Application for the inclusion of GATIFLOXACIN in the 20th WHO Model List of Essential Medicines (“EML”), as a reserve second-line drug for the treatment of multidrug-resistant tuberculosis (complementary lists of anti-tuberculosis drugs for use in adults and children) General items 1. Summary statement of the proposal for inclusion, change or deletion This application concerns the updating of section 6.2.4 Antituberculosis medicines in the 2015 editions of both the WHO Model List of Essential Medicines (19th list) and the WHO Model List of Essential Medicines for Children (5th list)(1),(2)). The proposal is to add gatifloxacin to both complementary lists in section 6.2.4 Antituberculosis medicines, as an alternative fluoroquinolone to moxifloxacin and levofloxacin. The applicant considers that this medication should be viewed as an essential medicine for patients with multidrug-resistant (combined resistance to rifampicin and isoniazid; MDR-TB) and extensively drug- resistant (MDR-TB with additional resistance to a fluoroquinolone and a second-line injectable; XDR-TB) disease. In many low resource settings, patients with these forms of tuberculosis are inadequately treated and often die because not enough medications are available to compose a suitable regimen(3). Second‐line drugs for the treatment of M/XDR-TB are frequently not available and global stock outs occur regularly. The revised WHO policy for the treatment of MDR-TB recommends the use of a shorter MDR-TB regimen(4); such regimens have shown promise to drastically reduce the length of treatment for MDR- TB patients to 9 months(5),(6),(7),(8) and are currently being used in various treatment programmes. The effectiveness and safety of these shorter regimens are also being studied in four countries under randomized controlled (RCT) conditions(9). Gatifloxacin may be included as part of both shorter MDR-TB regimens and longer regimens for M/XDR- TB. The 2016 update of the WHO treatment guidelines for drug-resistant tuberculosis now includes a regrouping of TB medicines which differs from the one in former guidelines(4),(10). The position of gatifloxacin however does not differ and it continues to feature alongside the other fluoroquinolones - levofloxacin and moxifloxacin – of Group A. Gatifloxacin used to be a mainstay fluoroquinolone of the shorter MDR-TB regimen until a global shortage of quality-assured formulations of the medicine occurred as a result of safety concerns(11). This constrained clinicians to replace this medicine with other later-generation fluoroquinolones in both shorter and longer regimens. Given that gatifloxacin is cheaper to manufacture than other later-generation fluoroquinolones, should production recommence it could substantially lower the costs of regimens. The inclusion of the drug as an antituberculosis agent on the EML will encourage pharmaceutical manufacturers to invest more in the production of this drug. A major initiative to help enhance the treatment of TB and MDR-TB patients has recently attracted UNITAID funding up to USD 60 million and aims to create new regimens using combinations of both the new TB medicines and these older medications(12). This request to the EML is thus very timely and in line with the position of WHO and its technical partners on the subject. If approved, it would synergise with their concerted efforts to improve patient access to treatment, ensure more favourable outcomes and reduce avoidable mortality for the 580,000 patients estimated to develop rifampicin-resistant or MDR-TB in the world every year and who would need second-line TB treatment regimens to increase their likelihood of a successful outcome. 1 2. Name of the WHO technical department and focal point supporting the application (where relevant) The focal point is the Unit of Laboratories, Diagnostics and Drug Resistance of the Global TB Programme of WHO Headquarters (WHO/HTM/GTB/LDR). The technical personnel directly concerned are Dennis FALZON, Tiziana MASINI and Ernesto JARAMILLO. 3. Name of the organization(s) consulted and/or supporting the application Dr Kaspars Lunte of Global Drug Facility (GDF) 4. International Nonproprietary Name (INN, generic name) and Anatomical Therapeutic Chemical (ATC) code of the medicine The WHO INN (generic name) of the medicine is Gatifloxacin(13),(14). The Anatomical Therapeutic Chemical (ATC) code is J01MA16(16). 5. Formulation(s) and strength(s) proposed for inclusion; including adult and paediatric (if appropriate) The formulations proposed, for both adults and children, are tablets in dosages of 200 mg or 400 mg. A drug information sheet for gatifloxacin is available in Annex 1(10). Details of the current market availability Gatifloxacin was marketed by Bristol-Myers Squibb (400 mg or 200 mg tablets) under the brand name Tequin®(17), having licensed the medication from Kyorin Pharmaceutical Company (Japan). However, following safety concerns reported in older patients, its production was stopped and the manufacturer announced its plan to stop producing and selling Tequin® in May 2006(18),(19). The company Allergan still manufactures a gatifloxacin-containing eye-drop formulation under the names Zymar® and Zymaxid®(20). In India and Bangladesh, generic manufacturers are known to produce gatifloxacin tablets for export. However, these manufacturers are not yet quality-assured. A number of manufacturers are listed as having GMP certificate for gatifloxacin in the “Database of approved Active Pharmaceutical Ingredients (APIs) and API manufacturers in China” of the China Food and Drug Administration(21). In October 2016 WHO added gatifloxacin to the list of TB medicines for which manufacturers will be invited to submit an Expression of Interest for API or Finished Pharmaceutical Products to the WHO Prequalification Team(22). It is expected that a number of manufacturers will respond to this invitation. 6. Whether listing is requested as an individual medicine or as representative of a pharmacological class This application is being made for gatifloxacin to be included with a square box symbol, alongside other fluoroquinolones which are already included as reserve second‐line drugs in the EML for both adults and children - levofloxacin and moxifloxacin(1),(2). There are other medications in the fluoroquinolone class (e.g. ofloxacin and ciprofloxacin) which are not included among the agents forming part of MDR and XDR-TB regimens. A separate application is being made to have ofloxacin eventually removed from the EML given that it has now been superseded by the other three fluoroquinolones. 2 Treatment details, public health relevance and evidence appraisal and synthesis 7. Treatment details (requirements for diagnosis, treatment and monitoring) Gatifloxacin could be an important component of both the intensive and the continuation phase of the shorter MDR-TB regimen recommended by WHO(4),(5). The regimen is usually composed of pyrazinamide, ethambutol, isoniazid, gatifloxacin (or moxifloxacin), kanamycin (or amikacin), prothionamide (or ethionamide) and clofazimine for four months (prolonged to six months in case of failure of sputum conversion), followed by a continuation phase of pyrazinamide, ethambutol, gatifloxacin (or moxifloxacin), and clofazimine for five months. Since May 2016, WHO recommends the shorter MDR-TB regimen in selected patients; gatifloxacin could thus have a central role in a regimen which is offered to patients as a standard of care unless they have specific exclusion criteria. Moreover, gatifloxacin could be the fluoroquinolone of choice for the longer regimens for both MDR-TB and XDR- TB, which is usually composed of pyrazinamide plus at least 4 second-line anti-TB drugs considered to be effective, including a later-generation fluoroquinolone, a second-line injectable, and two or more of : ethionamide (or prothionamide), cycloserine, linezolid or clofazimine(4). In the shorter MDR-TB regimen gatifloxacin is used for 9-11 months. A high dose based on body weight has been used (400-800 mg per day)(5),(6). The dose for the treatment of children with MDR-TB has not been well defined although when used to treat enteric infections gatifloxacin has been used at a dosage of 10 mg/kg/day, albeit for a few days(23),(24). Blood glucose monitoring every 1-2 weeks in patients taking gatifloxacin should be carried out(25). Electrocardiography should also be monitored regularly owing to concerns about potential cardiotoxicity(26),(27). These monitoring measures have proven to be feasible under programmatic conditions in low-resource settings. In August 2012, WHO advised countries to introduce shorter MDR-TB regimen only under operational research conditions, subject to the approval of a national ethics review, and with an appropriate assessment of the effectiveness and safety of treatment. Following a review of evidence which accrued from such studies, in May 2016 WHO conditionally recommended the use of a shorter MDR-TB regimen under normal programmatic conditions in patients who fulfil the eligibility criteria for this treatment(4),(28). 8. Information supporting the public health relevance Each year it is estimated that 580,000 new rifampicin-resistant and multidrug-resistant TB (MDR/RR-TB) cases emerge in the world and 250,000 MDR/RR-TB patients die(3). Many MDR-TB cases go undetected and are not placed on an appropriate treatment, increasing their risk of dying and of continued transmission of drug-resistant strains to others. About one half of MDR-TB cases globally have also lost susceptibility