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Studies in special populations: Information supporting the use of the drug in children, pregnant women, nursing women, elderly patients, patients with renal or other organ systems failure, and those on specific Drugs and Cosmetics Rules, 1945 509 concomitant medication is required to be submitted if relevant to the clinical profile of the drug and its anticipated usage pattern. Any claim sought to be made for the drug product that is not based on data submitted under preceding items of this Schedule should be supported by studies included under this item of the Schedule (Appendix I, item 8.3). (1) Geriatrics: Geriatric patients should be included in Phase III clinical trials (and in Phase II trials, at the Sponsor's option) in meaningful numbers, if- (a) the disease intended to be treated is characteristically a disease of aging; or (b) the population to be treated is known to include substantial numbers of geriatric patients; or (c) when there is specific reason to expect that conditions common in the elderly are likely to be encountered; or (d) when the new drug is likely to alter the geriatric patient's response (with regard to safety or efficacy) compared with that of the non-geriatric patient. (2) Paediatrics. (i) The timing of paediatric studies in the new drug development program will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments. For a drug expected to be used in children, evaluations should be made in the appropriate age group. When clinical development is to include studies in children, it is usually appropriate to begin with older children before extending the trial to younger children and then infants. (ii) If the new drug is for diseases predominantly or exclusively affecting paediatric patients, clinical trial data should be generated in the paediatric population except for initial safety and tolerability data, which will usually be obtained in adults unless such initial safety studies in adults would yield little useful information or expose them to inappropriate risk. (iii) If the new drug is intended to treat serious or life-threatening diseases, occurring in both adults and paediatric patients, for which there are currently no or limited therapeutic options, paediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit. In circumstances where this is not possible, lack of data should be justified in detail. (iv) If the new drug has a potential for use in paediatric patients – Paediatric studies should be conducted. These studies may be initiated at various phases of clinical development or after post marketing survelliance in adults if a safety concern exists. In cases where there is limited paediatric data at the time of submission of application – more data in paediatric patients would be expected after marketing authorisation for use in children is granted. (v) The paediatric studies should include - (a) clinical trials, (b) relative bioequivalence comparisons of the paediatric formulation with the adult formulation performed in adults, and (c) definitive pharmacokinetic studies for dose selection across the age ranges of paediatric patients in whom the drug is likely to be used. These studies should be conducted in the paediatric patient population with the disease under study. Drugs and Cosmetics Rules, 1945 510 (vi) If the new drug is a major therapeutic advance for the paediatric population – the studies should begin early in the drug development , and this data should be submitted with the new drug application. (vii) Paediatric Subjects are legally unable to provide written informed consent, and are dependent on their parent(s)/ legal guardian to assume responsibility for their participation in clinical studies. Written informed consent should be obtained from the parent/ legal guardian. However, all paediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand. Where appropriate, paediatric participants should additionally assent to enrol in the study. Mature minors and adolescents should personally sign and date a separately designed written assent form. Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the opinion of the Investigator and parent(s)/ legal guardian, the welfare of a pediatric patient would be jeopardized by his or her failing to participate in the study. In this situation, continued parental/ legal guardian consent should be sufficient to allow participation in the study. (viii) For clinical trials conducted in the paediatric population, the reviewing ethics committee should include members who are knowledgeable about pediatric, ethical, clinical and psychosocial issues. (3) Pregnant or nursing women.- (i) Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or foetuses/nursing infants and where the data generated from women who are not pregnant or nursing, is not suitable. (ii) For new drugs intended for use during pregnancy, follow-up data (pertaining to a period appropriate for that drug) on the pregnancy, foetus and child will be required. Where applicable, excretion of the drug or its metabolites into human milk should be examined and the infant should be monitored for predicted pharmacological effects of the drug. (4) Post Marketing Surveillance.- (i) Subsequent to approval of the product, new drugs should be closely monitored for their clinical safety once they are marketed. The applicants shall furnish Periodic Safety Update Reports (PSURs) in order to- (a) report all the relevant new information from appropriate sources; (b) relate these data to patient exposure ; (c) summarize the market authorization status in different countries and any significant variations related to safety; and (d) indicate whether changes should be made to product information in order to optimize the use of the product. (ii) Ordinarily all dosage forms and formulations as well as indications for new drugs should be covered in one PSUR. Within the single PSUR separate presentations of data for different dosage forms, indications or separate population need to be given. (iii) All relevant clinical and non-clinical safety data should cover only the period of the report (interval data). The PSURs shall be submitted every six months for the first two years after approval of the drug is granted to the applicant. For subsequent two years – the PSURs need to be submitted annually. Licensing authority may extend the total duration of submission of PSURs if it is considered necessary in the interest of public health. PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period. Drugs and Cosmetics Rules, 1945 511 However, all cases involving serious unexpected adverse reactions must be reported to the licensing authority within 15 days of initial receipt of the information by the applicant. If marketing of the new drug is delayed by the applicant after obtaining approval to market, such data will have to be provided on the deferred basis beginning from the time the new drug is marketed. (iv) New studies specifically planned or conducted to examine a safety issue should be described in the PSURs. (v) A PSUR should be structured as follows: (a) A title page stating: Periodic safety update report for the product, applicant’s name, period covered by the report, date of approval of new drug, date of marketing of new drug and date of reporting; (b) Introduction, (c) Current worldwide market authorization status, (d) Update of actions taken for safety reasons, (e) Changes to reference safety information, (f) Estimated patient exposure, (g) Presentation of individual case histories, (h) Studies, ( I) Other information, (j) Overall safety evaluation, (k) Conclusion, (l) Appendix providing material relating to indications, dosing, pharmacology and other related information. (5) Special studies: Bioavailability / Bioequivalence Studies.- (i) For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out wherever applicable. These studies should be conducted under the labelled conditions of administration. Data on the extent of systemic absorption may be required for formulations other than those designed for systemic absorption. (ii) Evaluation of the effect of food on absorption following oral administration should be carried out. Data from dissolution studies should also be submitted for all solid oral dosage forms. (iii) Dissolution and bioavailability data submitted with the new drug application must provide information that assures bioequivalence or establishes bioavailability and dosage correlations between the formulation(s) sought to be marketed and those used for clinical trials during clinical development of the product. (See items 8.1, 8.2 and 8.3 of Appendix I). (iv) All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed. Note.- The data requirements stated in this Schedule are expected to provide adequate information to evaluate the efficacy, safety and therapeutic rationale of new drugs (as defined under rule 122-E) prior to the permission for sale. Depending upon the nature of new drugs and disease(s), additional information may be required by the Licensing Authority. The applicant shall certify the authencity of the data and documents submitted in support of an Drugs and Cosmetics Rules, 1945 512 application for new drug. The Licensing Authority reserves the right to reject any data or any document(s) if such data or contents of such documents are found to be of doubtful integrity. APPENDIX I DATA TO BE SUBMITTED ALONG WITH THE APPLICATION TO CONDUCT CLINICAL TRIALS/IMPORT/MANUFACTURE OF NEW DRUGS FOR MARKETING IN THE COUNTRY