Per FDA Commissioner Scott Gottlieb:
Complex drugs comprise high cost medicines like metered dose inhalers used to treat asthma, as well as some costly injectable drugs. These medicines generally have at least one feature that makes them harder to “genericize” under our traditional approaches. As a consequence, these drugs can face less competition. In some cases, costly, branded drugs that are complex drugs have lost their exclusivity, but are subject to no generic competition.
When considering the scope of complex drugs, people often first think of drug products where the active ingredient itself is complex. Glatiramer acetate injection, a drug used in the treatment of multiple sclerosis, is a good example. However, the terms “complex drug product” and “complex generic drug” are used to refer to a much larger and diverse group of drug products. In addition to drug products with complex active ingredients, or sites of action, complex drug products also include complex drug-device combination products.
Together, this diverse collection of drug products has one or more elements that are more complex than an average drug product. This complexity, in turn, means that the scientific and regulatory pathways for approval of generic versions of these drug products are not as well traveled by generic drug developers. In some cases, use of another established regulatory pathway may be appropriate to streamline development.
Bioequivalence for complex generic drugs can be challenging with complex drug products that can’t be easily measured in the blood, or when the drug’s therapeutic effect is delivered locally to a particular organ, rather than systemically, through the bloodstream. In other instances, showing active ingredient sameness can be challenging when the drug product contains an active mixture of components and not a single active molecule.
We recognize these problems and are taking a number of new steps to support the development of high quality ANDAs for complex generic drugs.
First, FDA is issuing a draft guidance to assist ANDA applicants and prospective ANDA applicants in creating and submitting pre-ANDA meeting requests, including meeting package materials, so FDA can give better advice to sponsors looking to develop complex generic drugs.
The guidance provides information on requesting and conducting product development meetings, pre-submission meetings, and mid-review cycle meetings with FDA. These meetings will allow for enhanced communication between generic drug applicants and FDA early in the generic drug development process, allowing for more efficient generic drug development, review, and approval pathways. We’ve found from analyzing our new drug program, that early and better meetings between FDA and sponsors can improve development timelines. We want to bring these same types of opportunities to developers of complex generics.
Second, we’re issuing a draft guidance to help applicants determine when submission of ANDAs for certain complex products, known as peptides, would be appropriate. Peptides are compounds made up of 40 or fewer amino acids, the building blocks of proteins. There are a number of branded medicines that are peptides, where exclusivity has lapsed, but these drugs face little or no competition. This new guidance applies to ANDAs for certain specific synthetic peptides, namely, glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, that reference brand-name versions of these peptides manufactured using recombinant DNA technology.
We’re doing all of this without sacrificing the scientific rigor of the process one bit. A central aspect of our approach, and our efforts to spur innovation and generic competition, is focused on adopting more rigorous and sophisticated science, including sophisticated quantitative methods and computational modeling, in drug development, evaluation, and review.
We’ll soon release other important policies aimed at spurring competition to complex drugs. But we know that better guidance isn’t the only answer. Some drugs lack generic competition because they cannot be measured through traditional in vivo bioequivalence methods and there’s no efficient and convincing bioequivalence test method available.
In these instances, an applicant needs to conduct more extensive clinical endpoint testing to show bioequivalence of a generic drug to a brand-name drug. This can be burdensome and discourage generic product development. A further barrier to generic competition for certain complex drug products is the lack of established methods for showing the sameness of the active ingredient of a proposed generic drug to a brand-name drug for certain complex drugs.
Over the next year, FDA’s generic drug regulatory science program will work to identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing, where feasible. To help with this task, we’re holding a series of important scientific workshops, beginning today, that will identify opportunities for complex generic drug development, discuss quantitative modeling approaches and principles and aid product-specific guidance development. The workshops will also help in the development of new analytical tools that will help overcome the unique development and regulatory challenges for demonstrating active ingredient sameness in complex products. We intend for these efforts to speed product development, reduce development costs, and improve access to these products.
Scott's full announcement can be found here.
Complex drugs comprise high cost medicines like metered dose inhalers used to treat asthma, as well as some costly injectable drugs. These medicines generally have at least one feature that makes them harder to “genericize” under our traditional approaches. As a consequence, these drugs can face less competition. In some cases, costly, branded drugs that are complex drugs have lost their exclusivity, but are subject to no generic competition.
When considering the scope of complex drugs, people often first think of drug products where the active ingredient itself is complex. Glatiramer acetate injection, a drug used in the treatment of multiple sclerosis, is a good example. However, the terms “complex drug product” and “complex generic drug” are used to refer to a much larger and diverse group of drug products. In addition to drug products with complex active ingredients, or sites of action, complex drug products also include complex drug-device combination products.
Together, this diverse collection of drug products has one or more elements that are more complex than an average drug product. This complexity, in turn, means that the scientific and regulatory pathways for approval of generic versions of these drug products are not as well traveled by generic drug developers. In some cases, use of another established regulatory pathway may be appropriate to streamline development.
Bioequivalence for complex generic drugs can be challenging with complex drug products that can’t be easily measured in the blood, or when the drug’s therapeutic effect is delivered locally to a particular organ, rather than systemically, through the bloodstream. In other instances, showing active ingredient sameness can be challenging when the drug product contains an active mixture of components and not a single active molecule.
We recognize these problems and are taking a number of new steps to support the development of high quality ANDAs for complex generic drugs.
First, FDA is issuing a draft guidance to assist ANDA applicants and prospective ANDA applicants in creating and submitting pre-ANDA meeting requests, including meeting package materials, so FDA can give better advice to sponsors looking to develop complex generic drugs.
The guidance provides information on requesting and conducting product development meetings, pre-submission meetings, and mid-review cycle meetings with FDA. These meetings will allow for enhanced communication between generic drug applicants and FDA early in the generic drug development process, allowing for more efficient generic drug development, review, and approval pathways. We’ve found from analyzing our new drug program, that early and better meetings between FDA and sponsors can improve development timelines. We want to bring these same types of opportunities to developers of complex generics.
Second, we’re issuing a draft guidance to help applicants determine when submission of ANDAs for certain complex products, known as peptides, would be appropriate. Peptides are compounds made up of 40 or fewer amino acids, the building blocks of proteins. There are a number of branded medicines that are peptides, where exclusivity has lapsed, but these drugs face little or no competition. This new guidance applies to ANDAs for certain specific synthetic peptides, namely, glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, that reference brand-name versions of these peptides manufactured using recombinant DNA technology.
We’re doing all of this without sacrificing the scientific rigor of the process one bit. A central aspect of our approach, and our efforts to spur innovation and generic competition, is focused on adopting more rigorous and sophisticated science, including sophisticated quantitative methods and computational modeling, in drug development, evaluation, and review.
We’ll soon release other important policies aimed at spurring competition to complex drugs. But we know that better guidance isn’t the only answer. Some drugs lack generic competition because they cannot be measured through traditional in vivo bioequivalence methods and there’s no efficient and convincing bioequivalence test method available.
In these instances, an applicant needs to conduct more extensive clinical endpoint testing to show bioequivalence of a generic drug to a brand-name drug. This can be burdensome and discourage generic product development. A further barrier to generic competition for certain complex drug products is the lack of established methods for showing the sameness of the active ingredient of a proposed generic drug to a brand-name drug for certain complex drugs.
Over the next year, FDA’s generic drug regulatory science program will work to identify gaps in the science and develop more tools, methods, and efficient alternatives to clinical endpoint testing, where feasible. To help with this task, we’re holding a series of important scientific workshops, beginning today, that will identify opportunities for complex generic drug development, discuss quantitative modeling approaches and principles and aid product-specific guidance development. The workshops will also help in the development of new analytical tools that will help overcome the unique development and regulatory challenges for demonstrating active ingredient sameness in complex products. We intend for these efforts to speed product development, reduce development costs, and improve access to these products.
Scott's full announcement can be found here.
