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Today, though, we want to talk to you about complex generic drugs. In short, some drugs are harder to make or duplicate than others, which makes it difficult for generic drug companies to launch copies of brand-name drugs. This week, the FDA and its European counterpart, the EMA, said they will launch a new pilot program that seeks to make it easier to obtain development advice from both regulators at the same time. AgencyIQ’s Lily Rosenfield has the details on this cool new program below.
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FDA and EMA launch pilot program for complex generic products
The top line: Earlier this week the FDA, along with the European Medicines Agency (EMA), announced a pilot program which will allow both agencies to review scientific questions posed by sponsors of complex generics or hybrid medicines in order to improve harmonization and help sponsors avoid duplication.
First, let’s talk about generic drugs, complex generics, hybrid products and how they’re all regulated.
- Complex generics are defined by the FDA as products with a complex active ingredient, formulation, delivery route, dosage form or method of administration. Development of these products may be significantly more difficult due to the qualities of the product. For example, an inhalation product that requires a metered-dose inhaler may also be required to administer a specific amount of a product in a specific particle size to ensure proper absorption of the product. Alternately, an extremely small product (such as a nanomedicine) may be difficult to characterize, making it challenging to demonstrate bioequivalence.
- Hybrid medicines are defined by the EMA as drug products that depend both on comparisons to a reference product and on new data from clinical trials. In these cases, additional original data is warranted due to a different strength, different route of administration or different indication from the reference. These are sometimes referred to as the EMA’s version of complex generics.
- Getting a complex generic or hybrid medicine to market is challenging. FDA approval for non-complex generic drug products typically take advantage of product-specific guidances which detail how to establish bioequivalence through specific types of studies. This roadmap sets clear standards for generic companies and makes regulatory review—and ultimately approval—a much simpler and more expedient process. However, many complex generics do not yet have a roadmap for development, leaving companies to seek additional guidance and answers from regulators on an ad-hoc basis.
- At an FDA workshop in June 2021 industry members addressed some of the regulatory challenges they experience and offered ideas for improvements. Rosario LoBrutto, the Executive Director and Head of Scientific Affairs at Sandoz, observed that there are many off-patent complex products with no generic competition. LoBrutto said potential solutions to increase complex generic drug competition could include increased touchpoints with the FDA in addition to additional product-specific guidance documents. As LoBrutto asked, “could there be a dialogue enhancement to address outstanding scientific questions during the mid-cycle review?”
The FDA has taken some actions to make the path to market easier for complex generic drug products, but there are significant gaps remaining.
- For example, it has been working to publish additional product-specific guidance documents for complex generic products and has instituted a pre-ANDA program to help developers of complex generics work with FDA through the regulatory process and reduce the number of review cycles needed to obtain approval.
- From an international perspective, harmonization efforts in the generic drug space have been somewhat lacking. The International Council for Harmonization (ICH) – perhaps the most prominent of the harmonization groups due to its longevity and work output – has focused almost exclusively on issues related to the development of novel medicines. Only recently has it begun to advance efforts related to standards for generic drugs, such as the M13 guideline on bioequivalence for immediate-release solid oral dosage forms. However, information on complex generics has been relatively absent.
- One problem is that the way in which medical products are regulated across regions can differ significantly. As compared to novel drugs, where almost every country has a roughly comparable system to allow for the approval of a new drug, not every country has a similar legal process in place to support the approval of generic drugs or its substitution on the market. That means that similar harmonization efforts are both more important and more difficult to accomplish.
This week the FDA and EMA launched a pilot program to provide insight to sponsors of complex generic products in the US and EU.
- The Parallel Scientific Advice (PSA) Pilot Program for Complex Generic/Hybrid Products will provide a forum for sponsors to concurrently seek out scientific advice from the FDA and EMA related to Abbreviated New Drug Applications (ANDAs) and Marketing Authorization Applications (MAAs). The two agencies already operate a parallel scientific advice program for drugs and biologics; this pilot will act as an expansion of that program. The program officially launched on September 15, 2021.
- The pilot program aims to increase collaboration between the two agencies. Through this program, the FDA and EMA said they will “jointly exchange with applicants the agencies’ views on scientific questions during the development phase of hybrid/complex generic products.” This should “increase dialogue” between all parties starting in the early development stage, offer clear insight into regulatory decision making and limit unnecessary duplication or work.
- The pilot will operate in three stages. In the first stage, ANDA or MAA applicants will request a meeting with both the FDA and EMA. The request should include scientific questions related to development that require FDA and EMA input. Both agencies must grant the meeting request in order to move forward. If denied, a submitter can still utilize agency-specific operations for gaining additional insight (such as pre-ANDA meetings, for example). The announcement also cautions against using the same meeting request for both programs (the PSA and the pre-ANDA program) at the same time.
- If the meeting request is granted, submitters will then submit a full meeting package. This should include information about the development history of the product and the current status of development, as well as an organized list of discussion questions with contextual information and any relevant data related to the questions. The FDA and EMA will review the information provided and meet to discuss the package before having a meeting with both agencies and the submitter to provide direct insight.
The goal is to provide regulatory and scientific recommendations and increase harmonization.
- However, “each agency will retain its individual regulatory decision-making regarding drug development and marketing applications,” according to the notice, and advice may “still differ after the joint discussion.”
- After the meeting, both regulators will provide written responses related to the questions posed. The meeting will also not impact either agency’s regulatory decisions after the fact. The announcement also highlights that the PSA process “should not adversely impact either agency’s ability to meet its individual performance expectations.”
- The program is currently accepting meetings requests and will continue to “until a sufficient number of PSA meetings are held to support the pilot program.” The benefits, challenges and required resources will be assessed by FDA and EMA throughout with the ultimate goal of optimizing global product development.
- The development comes after the FDA made other advances on international harmonization for generic products. For example, the FDA launched the Generic Drug Cluster through its Global Generic Drug Affairs program in June 2021. The cluster is described as “the first forum established for the world’s leading regulatory agencies to address generic drug development globally.” Like some other regulatory efforts (e.g., IMDRF and ICRMA), the Generic Drugs Cluster is intended to be a forum of regulators – sorry, no industry involvement – that aims to increase “scientific alignment.” As AgencyIQ has previously noted, complex generics are a focus for the Cluster.
What we're watching and reading
- …this news that tensions are already visible at the FDA’s advisory committee meeting on boosters. (Link for POLITICO Pro subscribers).
- …this news that Reps. Diana DeGette and Fred Upton want their 21st Century Cures Act bill to be passed by the end of 2021. That’s an ambitious timeline for legislation that would have some major implications for the FDA.
- …the launch of the Rare Disease Cures Accelerator-Data and Analytics Platform initiative (RDCA-DAP), an FDA-funded initiative meant to help centralize and standardize data about rare diseases for the purposes of sharing de-identified data.
- …the FDA’s authorization of bamlanivimab and etesevimab for post-exposure prophylaxis for Covid-19 in adults and patients older than 12 at high risk for progression to severe Covid-19 and who are not fully vaccinated or expected to mount an adequate immune response to the virus.
- …this study looking at how the FDA could regulate Laboratory-Developed Tests. As the study notes, “Temporary regulatory deviations during the pandemic and regulatory science tools (ie, reference material) have generated valuable real-world evidence to inform pending legislation regarding LDT regulation.”
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