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Regulatory approaches for evaluating therapeutic equivalence of multisource (or generic) drug products vary among different countries and/or regions. Harmonization of these approaches may decrease the number of in vivo bioequivalence studies and avoid unnecessary drug exposure to humans. Global harmonization for regulatory requirements may be promoted by a better understanding of factors underlying product performance and expectations from different regulatory authorities. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to have open discussions on current regulatory issues and industry practices, facilitating harmonization of regulatory approaches for establishing therapeutic equivalence and interchangeability of multisource drug products.

This is a summary report of the workshop, organized by the European Federation of Pharmaceutical Scientists in association with the American Association of Pharmaceutical Scientists, the European Agency for the Evaluation of Medicinal Products, the European Pharmacopoeia, the US Food and Drug Administration and the United States Pharmacopoeia, on “Assuring Quality and Performance of Sustained and Controlled Release Parenterals” held in Basel, Switzerland, February 2003. Experts from the pharmaceutical industry, regulatory authorities and academia participated in this workshop to review, discuss and debate formulation, processing and manufacture of sustained and controlled release parenterals, and identify critical process parameters and their control. This workshop was a follow-up workshop to a previous workshop on Assuring Quality and Performance of Sustained and Controlled Release Parenterals that was held in Washington, DC in April 2001. This report reflects the outcome of the Basel 2003 meeting and the advances in the field since the Washington, DC meeting in 2001. As necessary, the reader is referred to the report on the 2001 meeting. Areas were identified at the 2003 Basel meeting where research is needed in order to understand the performance of these drug delivery systems and to assist in the development of appropriate testing procedures. Recommendations were made for future workshops and meetings.

This is a summary report of the American Association of Pharmaceutical Scientists, the Food and Drug Administration and the United States Pharmacopoeia cosponsored workshop on “Assuring Quality and Performance of Sustained and Controlled Release Parenterals.” Experts from the pharmaceutical industry, the regulatory authorities and academia participated in this workshop to review, discuss and debate formulation, processing and manufacture of sustained and controlled release parenterals and identify critical process parameters and their control. Areas were identified where research is needed in order to understand the performance of these drug delivery systems and to assist in the development of appropriate testing procedures. Recommendations were made for future workshops, meetings and working groups in this area.

FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.

Metrics are discussed which are used for the evaluation of bioequivalence of modified-release formulations. In order to ensure the therapeutic equivalence of the compared drug products, it would be important to contrast measures which are additional to area under the curve (AUC) and Cmax. For delayed-release products, the assessment of lag times is informative. For extended-release dosage forms, comparisons of the half-value duration and the midpoint duration time are useful. For some modified-release formulations with complicated, multiphasic concentration profiles, the comparison of partial AUCs is important. In determinations of the bioequivalence of extended-release dosage forms, investigations performed under steady-state conditions rather than after single dosing can yield enhanced probability of therapeutic equivalence, especially with substantial accumulation of the drug products. In steady-state investigations of bioequivalence, evaluation of the trough concentration and of the peak trough fluctuation is informative.

The workshop “Bioequivalence, Biopharmaceutics Classification System, and Beyond” was held May 21–23, 2007 in North Bethesda, MD, USA. This workshop provided an opportunity for pharmaceutical scientists to discuss the FDA guidance on the Biopharmaceutics Classification System (BCS), bioequivalence of oral products, and related FDA initiatives such as the FDA Critical Path Initiative. The objective of this Summary Workshop Report is to document the main points from this workshop. Key highlights of the workshop were (a) the described granting of over a dozen BCS-based biowaivers by the FDA for Class I drugs whose formulations exhibit rapid dissolution, (b) continued scientific support for biowaivers for Class III compounds whose formulations exhibit very rapid dissolution, (c) scientific support for a number of permeability methodologies to assess BCS permeability class, (d) utilization of BCS in pharmaceutical research and development, and (e) scientific progress in in vitro dissolution methods to predict dosage form performance.

In modern ‘representative’ democratic states, the legitimacy of governments’ actions rests on their publicly declared commitment to protect the interests of their citizens. Regarding the pharmaceutical sector in most democracies, new drug products are developed and marketed by a capitalist industry, whose member firms, via shareholders, have commercial interests in expanding product sales. In those democracies, states have established government agencies to regulate the pharmaceutical industry on behalf of citizens. State legislatures, such as the US Congress and European Parliaments, have charged government drug regulatory agencies with the legal responsibility to protect public health. Yet, this paper argues that government drug regulatory agencies in the EU, Japan, and USA have permitted the pharmaceutical industry to reshape the regulatory guidance for carcinogenic risk assessment of pharmaceuticals in ways that are not techno-scientifically defensible as bases for improved, or even equivalent, protection of public health, compared with the previous techno-regulatory standards. By adopting the industry’s agenda of streamlining carcinogenicity testing in order to accelerate drug development and regulatory review, it is contended that these regulatory agencies have allowed the techno-regulatory standards for carcinogenic risk assessment to be loosened in ways that are presented as scientific progress resulting from new genetics, but for which there is little evidence of progress in public health protection.

Background

Drug regulatory agencies (DRA) support prescription of generic products of intravenous antibiotics assuming therapeutic equivalence from pharmaceutical equivalence. Recent reports of deaths associated with generic heparin and metoprolol have raised concerns about the efficacy and safety of DRA-approved drugs.

Methodology/Principal Findings

To challenge the assumption that pharmaceutical equivalence predicts therapeutic equivalence, we determined in vitro and in vivo the efficacy of the innovator product and 20 pharmaceutically equivalent generics of gentamicin. The data showed that, while only 1 generic product failed in vitro (MIC = 45.3 vs. 0.7 mg/L, P<0.05), 10 products (including gentamicin reference powder) failed in vivo against E. coli due to significantly inferior efficacy (Emax = 4.81 to 5.32 vs. 5.99 log10 CFU/g, P≤0.043). Although the design lacked power to detect differences in survival after thigh infection with P. aeruginosa, dissemination to vital organs was significantly higher in animals treated with generic gentamicin despite 4 days of maximally effective treatment.

Conclusion

Pharmaceutical equivalence does not predict therapeutic equivalence of generic gentamicin. Stricter criteria based on solid experimental evidence should be required before approval for human use.

The workshop “Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications” was held November 15–16, 2008 in Atlanta, Georgia, USA. This workshop provided an opportunity for pharmaceutical scientists, clinical practitioners, clinical laboratory scientists, and FDA to discuss methods, regulatory, and the application of pharmacogenetics in clinical practice and drug discovery. Key highlights of the workshop were: (a) the use of genetic information in individualized medicine has significant potential in advancing drug development and human health by optimizing drug response, drug efficacy, and preventing adverse drug reactions; (b) various barriers exist preventing the advance of the individualized medicine in the society, industry, and clinical practice; and (c) the barriers may be overcome by integrated approaches; the education of researchers, clinical practitioners, and patients and fostering interactive communication among stakeholders. By targeting the AAPS audience, this workshop was one step among many steps that AAPS–FIP is intending to take towards removing the barriers to widespread uptake of pharmacogenetics in drug discovery and clinical practice.

The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.

The demonstration of bioequivalence (BE) is an essential requirement for ensuring that patients receive a product that performs as indicated by the label. The BE standard for a particular product is set by its innovator, and this standard must subsequently be matched by generic drug products. The Biopharmaceutics Classification System (BCS) sets a scientific basis for an improved BE standard for immediate-release solid oral dosage forms. In this paper, we discuss BE and the BCS, as well as the issues that are currently relevant to BE as a pharmaceutical product standard.

Under the Abbreviated New Drug Application pathway, a proposed generic salmon calcitonin nasal spray is required to demonstrate pharmaceutical equivalence and bioequivalence to the brand-name counterpart or the reference listed drug. This review discusses two important aspects of pharmaceutical equivalence for this synthetic peptide nasal spray product. The first aspect is drug substance sameness, in which a proposed generic salmon calcitonin product is required to demonstrate that it contains the same active ingredient as that in the brand-name counterpart. The second aspect is comparability in product- and process-related factors that may influence immunogenicity (i.e., peptide-related impurities, aggregates, formulation, and leachates from the container/closure system). The comparability of these factors helps to ensure the product safety, particularly with respect to immunogenicity. This review also highlights the key features of in vitro and/or in vivo studies for establishing bioequivalence for a solution nasal spray containing a systemically acting salmon calcitonin.

Traditional Chinese Medicines (TCM) are rapidly gaining attention in the West as sources of new drugs, dietary supplements and functional foods. However, lack of consistent manufacturing practices and quality standards, fear of adulteration, and perceived deficiencies in scientific validation of efficacy and safety impede worldwide acceptance of TCM. In addition, Western pharmaceutical industries and regulatory agencies are partial toward single ingredient drugs based on synthetic molecules, and skeptical of natural product mixtures. This review concentrates on three examples of TCM-derived pharmaceuticals and functional foods that have, despite these usual obstacles, risen to wide acceptance in the West based on their remarkable performance in recent scientific investigations. They are: Sweet wormwood (Artemisia annua), the source of artemisinin, which is the currently preferred single compound anti-malarial drug widely used in combination therapies and recently approved by US FDA; Thunder god vine (Tripterygium wilfordii) which is being developed as a botanical drug for rheumatoid arthritis; and green tea (Camellia sinensis) which is used as a functional beverage and a component of dietary supplements.

Background

Establishing the bioequivalence of topical drug products is a costly and time-consuming process since, with few exceptions, clinical efficacy trials are required.

Objective

To develop a surrogate for clinical bioequivalence testing through evaluation of the kinetics of drug absorption in vitro through excised human skin.

Methods

The percutaneous absorption of seven approved generic topical drug products was compared with their corresponding reference products during preclinical development using the Franz diffusion cell. Thereafter, following the conduct of bioequivalence trials and regulatory approval of these products in the United States, clinical data became available to which the in vitro data were compared.

Results

In six of the seven cases the in vitro test:reference ratio for total absorption was close to one and indicated that the products were equivalent, in agreement with the clinical data. Results from the seventh case, in which the test:reference ratio was only 0.63, indicated that the in vitro model actually had greater sensitivity than the clinical method to detect small differences between products.

Conclusion

These data demonstrate the relevance and predictive power of the in vitro human skin model and strongly support its use as a surrogate for in vivo bioequivalence studies.

The biopharmaceutical classification system (BCS) classifies compounds based on their solubility and permeability. Regulatory agencies and health organizations have utilized this classification system to allow dissolution to be used to establish bioequivalence for highly soluble and highly permeable compounds. The pharmaceutical industry has taken advantage of this and BCS-based waivers are becoming more routine and result in significant savings. Further, there is strong scientific rationale to allow BCS-based waivers for even more compounds to realize even more savings. Yet just as clear as the benefits are the barriers that limit application: lack of international regulatory harmonization, uncertainty in regulatory approval, and organizational barriers within the pharmaceutical industry. Once these barriers are overcome and additional applications are fully allowed, the full benefits of BCS applications will be realized.

Background

Demonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products (pharmaceutical equivalence) is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence. Physicochemical methods are preferred instead of biological assays to determine concentration of drugs in biological fluids, but it does not permit direct quantification of potency. Here, we report a microbiological assay using large plates designed to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator.

Methods

The assay is based on the concentration-dependent variation of the inhibitory effect of antibiotics on reference bacteria (B. subtilis ATCC 6633, S. aureus ATCC 6538p and S. epidermidis ATCC 12228) in a seeded agar (Difco™ Antibiotic Media), producing a concentration-response linear relationship with two parameters: y-intercept (concentration) and slope (potency). We compared the parameters of 22 generic products (amikacin 4, gentamicin 15, and vancomycin 3 products) against the innovator and the reference powder by Overall Test for Coincidence of the Regression Lines (Graphpad Prism 5.0).

Results

The validation method yielded excellent results for linearity (r2 ≥ 0.98), precision (intra-assay variation ≤ 11%; inter-assay variation ≤ 10%), accuracy, and specificity tests according to international pharmacopoeial requirements. Except for one generic of vancomycin that had 25% more API (Py-intercept = 0.001), the pharmaceutical equivalence was demonstrated in 21 generics with undistinguishable slopes and intercepts (P > 0.66). Potency estimates were 99.8 to 100.5, 99.7 to 100.2 and 98.5 to 99.9% for generic products of amikacin, gentamicin and vancomycin, respectively.

Conclusion

The proposed method allows rapid, cost-saving, precise, and accurate determination of pharmaceutical equivalence of drugs in pharmaceutical dosage-form, and may be used as a technique for testing generic antibiotics prior to their approval for human use.

As things stand today, whether we like it or not, industry funding is on the upswing. The whole enterprise of medicine in booming, and it makes sense for industry to invest more and more of one's millions into it. The pharmaceutical industry has become the single largest direct funding agency of medical research in countries like Canada, the United Kingdom and the United States.

Since the goals of industry and academia differ, it seems that conflicts of interest are inevitable at times. The crucial decision is whether the public welfare agenda of academia, or the corporate research agenda of industry, should occupy center stage when they conflict.

There is enough evidence to show that funding by industry is very systematic, and results that are supportive of the safety and efficacy of sponsor's products alone get the funds. It is no surprise, therefore, that one finds very few negative drug trials reports published, and whatever are, are likely to be by rival companies to serve their commercial interests.

Renewed and continued funding by industry decides the future prospects of many academic researchers. At the same time there is now evidence that pharmaceutical companies attempt suppression of research findings, may be selective in publishing results, and may delay or stymie publication of unfavourable results. This is a major area of concern for all conscientious researchers and industry watchers.

Industry commonly decides which clinical research/trial gets done, not academia, much though the latter may wish to believe otherwise. It finds willing researchers to carry this out. This can be one area of concern. Another area of pressing concern is when industry decides to both design and control publication of research.

It makes sense for researchers to refuse to allow commercial interests to rule research reporting. Research having been reported, the commercial implications of such reporting is industry's concern. But, doctoring of findings to suit commerce is to be resisted at all costs. In this even pliant researchers need have no fear, for if they indeed publish what will work, the concerned sponsor will benefit in the long run. The only decision academia has to make is refuse to comply with predestined conclusions of sponsors for the ‘thirty pieces of silver’. Instead do genuine research and make sixty for themselves.

The useful rule of thumb is: Keep the critical antenna on, especially with regard to drug trials, and more especially their methodology, and study closely the conflict of interest disclosed, and if possible undisclosed, before you jump on the band wagon to herald the next great wonder drug.

There are three important lessons to be learnt by academia in all academia-industry relationships:

i)Lesson number one: incorporate the right to publish contrary findings in the research contract itself. Which means, it makes great sense for academia to concentrate on the language and contractual provisions of sponsored research, to read the fine print very closely, and protect their research interests in case of conflict.ii)Lesson number two: a number of lawsuits successfully brought up against industry recently reflect earnest attempts by patient welfare bodies and others to remedy the tilt. It will result in a newfound confidence in academia that augurs well for academia industry relationship in the long run. Hence the second lesson for academia: do not get browbeaten by threats of legal actioniii)Lesson number three: Academia should keep itself involved right from inception of the clinical trial through to ultimate publication. And this must be an integral part of the written contract.

The time to repeat cliches about the exciting future of the academia-industry connect is past. A concerted effort to lay a strong foundation of the relationship on practical ethical grounds has become mandatory.

The Pfizer Healthcare Informatics team conducted a series of guided interviews with 35 Pfizer senior leaders to elicit their understanding, desires, and expectations of how Electronic Health Records (EHR) might be used in the pharmaceutical industry today and/or in the future. The interviews yielded fourteen use case categories comprising 42 specific use cases. The highest priority use cases were “Drug Safety & Surveillance,” “Clinical Trial Recruitment,” and “Support Regulatory Approval.” Fifteen EHR companies were surveyed to assess their functionality against the specified use cases. Self-reported responses from the EHR companies were highest for “Virtual Phase IV Trials” and “Document Management for Clinical Trials.” This research identifies preliminary opportunities for EHR products to provide aggregate, blinded data to address the interests of the pharmaceutical industry. However, further collaboration between the stakeholders will be necessary to ensure the full realization of the opportunities for data re-use.

In vitro dissolution testing is an important tool used for development and approval of generic dosage forms. The objective of this article is to summarize how dissolution testing is used for the approval of safe and effective generic drug products in the United States (US). Dissolution testing is routinely used for stability and quality control purposes for both oral and non-oral dosage forms. The dissolution method should be developed using an appropriate validated method depending on the dosage form. There are several ways in which dissolution testing plays a pivotal role in regulatory decision-making. It may be used to waive in vivo bioequivalence (BE) study requirements, as BE documentation for Scale Up and Post Approval Changes (SUPAC), and to predict the potential for a modified-release (MR) drug product to dose-dump if co-administered with alcoholic beverages. Thus, in vitro dissolution testing plays a major role in FDA’s efforts to reduce the regulatory burden and unnecessary human studies in generic drug development without sacrificing the quality of the drug products.

ABSTRACT

Purpose

A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided.

Method

We conducted a survey of the BE submissions to abbreviated new drug applications (ANDAs) over years 2001 to 2008 to identify the most commonly occurring BE deficiencies.

Results

Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA’s Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided.

As the efficacy and science of psychopharmaceuticals has become increasingly uncertain, marketing of these drugs to both physicians and consumers continues to a central part of a multi-billion dollar per year industry in the United States. We explore how such drug marketing portrays idealized scientific relationships between psychopharmaceuticals and depression; how multiple stakeholders, including scientists, regulatory agencies, and patient advocacy groups, negotiate neurobiological explanations of mental illness; and how the placebo effect has become a critical issue in these debates, including the possible role of drug advertising to influence the placebo effect directly. We argue that if and how antidepressants “work” is not a straightforward objective question, but rather a larger social contest involving scientific debate, the political history of the pharmaceutical industry, cultural discourses surrounding the role of drugs in society, and the interpretive flexibility of personal experience.

Drug product specifications are a critical element of a good control strategy. Parenteral microsphere products are complex dosage forms, requiring careful development of test methods and acceptance criteria for the specifications. In particular, the in vitro release test method and acceptance criteria require rigorous scientific consideration and should be developed with an eye toward understanding the mechanisms of drug release. The final specifications need to ensure the safety, identity, strength, performance, and quality of the drug product at release and during storage through the end of its shelf-life. The specification limits are typically established based upon regulatory guidance, available data from the manufacturing process (process capability), from non-clinical, clinical, and stability studies.

Emerging nanotechnologies have, and will continue to have, a major impact on the pharmaceutical industry. Their influence on a drug's life cycle, inception to delivery, is rapidly expanding. As the industry moves more aggressively toward continuous manufacturing modes, utilizing Process Analytical Technology (PAT) and Process Intensification (PI) concepts, the critical role of transport phenomena becomes elucidated. The ability to transfer energy, mass, and momentum with directed purposeful outcomes is a worthwhile endeavor in establishing higher production rates more economically. Furthermore, the ability to obtain desired drug properties, such as size, habit, and morphology, through novel manufacturing strategies permits unique formulation control for optimum delivery methodologies. Bottom-up processing to obtain nano-sized crystals is an excellent example. Formulation and delivery are intimately coupled in improving bio-efficacy at reduced loading and/or better controlled release capabilities, minimizing side affects and providing improved therapeutic interventions. Innovative nanotechnology applications, such as simultaneous targeting, imaging and delivery to tumors, are now possible through use of novel chaperones. Other examples include nanoparticles attachment to T-cells, release from novel hydrogel implants, and functionalized encapsulants. Difficult tasks such as drug delivery to the brain via the blood brain barrier and/or the cerebrospinal fluid are now easier to accomplish.

Globalization of the pharmaceutical industry has led to a need to harmonize the regulatory requirements governing the marketing of medicinal products. To minimize the barriers impeding global drug product registration, the International Conference on the Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) was established in 1990. The ICH has developed a series of guidelines that reflect agreements reached by participating nations on aspects of the chemistry and clinical technical sections that will fulfill the regulatory requirements of these various jurisdications. Nevertheless, there continue to be points of divergent perspectives and barriers that can impede the use of foreign clinical data. Given the importance of these issues, the Regulatory Science (RS) section of the American Association of Pharmaceutical Scientists (AAPS), in conjunction with the Regulatory Affairs Professional Society (RAPS) and the Canadian Association of Professional Regulatory Affairs (CAPRA) cosponsored a public forum on this topic. This manuscript provides a summary of the speaker presentations and audience discussions regarding the design of clinical trials and the extrapolation of results from these trials to support international drug registration.

The American Association of Pharmaceutical Scientists (AAPS) National Biotechnology Conference Short Course “Translational Challenges in Developing Antibody-Drug Conjugates (ADCs),” held May 24, 2012 in San Diego, CA, was organized by members of the Pharmacokinetics, Pharmacodynamics and Drug Metabolism section of AAPS. Representatives from the pharmaceutical industry, regulatory authorities, and academia in the US and Europe attended this short course to discuss the translational challenges in ADC development and the importance of characterizing these molecules early in development to achieve therapeutic utility in patients. Other areas of discussion included selection of target antigens; characterization of absorption, distribution, metabolism, and excretion; assay development and hot topics like regulatory perspectives and the role of pharmacometrics in ADC development. MUC16-targeted ADCs were discussed to illustrate challenges in preclinical development; experiences with trastuzumab emtansine (T-DM1; Genentech) and the recently approved brentuximab vedotin (Adcetris®; Seattle Genetics) were presented in depth to demonstrate considerations in clinical development. The views expressed in this report are those of the participants and do not necessarily represent those of their affiliations.