Since the promulgation of the Hatch-Waxman Act in 1984, in order to promote drug competition and improve public drug availability, FDA has formulated a number of policies aimed at accelerating the marketing of generic drugs. But with the development and approval of newer and more unique products, the complexity of drugs is also increasing. Many drugs have developed from simple small molecules to products with complex active ingredients, dosage forms, formulations or routes of administration, as well as products as a combination of drugs and machinery. Complex drugs have brought new challenges.
A- Definition of complex generic drugs
According to the definition of FDA's GDUFAII commitment letter, complex products generally include the following situations:
1.Products with complex active ingredients (e.g. peptides, macromolecular compounds, complex mixtures of APIs, ingredients from natural sources); Complex formula (such as liposome, colloid); Complex routes of Administration (for example, topical agents, such as Department of dermatology products, complex ophthalmic products, ear preparations formulated with suspension, emulsion or gel), or complex dosage forms (such as transdermal drugs, metered dose inhalers, sustained-release injections).
2. Complex drug - device combination products (e.g. automatic syringe, metered dose inhaler)
Other complexities or uncertainties associated with approval pathways or possible alternatives will benefit from products with early scientific involvement.
For these complex generic drugs, since the complex formulations and active ingredients, it is difficult to "copy" them (such as their formulations or drug delivery systems) by using traditional biological methods. Therefore, the number of the product is small, resulting in less market competition for these products. On the other hand, these products were not foreseen in the generic drug approval route determined at the beginning of the hatch Waxman act, and special evaluation of product attributes was needed during the review. In recent years, FDA has also paid special attention to complex generic drugs. From 2014 to 2020, FDA has basically listed "equivalence of complex products" as the focus of scientific research in GDUFA supervision, striving to improve and promote the process of R & D, application and approval of complex generic drugs, and improve the efficiency of application and listing of complex generic drugs.
B- FDA's promotion of complex generic drugs
On the one hand, FDA has issued a series of product specific guidelines (PSG), which describe FDA's current ideas and expectations on how to develop generic drugs equivalent to specific reference drugs. This will help the generic drug industry to determine the most appropriate method and evidence to support the approval of specific generic drugs. FDA has a database of PSG guidelines, which is updated regularly.
In addition, in order to pay special attention to complex generic drugs, FDA has opened a new webpage for PSG of complex generic drugs “Upcoming Product - Specific Guidances for Complex Generic Drug Product Development”. When FDA releases PSG batches every quarter, the webpage will be updated. Each update will delete the published PSG and add any new PSG under development or revision. This advance notice will help generic companies and wholesale medical supply companies plan or project their development of complex generic products. Generic drug applicants can also specifically track the new and revised guidelines for complex products planned by FDA, so as to avoid the lack of preventive measures due to the revised guidelines in the development or application review.
On the other hand, FDA has established pre-ANDA program according to the generic drug user fee amendment in 2017 （GDUFA II）, which aims to clarify the regulatory expectations of applicants through written communication and meetings at the early stage of drug development, assist applicants to submit com...
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