The Applicant also presented data from six placebo- controlled studies conducted in over 400 patients, showing no evidence of increase in resistance of the microbiological flora of the gastrointestinal tract (faeces), vagina, skin, saliva or dental plaque after long-term treatment with doxycycline 40 mg/ day for 6 to 18 months, which is in line with pharmacokinetic investigations on target site exposure.