Mehul Mehta

Biopharmaceutics classification system: the scientific basis for biowaiver extensions.

The current BSC guidance issued by the FDA allows for biowaivers based on conservative criteria. Possible new criteria and class boundaries are proposed for additional biowaivers based on the underlying physiology of the gastrointestinal tract. The proposed changes in new class boundaries for solubility and permeability are as follows: 1. Narrow the required solubility pH range from 1.0-7.5 to 1.0-6.8. 2. Reduce the high permeability requirement from 90% to 85%. The following new criterion and potential biowaiver extension require more research: 1. Define a new intermediate permeability class boundary. 2. Allow biowaivers for highly soluble and intermediately permeable drugs in IR solid oral dosage forms with no less than 85% dissolved in 15 min in all physiologically relevant dissolution media, provided these IR products contain only known excipients that do not affect the oral drug absorption. The following areas require more extensive research: 1. Increase the dose volume for solubility classification to 500 mL. 2. Include bile salt in the solubility measurement. 3. Use the intrinsic dissolution method for solubility classification. 4. Define an intermediate solubility class for BCS Class II drugs. 5. Include surfactants in in vitro dissolution testing.

Bioavailability and bioequivalence: an FDA regulatory overview.

Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivalence can generally be achieved by considering the following three questions. What is the primary question of the study? What are the tests that can be used to address the question? What degree of confidence is needed for the test outcome? This article reviews the regulatory science of bioavailability and bioequivalence and provides FDAs recommendations for drug sponsors who intend to establish bioavailability and/or demonstrate bioequivalence for their pharmaceutical products during the developmental process or after approval.

Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications.

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.

The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN‐38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN‐38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN‐38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Population Pharmacokinetic–Based Dosing of Intravenous Busulfan in Pediatric Patients

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty‐four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages ≤4 years or >4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1‐compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients ≤12 kg should be dosed at 1.1 mg/kg and those >12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

A Systemic Exposure-Based Alternative to the Maximum Tolerated Dose for Carcinogenicity Studies of Human Therapeutics

A systemic exposure-based alternative to the maximum tolerated dose (MTD) for high-dose selection in carcinogenicity studies for human therapeutics was accepted at the Second International Conference on Harmonization (ICH-2). The systemic exposure-based alternative to the MTD is suitable for nongenotoxic compounds with low rodent toxicity that are metabolized similarly in rodents and humans. This is the first product of an evaluation of current standards for rodent carcinogenicity studies of therapeutics. The relative systemic exposure is the ratio of the rat plasma area under the plasma concentration-time curve (AUC) at the MTD/human plasma AUC at the maximum recommended daily dose. An appropriate systemic exposure ratio for high-dose selection in carcinogenicity studies was empirically derived from the distribution of systemic exposure ratios attained by 35 compounds from 11 therapeutic categories in a Food and Drug Administration (FDA) database. Approximately one-third achieved a relative systemic exposure ratio <1 and two-thirds attained an exposure ratio of 10 or less, at the MTD. A systemic exposure ratio of at least 25 was accepted for high-dose selection in carcinogenicity studies at ICH-2. This ratio is high enough to detect all compounds with positive studies in the FDA database and would detect IARC 1 and 2A carcinogenic drugs. A ratio of 25 exceeds the systemic exposure ratio attained by 75% of drugs tested at the MTD in the FDA database and represents an adequate margin of safety which can be attained by a significant proportion of drugs.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified-release products: Workshop summary report

Modified-release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to discuss current regulatory expectations and industry practices for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA

The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were classified as BCS 1, 2, 3, and 4 drugs with certainty in the World Health Organization Model List of Essential Medicines. Applying this list to evaluation of 263 ANDA approvals of BCS drugs during the period of 2000 to 2011 indicated 110 approvals (41.8%) for Class 1 drugs (based on both biowaiver and in vivo bioequivalence studies), 55 (20.9%) approvals for Class 2 drugs, 98 (37.3%) approvals for Class 3 drugs, and no (0%) approvals for Class 4 drugs. The present data indicated a trend of more ANDA approvals of BCS Class 1 drugs than Class 3 or Class 2 drugs. Antiallergic drugs in Class 1, drugs for pain relief in Class 2 and antidiabetic drugs in Class 3 have received the largest number of approvals during this period.

Advancing Product Quality: a Summary of the Second FDA/PQRI Conference

Lawrence X. Yu, Ilgaz Akseli, Barbara Allen, Gregory Amidon, Tara Gooen Bizjak, Ashley Boam, Margaret Caulk, David Doleski, Joseph Famulare, Adam C. Fisher1, Scott Furness, Brian Hasselbalch, Henry Havel, Stephen W. Hoag, Robert Iser, Bruce D. Johnson, Robert Ju, Paula Katz, Emanuela Lacana, Sau L. Lee, Richard Lostritto, Grace McNally, Mehul Mehta, Ganapathy Mohan, Moheb Nasr, Roger Nosal, Mary Oates, Thomas O’Connor, Jim Polli, G.K. Raju, Mahesh Ramanadham, Giuseppe Randazzo, Susan Rosencrance, Anna Schwendeman, Arzu Selen, Paul Seo, Vinod Shah, Ramesh Sood, Michael P. Thien, Tony Tong, Bernhardt L. Trout, Katherine Tyner, Siva Vaithiyalingam, Martin VanTrieste, Fionnuala Walsh3, Russell Wesdyk1, Janet Woodcock1, Geoffrey Wu, Larisa Wu, Louis Yu, Diane Zezza

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine

Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipines solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products.