Introducing FDA s White Paper: Challenge and Opportunity on the Critical Path to New Medical Products

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1 Asian Journal of Pharmacodynamics and Pharmacokinetics Paper ID Copyright by Hong Kong Medical Publisher Received September 8, 2007 ISSN ; 8(1): Accepted October 30, 2007 Introducing FDA s White Paper: Challenge and Opportunity on the Critical Path to New Medical Products Yi-Tong Liu 1,2, Guang-Ji Wang 1, and Chang-Xiao Liu 2 1 Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, , China 2 Tianjing State Key Laboratory of Pharmacodynamics and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin , China Abstract Key words On March 2004, Food and Drug Administration published the White Paper: Challenge and Opportunity on the Critical Path to New Medical Products. And then, Critical Path Opportunities Report (March 2006), Critical Path Opportunities List (March 2006), and Critical Path Opportunities for Generic Drugs (May, 2007) were published by FDA. This review paper introduced the related information to understand the challenge and opportunity on the Critical Path to new medical products. Challenge; opportunity; new medical product; critical path; dimension Introduction and background On March 2004, Food and Drug Administration (FDA) published the FDA s White Paper: Challenge and Opportunity on the Critical Path to New Medical Products. And then, Critical Path Opportunities Report (March 2006), Critical Path Opportunities List (March 2006), and Critical Path Opportunities for Generic Drugs (May, 2007) were published by FDA. Here, we introduce the related information to understand the challenge and opportunity on the Critical Path to new medical products. Today s revolution in biomedical science has raised new hope for the prevention, treatment, and cure of serious illnesses. However, there is growing concern that many of the new basic science discoveries made in recent years may not quickly yield more effective, more affordable and safer medical products for patients. This is because the current medical product development path is becoming increasingly challenging, inefficient, and costly. During the last several years, the number of new drugs and biologic applications submitted to FDA has declined significantly; the number of innovative medical device applications has also decreased. The mission of the U.S. Food and Drug Administration (FDA) is, in part, to protect the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices. The sequencing of the human genome four years ago raised widespread hope for a new era in the prevention and treatment of disease created by the ongoing investment in biomedical research (Fig 1). But that new era has not yet arrived. Instead, the year 2000 marked the start of a slowdown in new drug and biologics submissions to regulatory agencies worldwide (Fig 2). The submission of innovative medical device applications has also decreased recently. This means fewer new products can be approved and made available to patients. Current costs of bringing a new medicine to market, estimated by some to be as high as $0.8 to 1.7 billion, 5 is a major barrier to investment in innovative, higher risk drugs or in therapies for uncommon diseases or diseases that predominantly afflict the poor. Product development in areas crucial to public health goals, such as antibiotics, has slowed down significantly during the past decade. Recent data suggest that the investment required to launch a new drug has risen by 55 percent during the last five years (Fig 3). Pharmaceutical, 67

2 biotechnology, and medical device productivity appear to be declining at the same time that the costs of developing a small number of treatments are rising. The critical path The medical product development process is no longer able to keep pace with basic scientific innovation. Only a concerted effort to apply the new biomedical science to medical product development will succeed in modernizing the critical path. If biomedical science is to deliver on its promise, scientific creativity and effort must also focus on improving the medical product development process itself, with the explicit goal of robust development pathways that are efficient and predictable and result in products that are safe, effective, and available to patients. We must modernize the critical development path that leads from scientific discovery to the patient usage (Fig 4). Fig 4 shows an idealized critical path that encompasses the drug, biological product, and medical device development processes. An ideal product coming out of basic scientific research enters the evaluation process. In drug development the discovery process needs to select or create a molecule with desired biological activities. The critical path begins when candidate products are selected for development. Fig 3. Investment escalation per successful compound Source: windhover s in vivo: The business & medicine report, Eain Drug Economics Model, 2003 In response to the widening gap between basic biomedical knowledge and clinical application, governments and the academic community have undertaken a range of initiatives. After decades of investment in basic biomedical research, the focus is widening to include translational research multidisciplinary scientific efforts directed at "accelerating therapy development". FDA is taking the initiative to identify and prioritize (1) the most pressing development problems and (2) the areas that provide the greatest opportunities for rapid improvement of public health. This will be done for all three dimensions along the critical path safety assessment, evaluation of medical utility, and product industrialization. It is critical that we enlist all relevant stakeholders in this effort. We will work together to identify the most important challenges by creating a Critical Path Opportunity List. The three dimension in critical path research Fig year trends in biomedical research spending PAREXEL s Pharmaceutical R&D Statistical Sourcebook 2002/2003 Fig year trends in major drug and biological product submissions to FDA Developers must manage the interplay between each dimension from the earliest phases of development. For example, the first dimension ensuring product safety is crucial to consider when designing a drug molecule, choosing production cell lines or reference strains for biological production, or selecting biomaterials for an implanted medical device (Fig 5). The traditional tools used to assess product safety animal toxicology and outcomes from human studies have changed little over many decades and have largely not benefited from recent gains in scientific knowledge. The inability to better assess and predict product safety leads to failures during clinical development and, occasionally, after marketing. The second dimension, demonstrating the medical utility of a new product showing that it will actually benefit people is the source of innumerable failures later in product development. Better tools are needed to identify successful products and eliminate impending failures more efficiently and earlier in the development process. This will protect subjects, improve return on R&D investment, and bring needed treatments to patients sooner. 68

3 The final dimension on the critical path can be described as the industrialization process turning a laboratory concept into a consistent and well-characterized medical product that can be mass produced. The challenges involved in successful industrialization are complex, though highly underrated in the scientific community. Problems in physical design, characterization, manufacturing scale up and quality control routinely derail or delay development programs and keep needed treatments from patients. These problems are often rate-limiting for new technologies, which are frequently more complex than traditional products and lack standard assessment tools. Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filling/ Approval & Launch Preparation Market Application Approval Critical Path Fig 4. The critical path for medical product development Basic Research Prototype Design or Discovery Preclinical Development Clinical Development FDA Filling/ Approval & Launch Preparation Safety Material Selection Structure Activity Relationship In Vitro and Animal Testing Human and Animal Testing Safety Follow Up Dimensions Medical Utility In Vitro and Computer Model Evaluation In Vitro and Animal Models Human Efficacy Evaluation Industrialization Physical Design Characterization Small-Scale Production Manufacturing Scale-up Refined Specification Mass Production Fig 5. Working in three dimensions on the critical path The Critical Path Opportunities In the 2004 Critical Path Report, the FDA presented its diagnosis of the scientific challenges underlying the medical product pipeline problem. The Critical Path Opportunities List identifies targeted research that we believe, if pursued, will increase efficiency, predictability, and productivity in the development of new medical products. Each opportunity on the list represents a highly targeted research project intended to improve product development in the short- and mid-terms. 1 Better evaluation tools: developing new biomarkers and disease models 69

4 Medical product development involves a sequence of tests intended to progressively reduce uncertainty about a candidate product s performance. At the start of the Critical Path, developers form hypotheses about performance characteristics such as safety, biological or mechanical action, and biocompatibility. They then seek to evaluate and confirm these hypotheses using in vitro, animal, and human testing. Once uncertainty about benefits and risks of a product has been reduced to an acceptable level, the product may be approved for marketing if the benefits outweigh the risks. The great challenge in development lies in predicting a potential product's performance as early as possible with the greatest degree of certainty. Biomarkers are measurable characteristics that reflect physiological, pharmacological, or disease processes in animals or humans. Changes in biomarkers following treatment reflect the clinical response to the product. Techniques as disparate as imaging, serum or genetic assays, or psychological tests can yield biomarkers that are useful in product development. Biomarkers can reduce uncertainty by providing quantitative predictions about performance. The existence of predictive efficacy biomarkers in particular can revolutionize product development in a disease area. Many of the biomarkers used in medical product development today have been in use for many years, even decades. These longstanding biomarkers were empirically derived; they often lack predictive and explanatory power. New biomarker development has stalled. A large number of potential new biomarkers have been proposed, but the essential work are needed to evaluate their utility known as biomarker qualification has not been carried out. In the Critical Path List, we enumerate some opportunities to qualify new biomarkers that are particularly promising. The new -omic technologies hold great promise as a source of powerful biomarkers. Some in vitro diagnostic tests which detect specific genetic variations that affect an individual's response to treatment are ready for use. These assays can identify patients who are at high risk for serious toxicity from cancer therapies because the recommended doses are too high for them. Pharmacogenetic tests for drug metabolism status are only the first step in a new generation of diagnostics that could transform product development. Development of more predictive safety biomarkers for use in animal toxicology studies would improve the effectiveness of safety screening prior to introducing products into humans, enable better selection of initial human doses, and help target toxicity monitoring in early trials. Development of markers and diagnostics to identify individuals at high risk for serious drug side effects such as cardiac arrhythmias could dramatically improve medical product safety while simplifying product development. Biomarkers are crucial for individualizing, or personalizing, medical treatment. For example, markers can be used to create more precise classifications of disease to target or stratify therapy. Markers of drug metabolism can be used to individualize drug dosage, prevent predictable underdosing in more rapid metabolizers and serious side effects from overdosing in slow metabolizers. Biomarkers are also useful for predicting dose-response characteristics and for monitoring response during treatment. New imaging techniques hold vast potential for use as biomarkers for an array of purposes in product development measuring treatment efficacy, patient stratification, and improved diagnosis. Animal models of disease are additional important tools in the selection and refinement of candidate medical products. Frequently, candidate products need to succeed in animal models prior to moving into testing in humans. Currently, there are significant needs, but also significant opportunities, for developing tools that can more reliably and more efficiently determine the safety of a new medical product. Because safety issues are a significant cause of delay and failure during development, some have advocated simply lowering safety standards. This is not a preferable solution. For ethical human testing, there is wide agreement that reasonable assurance of safety must be achieved before clinical trials begin. Patients, prescribers, payers, and the public share the expectation that marketed medical products will have a well-understood safety profile and a positive benefit/risk analysis. Today's problems arise from the inability to confidently predict safety performance in a timely and efficient manner. Current tools do not only cumber some, they are also imprecise and thus leave considerable residual uncertainty. The degree of uncertainty inherent in current techniques can result in conservative standard setting. Applied critical path research provides the real opportunity for improving our ability to identify safety issues early and manage the remaining risks appropriately. Opportunity 1 Proteomic and toxicogenomic approaches may ultimately provide sensitive and predictive safety assessment techniques; however, their application to safety assessment is in early stages and needs to be expanded. Targeted research aimed at specific toxicity problems should be undertaken. Opportunity 2 As biomedical knowledge increases and bioinformatics capability likewise grows, there is hope that greater predictive power may be obtained from in silico (computer modeling) analyses such as predictive toxicology. Some believe that extensive use of in silico technologies could reduce the overall cost of drug development by as much as 50 percent. 70

5 Opportunity 3 There is an urgent need to develop tools to accurately assess the risk of new drugs causing heart rhythm abnormalities. For instance, there are ongoing international efforts to develop, test, and validate non-clinical models that may be useful in predicting human risk. In addition, the clinical risks associated with a small degree of QTc interval prolongation need to be fully defined. 2 Streamlining clinical trials Clinical testing is the most expensive aspect of medical product development, often requiring the enrollment of large numbers of people and the collection of massive amounts of data. Stakeholders point to the costs of clinical trials as a barrier to innovation. Today, most clinical trials investigating product effectiveness compare the overall response of the treated population to the untreated population (i.e., the control population). These trials do not seek to understand which individuals respond to an intervention or why they respond. Again, this is primarily due to a lack of tools to perform such evaluations. However, as a new generation of biomarkers emerges capable of distinguishing among individuals with different variations of a disease or rapidly signaling status changes in organ systems or disease processes trial designs will need to evolve to make effective use of this information. As new designs and analytical principles of innovative trials are implemented, effort must also be invested in developing trials and outcome measures tailored to specific diseases. Because each disease has a particular time course, constellation of symptoms, outcome measures tailored to specific diseases. Because each disease has a particular time course, constellation of symptoms, need for monitoring, and set of therapeutic alternatives, disease specific trial designs that incorporate appropriate safety monitoring and standardized disease-specific efficacy measures are highly desirable. Standardized designs and metrics will (1) reduce the need to reinvent the wheel for each new trial, (2) assist clinical investigators and study personnel (who often conduct multiple trials in a given disease), (3) help reduce variation and error, and (4) facilitate cross-study analyses. Standardizing and automating clinical trial procedures, conduct, and data processing to the greatest extent possible could dramatically improve the efficiency of clinical development. 3 Harnessing bioinformatics The goal of the Critical Path Initiative is to take advantage of new scientific tools to meet existing challenges to medical product development. In no field is the opportunity greater than bioinformatics the application of mathematics, statistics, and computational, quantitative analysis to biological data. With recent advances in the bioinformation sciences, it should be possible to analyze and mine large sets of biological data about patients, with the goals of creating robust, quantitative computer models of normal human physiology, of the natural history of certain diseases, and of the course of a disease as affected by standard treatments. The concept of model-based product development can also be applied to drug, device, and biological product safety. It should be possible to exploit a variety of existing toxicology and adverse events data to facilitate more accurate predictions of product safety and more rapid postmarket identification of safety issues that could not be identified during product development. By making better use of data to improve knowledge about key aspects of product development, such as exposure-response relationships and longterm performance of devices, and by supporting innovative trial designs, a model-based development program could reduce uncertainty about dose selection, device design, and other key safety and efficacy issues. The findings from in silico testing (computer simulation, rather than laboratory or animal testing) could reduce the risk and cost of human testing by helping product sponsors make more informed decisions on how to proceed with product testing and when to remove a product from further development. Predictions of the safety and efficacy performance of medical product candidates would be more accurate, thus increasing the chances of product success. Model-based product development is particularly attractive to spur innovation in areas where human testing raises special concerns, such as with pediatric products or products to treat pregnant women. 4 Moving manufacturing into the 21 st century The characterization, manufacture, testing, and quality management of medical products are components of the third dimension of the Critical Path industrialization. Industrialization means developing the capacity to reliably manufacture a high-quality product at commercial scale. Combination products can present significant new challenges in characterization, manufacturing, and quality assessment. Problems in industrialization are frequent hurdles along the Critical Path, delaying trials, limiting access to products, and sometimes completely blocking development. In addition, manufacturing problems are a hidden public health challenge. Manufacturing problems sometimes occur when scale up to mass production which is attempted after product approval. In the post-market setting, poor product design, inadequate characterization 71

6 and testing, or poor manufacturing process design can result in problems with product performance or malfunctions. These problems can cause patient injury, regulatory action, recalls, or lack of product availability. In many cases, manufacturers lack the scientific tools to adequately identify and characterize critical product attributes; design well-controlled manufacturing processes, using modern process control technologies; or tightly manage product quality during production. A publicly accessible database of the biocompatibility profile of materials used in the design and manufacture of implanted medical devices would facilitate continuous improvement in design of these products. Novel dosage forms include patches, liposomes, topicals, and nasal and pulmonary inhalers. Such products are developed to target delivery of drugs, improve compliance and ease use for patients, and deliver drugs that are difficult to formulate. It can be difficult to assess the quality of a manufactured product. Nanotechnology holds huge promise for the design and manufacture of many types of novel medical products from devices to therapeutics to combination products. There remain, however, a number of questions about the behavior of nanoparticles and the potential effects of products containing nanoparticles once they are introduced into complex human physiology. The physical and chemical characteristics of different nanomaterials must be understood, and the new test methods, characterization protocols, and standards are needed to study. 5. Developing products to address urgent public health needs New scientific technologies hold the potential for developing rapid, point-of-care tests for pathogen identification. These technologies could also improve the speed and accuracy of resistance testing. Use of rapid diagnostic tests (either a single test or a panel of tests) could greatly improve the efficiency of clinical trials for infectious diseases. Research to adapt these new technologies for rapid pathogen identification would also facilitate the development of novel screening tests for biological products. Of particular interest in screening donated blood and tissue are technologies that can perform rapid analysis for multiple organisms, on smaller quantities of blood and tissues. In a public health emergency involving infectious agents, such screening tools would be a key bulwark against the risk of inadvertent or deliberate transmission of infection to recipients of donated blood and tissues. Today, limited animal models exist for determining biological activity of anthrax lethal toxin, and those that are available have questionable relevance to the mechanism of action of this virulence factor in humans. New animal models more appropriate to the human condition also are needed. Before a product is tested in animals, it is tested in living cells in the laboratory. A major hurdle facing the development and evaluation of vaccines for emerging viral diseases is the lack of a tissue culture assay that quantitatively measures and reliably predicts the protective immune response to candidate vaccines. Similarly, better cell culture systems to study the hepatitis C virus are needed to improve progress toward a hepatitis C vaccine. 6. Specific at-risk populations pediatrics Pediatric product testing often begins with extrapolating safety and efficacy data from adult experience to determine the dose and administration schedule to be tested. During the past several years, a substantial number of pediatric trials have been conducted using this approach. If the data from those trials could be compiled into a database for quantitative analysis, sponsors could exploit past experience to assess the accuracy of different methods of extrapolation and reveal the most effective methods. Analysis of such a database could reveal best practices for other aspects of pediatric trial designs. As a result, fewer children would be exposed to unnecessary or suboptimal clinical studies. It is likely that differences in drug metabolism among adolescents affect their responses to antidepressant drugs. With improved knowledge, sponsors could tailor drug doses being tested to the study participants according to their drug metabolic genotype. The hard work of identifying specific genetic polymorphisms and signals in children and teens that predict a heightened risk for adverse events or non-response to treatment is in the early stages. Many scientists and clinicians believe that depression is not a single disease, but a collection of several related but biologically distinguishable conditions. Better clinical definitions of depressive subtypes, along with better tools for classifying individuals, should help in achieving the goal of developing treatments targeted to the adolescent s particular syndrome. Even if a vaccine existed, several weeks are required post-vaccination to develop a protective response, leaving infants at risk during that time. One approach to this public heath issue would be safe and effective maternal vaccination, in which the pregnant woman develops a protective antibody response that is transferred to the fetus through the placenta or to the infant through breast-feeding. Development of animal models to evaluate the safety outcomes of maternal vaccination on infants could unlock innovation and eventually lead to products that reduce illness and death due to infant infections. Development of an artificial pancreas for 72

7 children and adults with diabetes could be accelerated by creating new clinical protocols and improved outcome measures for evaluating the performance of continuous glucose sensors and a closed loop artificial pancreas. This work could also revolutionize diabetes care and management. Critical Path Opportunities for Generic Drugs FDA s recent critical path initiative has focused on the challenges involved in the development of new innovator drugs, devices, and biologics. Some of the focus areas identified, such as manufacturing science, apply equally to the development of generic drugs. However, there are scientific challenges unique to the development of generic drugs. The purpose of this document is to bring these challenges to the attention of interested parties and identify opportunities for collaborative solutions. The development of new drugs and the expense of clinical trials to demonstrate the safety and efficacy of innovative drugs are rewarded through granting of a period of marketing exclusivity that shields the product from competition. Generic drug applicants must demonstrate that their products are pharmaceutically equivalent and bioequivalent to the reference product. Pharmaceutically equivalent products have the same active ingredient (s) in the same strength in the same dosage form. For many drug products, demonstrating pharmaceutical equivalence and bioequivalence is straightforward. Analytical chemistry can identify and quantitate the active ingredient. Comparison of pharmacokinetic parameters is used to evaluate bioequivalence. Bioequivalence based on plasma drug concentration has been identified as the most commonly used and successful biomarker of safety and efficacy. Complex drug products and locally acting drugs, scientific challenges have presented barriers to the development and approval of generic drugs. Critical Path Opportunity Areas FDA has identified four areas of opportunity where collaborative activities could advance public health by more efficient development of high quality generic products: (1) Improve the science underlying quality by design for the development and manufacture of generic drug products; (2) Improve the efficiency of current methods for assessment of bioequivalence of systemically acting drugs including products that use complex and novel drug delivery technologies; (3) Develop methods for the assessment of bioequivalence of locally acting drugs such as topical and inhalation products; and (4) Develop methods for characterizing complex drug substances and products. Progress in these areas will accelerate approval of generic drug products. More importantly, it will expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. Methods for equivalence based on sound science build the confidence of health care providers, patients, and the public that generic products are equivalent to innovator products. Model Development and In Vitro-In Vivo Correlations Current formulation development strategies are mainly based on trial and error, in-house databases, and/or formulator experience. A methodical and mechanistic approach to formulation development can be achieved through modeling and simulation. Absorption models could be used to estimate (or in some cases predict) the relation between an in vivo dissolution or release rate and the pharmacokinetic parameters that are used to evaluate bioequivalence and would offer an efficient tool to evaluate different formulations and select the optimal formulation. Critical path opportunities include: (1) Better Absorption Models: Mechanistic based models are beginning to predict this critical step, but validation would lead to improvement. Physiologically based models that replace the traditional well-mixed compartment model with known physiological and chemical processes such as blood flow rate, tissue volumes, partition coefficients, and solubilities are also under development. Modeling and simulation can aid scientists in determining the drug release profile needed to provide bioequivalence to the reference product. (2) Development of In Vitro-In Vivo Correlations: The most common quality assurance test during product development and process changes is dissolution, but the correlation of dissolution testing with in vivo performance varies from product to product. The large amount of available dissolution test and pharmacokinetic data could be used to develop and test models capable of predicting the relationships between dissolution and bioavailability/ bioequivalence. Formulation and Manufacture of Generic Drugs A generic product can be formulated to have a release mechanism that is different from the reference product as long as the generic product is pharmaceutically equivalent and bioequivalent to the reference product. QbD can be used by generic applicants to ensure that the new release mechanism produces a bioequivalent product. ANDA exhibit batches used for bioequivalence studies 73

8 are usually manufactured on 1/10 of the commercial scale. Only after approval of the application does the applicant scale up the process to commercial scale. Under QbD, identification and understanding of the critical process parameters in a manufacturing process should reduce the risk of failure during scale up. Critical path opportunities include: (1) Formulation Expert Systems: Formulation development can pose a challenge because of the wide range of excipients available. Methods that can efficiently screen formulation excipients and identify the optimal formulation can eliminate error strategies and make formulation development more efficient. (2) In Vitro Tests to Assess Formulation: Safety concerns associated with alcohol-induced dose dumping have led to the removal of one new drug product from the market. Establishing an in vitro test(s) that can identify formulation failure and enable comparison of the likelihood of dose dumping would aid in the development of safe and effective modified release generic products. (3) Development of Process Simulation Tools: Currently, manufacturing process selection and development are usually based on engineers knowledge and experience. Process simulation tools can help identify optimal and efficient processes and facilitate process scale up from exhibit batches to commercial manufacturing. Bioequivalence Methods for Systemically Acting Drugs For systemically acting drugs, a critical path goal is to increase the efficiency of a process that is already providing safe and effective generic drugs to the public. As discussed below, expanding the use of biowaivers in appropriate cases, improving dissolution methods, and improving the methods of assessing bioequivalence are three ways to accomplish this goal. Expanding Biopharmaceutics Classification System Biowaivers: The Biopharmaceutics Classification System (BCS) is a drug development tool that can be used to help applicants justify waivers of in vivo bioequivalence studies for highly soluble and highly permeable BCS Class I drugs dosed in rapidly dissolving immediate release products. There may be opportunities to expand biowaivers to poorly soluble and highly permeable BCS Class II drugs and highly soluble and poorly permeable BCS Class III drugs. (1) Biowaivers for BCS Class II Drugs: Many drugs are classified as BCS class II because they are highly soluble at low ph, but fail to meet the BCS limit at higher ph. Most of these drugs are rapidly absorbed in vivo before they are ever exposed to a ph at which they have low solubility. (2) Biowaivers for BCS Class III Drugs: For rapidly dissolving dosage forms of BCS Class III drugs (high solubility, low permeability), intestinal permeability is considered to be the major rate-controlling step in oral drug absorption. Absorption kinetics of BCS Class III drugs from the gastrointestinal tract could be controlled by biopharmaceutic and physiologic properties of the drug substance, rather than formulation factors, provided excipients do not affect drug permeability. Development of Biorelevant Dissolution: Development of a system of biorelevant dissolution methods would provide formulation scientists with reliable performance standards that are relevant to in vivo release and allow regulators to compare meaningful dissolution performance across multiple products. Fed Bioequivalence Studies Current FDA bioequivalence guidance recommends both fed and fasted bioequivalence studies for most products, even products whose labels say there is no food effect on absorption. The motivation for this fed study is to ensure that the generic product also has no food effect. For rapidly dissolving immediate release BCS class I drugs, this fed study can be waived. Critical path opportunities include: (1) Food and Drug Interactions: Through a better understanding of the mechanism of drug and food interactions, it may be possible to identify other classes of products for which a fed study is not recommended to demonstrate that a generic product will be bioequivalent to the reference product under fed conditions. (2) Bioequivalence for Novel Delivery Technologies Generic products that utilize delivery technologies that go beyond traditional immediate release orally administered tablets and capsules continue to be developed. For some novel delivery technologies, additional work is needed to optimize assessment of bioequivalence. Critical path opportunities include: (i) Bioequivalence for Pharmacokinetic Profiles with Multiple Peaks: Single doses of novel modified release formulations (such as subcutaneous depot formulations in development) can produce multiple peaks in the plasma concentration-time profile. FDA currently uses Cmax and AUC to assess bioequivalence. Exploration of other approaches to show bioequivalence would be valuable. (ii) Transdermal Products: Exploration of new clinical study designs and criteria for evaluation of skin irritation, sensitization potential, and adhesive performance in comparison to the reference product would be useful. Bioequivalence for Highly Variable Drugs Drugs and drug products that exhibit high within-subject variability in Cmax and AUC present a challenge for the design of bioequivalence studies. For example, a drug with a variability of 50% would require a study in

9 subjects to demonstrate equivalence, if the test and reference products were identical. By necessity, drugs that have high within-subject variabilities have a wide therapeutic index; otherwise, they could not be both safe and effective. Thus, under the FDA s current approach, products with wide therapeutic indices require studies that are much larger than studies for drugs with narrow therapeutic indices. Development of study designs that would allow demonstration of bioequivalence with a smaller number of subjects is needed. Bioequivalence Methods for Locally Acting and Targeted Delivery Drugs The assessment of bioequivalence for locally acting and targeted delivery products has presented scientific challenges to the approval of generic products. Currently, it may be difficult to demonstrate the bioequivalence of locally acting drug products when drug concentration profiles in the plasma or in vitro dissolution are not appropriate surrogates of pharmacological activity. The current method of comparative clinical trials can be prohibitively expensive and is the least efficient way to detect differences in product performance. The critical path opportunities of new methods and approaches include imaging, in vivo sampling, and new clinical trial designs and their application to specific product categories. Bioequivalence of Inhalation Products Currently, bioequivalence for oral inhalation products is demonstrated through in vitro testing for device performance, pharmacodynamic studies of lung function for local delivery, and pharmacokinetic studies for systemic exposure. Due to the difficulty in demonstrating bioequivalence by passing all of these tests, as well as other factors, FDA receives few applications for these kinds of products, even though many of the older MDI products are on the market without patent or exclusivity protection. FDA has identified many of the scientific challenges that need to be addressed to develop generic versions of these products. Critical path opportunities include (1) Molecular Level Imaging: Imaging techniques that can quantify the amount of drug at the site of action can be used to validate new in vitro tests or new biomarkers. Imaging of particle deposition for inhalation aerosols is a direct measure of local delivery and could establish the correlation of in vitro tests with in vivo local delivery; (2) Novel Pharmacodynamic Study Designs: Many asthma drugs have a very shallow dose-response curve and exhibit high within- and between-subject variability, requiring the use of a very large number of subjects in a pharmacodynamic equivalence test. Novel pharmacodynamic study designs that enable using a forced expiratory volume in 1 second (FEV1) endpoint in a crossover study would allow bioequivalence studies to be conducted using a much smaller number of subjects; (3) Study Design for Combination Products: Several inhalation products contain two active ingredients, an inhaled corticosteroid and a long-acting beta-agonist. To demonstrate bioequivalence, local delivery of both components must be equivalent. However, the FEV1 endpoint is initially affected by the beta-agonist and affected by both components at later times. An exhaled nitric oxide endpoint is affected only by the inhaled corticosteroid. Combining these endpoints could potentially allow bioequivalence determinations for both components; (4) Study Designs for COPD: Chronic obstructive pulmonary disease includes chronic bronchitis, emphysema, and chronic asthma, which have different degrees of reversibility to bronchodilator therapy. Reversibility is necessary to obtain a dose-response relationship. Unresolved issues in the design of a bioequivalence study are identification of a subgroup of COPD responders, improved understanding of the dose-response characteristics of anticholinergic bronchodilators, selection of doses for the study, and type of systemic exposure study for poorly absorbed drugs. An additional issue related to the prior bullet point is the design of studies that can establish the bioequivalence of each component in combination inhalers containing both anticholinergic and beta-agonist drugs; (5) Evaluation of Differences in Formulation Composition: In the past, FDA has requested applicants of ANDAs for nasal and inhalation products to formulate products that are qualitatively and quantitatively the same as the reference product. The acceptability of qualitatively and quantitatively differences for inhalation products should be explored. Scientific issues involved include the impact of chemical changes in the emitted aerosol, alteration of in vitro drug delivery due to changes in excipients, impact of formulation changes on local site (lung) safety, and whether changes in composition of liquid formulations modify the quality and quantity of leachable substances over the product s shelf life; and (6) Modeling and Simulation of Dry Powder Inhaler Product Performance and Drug Delivery: Identification of key formulation and device performance variables would aid FDA and applicants in establishing appropriate equivalence limits and quality specifications. Bioequivalence of Nasal Sprays In contrast to solution nasal sprays, for which in vitro tests are used to demonstrate bioequivalence, demonstrating 75

10 bioequivalence of suspension nasal sprays can include in vitro tests that characterize the equivalence of the device via measurements of droplet size distribution, plume geometry, and spray pattern; clinical equivalence studies; and pharmacokinetic studies to demonstrate equivalence of systemic exposure. Critical path opportunities include (1) Computational Modeling of Drug Delivery from Nasal Sprays: Could allow determinations of limits on in vitro device comparisons that are directly related to drug delivery and (2) Direct Measure of Particle Size Equivalence: If the drug particle size distribution of test and reference products can be demonstrated to be equivalent, then nasal spray suspensions could be treated like nasal spray solutions. The critical path opportunity is to develop methods to measure drug particle size in a suspension product with sufficient accuracy and precision so that in vivo studies can be waived. Bioequivalence of Topical Dermatological Products There are a variety of bioequivalence approaches that are or can be used for topical dermatological products. For topical solutions, bioequivalence is self-evident when the components of the product are qualitatively and quantitatively the same. For topical corticosteroids, pharmacodynamic skin blanching studies are recommended to demonstrate bioequivalence. For most other topical products, lengthy and costly clinical studies are recommended to establish bioequivalence because no alternative methods have been developed. Based on the analysis of the mechanisms for topical drug delivery, it may be possible to identify a limited number of key factors that determine product performance and to employ this understanding in the development of rational bioequivalence standards that are much more efficient. Critical path opportunities include: (1) Design of Bioequivalence Trials with Clinical Endpoints: New approaches to design clinical trials with the goal of more efficiently demonstrating equivalence could be investigated. Sometimes, pharmacokinetic methods can't be used to assess generics for approval, and we have to use trials with clinical endpoints or pharmacodynamics measures. In such cases, there is interest in better understanding when non-inferiority trial designs can be used. (2) In Vitro Characterization of Topical Dermatological Products: This includes rheological test methods and diffusion cells. These tests may be sufficient to demonstrate bioequivalence of products that have identical amounts of both active and inactive ingredients. (3) Local Delivery of Topical Dermatological Products: During formulation development and regulatory evaluation there is a need for new in vivo tools that can demonstrate whether changes in formulation will affect local delivery. FDA has identified four potential technologies to investigate (i) Pharmacokinetic studies: For many topical dermatological products, the amount of drug reaching the systemic circulation can be detected and compared. However, its relationship to local delivery is still unknown; (ii) Skin Stripping: Removes the top layers of the skin for assay of drug concentration; (iii) Microdialysis: Inserts a small semipermeable capillary tube into the dermis about 1000 mm under the skin. The capillary tube is permeable to the drug; therefore, as perfusion fluid flows through the capillary, it takes up drug from the extracellular fluid of the tissue; and (iv) Near Infrared Spectroscopy: Detects a unique signal that indicates the concentration of a particular drug and offers the possibility of a noninvasive assay of drug delivery to the skin. Bioequivalence of Gastrointestinal Acting Products Another category of locally acting products is the one that treats gastrointestinal conditions through local action as opposed to systemic exposure. FDA has recommended a wide variety of bioequivalence tests for these products, including an in vitro binding assay, in vitro dissolution studies, pharmacokinetic studies, and clinical equivalence studies. Critical path opportunities include (1) Biowaivers for Low Solubility Drugs: Based on the BCS, FDA has granted biowaivers for immediate release high solubility drugs that act locally in the GI tract. Further work can explore extension of this waiver to low solubility drugs; (2) In Vivo Drug Release for GI Acting Products: Direct comparison of in vivo drug release could be used to validate dissolution tests as a bioequivalence method for modified release products; and (3) Establishment of Biomarkers for Local Delivery to the GI Tract: For locally acting drugs that are absorbed and can be detected in plasma, the rate of absorption could be related to the local concentrations in the GI tract. Thus, it may be possible to establish a relationship between PK measurements and concentration at the site of action. Research to evaluate this connection for use as a bioequivalence test could involve constructing fast, medium, and slow release formulations and radiolabeling the drug. Imaging and PK studies could establish the correlation between the drug delivered to the site of action and the measured plasma concentration. Bioequivalence of Liposome Products Liposomes encapsulate drugs in spherical phospholipid vesicles that passively target drugs to specific tissues, especially cancer tumors. Critical path 76

11 opportunities in this area include: Bioequivalence Methods for Liposome-based Formulations: Because liposome products target specific tissues, the plasma concentration may not be related to the concentration of drugs at these specific tissues, and work is needed on novel bioequivalence methods to determine if two liposomes with the same composition but produced by different manufacturers have the same therapeutic profile. Complex Drug Substances and Products An ANDA must contain information to show that a proposed generic drug product contains the same active ingredient as the reference listed drug. For small molecules produced by chemical synthesis, this demonstration is usually straightforward. However, there is a diverse range of products for which characterization is such a challenge that it is very difficult to produce a generic version. Natural Source Drugs Products derived from natural sources may contain a large number of molecular species hat may contribute to the therapeutic activity and thus pose significant challenges for current analytical methods. Critical path opportunities include (1) Improved Analytical Methods for Identity: Better analytical methods would allow more precise characterization of the components of the reference product. Without a reliable array of analytical characterization tools, development of a generic product may be difficult and (2) Statistical Methods for Profile Comparisons: Many complex drug substances contain multiple molecular species and characterization of these materials is performed by evaluation of a spectrum with multiple peaks or a continuous distribution (such as a molecular weight distribution). Appropriate statistical tools are needed to allow comparisons of profiles from test and reference products in a way that accounts for the intrinsic variability of the reference product. References 1. FDA. Challenge and Opportunity on the Critical Path to New Medicinal Products (March 2004), 2. FDA. Critical Path Opportunities Report (March 2006), criticalpath/ reports/opp_ report.pdf. 3. FDA, Critical Path Opportunities List (March 2006), criticalpath/reports/opp_list.pdf. 4. FDA. Critical Path Opportunities for Generic Drugs (May, 2007), criticalpath/reports/ opp_generic drugs.pdf. 77