What are Complex Generics?
Complex generics are those that are inherently difficult to duplicate, reviewed by CDER – OGD (not CBER) using 505(j) Abbreviated New Drug Applications (ANDAs), are generally off-patent and represent markets with higher barriers to entry. According to Robert Lionberger, Ph.D. of OGD, Complex generics may be characterized by the following:
- Complex Active Ingredients – low molecular weight heparin, peptides, complex mixtures, natural source products
- Complex Formulations – liposomes, iron colloids
- Complex Route of Delivery – locally acting drugs
- Complex Drug-Device Combinations – dry powder inhalers, metered dose inhalers, nasal sprays, transdermal systems
Table 1: Specific examples of complex generics and the year they were first approved as generics
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Adapted from Drugs.com
Complex generics tend to be difficult to manufacture, requiring a high level of technical skill and expertise. For example, doxorubicin HCl liposome injection is used to fight several types of cancer. While a typical sterile, intravenous chemotherapy formulation requires only a few process vessels and one or two manufacturing steps, with batch completion typically taking a matter of hours, the steps for creating the complex formulation for DOXIL® requires 17 different process vessels, plus specialized equipment, requiring more time and adding complexity to the process.
Regulatory Challenges of Complex Generics
For applicants willing to take the risk and develop complex generics, the rewards can be great. However, complex generics are typically difficult to characterize and may require (in addition to pharmacokinetic endpoints), in vitro, pharmacodynamic, clinical and post-market data. Not surprisingly, it is generally difficult to establish an equivalency to the RLD (Reference Listed Drug).
The ANDA review process, traditionally employed for more standard generic approvals, does not work well for complex generics. As described in the FDA Orange book “Drug Products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.” This can’t always be proven with complex generics. Thus, when an applicant submits an ANDA for a complex generic drug following the traditional step-by-step processes, the risk of being rejected due to lack of adequate information related to equivalency to the RLD is much higher. In fact, complex generics are often reviewed for “sameness” as opposed to bioequivalence. According to Scott Gottlieb, newly appointed FDA commissioner, generic drug laws, crafted more than 30 years ago, “didn’t contemplate these ‘complex’ drugs, and so it doesn’t provide for an efficient and predictable path for enabling generic entrants”.
What to do?
Answers are sometimes straightforward: “In 2016, OGD issued 158 new product-specific guidances, many of which involved complex dosage forms, such as auto-injectors, inhalation powders, nasal sprays, topical products, and ophthalmic products. OGD develops product-specific guidances soon after brand-name drugs are approved to ensure that patients have access to a generic drug at the earliest possible opportunity. OGD develops and issues product-specific guidance based on requests from industry and public health priorities.”
In cases where there is no product-specific guidance, a Pre-ANDA meeting may be requested. However, these are not covered by GDUFA and OGD cannot and does not grant meetings to all who request them. The odds of securing a meeting are higher if the applicant presents a product with no generics available, unique regulatory/science issues, clear and specific questions, and data that is new to OGD, e.g. pilot studies of an alternative approach. Cited by FDA as frequently occurring reasons meetings are not granted are:
- Fishing for approaches
- Problems without proposed solutions
- Questions that can be answered in controlled correspondence
- Non-specific agenda
- Scope too broad
- No specific questions
- No data
It is anticipated that GDUFA II will become law sometime this year and will establish various types of product development meetings for complex generics including pre-submission and mid-review-cycle meetings. FDA also plans to issue new guidance concerning the pre-ANDA program, setting forth meeting policies and procedures.RAPS Regulatory Focus reports that “FDA also would grant appropriate requests for teleconferences concerning first cycle major and subsequent CRLs.”
Another option is the use of Controlled Correspondence (CC). In the context of GDUFA, FDA defines CC as “correspondence submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development.” A final Guidance was issued in September 2015  which provides information relating to the use of CC for generic drug development. However, the Guidance notes that “in certain circumstances, the controlled correspondence mechanism may not be the optimal mechanism to gain FDA feedback…For example, a pre-ANDA meeting that is more iterative in nature may provide a better forum in which to discuss certain issues, e.g., methods of characterization for complex products or clinically critical BE considerations.” 
ANDA submission without product-specific guidance or a Pre-ANDA meeting to see how FDA responds is always an option. While there is the chance of approval given sound methods of demonstrating sameness, a Complete Response Letter may include a description of all specific deficiencies (21 CFR 314.110(a)(1). On the other hand, if “the data submitted are inadequate to support approval, the agency might issue a complete response letter without first conducting required inspections…” (21 CFR 314.110(a)(1). This would be costly.
While there is no evidence to illustrate Mylan’s approach with generic Advair, Reuters recently reported that “Mylan NV said on Wednesday its application to market a generic copy of GlaxoSmithKline Plc’s blockbuster inhaled lung drug Advair was rejected by the U.S. Food and Drug Administration…The U.S. drugmaker did not disclose the reason behind the rejection, but said it was reviewing the FDA’s response…Since the generic is one of the first complex inhaled combination generic products to be reviewed by the U.S. agency, some analysts had estimated a low likelihood of a timely approval.” 
Akin to Biosimilars
We recently posted a paper on the development of Biosimilars, and note that complex generics tend to have analagous characteristics, manufacturing difficulties and regulatory challenges.  Hence, as with the development of biosimilars, complex generics require a substantial commitment of resources and high tolerance of financial risk. Hiring a consultant who has worked on a variety of complex drugs can make a substantial difference in managing resources, mitigating risks and developing methods to demonstrate sameness. This particularly applicable if there is no product-specific guidance, or in the case of a first complex generic.
About the Authors
Jodi Hutchins is an Independent Regulatory and Quality Consultant with over 15 years of global medical device registration experience, to include FDA 510(k) submissions. She held her most recent position for 9 years, as QA/RA Director for a Worldwide distributor of medical devices.
Charles Jaap is Vice-President of Operations and Business Development for PDG®, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices. Please feel free to contact us for more information.
The opinions and statements in this paper are solely those of Charles Jaap and Jodi Hutchins and do not necessarily reflect those of PDG®.