Bioequivalence Trial Information -SAHPRA

GENERAL INSTRUCTIONS:

Bioequivalence Trial Information Please review all the instructions thoroughly and carefully prior to completing the Bioequivalence Trial Information Form (BTIF).
Provide as much detailed, accurate and final information as possible. Note that the greyed areas are NOT to be filled in by the applicant. Please state the exact location (Annex number) of appended documents in the relevant sections of the BTIF. For example, in section 3.4.3.1 under point b), indicate in which Annex (number) the Certificate of Analysis can be found. This procedure must be followed throughout the entire document where location of annexed documents is requested. Before submitting the completed BTIF, kindly check that you have provided all requested information and enclosed all requested documents. 

Before submitting the completed BTIF, kindly check that you have provided all requested information
and enclosed all requested documents.

[1] Bioequivalence batches must meet a minimum of pilot scale, which constitutes 10% of the production scale or 100,000 capsules/tablets, whichever is greater. Moreover, the manufacturing method must mirror that of the production scale.

The product assessment report ought to be composed in clear, unequivocal language, addressing any deficiencies or lack of submitted data, as it may prompt communication with the manufacturer. It must be completed by a minimum of two evaluators. Additionally, the assessment report should adhere to the “Times New Roman 12” font requirement, and the format of tables must remain unchanged.

Furthermore, a properly filled out and signed original copy of the BTIF, along with all its annexes (including a copy on CD-ROM), is required.

Module 2.7 of the dossier should encompass the following details:

1. Catalog of all bioequivalence trials, comprising pilot studies, undertaken using the proposed product, which shares the same formulation and manufacturing process as that submitted for prequalification. This encompasses studies irrespective of the comparator (reference) product utilized and the study outcome. Comprehensive synopses of each study should be included, adhering to Annex I of the ICH Guideline E3: Structure and Content of Clinical Study Reports.

Inventory of all bioequivalence or comparative bioavailability studies, encompassing pilot studies, conducted throughout the pharmaceutical development phase (including formulation and/or manufacturing processes) of the product. These studies should be listed regardless of the comparator (reference) product employed and the study outcome. Detailed synopses of each study should be provided, following Annex I of the ICH Guideline E3: Structure and Content of Clinical Study Reports..

1 BIOEQUIVALENCE TRIAL INFORMATION-SAHPRA

1.1  SUMMARY OF BIOAVAILABILITY/BIOEQUIVALENCE STUDIES PERFORMED

(Provide a brief description of each comparative bioavailability study included in the submission)

1.2  TABULATION OF THE COMPOSITION OF THE FORMULATION(S) PROPOSED
FOR MARKETING AND THOSE USED FOR BIOEQUIVALENCE STUDIES

(State the location of the master formulae in the quality part of the submission)
(Tabulate the composition of each product strength using the table below. For solid oral dosage forms the table
should contain only the ingredients in tablet core /contents of a capsule. A copy of the table should be filled in for
the film coating / hard capsule, if any.
Important: If the formulation proposed for marketing and those used for bioequivalence studies are not identical,
copies of this table should be filled in for each formulation with clear identification in which bioequivalence study
the respective formulation was used) HAS COMPARATIVE BIOAVAILABILITY DATA BEEN SUBMITTED FOR ALL
STRENGTHS (If comparative bioavailability data has not been submitted for all strengths, provide a scientific justification for
not submitting such data; append copies of all references cited in the justification. Justification should include –
but is not limited to – argumentation related to dose-proportional composition, dose-linearity of pharmacokinetics
(Cmax and AUC,), discriminatory (with regard to bioavailability differences) power of dissolution tests employed)

2 CLINICAL STUDY REPORT

1. Study #:2. Study Title:3. Location of Study Protocol:4. Start and stop dates for each phase of the clinical study:5. Date of Product administration: 2.1 ETHICSa)State the name of review committee, date of approval of protocol and consent form and the location of approval letter in the submission b)State location of a reference copy of the informed consent form 2.2 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTUREa)Name of principal investigator(s) (State location of c.v. in the submission) b)Clinical Facility (Name and full mailing address) c)Clinical Laboratories (Name and full mailing address) d)Analytical Laboratories (Name and full mailing address) e)Company performing pharmacokinetic/statistical analysis (Name and full mailing address) 2.3 STUDY OBJECTIVESBriefly state the study objectives 2.4 INVESTIGATIONAL PLAN2.4.1 Overall study design and plan — description(Describe the type of study design employed in 1-2 sentences) 2.4.2 Selection of study population 2.4.2.1 Inclusion Criteria(List the inclusion criteria applied to subjects) 2.4.2.2 Exclusion Criteria(List the exclusion criteria applied to subjects) 2.4.2.3 Health Verification(State location of the individual data included in the submission)a)List criteria used and all tests performed in order to judge health status b) Indicate when tests were performed c) Study site normal values(State location in submission of study site normal values for blood clinical chemistry, haematology, and urinalysis clinical screen) d)Report any results that were outside of study site normal values(State location in submission of the summary of anomalous values) 2.4.2.4 Removal of Trial subjects from Trial or Assessmenta)Number of subjects enrolled in the study(All subjects including alternates, withdrawals, and dropouts)  b)Alternates(Please note: Generally all subjects enrolled in the study should be included in the data set i.e., alternate subjects are strongly discouraged. However, in cases where there are alternate subjects, describe the procedure of including/excluding the alternates and whether alternates have been included in the study)  c)Withdrawals/dropouts(Identify each withdrawal/dropout by subject and provide the reason for withdrawal/dropout and at what point in the study the withdrawal/dropout occurred) 2.4.3 Products Administered2.4.3.1 Test Producta)Batch number, size, date of manufacture and expiry date for the test product  b)Potency (measured content) of test product as a percentage of label claim as per validated assay method(This information should be cross-referenced to the location of the certificate of analysis in the submission) 2.4.3.2 Comparator (Reference) Product(Append to this template a copy of product labelling (snap shot of the box, on which the name of the product, name and address of the manufacturer, batch number, and expiry date are clearly visible on the labelling)a)Name and manufacturer of the comparator product and market where the comparator product was purchased b)Batch number and expiry date for the comparator product c)Purchase, shipment, storage of the comparator product (Indicate from which company/pharmaceutical distributor the comparator product has been obtained. Clearly indicate in chronological order the steps and dates of shipment/transport from company of purchase to the study site. In addition, the storage conditions should be given. This information should be cross-referenced to location in submission of documents (e.g. receipts) proving conditions.For example:A = Name and location of Pharmaceutical Distributor (date of purchase); location in dossier of purchase invoice;Shipped from A to B (date shipped, method of shipment); location in dossier of bill of lading and shipping temperature record;B = Sponsor’s site (date received, storage conditions at site); location in dossier of record of storage conditions over period stored at siteShipped from B to C (date shipped, method of shipment); location in dossier of bill of lading and shipping temperature record;C = CRO site (date received, storage conditions at site); location in dossier of record of storage conditions over period stored at site) d)Potency (measured content) of the comparator product as a percentage of label claim, as measured by the same laboratory and under the same conditions as the test product(This information should be cross-referenced to the location of the certificate of analysis in the submission)  e)Justification of choice of comparator product(Provide short summary here and cross-reference to location of comprehensive justification in study protocol) 2.4.4  Selection of doses in the studya)State dose administered(Indicate the number of dosage units comprising a single dose, e.g., 400 mg as 1 x 400 mg or 2 x 200 mg tablets) 2.4.5  Selection and Timing of Dose for Each Subjecta)State volume and type of fluid consumed with dose b)Interval between doses (i.e., length of washout) c)Protocol for the administration of food and fluid d)Restrictions on posture and physical activity during the study 2.4.6  BlindingIdentify which of the following were blinded. If any of the groups were not blinded, provide a justification for not doing soa)study monitors: Yes •  /  No •  If No, justify: b)subjects: Yes •  /  No •  If No, justify: c)analysts: Yes •  /  No •  If No, justify: Identify who held the study code and when the code was broken 2.4.7  Drug Concentration Measurements2.4.7.1 Biological fluid(s) sampled2.7.4.2  Sampling protocola)Number of samples collected per subject b)Volume of fluid collected per sample c)Total volume of fluid collected per subject per phase of the study d)List the study sampling times e)Identify any deviations from the sampling protocol(State location of summary in the submission)(Describe and explain reasons for deviations from sampling protocol. Comment on impact on study. Indicate whether the deviations were accounted for in the pharmacokinetic analysis) 2.4.7.3 Sample Handlinga)Describe the method of sample collection b)Describe sample handling and storage procedures

3  TRIAL SUBJECTS

3.1 Demographic and other baseline characteristicsa)Identify study population (i.e., normal, healthy adult volunteers or patients) b)Summary of ethnic origin and gender of subjects c)Identify subjects noted to have special characteristics and state notable characteristics(e.g. fast acetylators of debrisoquine) d)Range and mean age  SD of subjects e)Range and mean height and weight  SD of subjects f)Identify subjects whose ratio is not within 15% of the values given on a standard height/weight table 3.2 Subjects who smokea)Number of smokers included in the study b)Indicate how many cigarettes smoked per day per subject c)Comment on the impact on study

4  PROTOCOL DEVIATIONS4.1 Protocol deviations during the clinical study(Describe any such deviations and discuss their implications with respect to bioequivalence)

5   SAFETY EVALUATION5.1 Identify adverse events observed(List any adverse events by subject number. State whether a reaction occurred following administration of the test or reference product, identify any causal relationships, and note any treatments required. State location of this summary in the submission.)(Discuss the implications of the observed adverse events with respect to bioequivalence.)

6  EFFICACY EVALUATION

EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL TRIAL SUBJECTS DATA

6.1  Presentation of data

a)State location in submission of tables of mean and individual subject concentrations

b)State location in submission of (mean and individual) linear and semi-logarithmic subject drug concentration vs. time plots

6.2 Pharmacokinetic (PK) parameters

a)State how the pharmacokinetic parameters where calculated/obtained for AUC0-inf, AUC0-t, Cmax, tmax, the elimination rate constant, and t½ (indicate location of description in protocol)

b)State whether actual sampling time points were used for estimation of the pharmacokinetic parameters

c)Complete the table below

Ratio of AUC0-t to AUC0-inf(State mean ratio for both test and reference, state location in submission where individual ratios can be found) 6.3  Statistical analysis(State the method of calculation of the 90% confidence intervals for the ratio of test formulation over the reference formulation and indicate how treatment, period, sequence and subjects within sequence were included as factors in the ANOVA. Provide the following results from the ANOVA (parametric) on the logarithmically transformed AUC0-t and CMAX and other relevant parameters. State software  used for computing ANOVA.) a)Geometric means, results from ANOVA, Degrees of Freedom (DF) and derived CV (intra-subject)

b)Comparison of the results(Compare the results, including mean values, inter- and intra-individual variability, of this study with published results (literature, product information of reference product (innovator), WHOPARs), and copies of the references used should be appended to this document)  6.4 Discussion of results(State location of the discussion of the results in the submission)

ANALYTICAL VALIDATION REPORT7.1 Analytical technique7.1.1 Validation protocol(State the location of the validation protocol)7.1.2 Identify analyte(s) monitored 7.1.3 Comment on source and validity of reference standard 7.1.4 Identify internal standard  7.1.5 Comment on source and validity of internal standard  7.1.6 Identify method of extraction 7.1.7 Identify analytical technique or method of separation employed 7.1.8 Identify method of detection 7.1.9 Identify anticoagulant used (if applicable) 7.1.10 If based on a published procedure, state reference citation 7.1.11 Identify any deviations from protocol 7.2 Selectivity(Address the methods to verify selectivity against endogenous/exogenous compounds & results) 7.3  Sensitivity(Address the methods to verify sensitivity & results) 7.4 Carry-over(Summarize the method to verify carry-over & results) 7.5 Standard curves(State location in submission of tabulated raw data and back calculated data with descriptive statistics) a) List number and concentration of calibration standards used b) Describe the regression model used including any weighting c) List the back-calculated concentrations of the calibration standards of the validation runs (highlight the values outside of the acceptance range, e.g., 15%, except 20% for LLOQ) 7.6 Quality control samplesa) Identify the concentrations of the QC samples and the storage conditions employed prior to their analysis 7.7 Precision and accuracy during validationa) Summarize inter-day/inter-run accuracy and precision of the calibration standards during assay validation b) Summarize inter-day/inter-run accuracy and precision of the calibration standards during assay re-validation(If applicable) c) Summarize inter-day/inter-run and intra-day/intra-run accuracy and precision of the QC samples during assay validation d) Summarize inter-day/inter-run and intra-day/intra-run accuracy and precision of the QC samples during assay re-validation(If applicable) 7.8 Dilution integrity(Summarize the method to verify dilution integrity & results) 7.9 Matrix effect (in case of MS detection)(Summarize methods to verify the matrix effect & results) 7.10 Stability(For each section provide the location of the raw data, a description of the methodology employed and a summary of the data.)a) Summarize data on long-term storage stability b) Summarize data on freeze-thaw stability c) Summarize data on bench top stability d) Summarize data on auto-sampler storage stability(e) Summarize data from any other stability studies conducted(e.g. long-term stock solution and working solution stability, short-term stock solution and working solution stability, dry-extract stability, wet-extract stability, stability in blood before sample processing) 7.11 Re-injection reproducibility(Summarize the method to verify re-injection reproducibility & results)

8 BIOANALYTICAL STUDY REPORT(State the location of the bioanalytical report for the analysis of the study subject samples) 8.1 Analytical technique(Confirm whether the method is the same as the validated method and whether the same equipment was employed. Identify any differences between the validated method described above in Section 7 and the method employed for subject sample analyses) 8.1.1 Analytical protocol(State the location of the analytical protocol) 8.1.2 Identify any deviations from protocol 8.1.3 Dates of subject sample analysis 8.1.4 Longest period of subject sample storage(Identify the time elapsed between the first day of sample collection and the last day of subject sample analysis) 8.1.5 State whether all samples for a given subject were analysed together in a single analysis run 8.2 Standard curves(State location in submission of tabulated raw data and back calculated data with descriptive statistics)a) List number and concentration of calibration standards used b) State number of curves run during the study (valid and failed runs, including reasons of failure). c) Summarize descriptive data including slope, intercept, correlation coefficients d) List the back-calculated concentrations of the calibration standards of the study runs (highlight the values outside of the acceptance range, e.g., 15%, except 20% for LLOQ) 8.3 Quality control samplesa) Identify the concentrations of the QC samples, their date of preparation and the storage conditions employed prior to their analysis b) State the number of QC samples in each analytical run per concentration c) List the back-calculated concentrations of the QC samples of the study runs (highlight the values outside of the acceptance range, e.g., 15%) d) Discuss whether the concentrations of the QC sample concentrations are similar to the concentrations observed in the study samples e) State the percentage of QC samples per run with respect to the total number samples assayed in each run 8.4 Precision and accuracya) Summarize inter-day precision of back-calculated standards and, inter-day precision and accuracy of QC samples analysed during subject sample analysis 8.5 Repeat analysis (re-analysis, re-injection and re-integration)a) List re-analysed samples by sample identification and include the following information for each re-analysis: initial value; reason for re-analysis; re-analysed value(s); accepted value; and reason for acceptance b) Report the number of re-analysis as a percentage of the total number samples assayed c) List re-injected samples by sample identification and include the following information for each re-injection: initial value; reason for re-injection; re-injected value; accepted value; and reason for acceptanced) Report the number of re-injections as a percentage of the total number samples assayed e) List re-integrated chromatograms by sample identification and include the following information for each re-integration: initial value; reason for re-integration; re-integrated value(s); accepted value; and reason for acceptance f) Report the number of re-integrated chromatograms as a percentage of the total number of samples assayed 8.6 Incurred sample reanalysis(State location in the submission and summarize the results of incurred sample reanalysis, including the number of subject samples included in ISR and the total number of samples analysed in the study) 8.7 Chromatograms(State the location in the submission where the sample chromatograms can be found. The chromatograms should be obtained from a minimum of two analytical batches and include at least 20% of the subjects, up to a maximum of five. A complete set includes standards, QC samples, pre-dose and post-dose subject samples for both phases. Each chromatogram should be clearly labelled with respect to the following: date of analysis; subject ID number; study period; sampling time; analyte; standard or QC, with concentration; analyte and internal standard peaks; peak heights and/or areas)

9 QUALITY ASSURANCE9.1 Internal quality assurance methods(State locations in the submission where internal quality assurance methods and results are described for each of study sites (see 3.2 b-d.) 9.2 Monitoring, auditing, inspections(Provide a list of all monitoring and auditing reports of the study, and of recent inspections of study sites by regulatory agencies. State locations in the submission of the respective reports for each study site (see 3.2 b-d.)

10 ADDITIONAL SUPPORTING DATA10.1 Electronic copy of Study AUC and Cmax data in Appendix 1 to BTIF (A MS Excel file containing the AUC and Cmax data from the study should be included in Module 1.4.1 of the CTD identified as Appendix 1 to the BTIF. The Excel file template provided on the PQTm website should be used and its format should not be modified except to add extra columns for studies larger than a two-way design.Confirm below that the requested Excel spreadsheet has been provided in the dossier.) 10.2 List of all bioequivalence studies conducted with proposed product and studies conducted during product development  (Module 2.7 of the dossier should include the following information:1. A list of all bioequivalence studies, including pilot studies, conducted with the proposed product i.e., same formulation and manufacturing process as that submitted for prequalification, regardless of the comparator (reference) product employed and regardless of the study outcome. Complete study synopses should be provided for all listed studies, in accordance with Annex I of ICH Guideline E3: Structure and Content of Clinical Study Reports.2. A list of all bioequivalence or comparative bioavailability studies, including pilot studies, conducted during pharmaceutical development (development of formulation and/or manufacturing processes) of the product, regardless of the comparator (reference) product employed and regardless of the study outcome. Complete study synopses should be provided for all listed studies, in accordance with Annex I of ICH Guideline E3: Structure and Content of Clinical Study Reports.Full study reports for all listed studies should be available upon request.Confirm below that the list of studies is provided as required. If no additional studies (beyond the study summarized in this BTIF) have been conducted, please so indicate here.)

Reference: Application Form:Presentation of Bioequivalence Trial Information WHO Prequalification Team – Medicines. http://www.who.int/prequal/info_applicants/