The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Current Status and Future Directions of Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer.

PURPOSE: The standard of care for patients with locally advanced cervical cancer is definitive chemoradiation followed by a brachytherapy boost. This review describes the current status and future directions of image-guided adaptive brachytherapy for locally advanced cervical cancer. METHODS: A systematic search of the PubMed and Clinicaltrials.gov databases was performed, focusing on studies published within the last 10 years. The search queried "cervical cancer [AND] image-guided brachytherapy [OR] magnetic resonance imaging (MRI) [OR] adaptive brachytherapy". DISCUSSION: The retroEMBRACE and EMBRACE-I trials have established the use of MRI as the standard imaging modality for brachytherapy application and planning. Quantitative imaging and radiomics have the potential to improve outcomes, with three ongoing prospective studies examining the use of radiomics to further risk-stratify patients and personalize brachytherapy. Another active area of investigation includes utilizing the superior soft tissue contrast provided by MRI to increase the dose per fraction and decrease the number of fractions needed for brachytherapy, with several retrospective studies demonstrating the safety and feasibility of three-fraction courses. For developing countries with limited access to MRI, trans-rectal ultrasound (TRUS) appears to be an effective alternative, with several retrospective studies demonstrating improved target delineation with the use of TRUS in conjunction with CT guidance. CONCLUSIONS: Further investigation is needed to continue improving outcomes for patients with locally advanced cervical cancer treated with image-guided brachytherapy.

Perception and Utilization of Cannabinoids in Patients Undergoing Radiation Treatment: Our Patients Are Curious.

PURPOSE: Limited studies have described the utilization of cannabinoids among patients with cancer. This survey study aimed to characterize utilization patterns and perceptions of cannabinoid use for treatment-related side effects among patients receiving radiation treatment. METHODS AND MATERIALS: This was an anonymous survey study of patients who were undergoing or recently completed radiation treatment at a comprehensive cancer center. Data on cannabinoid use during cancer treatment, reasons for the use of cannabinoids, perceived effects of cannabinoids, and formulations of usage were collected and summarized using descriptive statistics. RESULTS: Of the 431 respondents, 111 (25.8%) patients reported cannabinoid use since their cancer diagnosis. Among the cannabinoid users, a majority (73.9%) experienced improvement in symptoms; 38.7% had better relief of cancer-treatment symptoms from cannabinoids in comparison to their prescription medications, and 16.2% lowered the amount of prescription pain medications needed after using cannabinoids. Cannabinoids appeared to be most effective in helping patients manage sleep (76.6%) and anxiety (72.1%). When asked about whether physicians should be discussing cannabinoid use, 45.1% of cannabinoid users wanted to speak with their doctors regarding its utilization. For patients who did not report cannabinoid use, a large majority (83.1%) never had discussions with their doctors regarding its utilization as part of their cancer care, and 34.8% wanted to learn more about cannabinoids from their doctors. CONCLUSIONS: About 1 in 4 patients with cancer reported cannabinoid use to assist in symptom control. A majority had subjective alleviation of treatment-related symptoms from cannabinoid use. Regardless of cannabinoid use, a sizable percentage of patients never had any discussions about cannabinoids with their oncologists, with some expressing interest in learning more. Guidelines are needed to assist radiation oncologists on how cannabinoids may play a role in caring for patients.

Vegetation biomass and topography are associated with seasonal habitat selection and fall translocation behavior in Arctic hares.

Habitat selection theory suggests that environmental features selected at coarse scales reveal fundamental factors affecting animal fitness. When these factors vary across seasons, they may lead to large-scale movements, including long-distance seasonal migrations. We analyzed the seasonal habitat selection of 25 satellite-tracked Arctic hares from a population on Ellesmere Island (Nunavut, Canada) that relocated over 100 km in the fall. Since no other lagomorph is known to perform such extensive movements, this population offered an ideal setting to test animal movement and habitat selection theory. On summer grounds hares selected low elevation areas, while on winter grounds they selected high vegetation biomass, high elevation, and steep slopes. During fall relocation, they alternated between stopover and traveling behavioral states (ratio 2:1). Stopover locations were characterized by higher vegetation heterogeneity and lower rugosity than traveling locations, while vegetation biomass and elevation interacted to explain stopover locations in a more complex way. The selected combination of environmental features thus varied across seasons and behavioral states, in a way broadly consistent with predictions based on the changing food and safety needs of hares. Although causality was not demonstrated, our results improve our understanding of long-distance movements and habitat selection in Arctic hares, as well as herbivore ecology in the polar desert. Results also provide strong support to animal movement and habitat selection theory, by showing how some important hypotheses hold when tested in a species phylogenetically distinct from most animal models used in this research field.

Grade 5 Radiation Necrosis After Whole-Brain Radiation Therapy.

Whole-brain radiation treatment is often considered for patients with leptomeningeal disease. There are limited reports of the development of radiation necrosis after whole-brain radiation treatment and fewer associating the presence of germline mutations with risk. We present a case report to highlight the need for consideration of radiosensitizing mutations when recommending radiation therapy.

Moving the Needle Forward in Genomically-Guided Precision Radiation Treatment.

Radiation treatment (RT) is a mainstay treatment for many types of cancer. Recommendations for RT and the radiation plan are individualized to each patient, taking into consideration the patient's tumor pathology, staging, anatomy, and other clinical characteristics. Information on germline mutations and somatic tumor mutations is at present rarely used to guide specific clinical decisions in RT. Many genes, such as ATM, and BRCA1/2, have been identified in the laboratory to confer radiation sensitivity. However, our understanding of the clinical significance of mutations in these genes remains limited and, as individual mutations in such genes can be rare, their impact on tumor response and toxicity remains unclear. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN), provide limited guidance on how genetic results should be integrated into RT recommendations. With an increasing understanding of the molecular underpinning of radiation response, genomically-guided RT can inform decisions surrounding RT dose, volume, concurrent therapies, and even omission to further improve oncologic outcomes and reduce risks of toxicities. Here, we review existing evidence from laboratory, pre-clinical, and clinical studies with regard to how genetic alterations may affect radiosensitivity. We also summarize recent data from clinical trials and explore potential future directions to utilize genetic data to support clinical decision-making in developing a pathway toward personalized RT.

Explainable Artificial Intelligence to Identify Dosimetric Predictors of Toxicity in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Secondary Analysis of RTOG 0617.

PURPOSE: Dosimetric predictors of toxicity in patients treated with definitive chemoradiation for locally advanced non-small cell lung cancer are often identified through trial and error. This study used machine learning (ML) and explainable artificial intelligence to empirically characterize dosimetric predictors of toxicity in patients treated as part of a prospective clinical trial. METHODS AND MATERIALS: A secondary analysis of the Radiation Therapy Oncology Group (RTOG) 0617 trial was performed. Multiple ML models were trained to predict grade ≥3 pulmonary, cardiac, and esophageal toxicities using clinical and dosimetric features. Model performance was evaluated using the area under the curve (AUC). The best performing model for each toxicity was explained using the Shapley Additive Explanation (SHAP) framework; SHAP values were used to identify relevant dosimetric thresholds and were converted to odds ratios (ORs) with confidence intervals (CIs) generated using bootstrapping to obtain quantitative measures of risk. Thresholds were validated using logistic regression. RESULTS: The best-performing models for pulmonary, cardiac, and esophageal toxicities, outperforming logistic regression, were extreme gradient boosting (AUC, 0.739), random forest (AUC, 0.706), and naive Bayes (AUC, 0.721), respectively. For pulmonary toxicity, thresholds of a mean dose >18 Gy (OR, 2.467; 95% CI, 1.049-5.800; P = .038) and lung volume receiving ≥20 Gy (V20) > 37% (OR, 2.722; 95% CI, 1.034-7.163; P = .043) were identified. For esophageal toxicity, thresholds of a mean dose >34 Gy (OR, 4.006; 95% CI, 2.183-7.354; P < .001) and V20 > 37% (OR, 3.725; 95% CI, 1.308-10.603; P = .014) were identified. No significant thresholds were identified for cardiac toxicity. CONCLUSIONS: In this data set, ML approaches validated known dosimetric thresholds and outperformed logistic regression at predicting toxicity. Furthermore, using explainable artificial intelligence, clinically useful dosimetric thresholds might be identified and subsequently externally validated.

Born in the cold: contrasted thermal exchanges and maintenance costs in juvenile and adult snow buntings on their breeding and wintering grounds.

Several species of passerines leave their nest with unfinished feather growth, resulting in lower feather insulation and increased thermoregulatory demands compared to adults. However, feather insulation is essential for avian species breeding at northern latitudes, where cold conditions or even snowstorms can occur during the breeding season. In altricial arctic species, increased heat loss caused by poor feather insulation during growth could be counter-adaptative as it creates additional energy demands for thermoregulation. Using flow-through respirometry, we compared resting metabolic rate at thermoneutrality (RMRt), summit metabolic rate (Msum) and heat loss (conductance) in adult and juvenile snow buntings on their summer and winter grounds. In summer, when buntings are in the Arctic, juveniles had a 12% higher RMRt, likely due to unfinished growth, and lost 14% more heat to the environment than adults. This pattern may result from juveniles fledging early to avoid predation at the cost of lower feather insulation. Surprisingly, an opposite pattern was observed at lower latitudes on their wintering grounds. Although they showed no difference in RMRt and Msum, adults were losing 12% more heat than juveniles. We suggest that this difference is due to poorer insulative property of plumage in adults stemming from energetic and time constraints encountered during their post-breeding molt. High plumage insulation in first-winter juvenile buntings could be adaptive to reduce thermoregulatory demands and maximize survival in the first winter of life, while adults could use behavioral strategies to compensate for their greater rate of heat loss.

Implications of updated staging system for p16+ oropharyngeal squamous cell carcinoma: Is valuable prognostic information being omitted?

BACKGROUND: This study characterized whether the updated AJCC 8th edition nodal staging system for p16+ oropharyngeal squamous cell carcinoma (OPSCC) resulted in the loss of prognostic value. METHODS: The NCDB was queried for patients with node-positive p16+ OPSCC. The prognostic impact of nodal size, nodal quantity, nodal laterality, and extracapsular extension (ECE) on overall survival (OS) was assessed. RESULTS: In the clinical cohort, inferior 5-year OS was observed in patients with more than one positive lymph node (p < 0.001; 82% vs. 86%), ECE (p < 0.001; 82% vs. 75%), or nodal size >6 cm (p < 0.001; 66% vs. 82%). In the pathologic cohort, inferior 5-year OS was observed in patients with > four positive lymph nodes (p < 0.001; 76% vs. 90%), ECE (p < 0.001; 83% vs. 92%), or largest nodal size >6 cm (p < 0.001; 81% vs. 89%). CONCLUSIONS: Simplifications in the current p16+ OPSCC staging system led to loss of prognostic information in nodal staging.

The Emerging Role of Radiotherapy in Oligoprogressive Non-Small Cell Lung Cancer.

Oligoprogressive disease (OPD) is an emerging concept that describes patients who have progression of disease in a limited number of metastatic sites while on systemic therapy. Growing evidence has suggested the integration of local ablative therapy with systemic agents in patients with OPD further improves survival. In oligoprogressive non-small cell lung cancer, stereotactic body radiotherapy may have an important role in the effective local control of selective progressing metastases, which may translate to better patient outcomes. This review explores the treatment paradigm of this subset of patients and provides an update on the current existing literature on this topic.

Current landscape of radiation oncology in esophageal cancer: a narrative review.

Background and Objective: Esophageal cancer is an aggressive disease that is the sixth leading cause of cancer-related death worldwide. The overall treatment paradigm for esophageal cancer has changed considerably over the past decade. This narrative review aims to summarize the current landscape of radiation oncology for esophageal cancer. Methods: A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "esophageal cancer [AND] neoadjuvant radiation" as well as "locally advanced esophageal cancer [AND] definitive radiation". Our search resulted in 298 total references. These were manually reviewed, and only 58 references were within our scope of interest ranging from 2012-2022. Key Content and Findings: For resectable esophageal cancer, neoadjuvant chemoradiation followed by surgery has been defined as the standard of care over the past decade. In patients with incomplete response to neoadjuvant chemoradiation, the benefit of immunotherapy in the adjuvant setting has recently been established. Ongoing studies are examining whether perioperative chemotherapy may be equivalent to neoadjuvant chemoradiation in resectable esophageal adenocarcinoma. For locally advanced esophageal cancer, recent studies have failed to show a benefit with radiation dose escalation in an unselected population, although the use of early positron emission tomography (PET) response to guide dose escalation is currently being studied. Other ongoing studies aiming to improve outcomes in locally advanced esophageal cancer involve using proton beam therapy to reduce toxicity and combining immunotherapy or targeted therapies with chemoradiation to amplify response. Conclusions: Recent advances in radiation oncology may continue to improve outcomes for patients with esophageal cancer.

Utilization of model-agnostic explainable artificial intelligence frameworks in oncology: a narrative review.

Background and Objective: Machine learning (ML) models are increasingly being utilized in oncology research for use in the clinic. However, while more complicated models may provide improvements in predictive or prognostic power, a hurdle to their adoption are limits of model interpretability, wherein the inner workings can be perceived as a "black box". Explainable artificial intelligence (XAI) frameworks including Local Interpretable Model-agnostic Explanations (LIME) and SHapley Additive exPlanations (SHAP) are novel, model-agnostic approaches that aim to provide insight into the inner workings of the "black box" by producing quantitative visualizations of how model predictions are calculated. In doing so, XAI can transform complicated ML models into easily understandable charts and interpretable sets of rules, which can give providers with an intuitive understanding of the knowledge generated, thus facilitating the deployment of such models in routine clinical workflows. Methods: We performed a comprehensive, non-systematic review of the latest literature to define use cases of model-agnostic XAI frameworks in oncologic research. The examined database was PubMed/MEDLINE. The last search was run on May 1, 2022. Key Content and Findings: In this review, we identified several fields in oncology research where ML models and XAI were utilized to improve interpretability, including prognostication, diagnosis, radiomics, pathology, treatment selection, radiation treatment workflows, and epidemiology. Within these fields, XAI facilitates determination of feature importance in the overall model, visualization of relationships and/or interactions, evaluation of how individual predictions are produced, feature selection, identification of prognostic and/or predictive thresholds, and overall confidence in the models, among other benefits. These examples provide a basis for future work to expand on, which can facilitate adoption in the clinic when the complexity of such modeling would otherwise be prohibitive. Conclusions: Model-agnostic XAI frameworks offer an intuitive and effective means of describing oncology ML models, with applications including prognostication and determination of optimal treatment regimens. Using such frameworks presents an opportunity to improve understanding of ML models, which is a critical step to their adoption in the clinic.

A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme.

The safety and efficacy of a generic product are partly based on demonstrating bioequivalence to the innovator product; however, when the innovator product is no longer available as a comparator product, a survey conducted within the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP) indicated that the criteria for selecting an alternative comparator product varies. For most members of the BEWGG, an existing marketed generic that was approved based on a comparison with the locally registered innovator product can be used, contingent on criteria that ranges from allowing any generic to be used, to allowing only specific criteria-defined generics to be used. Notwithstanding the acceptability of a generic as an alternative comparator, it is not always the preferred comparator for several jurisdictions. Some jurisdictions require the use of a locally sourced alternative innovator comparator (e.g., the same medicinal ingredient manufactured by a different company) or a foreign innovator comparator. Unlike the other members of the BEWGG, the European Union (EU) has no such options available, rather mechanisms are in place to allow manufacturers to develop a new comparator. The criteria described herein regarding the use of an alternative comparator product can also be applied to scenarios where a specific strength of a series of strengths or an innovative fixed dose combination are discontinued. The results of the survey demonstrate that while criteria for selecting alternative comparator products are not harmonized among the BEWGG participants, the common concern for all jurisdictions is to select a comparator product that meets the safety and efficacy standards of the original innovator product.

Warming in the land of the midnight sun: breeding birds may suffer greater heat stress at high- versus low-Arctic sites.

Rising global temperatures are expected to increase reproductive costs for wildlife as greater thermoregulatory demands interfere with reproductive activities. However, predicting the temperatures at which reproductive performance is negatively impacted remains a significant hurdle. Using a thermoregulatory polygon approach, we derived a reproductive threshold temperature for an Arctic songbird-the snow bunting (Plectrophenax nivalis). We defined this threshold as the temperature at which individuals must reduce activity to suboptimal levels (i.e. less than four-time basal metabolic rate) to sustain nestling provisioning and avoid overheating. We then compared this threshold to operative temperatures recorded at high (82° N) and low (64° N) Arctic sites to estimate how heat constraints translate into site-specific impacts on sustained activity level. We predict buntings would become behaviourally constrained at operative temperatures above 11.7°C, whereupon they must reduce provisioning rates to avoid overheating. Low-Arctic sites had larger fluctuations in solar radiation, consistently producing daily periods when operative temperatures exceeded 11.7°C. However, high-latitude birds faced entire, consecutive days when parents would be unable to sustain required provisioning rates. These data indicate that Arctic warming is probably already disrupting the breeding performance of cold-specialist birds and suggests counterintuitive and severe negative impacts of warming at higher latitude breeding locations.

Long-distance, synchronized and directional fall movements suggest migration in Arctic hares on Ellesmere Island (Canada).

Animal migration contributes largely to the seasonal dynamics of High Arctic ecosystems, linking distant habitats and impacting ecosystem structure and function. In polar deserts, Arctic hares are abundant herbivores and important components of food webs. Their annual migrations have long been suspected, but never confirmed. We tracked 25 individuals with Argos satellite telemetry to investigate the existence of migration in a population living at Alert (Ellesmere Island, Nunavut, Canada). During fall, 21 hares undertook directional, long-distance movements in a southwestern direction towards Lake Hazen. Daily movement rates averaged 1.3 ± 0.5 km, 4.3 ± 1.6 km, and 1.7 ± 0.9 km before, during, and after relocation, respectively. Straight-line and minimum cumulative distances traveled averaged 98 ± 18 km (range: 72-148 km) and 198 ± 62 km (range: 113-388 km), respectively. This is the first report of large-scale seasonal movements in Arctic hares and, surprisingly, in any lagomorph species. These movements may be part of an annual migratory pattern. Our results redefine our understanding of the spatial ecology of Arctic hares, demonstrate unsuspected mobility capacities in lagomorphs, and open new perspectives regarding the ecological dynamics of the northern polar deserts.

Propensity-score matched oncological outcomes and patterns of recurrence following open and minimally-invasive partial nephrectomy for renal cell carcinoma.

BACKGROUND: Oncological equivalency of minimally-invasive partial nephrectomy compared to open partial nephrectomy (OPN) continues to be challenged by proponents of open urologic oncology surgery. OBJECTIVE: To compare patterns of recurrence, recurrence-free survival, cancer-specific survival, and overall survival between patients who underwent open or minimally-invasive partial nephrectomy. MATERIALS AND METHODS: Data from prospectively maintained databases from 2 urban quaternary referral centers was retrospectively collected from 2003 to 2018. Patients who underwent either open or minimally-invasive (laparoscopic or robotic-assisted) partial nephrectomy and found to have malignant pathology were included. The groups subsequently underwent propensity-score matching to ensure homogeneity prior to analysis. The primary outcomes were incidence of recurrence, time to recurrence, time from recurrence to death, location of recurrence, and recurrence-free survival. Secondary outcomes included overall survival and cancer-specific survival. RESULTS: A total of 190 patients underwent OPN and 190 underwent minimally-invasive partial nephrectomy. Recurrence was more common in patients undergoing OPN (10% vs. 3.2%, P = 0.01), but surgical approach was not predictive of location of recurrence (P = 1) or time to recurrence (23.8 vs. 26.3 months, P = 0.73). All-cause mortality was more common in the OPN group (10.5% vs. 2.6%, P = 0.003). On multivariable analysis, only surgical approach was associated with increased risk for recurrence (OR 3.88, P = 0.009). CONCLUSION: This propensity-score matched analysis of patients undergoing partial nephrectomy suggests that minimally invasive surgical approach is resulted in decreased risk of recurrence and overall survival, and does not increase the risk for atypical sites of recurrence.

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting.

INTRODUCTION: Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration. METHODS: A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction. RESULTS: Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, p = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, p = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, p = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h, p = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction. CONCLUSION: Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.