2.0 LITERATURE REVIEW

Transcription

1 2.0 LITERATURE REVIEW 2.1 BIOAVAILABILITY (BA) AND BIOEQUIVALENCE (BE) The importance of generic drugs in health care has increased globally during the last three decades due to the new drug discovery (brand-name drugs) as well as generic drug production Thus, it is imperative that the pharmaceutical quality, safety, and efficacy of generics should be reliably compared with the corresponding innovator drugs (brand-name drugs). Bioavailability (BA) and bioequivalence (BE) studies provide important information in the overall set of data that ensure the availability of safe and effective medicines to patients and practitioners. BA and BE measures are frequently expressed in systemic exposure measures, such as area under the plasma concentration-time curve (AUC) and maximum concentration (C max ) A Historical Perspective The concepts of BA and BE have gained considerable importance during the last three decades and have become the cornerstones for the approval of brand-name and generic drugs globally. Consequently regulatory authorities also started developing and formulating regulatory requirements for approval of generic drug products. Using the BE as the basis for approving generic drugs was established by the Drug Price Competition and Patent Restoration Act of 1984 (Hatch-Waxman Act). Subsequently various criteria and approaches for conducting and reporting BE studies for generic products from various regulatory authorities have been progressing Hatch-Waxman Act The Hatch-Waxman Act (Melethil 2005 ) was an attempt to resolve two major issues: 1) regulatory delays in marketing of pharmaceutical products faced by innovator (also called pioneer or research) drug companies and 2) difficulties generic drug companies had at that time in marketing generic versions of pioneer products following expiry of pertinent patent(s) (Levitt 2002; Beers 1999). In practical terms, this Act made the following three important provisions: 1) it provided for the extension of the term of one existing patent for innovator drugs; 2) it made provisions for the marketing of generic versions of patented drugs on the day after patent expiry; and 3) it provided opportunities to challenge the validity of patents issued to innovator drug companies. Dept. of Pharmaceutical Medicine 4 Jamia Hamdard

2 2.1.3 Regulatory Authorities Every country now has its own individual regulatory authority as well as regulatory guidance for BA/BE studies, and the magnitude of assessment of BE of drug product is influenced by the regulatory environment of the respective country of marketing. The regulatory authorities of various countries and international organizations are listed and briefly described (Table 1.1A). In the United States, the FDA approves and grants marketing authorization of generic drugs by applying the regulatory requirements provided in the Code of Federal Regulations (CFR). Some of the relevant sections in the CFR related to BA/BE are listed (Table 1.1B) Assessment of Bioequivalence The assessment of BE of different drug products is based on the fundamental assumption that two products are equivalent when the rate and extent of absorption of the test/generic drug does not show a significant difference from the rate and extent of absorption of the reference/brand drug under similar experimental conditions as defined. As per the different regulatory authorities, BE studies are generally classified as: 1. Pharmacokinetic endpoint studies, 2. Pharmacodynamic endpoint studies, 3. Clinical endpoint studies and 4. In vitro endpoint studies. The general descending order of preference of these studies includes pharmacokinetic, pharmacodynamic, clinical, and in vitro studies (Chen et al. 2001) Pharmacokinetic Endpoint Studies Regulatory guidance recommends that measures of systemic exposure be used to reflect clinically important differences between test and reference products in BA and BE studies (Chen et al. 2001). These measures include; i) total exposure (AUC 0-t or AUC 0- for single-dose studies and AUC 0-τ for steady-state studies), ii) peak exposure (C max ), and iii) early exposure (partial AUC to peak time of the reference product for an immediate- release drug product). Single dose studies to document BE were preferred because they are generally more sensitive in assessing in vivo release of the drug substance from the drug product when compared to multiple dose studies. General pharmacokinetic parameters Dept. of Pharmaceutical Medicine 5 Jamia Hamdard

3 (primary and secondary) for single-dose, multiple-dose, and urinary data are described (Table 1.2). The following are the circumstances that demand multiple -dose study/steady state pharmacokinetics (CDSCO 2005, TGA 2002, CHPB 1992 EMEA 2010, KSAFDD 2005; KFDA 2008). Dose- or time-dependent pharmacokinetics. For modified-release products for which the fluctuation in plasma concentration over a dosage interval at steady state needs to be assessed. If problems of sensitivity preclude sufficiently precise plasma concentration measurements after single-dose administration. If the intra -individual variability in the plasma concentration or disposition precludes the possibility of demonstrating BE in a reasonably sized singledose study and this variability is reduced at steady state. When a single-dose study cannot be conducted in healthy volunteers due to tolerability reasons and a single-dose study is not feasible in patients. If the medicine has a long terminal elimination half-life and blood concentrations after a single dose cannot be followed for a sufficient time. For those medicines that induce their own metabolism or show large intraindividual variability. For combination products for which the ratio of plasma concentration of the individual substances is important. If the medicine is likely to accumulate in the body. For enteric coated preparations in which the coating is innovative. Under normal circumstances, blood should be the biological fluid sampled to measure drug concentrations. Most drugs may be measured in serum or plasma; how- ever, in some drugs, whole blood (eg: tacrolimus) may be more appropriate for analysis. If the blood concentrations are too minute to be detected and a substantial amount (40%) of the drug is eliminated unchanged in the urine, the urine may serve as the biological fluid to be sampled (eg: alendronic acid) (MCC 2010, EMEA 2007; NZRGM 2001). Dept. of Pharmaceutical Medicine 6 Jamia Hamdard

4 India Table 1.1A: A Brief Description of Regulatory Authorities of Various Countries and International Organizations Country Regulatory Authority Website Central Drugs Standard Control Organization (CDSCO) Unites States US Food and Drug Administration (FDA) Europe European Medicines Agency (EMEA) United Kingdom Medicines and Health care products Regulatory Agency (MHRA) Canada Health Canada South Africa Medicines Control Council (MCC) Australia Therapeutic Goods Administration (TGA) Korea Korea Food and Drug Administration (K-FDA) Mexico Ministry of Health Japan People s Republic of China New Zealand Pharmaceuticals and Medical Devices Agency (PMDA) National institute for the Control of Pharmaceutical and Biological Products Medicines and Medical Devices Safety Authority (MEDSAFE) Malaysia National Pharmaceutical Control Bureau Hong Kong Department of Health Fiji Ministry of Health indonesia Ministry of Health Singapore Health Sciences Authority (HAS) Sri Lanka Ministry of Health Armenia Scientific Center of Drug and Medical Technologies Expertise (SCDMTE) Taiwan Department of Health (DOH) Belgium Pharmaceutical inspectorate Bulgaria Drug Agency Czech Republic State institute for Drug Control Finland National Agency for Medicines France Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSAPS) Germany Federal institute for Drugs and Medical Devices Greece National Organization for Medicines iceland Icelandic Medicines Agency (IMA) ireland Medicines Board italy National institute of Health Netherlands Medicines Evaluation Board Norway Norwegian Medicines Agency Poland Drug institute Spain Spanish Drug Agency Sweden Medical Products Agency Switzerland Swiss Agency for Therapeutic Products Saudi Arabia Ministry of Health United Arab Emirates Federal Department of Pharmacies Kenya Ministry of Health Dept. of Pharmaceutical Medicine 7 Jamia Hamdard

5 Namibia Ministry of Health and Social Services Tanzania Ministry of Health Zimbabwe Ministry of Health and Child welfare Brazil National Health Surveillance Agency (ANVISA) Colombia instituto Nacional de vigilancia de Medicamentos Y Alimentos (INVIMA) International Organizations International Conference on Harmonisation (ICH) World Health Organization (WHO) Global GMP Harmonization by Japan European Union (European Commission and EMEA) Global Harmonization Task Force (GHTF) Association of Southeast Asian Nations Consultative Committee for Standards and Quality ASEAN iyama pdf Table 1.1B: Some of Relevant Sections in the Code of Federal Regulations Related to BA/BE Studies 21CFR Section Type of Provision/Information 21CFR (a)(9) 21CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR CFR Chemistry, manufacturing, and controls; permitted changes in inactive ingredients for parenteral, otic, ophthalmic, and topical drug products Definitions of bioavailability, pharmaceutical equivalents, pharmaceutical alternatives, and bioequivalence Regulatory requirements related to submission of in vivo bioavailability and bioequivalence data Criteria for waiver of evidence of in vivo bioavailability or bioequivalence data Basis for measuring in vivo bioavailability or demonstrating bioequivalence Types of evidence to measure bioavailability or establish bioequivalence Guidelines for the conduct of an in vivo bioavailability study Guidelines on the design of a single dose in vivo bioavailability or bioequivalence study Guidelines on the design of a multiple-dose in vivo bioavailability study Correlation of bioavailability with an acute pharmacological effect or clinical evidence Analytical methods for an in vivo bioavailability or bioequivalence study inquiries regarding bioavailability and bioequivalence requirements and review of protocols by the FDA Procedures for establishing or amending a bioequivalence requirement Criteria and evidence to assess actual or potential bioequivalence problems Requirements for maintenance of records of bioequivalence testing Retention of bioavailability samples Retention of bioequivalence samples Dept. of Pharmaceutical Medicine 8 Jamia Hamdard

6 Table 1.2: Brief Description of Pharmacokinetic Parameters Used for BA/BE Studies Study Type Primary Pharmacokinetic Secondary Pharmacokinetic Parameters Parameters Single Dose C max, AUC 0-t, AUC 0- Tmax, AUC % extrapolation, MRT, K el, and T 1/2 Steady State C max (ss), C min (ss), AUC 0-τ T min (ss), T max (ss), C avg, % swing, % fluctuation Urinary Based Ae (0-t), Ae (0- ), R max T lag Notes: Cmax, Maximum plasma concentration; Cmin, Minimum plasma concentration; Cmax(ss), Maximum plasma concentration at steady-state; Cmin(ss), Minimum plasma concentration at steady-state; Cavg, Average plasma concentration; Tmax, Time to Cmax, AUC0-t, Area under the plasma/serum/blood concentration-time curve from time zero to time t, where t is the last time point with measurable concentration; AUC0-, Area under the plasma/serum/blood concentration-time curve from time zero to time infinity; AUC0-τ, AUC during a dosage interval at steady state; MRT, Mean residence time; Ae(0-t), Cumulative urinary excretion from pharmaceutical product administration until time t; Ae(0- ), Amount of unchanged API excreted in the urine at infinite time (7-10 half-lives); T1/2, Plasma concentration elimination half-life; % fluctuation, (Cmax(ss) - Cmin(ss))/Cavg 100; % swing, (Cmax(ss) - Cmin(ss))/Cmin General Regulatory Considerations For BA/BE Studies The processes of study design and workflow of BA/BE studies are presented in brief (Figures 1.1 and 1.2). The general considerations for the advancement of conducting BA/BE studies are: Study Design and Protocol. Bioanalysis. Selection of Appropriate Analyte(s). Be Metrics and Data Treatment. Statistical Approaches and Analysis. Acceptance Criteria For Be Study Design and Protocol Successfully determining the BE of generic drugs to their respective reference drugs depends mostly on design and managing the conduct of study such that the highest quality samples are obtained. Some regulatory authorities (US: data.fda.gov/scripts/cder/drugsatfda/index.cfm; Europe: EMC/browsedocuments. aspx; Canada: Australia: are providing specific information about Reference Listed Drug (RLD)/ reference product information on their websites, Dept. of Pharmaceutical Medicine 9 Jamia Hamdard

7 which makes it easy for investigators to proceed with BA/BE study design. Generally the study design and number of studies (single- dose and/or multiple-dose and/or fasting and/or fed) depend on the RLD or reference product, physicochemical properties of the drug, its pharmacokinetic properties, and proportionality in composition with justification along with respective regulatory guidance and specifications. Various study designs generally used for BA/BE studies (Table 1.3). Figure 1.1: Brief Process of Bioequivalence Study Design and Protocol Approval Dept. of Pharmaceutical Medicine 10 Jamia Hamdard

8 Figure 1.2: Brief Work Flow of Bioavailability/Bioequivalence Study The regulatory specifications on demographics, sample size, sampling and washout period, regulatory acceptance criteria for bioequivalence and regulatory acceptance criteria for special class drugs are briefly described (Tables 1.4, 1.5, 1.6, 1.7 and 1.8). Dept. of Pharmaceutical Medicine 11 Jamia Hamdard

9 Bioanalysis In a general prospective of BA/BE studies, bioanalysis should be the subsequent step following clinical operations of the study (Figure 1.2), and it should be executed with strict adherence to good laboratory practices, standard operating procedures, and specific regulatory requirements. Bioanalysis is a term generally used to describe the quantitative measurement of a compound (drug) or its metabolite in bio- logical fluids, primarily blood, plasma, serum, urine, or tissue extracts (James et al. 2004). Bioanalysis typically consists of two important components 1) sample preparation and 2) detection of the desired compound using a validated method Selection of Appropriate Analyte(s) Parent Drug vs Metabolite(s) BE based on test/reference comparisons of pharmacokinetic measures serves two purposes 1) to act as a surrogate for thera- peutic equivalence, 2) to provide in vivo evidence of phar- maceutical quality. Traditional BE studies have been carried out on the basis of measurement of only the parent drug in body fluids such as plasma or serum. In some cases, however, monitoring a metabolite, or the parent and metabolite(s), may be more appropriate. A number of reasons for use of metabolite data have been put forward (Midha et al. 2004), such as i) the parent is an inactive prodrug, ii) plasma concentrations of the parent drug are too low to monitor because of inadequate assay sensitivity, iii) the parent drug is metabolized rapidly to an active metabolite, and iv) the parent drug and a metabolite both have therapeutic activities but the metabolite is present in higher concentrations when the parent drug is rapidly and extensively metabolized such that only metabolite(s) data are available (Chen et al ) BE Metrics and Data Treatment The most frequent data treatment involves analysis of variance using a suitable program such as SAS (Statistical Analysis System, SAS Institute, Cary, NC) or WinNonlin (Pharsight Corporation, St. Louis, MO) so that contributions from subject, period, product/formulation, and interactions between these can be examined. Geometric mean ratios and log transformed data are examined to test the hypothesis Dept. of Pharmaceutical Medicine 12 Jamia Hamdard

10 that the 90% confidence interval of extent (AUC 0-t and AUC 0- ) and the maximum concentration (C max ) fall within the acceptance limits of 80% to 125%. More recently, other data treatments have been popular, which include partial area measurements and exposure metrics including C max / AUC, especially with highly variable drugs (HVDs), and with drugs having a long terminal t 1/2, specialized dosage forms, and/or whose time to C max is considered important (e.g., certain analgesics) Statistical Approaches The various pharmacokinetic parameters derived from the plasma concentration-time curve are subjected to ANOVA in which the variance is partitioned into components due to subjects, periods, and treatments. The FDA therefore recognized that a finding of no statistical signifycance in the first case was not necessarily evidence of BE and consequently asked for a retrospective examination of the power of the test of null hypothesis (Rani et al. 2004). Adequate statistical approaches should be considered to establish the BE of generic product to that of reference product. Much worldwide discussion and interaction has focused on facilitating the appropriate statistical approaches to establish interchangeability between generic drug and reference drug. The pertinent statistical approaches include i) study power; ii) 75/75 rule; and iii) 90% confidence interval (Midha1 2009). Dept. of Pharmaceutical Medicine 13 Jamia Hamdard

11 Table 1.3: Brief Description About Various Study Designs Used in BA/BE Studies Design Significance Advantages Disadvantages Crossover Parallel Replicate Variance Balanced Design When intra-subject CV (approx. 15%) is usually substantially smaller than that intersubject CV (approx. 30%) Generally recommended by all regulatory authorities If the drug has a very long terminal elimination half-life Duration of the washout time for the twoperiod crossover study is so long (if >1 month) If the intra-subject CV is higher with crossover design Useful for the highly variable drugs (intrasubject CV 30%) For more than two formulations Desirable to estimate the pair wise effects with the same degree of precision Since the treatments are compared on the same subject, the intersubject variability does not contribute to the error variability Subject randomization causes unbiased determination of treatment effects Large information based on minimum sample size Straightforward statistical analysis Design is simple and robust Drop outs will be comparatively less Duration of the study is less than crossover study Study with patients is possible Straightforward statistical analysis Allows comparisons of within-subject variances for the test and reference products Indicates whether a test product exhibits higher or lower withinsubject variability in the bioavailability measures when compared to the reference product Provides more information about the intrinsic factors underlying formulation performance Reduces the number of subjects needed in the BE study The number of subjects required to demonstrate bioequivalence can be reduced by up to about 50% Design increases the power of the study when the variability in the systemic exposure of the test drug and formulation is high Allows to choose between two more candidate test formulations Comparison of test formulation with several reference formulations Standard design for the establishment of dose proportionality Carryover effects and period effects are possible due to inappropriate wash-out period Long duration Possibility of more drop outs leads to insufficient power Not suitable for long half-life drugs Not optimal for studies in patients and highly variable drugs Subjects cannot serve as their own controls for intrasubject comparisons Large sample size is required Lower statistical power than crossover Phenotyping mandatory for drugs showing polymorphism Involves larger volume of blood withdrawn from each subject Longer duration of the entire study Increased possibility of subject drop outs Expensive Statistical analysis is more complicated (especially when dropout rate is high) May need measures against multiplicity (increasing the sample size) Dept. of Pharmaceutical Medicine 14 Jamia Hamdard

12 Study Power The conduct of a BE study should require some prior knowledge of the performance of the products (generic and brand drugs) in the human body so that an appropriate number of test subjects can be enrolled and provide adequate power to test the hypothesis with a reasonable likelihood (ie, at least 80%) that the two products are indeed bioequivalent. The two criteria considered most important to understand are the inherent variability of the drug and the geometric mean ratio between the test and reference product. Both of these parameters can be determined through the conduct of a pilot study (n = 6-12) to determine the proper sample size required for the pivotal study to establish BE as well as to minimize the possibility of undersizing the study (Midha1 2009) /75 Rule This approach was the first application wherein individual BE (ABE) was being tested. The biomedical community felt that unless the change in the biological system was greater than 20% to 25%, it would really not pose a significant clinical risk of invalidating the use of one therapeutic strategy versus another. This formed the basis for the 75/75 rule, which states that two products are equivalent if, and only if, at least 75% of the individuals being tested had ratios (of the various pharmacokinetic parameters obtained from the individual results) between the 75% and 125% limits, and the study conducted has the statistical power to detect a 20% difference between the two products (Midha1 2009). This approach was sound until the arrival of the 90% confidence interval % Confidence Interval Westlake38 was the first to suggest the use of confidence intervals as a BE test to evaluate whether the mean amount of drug absorbed using the test formulation was close to the mean amount absorbed of the reference product. Subsequently, in July 1992, the guidance on Statistical Procedures for Bioequivalence Studies Using a Standard Two-treatment Crossover Design was released by the FDA. It was revised in 2001, and is available as Statistical Approaches to Establishing Bioequivalence ( GuidanceComplianceRegulatoryInformation/ Guidances/ucm pdf). This is based primarily on average BE (ABE), wherein Dept. of Pharmaceutical Medicine 15 Jamia Hamdard

13 the average values for the pharmacokinetic parameters were determined for the test and reference products and compared using a 90% confidence interval for the ratio of the averages using a two one-sided t-tests procedure (Schuirmann 1987). This concept was really based on the fact that if the ratios of the two pharmacokinetic parameters of clinical interest (such as AUC, C max ) are to be compared, each with their own variability which may or may not be randomly distributed, then such a comparison can truly be done only through a confidence interval approach. This concept is well accepted by almost all regulatory authorities to establish the BE. The general statistical deliverables for a single-dose cross- over BE study include summary statistics, ANOVA, 90% confidence interval, ratio analysis, and intrasubject variability in addition to sequence, treatment, and period effects Acceptance Criteria for Bioequivalence An equivalence approach is generally recommended, which usually relies on i) a criterion to allow the comparison; ii) a confidence interval for the criterion; and iii) a BE limit. Log transformation of exposure measures (C max and AUC) is generally recommended by various regulatory authorities. To compare measures in these studies, data are generally analyzed by using an average BE criterion with some considerations allowed for special category drugs General To establish BE, the calculated 90% confidence interval should fall within a BE limit of 80% to 125% using logarithm transformed data (adopted since the concentration parameters C max and AUC may or may not be normally distributed). Currently, the BE limits of 80% to 125% have been applied to almost all drug products by regulatory authorities. More detailed information on acceptance criteria for BE is given (Table 1.7) For Highly Variable Drugs In the context of BE, HVDs are considered to be drugs and drug products exhibiting intra-subject variability greater than 30% coefficient of variation in the pharmacokinetic measures, AUC and/or C max (Schuirmann 1987; Haidar et al ). Dept. of Pharmaceutical Medicine 16 Jamia Hamdard

14 Due to this high variability, large sample size may be needed in BE studies to give adequate statistical power to meet FDA BE limits, and thus designing BE studies for HVDs is challenging. Major regulatory agencies also considered different approaches for evaluating BE of highly variable drugs (NIHS 2010, AGCB 2010, Tamboli et al. 2010). From 2004 onward the FDA started looking for alternative approaches to resolve this issue, and eventually found that replicate crossover design and scaled average BE provides a good approach for evaluating the BE of highly variable drugs and drug products as it would effectively decrease sample size, without increasing patient risk (Haidar1 et al. 2008). Table 1.4: Regulatory Criteria on Subject Demographics for BA/BE Studies Regulatory Authority India Sex Male or female Age (years) Healthy adult volunteers Body Mass Index (BMI) (kg/m 2 ) Not specified Asia Either sex ; Asians: United States Both sexes 18 Not specified Europe Either sex Canada Both sexes Height/weight ratio for healthy volunteer subjects should be within 15% of the normal range Australia Either sex Accepted normal BMI South Africa Either sex Russia Both sexes Korea Healthy adult Not specified Japan People s Republic of China Mexico Saudi Arabia New Zealand Healthy adult Not specified Accepted normal BMI or within 15% of the ideal body mass or any other recognized reference weight of body does not fall outside the limits ±15% on Ketle totalheight index Not specified Both sexes Standard weight range Avoiding pharmacokinetic differences between sexes is well documented; volunteers of just one sex must be included if females are included in the study, the effects of gender differences and menstrual cycle (if applicable) are examined statistically., Both sexes weight 10% from the ideal weight Age range prior to the onset within 15% of ideal body weight, height, and body fluid Average weight (eg, within ±15% of their ideal weight as given in the current Metropolitan Life Insurance Company Height and Mass Tables) Dept. of Pharmaceutical Medicine 17 Jamia Hamdard

15 For Narrow Therapeutic Index Drugs (NTIDs) NTIDs can be defined as drugs that require therapeutic drug concentration or pharmacodynamic monitoring and/or drugs for which drug product labeling indicates a narrow therapeutic range designation. Regulatory Authority India Table 1.5: Regulatory Criteria on Sample Size for BA/BE Studies Minimum Should not be<16 unless justified for ethical reasons Asia Should not be <12 United States 12 Europe Should not be <12 Canada 12 Australia South Africa Should not be<16 unless justified Should not be,12 (general); 20 subjects (for modified release oral dosage forms) Russia 18 Korea 12 Japan 20 Saudi Arabia New Zealand Brazil A number of ubjects of less than 24 may be accepted (with a minimum of 12 subjects) when statistically justifiable 12 Sample Size Specifications The number of subjects required for a study should be statistically significant and should be sufficient to allow for possible withdrawals or removals (drop outs) from the study The number of subjects required is determined by a) The error variance associated with the primary characteristic to be studied as estimated from a pilot experiment, from previous studies or from published data; b) The significance level desired; c) The expected deviation from the reference product compatible with BE (delta, ie, percentage difference from 100%); and d) the required power A sufficient number of subjects should complete the study to achieve adequate power for a statistical assessment The number of subjects to be included in the study should be based on an appropriate sample size calculation a) Obtain an estimate of the intra-subject CV from the literature or from a pilot study; b) choose one of Figures 3.1 through 3.3 (mentioned in BE guidance document) by determining which one has the closest rounded-up CV to that estimated in a), above; c) choose an expected true ratio of test over reference means (usually 100%) and move up the graph to the 0.90 probability of acceptance; d) a linear extrapolation between given sample sizes is adequate. This sample size calculation must be provided in the study protocol. More subjects than the sample size calculation required should be recruited into the study. This strategy allows for possible drop-outs and withdrawals Same as that of Asian guidelines The number of subjects should be justified on the basis of providing at least 80% power of meeting the acceptance criteria; Alternatively, the sample size can be calculated using appropriate power equations, which should be presented in the protocol In quantity sufficient for ensuring statistical importance of study. Thus capacity of the statistical test for BE study must be supported at a level of not less than 80% for revealing 20% distinctions between comparison parameters The number of subjects should meet the requirements for statistical validity. The number of subjects can be determined based on the characteristics of the active component of the pertinent drug products A sufficient number of subjects for assessing BE should be included. If BE cannot be demonstrated because of an insufficient number, an add-on subject study can be performed using not less than half the number of subjects in the initial study. A sample size of 20 (n = 10/group) for the initial study and pooled size of 30 for initial plus addon subject study may suffice if test and reference products are equivalent in dissolution and similar in average AUC and Cmax Generally recommends a number of 24 normal healthy subjects. Should enroll a number of subjects sufficient to ensure adequate statistical results, which is based on the power function of the parametric statistical test procedure applied. The number of subjects should be determined using appropriate methods taking into account the error variance associated with the primary parameters to be studied (as estimated for a pilot experiment, from previous studies or from published data), the significance level desired (α = 0.05), and the deviation from the reference product compatible with BE (±20%) and compatible with safety and efficacy The number of subjects should provide the study with a sufficient statistical power (usually $80%) to detect the allowed difference (usually 20%) between the test and reference medicines for AUC and Cmax. This number (n) may, in many cases, be estimated in advance from published or pilot study data using formula. If the calculated number of subjects appears to be higher than is ethically justifiable, it may be necessary to accept a statistical power which is less than desirable. Normally it is not practical to use more than about 40 subjects in a bioavailability study The number of healthy volunteers shall all times assure an adequate statistical power to guarantee reliability of BE study results Dept. of Pharmaceutical Medicine 18 Jamia Hamdard

16 A NTIDs list was prepared by the Center for Drug Evaluation and Research and available in the Scale-Up and Post-Approval Changes for Intermediate Release Products (more information is available at downloads/ Drugs/ Guidance Compliance Regulatory Information/ Guidances/ ucm pdf). The regulatory acceptance criterion for NTIDs are presented (Table 1.8). Table 1.6: Regulatory Criteria on Sampling and Washout Period for BA/BE Studies Regulatory Authority India United States Europe Australia South Africa Canada Sampling criteria Blood sampling : Should be extended to at least 3 elimination half lives; at least 3 sampling pointsduring absorption phase, 3-4 at the projected Tmax, and 4 points during elimination phase; sampling should be continued for a sufficient period to ensure that AUC0-t to AUC0- is only a small percentage (normally <20%) of the total AUC. Truncated AUC is undesirable except in the presence of enterohepatic recycling Urinary sampling: Collect urine samples for 7 or more half-lives Blood samples should be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug; samples, including a period predose sample, should be collected per subject per dose; should continue for at least 3 or more terminal half-lives of the drug Single-dose blood sampling: Sufficient sampling is required; frequent sampling around predicted Tmax; avoid Cmax be the first point; accommodate reliable estimate (AUC0-t) covers at least 80% of AUC0- ); at least 3-4 points during the terminal log-linear phase; AUC truncated at 72 h (AUC0-72h) may be used as an alternative to AUC0-t or comparison of extent of exposure Multiple-dose blood sampling Pre-dose sample should be taken immediately before (within 5 min) dosing and the last sample is recommended to be taken within 10 min of the nominal time for the dosage interval to ensure an accurate determination of AUC0-τ Urinary sampling: Urine should normally be collected over no less than 3 times the terminal elimination half-life Single-dose blood sampling: Should provide adequate estimation of Cmax; cover plasma concentration time curve long enough to provide a reliable estimation of the extent of absorption; 3-4 samples during the terminal log-linear phase. AUC truncated at 72 h is permitted for long half-life drugs Multiple-dose blood sampling when differences between morning and evening or nightly dosing are known, sampling should be carried out over a full 24-h cycle Blood sampling: Sampling should be sufficient to account for at least 80% of the known AUC0-, Cmax; collecting at least 3-4 samples above the LOQ during the terminal log-linear phase; sampling period is approximately three terminal half-lives of the drug; AUC truncated at 72 h is permitted for long half-life drugs; samples should be collected per each subject per dose; at least 3-4 samples above LOQ should be obtained during the terminal log-linear phase. Urine sampling: Sufficient urine should be collected over an extended period and generally no less than 7 times the terminal elimination halflife; for a 24-h study, sampling times of 0-2, 2-4, 4-8, 8-12, and h post dose are usually appropriate Blood sampling: Sampling should be sufficient to account for at least 80% of the known AUC0-, Cmax and terminal disposition; 3 times the terminal half-life of the drug; samples should be collected per each subject per dose; 4 or more points be determined during the terminal loglinear phase Urine sampling: Urine should be collected over no less than 3 times the terminal elimination half-life. For a 24-h study, sampling times of 0-2, 2-4, 4-8, 8-12, and h Washout Criteria Adequate and ideally it should be 5 halflives of the moieties to be measured An adequate washout period (eg, more than 5 half-lives of the moieties to be measured) Sufficient washout period (usually at least 5 terminal halflives) Adequate washout period Adequate washout period Normally should be not less than 10 times the mean terminal half-life of the drug. Normally, the interval between study days should not exceed 3-4 weeks Dept. of Pharmaceutical Medicine 19 Jamia Hamdard

17 Table 1.7: Regulatory Acceptance Criteria for Bioequivalence 90% Confidence Interval on Log Transformed Data Regulatory Single-Dose Study Steady-State Study authority C max AUC 0-t AUC 0- C max C min AUC τ India Asia United States Europe Canada Ratio must be Need to pass also on potency corrected data Add-on studies may be allowed if intra-cv greater than expected Australia South Africa Not applicable Not applicable Not applicable Not applicable Not applicable (including % swing and % fluctuation) Russia Korea Mexico Not applicable Saudi Arabia (including % swing and % fluctuation) New Zealand Regulatory Authority Table 1.8: Regulatory BA/BE Acceptance Criteria for Special Class Drugs Highly variable drugs 90% confidence interval Log transformed data Narrow therapeutic index drugs 90% confidence interval Log transformed data C max AUC C max AUC 0-t Asia The interval must be prospectively defined, eg, and justified for addressing in particular any safety or efficacy concerns for patients switched between formulations in rare cases a wider acceptance range may be acceptable if it is based on sound clinical justification Acceptance interval may need to be tightened Acceptance interval may need to be tightened United States GMR (80-125) 95% upper bound for (µt-µr)/δ2 WR # (using scaled average approach) GMR (80-125) 95% upper bound or (µt- µr)/δ2 wr # (using scaled average approach) Europe* Canada GMR (80-125) GMR (80-125) 90% CI (80-125) - - Saudi Arabia wider acceptance range may be acceptable and this should be justified clinically Japan Notes: *For highly variable drugs: a wider difference in Cmax is considered relevant based on a sound clinical justification. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84% %. For this acceptance BE study must be a replicate design where it has been demonstrated that intra-subject Cv for Cmax of reference drug is.30%. The applicant should justify the calculated intra-subject Cv is a reliable estimate and that it is not the result of outliers and the request for widened interval must be prospectively specified in the protocol. Dept. of Pharmaceutical Medicine 20 Jamia Hamdard

18 2.2 FIXED DOSE COMBINATION The development of fixed-dose combinations (FDCs) is becoming increasingly important from a public health perspective. They are being used in the treatment of a wide range of conditions and are particularly useful in the management of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria and tuberculosis, which are considered to be the foremost infectious disease threats in the world today. FDCs have advantages when there is an identifiable patient population for whom treatment with a particular combination of actives in a fixed ratio of doses has been shown to be safe and effective, and when Additionally, in a situation of limited resources, the cost of an FDC finished pharmaceutical product (FDC-FPP) may be less than that of separate products given concurrently, and there are simpler logistics of distribution. Improved patient adherence and reduced development of resistance in the case of antimicrobials can be difficult to prove, but may be additional benefits. Notwithstanding these potential benefits, FDCs must be shown to be safe and effective for the claimed indications. It should not be assumed that benefits outweigh risks. As for any new medicine, the risks and benefits should be defined and compared. The World Health Organization has published a series of guidelines relating to marketing authorization of finished pharmaceutical products (FPPs) Scenarios An application to register an FDC-FPP may fall into any one of the following four scenarios. These guidelines are intended to address the different requirements for each scenario. a) Scenario 1: The new FDC-FPP contains the same actives in the same doses as an existing FDC-FPP; that is it is a generic of the existing FDC-FPP; they are multisource products. The quality, safety and efficacy of the existing product have been established. b) Scenario 2: The new FDC-FPP contains the same actives in the same doses as an established regime of single entity products, and the dosage regimen is the same. Alternatively the established regime may involve combinations of single Dept. of Pharmaceutical Medicine 21 Jamia Hamdard

19 entities and FDCs, for example, a single entity FPP combined with an FDC- FPP that contains two actives. In all cases, the established regime has a wellcharacterized safety and efficacy profile, and all of the FPPs used in obtaining clinical evidence have been shown to be of good quality. c) Scenario 3: 1) The new FDC-FPP combines actives that are of established safety and efficacy but have not previously been used in combination for this indication. 2) The new FDC-FPP comprises a combination for which safety and efficacy have been established, but that will be used in a different dosage regimen. d) Scenario 4: The new FDC-FPP contains one or more new chemical entities Balancing the Advantages and Disadvantages of A New Fixed-Dose Combination In determining whether it is rational to combine actives into a single product, there are medical, quality and bioavailability considerations. Quality issues may be addressed by much the same criteria that apply to single-component products and it is difficult to imagine a case in which essentially the same standards would not apply. Medical considerations are more complex and sometimes contradictory, for example, when increased efficacy is ac- companied by increased toxicity. The decision as to whether to give marketing approval for a new FDC-FPP in scenarios 3 and 4 is often based on a consideration of the balance of advantages and disadvantages from the medical perspective. Interpretation of the results of bioavailability and bioequivalence tests involves both quality and medical considerations. For example it is not acceptable that bioavailability is reduced or variable, when compared with that of single entity products, because of poor formulation, but an interaction between two actives that leads to an increased bioavailability may be one of the advantages that is taken into account when balancing advantages and disadvantages. Dept. of Pharmaceutical Medicine 22 Jamia Hamdard

20 Balancing the advantages and disadvantages of a new FDC-FPP should form a major component of submissions pursuant to this guideline Submissions for marketing approval of a new FDC in scenarios 2, 3 and 4 should include a section in which the advantages of the new combination are weighed against the disadvantages. All the possible advantages and disadvantages of the combination should be listed and discussed. The discussion should be based on the available data and on scientific and medical principles. In less well-developed nations, and particularly where there are difficulties with transport and the logistics of distribution, other matters may need to be taken into account, such as: The cost of the combination as compared with the cost of individual components. Evidence as to whether the new FDC will improve the reliability of supply as a result of simplified distribution procedures. Improved patient adherence may result from more reliable (continuing) availability of the FDC-FPP than of all of the components as loose combinations of single entity products. However, issues of cost and procurement alone are not sufficient reason to approve an FDC if it has not been justified by appropriate data and on scientific and medical principles From a scientific or medical perspective, FDCs are more likely to be useful when several of the following factors apply: There is a medical rationale for combining the actives. There is an identifiable patient group for which this combination of actives and doses is suitable therapy. The larger the patient group in question, the more significant is this factor. It is not appropriate to combine actives that separately treat conditions that do not commonly coexist. The combination has a greater efficacy than any of the component actives given alone at the same dose. Dept. of Pharmaceutical Medicine 23 Jamia Hamdard

21 The incidence of adverse reactions in response to treatment with the combination is lower than in that response to any of the component actives given alone, for example as a result of a lower dose of one component or a protective effect of one component, and particularly when the adverse reactions are serious. For antimicrobials, the combination results in a reduced incidence of resistance. One drug acts as a booster for another (for example in the case of some antiviral drugs). The component actives have compatible pharmacokinetics and/or pharmacodynamics. Therapy is simplified, particularly when the existing therapy is complex or onerous (e.g. because of a high tablet load ). One of the ingredients is intended to minimize abuse of the other ingredient (e.g. the combination of diphenoxylate with atropine, or buprenorphine with naloxone). The active pharmaceutical ingredients are chemically and physicochemically compatible, or special formulation techniques have been used that adequately address any incompatibility. Other potential advantages of FDCs over single entity products given concurrently in the same dose may include: Convenience for prescribers and patients. Better patient adherence (but the evidence for this is largely anecdotal) (1, and Haynes, RB, personal communication, 2003). Simplified logistics of procurement and distribution. Lower cost. Dept. of Pharmaceutical Medicine 24 Jamia Hamdard

22 These factors are important, but there may not necessarily be evidence to support them; they may be more significant when there is specific evidence available to support a particular case From a scientific or medical perspective, FDCs are less likely to be useful when one or more of the following factors apply: The component actives are normally separately titrated to meet the patient s needs. Consequently: o Either the doses of the components, and/or the ratio of doses, typically differ from patient to patient, and/or o Patients are likely to be taking different doses at different stages of treatment (for example initial treatment compared with long-term treatment). These two factors are particularly significant when one or more of the actives has a narrow therapeutic index and/or a steep doseresponse curve in the therapeutic range. There is a higher incidence or greater severity of adverse reactions to the combination than with any of the ingredients given alone, or there are adverse reactions not seen in response to treatment with any of the individual ingredients. There are unfavorable pharmacokinetic interactions between the ingredients, for example when one drug alters the metabolism, absorption or excretion of another. Dose adjustment is necessary in special populations, such as in people with renal or hepatic impairment. The product (tablets or capsules), is so large that patients find it difficult to swallow. Dept. of Pharmaceutical Medicine 25 Jamia Hamdard

23 2.2.3 Bioavailability and Bioequivalence for Fixed Dose Combination Product Data on bioequivalence provide a bridge between two pharmaceutical equivalents, when safety and efficacy data are available for one of the FPPs, but not for the other. By demonstrating that the two products lead to the same profile for plasma concentration over time, available safety and efficacy data for one of the products can be extrapolated to the other. The two products being compared may be different brands, or different batches of the same brand, for example when manufactured by different methods, at different sites or according to different formulations Data on bioequivalence may also be important when the same FPP is administered under different circumstances, for example before or after food, in different patient populations (such as children versus adults), or by different routes of administration (such as subcutaneous versus intramuscular injection) In the context of these guidelines, an additional application of bioequivalence studies is in scenario 2 in which safety and efficacy data on single entity products given concurrently may be extrapolated to an FDC- FPP, provided that all of the conditions described elsewhere in these guidelines are met. There are two common circumstances in which data on bioequivalence are likely to be generated for pharmaceutical equivalents: Pivotal clinical trials were generated on one formulation and another is to be marketed by the same company (for example because the second formulation is more stable or more marketable than the first); or A relevant patent has expired and a multisource pharmaceutical equivalent has been developed Evidence as to bioequivalence is required for scenarios 1 and 2, and sometimes for scenarios 3 and 4, for example when there are major differences between the formulation and/or method of manufacture of the product to be registered and that used in pivotal clinical trials. Dept. of Pharmaceutical Medicine 26 Jamia Hamdard

24 If a study of bioequivalence finds that the two treatments are bioequivalent, it may be assumed that any pharmacokinetic interactions between the actives were the same, even if one treatment comprised an FDC-FPP and the other comprised separate products Data on absolute bioavailability are usually required in scenario 4, i.e. comparison of the area under the curve for plasma concentration over time after an intravenous injection with that after administration of the dosage form to be marketed, for example a tablet given orally A decision as to whether it is necessary to conduct a study of the effect of food on the bioavailability of an FDC-FPP should be based on what is known of the effect of food on the individual actives, and any relevant recommendations in the product information for the single entity products. The effect of food should normally be studied in scenario Recommendations as to the conduct and analysis of bioequivalence studies are provided in the WHO guidelines, Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (1996, or later updates). Other guidelines may be relevant depending on the jurisdiction in which the application is submitted During analysis of the results of a bioavailability or bioequivalence study for an FDC-FPP, the parameters to be re- ported and assessed are those that would normally be required of each active if it were present as a single entity and the same statistical confidence intervals and decision criteria should be applied An additional scientific consideration that has been elaborated in recent years is the option for biowaivers based on the Biopharmaceutics Classification Scheme (BCS). This is an area in which further developments are expected. The main relevant publication to date is Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dos- age forms based on a biopharmaceutics classification system. US Food and Drug Administration (2000). At Dept. of Pharmaceutical Medicine 27 Jamia Hamdard

25 present, and in the absence of clear guidance for FDCs, it is recommended that biowaivers based on the BCS classification as the sole criterion for a decision be handled cautiously because there is at present no guidance as to how to consider the possibility of a chemical or pharmacokinetic interaction between actives that may affect bioequivalence. However there are circum- stances in which the BCS classification may nevertheless be relevant to FDCs. In such a case the BCS classification of all the actives in the FDC should be taken into account Validation of assays of actives in biological media is crucial in order to generate a meaningful bioavailability and bioequivalence study. See, for example, the guidelines Bioanalytical method validation. US Food and Drug Administration (2001) Selection of a suitable comparator for the purpose of bioequivalence is described in Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products. World Health Organization (2002). Some additional comments follow. The comparator should be of known quality, safety and efficacy. For applications in scenario 1, the decision as to the comparator depends on whether there is more than one existing brand of the combination whose safety and efficacy is known to be acceptable. If only one brand is known to have acceptable safety and efficacy, this should be used as comparator. In other circumstances, the decision is more difficult and should be justified by cogent argument and data. The WHO Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products (2002) may be of assistance. For applications in scenario 2, single entity products will have been used in the majority of pivotal clinical trials. The same brands of those single entity FPPs should be the comparator and should be given concurrently as was the case in the pivotal clinical trials. Dept. of Pharmaceutical Medicine 28 Jamia Hamdard

26 For applications in scenarios 3 and 4 (with which evidence as to safety and efficacy will be submitted), the new product should be shown to be bioequivalent to the product(s) that was (were) used in pivotal clinical trials Superiority, Equivalence and Non-Inferiority Trials and Fixed-Dose Combinations Regulatory guidelines define superiority, equivalence and non-inferiority trials and make some general points concerning different types of study. In the context of FDCs, equivalence trials are largely confined to bioequivalence studies An FDC-FPP should be shown, directly or indirectly, to be superior to the component actives given as single entity treatments. Only a superiority trial can give the necessary statistical confidence. Submissions should discuss both the statistical significance and clinical relevance of the results. Any alter- native form of evidence that purports to address the same issues, for example one that concerns a dose-response surface, must be explained and justified with appropriate statistical confidence In clinical trials that are intended to test for superiority and/or noninferiority, the choice of comparator should be carefully considered and will depend in part on the medical and ethical circumstances. The comparator may be: The treatment whose risk-benefit profile is best sup- ported by evidence or is at least well established. One or more of the actives in the FDC given as a single treatment. A placebo Depending on the claim, superiority or non-inferiority should be demonstrated for each specified clinical outcome. For example if the claim is less bone marrow depression, but similar efficacy, a non-inferiority outcome should be demonstrated for efficacy and a superiority outcome for safety. Dept. of Pharmaceutical Medicine 29 Jamia Hamdard

27 2.3 DIABETES Diabetes has become an increasingly prevalent and costly chronic disease state and presents a significant medical and economic burden to the U.S. health care system. The increasing prevalence of diabetes has been most pronounced among younger age groups (Mokdad et al. 2000). Much of the morbidity and cost is attributable to longterm, diabetes-related complications, particularly cardiovascular disease (CVD). Prevention of these complications requires a management strategy that addresses multiple physiologic conditions including hyperglycemia, dyslipidemia, and hypertension Definition Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. The growth of knowledge regarding the etiology and pathogenesis of diabetes has led many individuals and groups in the diabetes community to express the need for a revision of the nomenclature, diagnostic criteria, and classification of diabetes. As a consequence, it was deemed essential to develop an appropriate, uniform terminology and a functional, working classification of diabetes that reflects the current knowledge about the disease. (NDDG) Classification The current Expert Committee has carefully considered the data and rationale for what was accepted in 1979, along with research findings of the last 18 years, and we are now proposing changes to the NDDG/WHO classification scheme (Table 2.1A). The main features of these changes are as follows: 1. The terms insulin-dependent diabetes mellitus and non insulin dependent diabetes mellitus and their acronyms, IDDM and NIDDM, are eliminated. These terms have been confusing and have frequently resulted in classifying the patient based on treatment rather than etiology. Dept. of Pharmaceutical Medicine 30 Jamia Hamdard

28 2. The terms type-1 and type-2 diabetes are retained, with arabic numerals being used rather than roman numerals. Table 2.1A: Etiologic Classification of Diabetes Mellitus I. Type-1 diabetes* (β-cell destruction, usually leading to absolute insulin deficiency) A. Immune mediated B. Idiopathic II. Type-2 diabetes* (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) III. Other specific types A. Genetic defects of β-cell function 1. Chromosome 12, HNF-1α (MODY3) 2. Chromosome 7, glucokinase (MODY2) 3. Chromosome 20, HNF-4α (MODY1) 4. Mitochondrial DNA 5. Others B. Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4. Lipoatrophic diabetes 5. Others C. Diseases of the exocrine pancreas 1. Pancreatitis 2. Trauma/pancreatectomy 3. Neoplasia 4. Cystic fibrosis 5. Hemochromatosis 6. Fibrocalculous pancreatopathy 7. Others D. Endocrinopathies 1. Acromegaly 2. Cushing s syndrome 3. Glucagonoma 4. Pheochromocytoma 5. Hyperthyroidism 6. Somatostatinoma 7. Aldosteronoma 8. Others E. Drug- or chemical-induced 1. Vacor 2. Pentamidine 3. Nicotinic acid 4. Glucocorticoids 5. Thyroid hormone 6. Diazoxide 7. β-adrenergic agonists 8. Thiazides 9. Dilantin 10. α -Interferon 11. Others F. Infections 1. Congenital rubella 2. Cytomegalovirus 3. Others G. Uncommon forms of immunemediated diabetes 1. Stiff-man syndrome 2. Anti-insulin receptor antibodies 3. Others H. Other genetic syndromes sometimes associated with diabetes 1. Down s syndrome 2. Klinefelter s syndrome 3. Turner s syndrome 4. Wolfram s syndrome 5. Friedreich s ataxia 6. Huntington s chorea 7. Laurence-Moon-Biedl syndrome 8. Myotonic dystrophy 9. Porphyria 10. Prader-Willi syndrome 11. Others IV. Gestational diabetes mellitus (GDM) *Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not, of itself, classify the patient. Dept. of Pharmaceutical Medicine 31 Jamia Hamdard

29 The degree of hyperglycemia (if any) may change over time, depending on the extent of the underlying disease process (Figure 2.1). *Even after presenting in ketoacidosis, these patients can briefly return to normoglycemia without requiring continuous therapy (i.e., honeymoon remission); **in rare instances, patients in these categories (e.g., Vacor toxicity, type-1 diabetes presenting in pregnancy) may require insulin for survival. Figure 2.1: Disorders of Glycemia: Etiologic Types and Stages Type-1 diabetes, β-cell destruction, usually leading to absolute insulin deficiency, Immune-mediated diabetes. This form of diabetes, previously encompassed by the terms insulin-dependent diabetes, type-1 diabetes, or juvenile-onset diabetes, results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas (Atkinson & Maclaren 1994). Markers of the immune destruction of the β-cell, include islet cell auto antibodies (ICAs), auto antibodies to insulin (IAAs), auto antibodies to glutamic acid decarboxylase (GAD65), and auto antibodies to the tyrosine phosphatases IA-2 and IA-2β (Baekkeskov et al. 1982, Atkinson et al. 1986, Kaufman et al. 1992, Christie et al. 1992, Schott et al. 1994, Schmidli et al Myers et al Lan et al. 1996; Lu et al. 1996). Type-2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance) this form of diabetes, previously referred to as non-insulin-dependent diabetes, type-2 diabetes, or adult-onset diabetes, is a term used for individuals who have insulin Dept. of Pharmaceutical Medicine 32 Jamia Hamdard

30 resistance and usually have relative (rather than absolute) insulin deficiency (Reaven et al. 1976, Olefsky et al. 1982, DeFronzo et al. 1979; Turner et al. 1978). Insulin resistance may improve with weight reduction and/or pharmacological treatment of hyperglycemia but is seldom restored to normal (Scarlett et al. 1982, Firth et al. 1986, Simonson et al. 1984, Henry et al. 1986; Wing et al. 1994).Other specific types of diabetes are 1) Genetic defects of the β-cell. They are referred to as maturity onset diabetes of the young (MODY) and are characterized by impaired insulin secretion with minimal or no defects in insulin action (Herman et al. 1994, Byrne et al. 1996; Clement et al. 1996). 2) Genetic defects in insulin action. There are unusual causes of diabetes that result from genetically determined abnormalities of insulin action. Endocrinopathies. Several hormones (e.g., growth hormone, cortisol, glucagon, epinephrine) antagonize insulin action. Excess amounts of these hormones (e.g., acromegaly, Cushing s syndrome,glucagonoma, pheochromocytoma) can cause diabetes (Soffer et al. 1961, Jadresic et al. 1982, Stenstrom et al. 1988; Berelowitz et al. 1996) Incidence and Prevalence According to the most recent data from the Centers for Disease Control and Prevention (CDC 2005), nearly 15 million people in the United States, or 5% of the population, have been diagnosed with diabetes, with an additional 6 million cases, as yet, undiagnosed. Diabetes is particularly prevalent among older adults and is present in approximately 6 million individuals aged 65 years. However, the prevalence of type-2 diabetes is increasing in younger adults (CDC 2007). The increasing rate of diabetes is expected to continue, with projections of 29 million total diagnosed cases by 2020 and 48 million cases by 2050 (Narayan et al. 2006) Burden of Illness Annual expenditures for diabetes in the United States have been conservatively estimated at $132 billion in direct and indirect costs (Figure 2.2), with costs only expected to increase as the prevalence of diabetes continues to rise (ADA2003). Cumulative costs of diabetes-related complications, particularly macrovascular complications, rise substantially as time elapses since the original diagnosis (Figure 3.1) (Caro et al. 2002). Dept. of Pharmaceutical Medicine 33 Jamia Hamdard

31 Figure 2.2 Figure Diagnostic Criteria for Diabetes Mellitus The diagnostic criteria for diabetes mellitus have been modified from those previously recommended by the NDDG or WHO. The revised criteria for the diagnosis of diabetes are shown (Table 2.1B). Three ways to diagnose diabetes are possible, and each must be confirmed, on a subsequent day, by any one of the three methods given (Table 2.1B). For example, one instance of symptoms with casual plasma glucose 200 mg/dl (11.1 mmol/ l), confirmed on a subsequent day by 1) FPG 126 mg/dl (7.0 mmol/l), 2) An OGTT with the 2-h postload value 200 mg/dl (11.1 mmol/l), or 3) Symptoms with a casual plasma glucose 200 mg/dl (11.1 mmol/l), warrants the diagnosis of diabetes. Patients with undiagnosed type-2 diabetes are at significantly increased risk for coronary heart disease, stroke, and peripheral vascular disease. In addition, they have a greater likelihood of having dyslipidemia, hypertension, and obesity (Klein 1995). Suggested criteria for testing are given (Table 2.2). The Expert Committee recognizes an intermediate group of subjects whose glucose levels, although not meeting criteria for diabetes, are nevertheless too high to be considered altogether normal. This group is defined as having FPG levels 110 mg/dl (6.1 mmol/l) but < 126 mg/dl (7.0 mmol/l) or 2-h values in the OGTT of 140 mg/dl Dept. of Pharmaceutical Medicine 34 Jamia Hamdard

32 (7.8 mmol/l) but < 200 mg/dl (11.1 mmol/l). Thus, the categories of FPG values are as follows: FPG <110 mg/dl (6.1 mmol/l) = normal fasting glucose; FPG 110 (6.1 mmol/l) and <126 mg/dl (7.0 mmol/l) = IFG; FPG 126 mg/dl (7.0 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above). The corresponding categories when the OGTT is used are the following: 2-h postload glucose (2-h PG) < 140 mg/dl (7.8 mmol/l) = normal glucose tolerance; 2-h PG 140 (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l) = IGT; 2-h PG 200 mg/dl (11.1 mmol/l) = provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above). Because the 2-h OGTT cutoff of 140 mg/dl (7.8 mmol/l) will identify more people as having impaired glucose homeostasis than will the fasting cutoff of 110 mg/d (6.1 mmol/l), it is essential that investigator always report which test was used. Table 2.1B Criteria for the Diagnosis of Diabetes Mellitus 1. Symptoms of diabetes plus casual plasma glucose concentration 200 mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia and unexplained weight loss. Or 2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h. Or 3. 2-h PG 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by WHO (2), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. Dept. of Pharmaceutical Medicine 35 Jamia Hamdard

33 Table 2.2: Testing for Diabetes in Asymptomatic, Undiagnosed Individuals 1. Testing for diabetes should be considered in individuals at age 45 years and above, particularly in those with a BMI 25 kg/m 2 *; if normal, it should be repeated at 3-year intervals. 2. Testing should be considered at a younger age or be carried out more frequently in individuals who are overweight (BMI 25 kg/m 2 *) and have additional risk factors: have a first-degree relative with diabetes are habitually physically inactive are members of a high-risk ethnic population (e.g., African-American, Hispanic American, Native American, Asian American, Pacific Islander) have delivered a baby weighing > 9 lb or have been diagnosed with GDM are hypertensive ( 140/90) have an HDL cholesterol level 35 mg/dl (0.90 mmol/l) and/or a triglyceride level 250 mg/dl (2.82 mmol/l) have PCOS on previous testing, had IGT or IFG have a history of vascular disease The OGTT or FPG test may be used to diagnose diabetes; however, in clinical settings the FPG test is greatly preferred because of ease of administration, convenience, acceptability to patients, and lower cost. *May not be correct for all ethnic groups Value of Aggressive Management Adequate glycemic control is a critical component in preventing microvascular complications associated with type-2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated a 25% reduction in the risk of microvascular endpoints in patients with type-2 diabetes who were treated using an intensive glucose-lowering strategy compared with a conventional approach (UKPDS 33). Subsequent observational analyses from the UKPDS trial showed reductions in mortality and other diabetes related complications, including cardiovascular complications (Stratton et al. 2000). For example, a 1% decrease in glycated hemoglobin (HbA1c) was associated with a 14% reduction in the incidence of MI Dept. of Pharmaceutical Medicine 36 Jamia Hamdard

34 (Table 2.3). Reductions in HBA1C have also been shown to decrease medical costs and health care utilization (Shetty et al. 2005, Gilmer et al. 2005, Menzin et al. 2001; Wagner et al. 2001). 2.3 a Result are based on an observational analysis of the association between glycemic exposure and diabetes complications Pathophysiology and the Rationale for Aggressive Management Techniques Four intrinsic defects are present in individuals with type-2 diabetes: (1) insulin resistance in muscle and adipose tissue, (2) decreased insulin production by pancreatic beta cells, (3) increased production of glucose by the liver (Figure 3.2), (DeFronzo 1988, Ramlo-Halsted 2000; Bays et al. 2004) and (4) decreased glucagonlike peptide-1 (GLP-1) levels(toft-nielsen et al. 2001). Some data suggest that chronic insulin resistance places increased secretory demands on beta cells, resulting in progressive beta-cell dysfunction (Buchanan et al. 2002, Xiang et al. 2006). Loss of beta-cell function is gradual, and individuals generally have < 20% of normal beta-cell function by the time they are diagnosed with diabetes (Gastaldelli et al. 2004). The ideal treatment strategy would address all 4 defects resulting in type-2 diabetes: reduced disposal of glucose by muscle and other tissues, impaired function of pancreatic beta cells, increased hepatic glucose production, and reduced GLP-1 levels. Dept. of Pharmaceutical Medicine 37 Jamia Hamdard

35 Figure Currently Recommended Treatments The ADA and the European Association for the Study of Diabetes (EASD) have published consensus guidelines for the management of hyperglycemia in type-2 diabetes (Figure 3.3) (Nathan et al. 2006). Initial management of both IGT and diabetes should always include lifestyle modifications, such as exercise and weight loss; however, long-term efficacy of lifestyle modification alone is limited, often requiring the addition of drug therapy to reach or maintain the goal HBA1C of < 7%. The benefits of intensive lifestyle modification of 5%-10% weight loss and 150 minutes of exercise/week were well demonstrated in the Diabetes Prevention Program (DPP) study of patients with IGT. Current ADA guidelines recommend that individuals with IGT or IFG lose 5%-10% of their body weight and increase their physical activity to at least 150 minutes per week of moderate activity (such as walking) to prevent or delay the onset of type-2 diabetes(ada 2008). In addition to promoting lifestyle modifications, the ADAEASD guidelines recommend use of Metformin for initial pharmacotherapy. A comparison of available glucose-lowering agents is presented (Table 2.4). Dept. of Pharmaceutical Medicine 38 Jamia Hamdard