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Critical Path Opportunities for Generic Drugs
Office of Generic Drugs
Office of Pharmaceutical Science
Center for Drug Evaluation and Research
May 1, 2007

Table of Contents

1   Introduction
2   Generic Drug Development Process
3   Research Collaborations
4   Critical Path Opportunity Areas
4.1  Quality by Design
4.1.1  Model Development and In Vitro-In Vivo Correlations
4.1.2  Formulation and Manufacture of Generic Drugs
4.2  Bioequivalence Methods for Systemically Acting Drugs
4.2.1  Expanding Biopharmaceutics Classification System Biowaivers
4.2.2  Fed Bioequivalence Studies
4.2.3  Bioequivalence for Novel Delivery Technologies
4.2.4  Bioequivalence for Highly Variable Drugs
4.3  Bioequivalence Methods for Locally Acting and Targeted Delivery Drugs
4.3.1  Bioequivalence of Inhalation Products
4.3.2  Bioequivalence of Nasal Sprays
4.3.3  Bioequivalence of Topical Dermatological Products
4.3.4  Bioequivalence of Gastrointestinal Acting Products
4.3.5  Bioequivalence of Liposome Products
4.4  Characterization of Complex Drug Substances and Products
4.4.1  Natural Source Drugs
References

1. Introduction

FDA’s recent critical path initiative¹,²,³ 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.

2. Generic Drug Development Process

The development of new drugs and the expense of clinical trials to demonstrate the safety and efficacy of innovative drugs is rewarded through granting of a period of marketing exclusivity that shields the product from competition. In anticipation of the expiration of marketing exclusivity and applicable patent protections, potential generic manufacturers begin the scientific and technical process of generic drug development. To receive approval, 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.

Bioequivalent products show no significant difference in the rate and extent of absorption of the active ingredient at the site of action.⁴ 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.⁵

When common approaches to the assessment of bioequivalence and pharmaceutical equivalence are not applicable, as is the case for complex drug products and locally acting drugs, scientific challenges have presented barriers to the development and approval of generic drugs. Examples of these challenges where these challenges have limited development include topical and inhaled drug products. This report identifies classes of products for which the development of equivalent products has been difficult historically, and presents as critical path opportunities, the scientific issues that are the cause of these difficulties.

3. Research Collaborations

The goal of this report is to bring the critical path challenges related to generic drugs to the attention of interested parties and to stimulate additional discussion and collaboration about the science needed to meet these challenges, with a goal of facilitating generic product development.
Examples of potential collaborators include:

• The Office of Generic Drugs in CDER
• FDA laboratories, including the Office of Testing and Research in CDER
• Individual firms developing generic drug products
• GPhA (Generic Pharmaceutical Association)
• NIH (National Institutes of Health)
• NSF (National Science Foundation)
• NIST (National Institute of Standards and Technology)

4. 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:

• Improve the science underlying quality by design for the development and manufacture of generic drug products
• Improve the efficiency of current methods for assessment of bioequivalence of systemically acting drugs including products that use complex and novel drug delivery technologies
• Develop methods for the assessment of bioequivalence of locally acting drugs such as topical and inhalation products
• 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.

4.1 Quality by Design

Under the current development and manufacturing paradigm, product quality and performance are predominantly ascertained by endproduct testing. Under the Quality by Design (QbD) paradigm, quality is built into the final product by understanding and controlling formulation and manufacturing variables: testing is used to confirm the quality of the product. Consumers will receive a high quality product while manufacturers may have the ability to improve their process through manufacturing changes.⁶ Although the FDA is encouraging the implementation of QbD for all pharmaceutical products, there are unique issues in the application of QbD to generic products. To use QbD to develop a product that is bioequivalent to a reference product, a generic applicant must understand attributes of the formulation and manufacturing process that have the potential to change the bioavailability of a particular active ingredient.

4.1.1 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:

• 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.
• Development of In Vitro-In Vivo Correlations (IVIVC): 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.

4.1.2 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 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:

• 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 trial and error strategies and make formulation development more efficient.
• In Vitro Test(s) 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.  
• 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.

4.2 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.

4.2.1 Expanding Biopharmaceutics Classification System Biowaivers

The Biopharmaceutics Classification System (BCS)⁷ 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.

• 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.
• 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 (GI) tract could be controlled by biopharmaceutic and physiologic properties of the drug substance, rather than formulation factors, provided excipients do not affect drug permeability (or drug intestinal residence time).
• 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.

4.2.2 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:

• 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.

4.2.3 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:      

• 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.
• 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.

4.2.4 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 (BE) studies. For example, a drug with a variability of 50% would require a study in 100 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.
Critical path opportunities include:     

• Bioequivalence Study Designs: Development of study designs that would allow demonstration of bioequivalence with a smaller number of subjects is needed.

4.3 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 (as well as being relatively insensitive). In this section, we identify as critical path opportunities new methods and approaches including imaging, in vivo sampling, and new clinical trial designs and their application to specific product categories.

4.3.1 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:

• 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.
• 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.
• 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 (eNO) endpoint is affected only by the inhaled corticosteroid. Combining these endpoints could potentially allow bioequivalence determinations for both components.
• 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.
• 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 (Q1) and quantitatively (Q2) the same as the reference product. The acceptability of Q1 and Q2 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.
• 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.

4.3.2 Bioequivalence of Nasal Sprays

In contrast to solution nasal sprays, for which in vitro tests are used to demonstrate bioequivalence,⁸ demonstrating 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:

• 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.
• 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 biostudies can be waived.

4.3.3 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:

• 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.
• 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.
• 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:
• 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.
• Skin Stripping: Removes the top layers of the skin for assay of drug concentration.
• 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.
• 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.

4.3.4 Bioequivalence of Gastrointestinal Acting Products

Another category of locally acting products is one that treats gastrointestinal (GI) 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:

• 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.
• In Vivo Drug Release for GI Acting Products: Direct comparison of in vivo drug release (perfusion, tissue sampling, or imaging) could be used to validate dissolution tests as a bioequivalence method for modified release products.
• 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 (both enteric coated and slow release pellets) 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.

4.3.5 Bioequivalence of Liposome Products

Liposomes encapsulate drugs in spherical phospholipid vesicles that passively target drugs to specific tissues, especially cancer tumors. Critical path 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 (e.g., by assessing how they deliver drug to relevant tissues).

4.4 Characterization of 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.

4.4.1 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:

• 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.
• 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

¹FDA, Challenge and Opportunity on the Critical Path to New Medicinal Products (March 2004), http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf.

² FDA, Critical Path Opportunities Report (March 2006), http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_report.pdf.

³ FDA, Critical Path Opportunities List (March 2006), http://www.fda.gov/oc/initiatives/criticalpath/reports/opp_list.pdf.

⁴ Center for Drug Evaluation and Research, Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book), 26th ed. (2006), http://www.fda.gov/cder/orange/obannual.pdf.

⁵ J. Woodcock, Biomarkers: Physiological & laboratory markers of drug effect, FDA (2006), http://clinicalcenter.nih.gov/researchers/training/principles/ppt/Physiological_Laboratory_Markers_of_Drug_Effect_2005-2006.ppt.

⁶ J. Woodcock, The concept of pharmaceutical quality, American Pharmaceutical Review p. 106 (November/December 2004).

⁷ Guidance for Industry:Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System (August 2000), http://www.fda.gov/cder/guidance/3618fnl.pdf.

⁸ Draft Guidance for Industry Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April 2003), http://www.fda.gov/cder/guidance/5383DFT.pdf.

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