP at test of cure for telithromycin and Azithromycin and Cefuroxime.

• Hepatic adverse events

• Cardiac adverse events (including QTc prolongation)

• Visual adverse events

• Syncope

• Treatment emergent adverse events (TEAEs)

• Serious adverse events (SAEs)

• Telithromycin

• Comparators (single alternative of standard treatment antibiotics, this is done since all safety data are pooled in the EPAR)

The judgement about the benefit-risk balance: In 2001 CHMP judged that the benefit-risk balances for treatment with telithromycin in CAP, ABS, AECB and TP was positive. In 2007 FDA judged the balance to be negative for the indications ABS and AECB. At the same time CHMP found the balance to be positive for all four indications, provided any infections are caused by known or suspected beta-lactam and/or macrolide resistant strains covered by the antibacterial spectrum of telithromycin.

The basis for and extent of uncertainty in addition to statistical probabilities (e.g., possible biases in the data, soundness and representativeness of the clinical trials, potential for unobserved adverse effects) and the extent to which the benefit-risk balance is reduced by considering all sources of uncertainty, to provide a benefit-risk balance, and the reasons for the reduction.

• Medical need is covered by several other therapeutic options

• Increasing infection by beta-lactam and/or macrolide resistant strains

The basis for the decision maker's decision as to how tolerable the benefit-risk balance is judged to be (taking into account stakeholders' views of risk?)

• Decision on antibiotic treatments for respiratory tract infections

• Consideration to antibacterial resistance