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Something to Chew On: New FDA Draft Guidance on Chewables

Something to Chew On: New FDA Draft Guidance on Chewables

An idea for a more convenient dosage form for an existing drug product often presents an opportunity for a commercial advantage. Fortuitously, it also presents the possibility for using the 505(b)(2) regulatory pathway to product approval, which is often faster and less expensive than the 505(b)(1) route.

Recently, FDA issued a brief draft guidance describing the important quality characteristics of a seldom used alternate dosage form: Quality Attribute Considerations for Chewable Tablets-Guidance for Industry (CDER, June 2016). The guidance suggests that chewable tablets could be an attractive method of oral drug delivery “…in a diverse patient population, pediatric, adult or elderly patients who are unable or unwilling to swallow intact tablets due to the size of the tablet or with difficulty swallowing.” The draft guidance is designed to assist the drug development of chewable tablet products, focusing on the requisite quality attributes needed for a successful NDA or ANDA application.

Something to Chew on: New FDA Draft Guidance on Chewables

New FDA Draft Guidance on Chewables

FDA’s guidance defines a “chewable tablet” as “…an immediate release (IR) oral dosage form intended to be chewed and then swallowed by the patient rather than swallowed whole.” Citing the USP, FDA notes that there are two different types of chewable tablets: 1) those that may be chewed for of administration and 2) those that must be chewed or crushed before swallowing to avoid choking and/or ensure the release of the active ingredient. The guidance focuses on fur characteristics considered important for the “…ideal chewable tablet…”:

  • Easy to chew (FDA discusses at some length a “Chewing Difficulty Index”)
  • Palatable (taste masked or of acceptable taste)
  • Of appropriate size and shape
  • Able to disintegrate readily to minimize aspiration and facilitate dissolution

The guidance correspondingly notes the adverse events most likely associated with a chewable tablet not developed with adequate attention to the aforementioned characteristics: gastrointestinal obstruction resulting from patients swallowing whole or incompletely chewed tablets, tooth damage and denture breakage from excessive tablet hardness, as well as esophageal irritation from the chewable tablet.

The guidance provides further specifics on the primary measures to be employed in achieving the desired drug quality attributes: hardness, disintegration, and dissolution. Also included are some specifics on measuring each.

Several pages of recommendations (Section IV) are provided for consideration during drug development. In summary, the recommendations are:

  • Use of a disintegrant(s) to facilitate release of the active ingredient
  • Use of sweeteners and flavoring agents for palatability and/or taste masking
  • Investigation into possible interaction between excipients and/or the active ingredient
  • Elements to be included in the (A)NDA
    • During pivotal clinical studies, were chewable tablets swallowed intact or after being thoroughly chewed?
    • If swallowed intact, does the does the size/shape pose a risk of choking or bowel obstruction?
    • If water was used to aid swallowing, what volume?
    • What were subjects sensory experience, e.g., taste, mouthfeel, aftertaste
  • Potential for buccal absorption and stability in the buccal environment (assessable in vitro)

The recommendations expand on the specified measures useful in achieving the desired quality attributes:


The guidance recommends that hardness be kept low (<12 KP) while allowing for higher hardness in the presence of significant disintegration in the presence of significant in the presence of saliva before chewing, OR the demonstration of the absence of damage to teeth, dentures or other problems in the use of higher hardness.

Disintegration and Dissolution

Disintegration and dissolution should meet the same specification as IR tablets. The guidance points to the use of in vitro testing, but cautions against unquestioning acceptance because of the probability of variability of “chewing patterns” in patients. Additional assessments “…may be needed on a case-by-case basis.”

The guidance provides information on some labeling considerations for chewable tablets, again distinguishing between tablets that MAY be chewed versus tablets that MUST be chewed and/or, not swallowed.

Finally, two Appendices are provided, one providing a detailed method for the determination of a product’s “Chewing Difficulty Index” and a second which lists a formulation for simulated salivary fluid.

So, FDA has provided a fairly useful blueprint for a robust product development program for chewable tablets. Using the guidance in concert with all the other components of a successful product development plan could yield an approved new dosage form with a substantial commercial advantage over existing ones, especially those which, for whatever reason, are large solid oral dosage forms. Camargo has an experienced CMC staff, adept at formulation and analytical development available to assist if needed. Contact us for more information.

Author: William Stoltman, J.D., Senior Director of Quality Assurance / Compliance at Camargo

The GRAS Is Not Always Greener

The GRAS Is Not Always Greener: Why GRAS Status Does Not Guarantee Excipient Safety

Many, if not most, 505(b)(2) submissions represent a change to an approved drug, usually involving a formulation change. Understandably, the focus of sponsors is often primarily on supporting the safety and efficacy of the active ingredient(s). However, the safety of the inactive ingredients (excipients) needs to be supported as well. Choice of excipients can therefore have a significant impact on the ability to streamline a drug development program.

Often we hear from clients, “The excipients are not an issue. Everything we’re using is GRAS.” Now, “GRAS” stands for Generally Recognized as Safe. With an acronym like that, it’s tempting to think that selecting excipients that are GRAS should do the trick. But GRAS status is not sufficient to meet the regulatory requirements to demonstrate safety of an excipient in a drug product, and sponsors are often surprised when the Agency requests additional (and sometimes substantial) nonclinical or even clinical data to support the safety of the proposed product formulation.

Why isn’t “GRAS” status sufficient? To understand that, let’s review what “GRAS” is, and what it isn’t.

GRAS and Drugs

As it applies to drugs, “GRAS” refers to drugs that were approved between 1938 and 1962 on the basis of safety alone. These are the drugs that underwent the Drug Efficacy Study Implementation (DESI) reviews by the National Academy of Sciences/National Research Council – i.e., the DESI drugs with which many readers of this blog may be familiar. Drugs that were found to be efficacious in a DESI review were awarded “GRASE” status, or Generally Recognized as Safe and Effective (sometimes referred to as GRAE/GRAS) for the specific condition(s) of use studied.

Importantly, drugs that were not determined to be GRASE – either because they just didn’t work or there was insufficient evidence of efficacy – did not retain “GRAS” as a marketing status. Most of these drugs were officially pulled from the market and left to languish in 21 CFR §310.545 (although some can be found as unlawfully marketed, unapproved drugs). A lucky few remain legally marketed while the awaiting Agency completion of the DESI review process or finalization of an over-the-counter (OTC) monograph (OTC monographs also utilize the “GRASE” designation[1]).

Notice that “GRAS” and “GRASE” as used above refer only to active ingredients – not to excipients.

Generally Recognized as Safe: GRAS Excipients and 505(b)(2


The GRAS List

The current use of “GRAS” applies to food additives. This is where the infamous “GRAS List” comes into play. Nice reviews on this topic can be found on the FDA website or 62 FR 18938. Briefly, in 1958 the Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act defined any substance intentionally added to food as a “food additive” and stipulated that these substances were subject to pre-market approval by FDA unless the use of the substance was “GRAS.” Initially, recognition by “qualified experts” or experience based on common use in food was sufficient evidence that a substance was GRAS, and the FDA published the first “GRAS list” in the Code of Federal Regulations (CFR).

However, many substances that the food industry considered GRAS were not included in the 1958 list, and manufacturers requested opinion letters from FDA. In these letters, FDA rendered informal opinions regarding GRAS status. This process was deemed insufficient to ensure safety, and in 1972 FDA initiated a comprehensive study of substances presumed to be GRAS, to be conducted by the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology (FASEB). The LSRO selected qualified scientists (known as the Select Committee on GRAS Substances [SCOGS]) to conduct these studies. When a study was completed, the Agency reviewed the SCOGS report and, if merited, issued a final rule affirming GRAS status based on the findings. At the same time, the Agency reviewed GRAS Affirmation Petitions from industry for substances that were not part of the FDA review; final rules on the GRAS status for these substances were also issued. The current GRAS list can be found at 21 CFR §182, §184, and §186.

The GRAS Notification Process

Eventually the GRAS Affirmation process became too burdensome for the Agency’s limited resources, and was replaced by the current GRAS Notification process in 1997.[2] In the current process, industry submits a GRAS Notice along with supporting data, but the Agency does not affirm or deny GRAS status. Rather, FDA responds to the notifier by letter stating either that it does not question the basis for the notifier’s GRAS determination, or that the notice does not provide a sufficient basis for a GRAS determination.2 GRAS Notices are published on the FDA website, but neither of these responses qualifies as an actual “finding.”

Importantly, GRAS applies to a specific use for the substance in question, not to the substance itself. The intended use(s) for substances are included in the GRAS list or GRAS Notice. While there may be similarity in the “intended use” – for example, guar gum is used as an emulsifier and thickener in both foods and drugs – the dose, frequency of administration, duration of administration, and route of administration often differ between the food use and the use of a proposed drug product. The Agency has cited these differences as a primary reason why GRAS status is insufficient to establish excipient safety in a proposed drug product.

To Recap:

  • GRAS is no longer used for drugs, but when it was, it applied only to the active ingredient.
  • GRAS is currently used only for food additives, and is a mixture of Agency GRAS affirmations (the GRAS list) and informal notices that carry little to no regulatory weight in the drug arena.
  • GRAS applies to a food additive substance only in the context of its intended food use, and there are often significant differences between the food and drug uses, especially in potential exposure to a substance.
  • GRAS status or the existence of a GRAS Notification does not guarantee that a substance has sufficient information to support its use in a potential drug product. The Agency has, in some cases, determined that a GRAS substance is, in fact, a novel excipient.

Where Do I Start?

So, if GRAS status does not provide the necessary support, how do sponsors select excipients that will meet their needs while streamlining a development program? A good place to start is FDA’s Inactive Ingredient Database (IID). The IID provides information on excipients in FDA-approved drug products. Once an excipient has appeared in an approved drug product for a particular route of administration, it is not considered “new” and may require less extensive support in a future drug product.[3] For many potential drug products, this may be all the support that is needed.

Additional support may be needed if the route of administration is not listed in the IID (the list is not always up-to-date), the listed potency is less than that in the sponsor’s proposed product, the overall exposure to the substance from the sponsor’s product will be higher than that from the approved product (something that cannot be gleaned from the IID), or if the sponsor’s product will be used in a different patient population (also not obvious from the information in the IID). This support can come from many sources, so sponsors should not always assume that they will need to conduct additional studies. Camargo can assess the information available to support your formulation, and can help you determine if further studies will be needed, identify the studies will get you the information you need while minimizing cost and time, and, if needed, assist with reformulation strategies.

For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways Camargo’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.

Author: Karen Seta-Aust, Ph.D., Associate Director of Research Services, Camargo Pharmaceutical Services


[1] http://www.accessdata.fda.gov/scripts/cder/training/OTC/topic3/topic3/da_01_03_0070.htm

[2] The process was implemented even though the proposed rule has not yet been finalized. See “About the GRAS Notification Program,” http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/ucm2006851.htm.

[3] See “Inactive Ingredient Search for Approved Drug Products: Frequently Asked Questions,” http://www.fda.gov/Drugs/InformationOnDrugs/ucm080123.htm.

Back to Basics: 505(b)(2) FAQs Part 3: Regulatory Strategies

Back to Basics: 505(b)(2) FAQs Part 3: Regulatory Strategies – Marketing Exclusivity, Patent Certification, and Rx to OTC Switch

As the 505(b)(2) expert, Camargo is frequently asked questions about how to get a product approved via the 505(b)(2) regulatory pathway and if this pathway is appropriate. Given the growing popularity of the 505(b)(2) pathway for approval of repurposed, reformulated, or unapproved-marketed products, we thought it would be worth providing a refresher. Here is Part 3 in our series of frequently asked questions (FAQs). Stay tuned to this blog for more FAQs and Camargo’s responses in the coming weeks.

Marketing Exclusivity

Q1      505(b)(1) vs. 505(b)(2) – what are the timeline differences for the possible intrusion of generic competitors (assuming that the 505(b)(2) was assigned 5 years of exclusivity)?

Most new chemical entities (that is active moieties that have not previously been approved by the FDA) are approved via the 505(b)(1) pathway, and are assigned 5 years of marketing exclusivity if clinical studies* were performed. This means that a generic (ANDA) application for the product cannot be filed until the end of the 5th year, or the end of the 4th year if a certification of patent invalidity or noninfringement (Paragraph IV challenge) is submitted in the application. Products approved via the 505(b)(2) pathway, however, may be assigned 0, 3, 5, or 7 years of marketing exclusivity depending on the regulatory situation (see Q3 below). Assuming a 505(b)(2)-approved product is a new chemical entity and is therefore assigned 5 years of marketing exclusivity, as per the question, then the theoretical timeline for potential generic competition is the same as for a 505(b)(1)-approved product: 5 years. In reality, as current ANDA review times can exceed 3 years**, most products with 5 years exclusivity are on the market for 6-8 years before the arrival of generic competition.

*As per the definition of “clinical investigations” defined in 21 CFR 314.108
**The progressive GDUFA performance goals are expected to reduce FDA review time.

Q2      For the unapproved drugs that are on market (NCE), would regulatory exclusivity be 5 years?

Unapproved drugs are eligible for 5 years of marketing exclusivity, if they have never been approved by the FDA, known as a new chemical entity (NCE) or new molecular entity (NME). Although most products that have been approved (current and discontinued) are listed in the Orange Book, some are not listed. Camargo can perform a search of the Federal Register to find if evidence of a prior approval or withdrawal of application is listed.

Q3      How is the exclusivity period determined for a 505(b)(2) application?

The FDA determines whether a drug product receives exclusivity at the time of NDA approval. Exclusivity periods are not available for Phase 1-only programs, 3 years for products that required Phase 2 and/or 3 (clinical) studies* for approval, 5 years for an NCE, and 7 years for an orphan drug. However, granting marketing exclusivity can be complicated for some products and can result in lengthy litigation, particularly for products designated as orphan. See our previous blogs on exclusivity for further discussion and examples.

*As per the definition of “clinical investigations” defined in 21 CFR 314.108

Patent Certification

Q4      Can you explain the situation regarding potential Paragraph IV legal issues prior to approval?

NDAs approved via the 505(b)(2) pathway and that rely on a Listed Drug are subject to the same patent regulations as products approved via the 505(j) pathway (ANDAs). Briefly, this means that the company filing the 505(b)(2) application must certify that there are no patents listed in the Orange Book (Paragraph I), that all patents have already expired (Paragraph II), that the application should be approved after all patents expire (Paragraph III), or that any patents are invalid or not being infringed upon (Paragraph IV). If the latter, the company holding the application for the Listed Drug product can file a patent infringement suit within 45 days of notification by FDA, and a 30-month stay on the application’s approval takes effect unless the sponsor can successfully defend the suit earlier than this. Until then, FDA can only tentatively approve the 505(b)(2) application. In practical terms, as either option will usually delay the approval of the 505(b)(2) application by several years, it is best to be aware of the patent situation as early as possible.

Q5      If the patent of parent drug is still effective, can its prodrug be filed as 505(b)(2)?

In this case, the parent drug will be used as the Listed Drug for approval of the 505(b)(2) application. This will require certification against each existing unexpired patent for the Listed Drug in the Orange Book, as summarized in Q4.

Rx to OTC Switch

Q6      How do we decide if we go OTC or NDA?

If a drug product does not comply with the requirements of an OTC drug monograph (21 CFR Part 330), it must be approved as an NDA (or an ANDA if an innovator, or Reference Listed Drug product exists) as per the respective requirements under 21 CFR Part 314. The product can be approved for OTC use if the sponsor can demonstrate that it is safe and effective for use by consumers without the assistance of a healthcare professional. If already approved, the 505(b)(2) pathway is appropriate for a switch from prescription to OTC status.


The 505(b)(2) regulatory pathway allows for the approval of a broad range of products that represent a broad range of regulatory and patent scenarios. It is therefore not surprising that the outcomes for exclusivity determinations and patent certifications can be highly variable and occasionally litigated. Similarly, an Rx to OTC switch is almost always a unique scenario with unique requirements for approval. Experience with the 505(b)(2) pathway is naturally important in assessing the options and outcomes for a proposed drug product.

For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways that Camargo’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.

Part 1 of this blog series focused on general 505(b)(2) questions, including where the name comes from, and what is or is not allowed for a 505(b)(2) application. It can be found here. Part 2 focused on the need for clinical and/or nonclinical studies in a 505(b)(2) application and can be found here.

Further topics of FAQs in the final upcoming blog include:

  • Pharmaceutical Quality (CMC)
  • Pharmacokinetic Studies


Author: Angela Drew, Ph.D., Product Ideation Consultant, Camargo Pharmaceutical Services

Key Inflection Point in a Drug’s Time to Market: Choice of Regulatory Pathway

Key Inflection Point in a Drug’s Time to Market: Choice of Regulatory Pathway

Traditional drug development follows a standard process beginning with nonclinical studies and moving into clinical studies, all with the purpose of proving a new drug candidate is safe and effective. When the U.S. opened up an alternate path, 505(b)(2), the primary purpose was to utilize existing data and knowledge, minimize costly animal and human studies, and cut down on the lengthy time to market for new life-saving drugs. But how much savings is possible by utilizing the 505(b)(2) pathway? Could choosing a 505(b)(2) route to market for a drug candidate save upwards of $20 million in development cost and more than 2 years in development time? You might be surprised by the answer.

A Comparison of the Regulatory Pathways

A new drug product can be approved by the US Food and Drug Administration (FDA) via one of three regulatory pathways covered under Section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act):

  • 505(b)(1) new drug application (NDA), or an application that contains full reports of investigations of safety and effectiveness;
  • 505(j) abbreviated new drug application (ANDA) or generic drug application wherein the application contains information to show that the proposed product is identical to a previously approved product in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use (among other things) – noting that there are allowable formulation differences for certain routes of administration; or
  • 505(b)(2), which is a combination of the 505(b)(1) and 505(j) pathways and involves full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by the application (or for which the applicant has not obtained a “right of reference”).

Pathways at a glance

The 505(b)(2) NDA regulatory pathway was created by the Hatch-Waxman Amendments of 1984, in part, to help avoid unnecessary duplication of studies already performed on a previously approved product. Similar to a 505(j) application, a 505(b)(2) may “rely” on the Agency’s previous findings of safety and/or efficacy of a reference product (the “listed drug” in the case of a 505(b)(2) application or a “reference listed drug” for a 505(j)) to reduce the burden for approval in terms of number of studies required. Alternatively, a 505(b)(2) application may also rely on information from other publically available sources, such as the published clinical literature, provided an adequate scientific bridge can be established that links the Sponsor’s product to the product or products referenced in the literature studies.

In a 505(b)(1), all information required for approval must be completed de novo by the Sponsor with the proposed product, including required nonclinical (animal) pharmacology, pharmacokinetics, and toxicology studies, preformulation studies, analytical methods development, stability work on the active ingredient and dosage form, and all clinical studies (Phase 1, 2, and 3). On the other hand, a 505(j) application is based largely on establishment of bioequivalence to a reference product using established methods (although methods validation may still be required).

A 505(b)(2) program differs from these other regulatory pathways in that 505(b)(2)s are unique and can vary greatly in terms of size and structure. A 505(b)(2) program could involve no clinical studies, with reliance on all literature to support both safety and efficacy of a product; or, a simple program may just involve single bioequivalence study bridging the Sponsor’s product to a listed drug to demonstrate safety and efficacy through similarity in systemic exposure to the approved product. 505(b)(2) programs can also be larger, involving a single pivotal study, with support provided by safety information from a listed drug or published literature. Alternatively, some 505(b)(2) programs rely only on nonclinical information from a publically available source, while a full clinical program is required.  The key aspects of product planning as outlined in the figure below are described in more detail here.

Navigating the 505(b)(2) Pathway

In addition to the size and complexity of the program, the 505(b)(2) pathway differs from 505(b)(1) in terms of the order of the steps. For instance, while a Pre-IND meeting with 505(b)(1) generally occurs after nonclinical work and formulation development, a Pre-IND meeting in 505(b)(2) is often the beginning of the process. In many cases, the goals of this meeting also differ between the regulatory pathways. For 505(b)(2), the Pre-IND is focused on gaining FDA input and concurrence with the development strategy, including what studies are required and what publically available information can be relied upon in the eventual NDA application. In some cases, a Pre-IND meeting for 505(b)(2) can function more like a Pre-NDA meeting, depending on the complexity of the program.

As discussed above, the number of studies are also often different, with a 505(b)(2) program potentially requiring no studies or a single bioequivalence study, compared to a full 505(b)(1) program. In some cases, a Phase 3 study may be conducted, but with fewer patients and supported by a Phase 2 study or data available from the published literature. The timing of studies differs between the 2 regulatory pathways; as 505(b)(2) relies on pre-existing data, nonclinical and clinical studies can often be run in parallel rather than sequentially, shortening the overall time to market for the Sponsor’s product. The timing of when clinical trial material (CTM) is required also may differ between the two pathways. In a 505(b)(2) program that involves demonstration of clinical bioequivalence (Phase 1), CTM should be representative of the commercial manufacturing process, including packaging. As a consequence, CMC work should be invested prior to initiating even Phase 1 studies.

Taken together, these differences between 505(b)(1) and 505(b)(2) represent a formidable, multifaceted challenge. In 505(b)(2), mishandling of these steps, particularly those early on, could result in product-development failure. Alternatively, when managed skillfully, the 505(b)(2) pathway can result in important victories for a sponsor, including promoting interest from investors, demonstrating a clear path to approval, and reducing costs and time to market.

Why Choose Camargo to Help Navigate the 505(b)(2) Regulatory Pathway? 

In one recent example, Company A initiated product development discussions with FDA through a regulatory consultant using existing 505(b)(1) guidance. The result of their first Pre-IND meeting was a recommendation from FDA to conduct many clinical trials estimated to cost $25 million and take longer than 3 years. Company A did not have funding for the plan and sought assistance from Camargo to rescue the project. Through analysis of the product’s scientific and medical viability, Camargo identified a possible solution. The previous development program did not make use of existing data from outside sources, a unique possibility in the 505(b)(2) pathway. Armed with this new information and following Camargo’s approach and recommendations, Company A conducted another Pre-IND meeting with FDA. The Agency reversed its decision and required only a single Phase 1 bioequivalence study, which reduced the initial 3 year plan to mere months and cost less than 10% of the initial projected total. The key is in the experience and relationship with FDA, and in the expertise leveraging relevant existing data. The difference is Camargo.

505(b)(2) Can Reduce Cost and Time to Market

Using the 505(b)(2) regulatory pathway, a Sponsor may be able to provide safety and effectiveness data for NDA approval without expending the same amount of money and time required to complete all the requisite studies de novo, resulting in a less expensive and faster route to approval compared with the traditional 505(b)(1) development path.

The range in complexity in 505(b)(2) programs is wide. Learn more about ways Camargo can help navigate the 505(b)(2) regulatory approval pathway successfully or contact Camargo here.

Author: Kristi Norris, Ph.D., Camargo Scientific and Regulatory Manager

Back to Basics: 505(b)(2) FAQs Part 2: Clinical and Nonclinical Studies

Back to Basics: 505(b)(2) FAQs Part 2: Clinical and Nonclinical Studies
As the 505(b)(2) expert, Camargo is frequently asked questions about how to get a product approved via the 505(b)(2) regulatory pathway and if this pathway is appropriate. Given the growing popularity of the 505(b)(2) pathway for approval of repurposed, reformulated, or unapproved-marketed products, we thought it would be worth providing a refresher. Here is Part 2 in our series of frequently asked questions (FAQs). Stay tuned to this blog for more FAQs and Camargo’s responses in the coming weeks.

Navigating the 505(b)(2) Pathway
Q1      Can you skip Phase 1 and Phase 2 [studies] for a 505(b)(2)?
In theory, yes. A 505(b)(2) application may be approved on the basis of any combination of studies or even no studies. However, more typically, a Phase 1 study will be required. This is because a 505(b)(2) application relies on existing information from approved products or products in the literature. This is in contrast to a 505(b)(1) or new chemical entity application in which the sponsor conducts all studies required for approval. To rely on existing information, a sponsor must demonstrate how similar or different their product is from the product used in the existing information. This is known as establishing a scientific or clinical bridge, and is frequently fulfilled through a Phase 1 bridging study.

Having said this, an in-depth knowledge of, and experience with the 505(b)(2) pathway can allow a sponsor to eliminate costly and time-consuming studies, including Phase 1 studies. Camargo has accomplished this is the past via innovative animal or in vitro studies, or for some products by leveraging specific information in the literature. As every 505(b)(2) is different, different strategies can be employed to reduce a sponsor’s clinical (and nonclinical) program.
Q2      For a fast route for NDA filing via 505(b)(2), is it feasible to do so via BA/BE studies instead of following the routine steps of Phase 1,  Phase 2 and Phase 3?
Absolutely! As discussed in the previous question, a ‘typical’ 505(b)(2) application (if there is such a thing) is more likely to contain a Phase 1 bioavailability/bioequivalence (BA/BE) bridging study and fewer, if any, Phase 2 or Phase 3 studies than an application for a new molecular entity. A faster development program with fewer studies is one of the major benefits of the 505(b)(2) pathway.
Q3      Are clinical trials required for a 505(b)(2)? If so, how is that different from 505(b)(1)?
The requirement for clinical studies will depend on various factors, including how different the proposed product is from the existing product, including indication, dosage, route of administration, and on the type and quality of the information available in the literature or in approved-product labeling. If the Phase 2 and/or Phase 3 studies have already been conducted, this data can be referenced in the 505(b)(2) application in place of sponsor studies.

This is in contrast to a 505(b)(1) application in which the sponsor must submit full reports of safety and efficacy for its proposed product. This means all studies required for approval must be conducted by the sponsor.
Q4      Are nonclinical studies required for a 505(b)(2) application?
Many 505(b)(2) applications do not require the sponsor to conduct nonclinical studies. In these cases, the successful application will contain adequate evidence of safety for the proposed product. This may include clinical data, nonclinical studies reported in the literature or approved product labeling, or other justification of why the product is safe for its proposed use.
Q5      Can we refer to the original NDA for Toxicology and Bioavailability data when we file 505(b)(2)? If yes, then how does that process work?
Information in the product labeling can be referred to if it is appropriate for the proposed product. However, while toxicity or bioavailability data that only appears in the Drug Approval Package (Summary Basis of Approval or SBA) can be referenced as supportive information, it cannot be relied on to avoid conducting a study. This is because the product labeling represents a finding of safety and efficacy by the FDA, but the Approval Package represents only the comments of individual reviewers rather than the FDA.

What happens if you need the information in the Approval Package for the 505(b)(2) submission? Once again, experience with 505(b)(2) may offer innovative options for referencing data from other sources such as the literature or toxicology databases that may fulfill the requirement for nonclinical studies.
From the answers above, you can see that every 505(b)(2) submission differs. While one 505(b)(2) development plan may contain one required clinical study, another may require two, for different reasons. And the possibility of a literature-only submission also exists.

The one common factor in 505(b)(2) applications is that each one relies on existing material. The discovery and application of the existing information requires creativity, depth and breadth of knowledge, long-standing experience with the FDA to understand the current reasoning and history, as well as multi-disciplinary expertise within 505(b)(2) to pull the entire program together. Without this, a program aiming to become approved via the 505(b)(2) pathway may be misaligned (risking clinical hold), or over-programmed such that the benefits of 505(b)(2) are not fully realized.

For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways Camargo’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.

Part 1 of this blog series focused on general 505(b)(2) questions, including where the name comes from, and what is or is not allowed for a 505(b)(2) application. It can be found here.

Further topics of FAQs in upcoming blogs include:

  • Pharmaceutical Quality (CMC)
  • Pharmacokinetic Studies
  • Patent Certification
  • Marketing Exclusivity and Generic Competition
  • OTC or NDA?


Author: Angela Drew, Ph.D., Product Ideation Consultant, Camargo Pharmaceutical Services

Back to Basics: 505(b)(2) FAQs Part 1

As the 505(b)(2) expert, Camargo is frequently asked questions about how to get a product approved via the 505(b)(2) regulatory pathway and if this pathway is appropriate. Given the growing popularity of the 505(b)(2) pathway for approval of repurposed, reformulated, or unapproved marketed products, we thought it would be worth providing a refresher. Here are questions that Ken Phelps, our President and CEO, recently answered at a webinar focused on the 505(b)(2) pathway. The topic of this post will be general 505(b)(2) questions, including what is and is not allowed for an approval via the 505(b)(2) regulatory pathway. Stay tuned to this blog for more FAQs and Camargo’s responses in the coming weeks. But first, why the name? 505b2

Where does the name “505(b)(2)” come from? 505b2

The “505(b)(2)” name comes from Section 505 of the Federal Food, Drug, and Cosmetic Act. Section 505(b)(2) was added by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Amendments). Section 505 has subsections that describe 3 types of applications:

  1. 505(b)(1) – new molecular entity containing full reports of safety and efficacy
  2. 505(b)(2) – applications in which some of the information required for approval comes from sources other than sponsor studies, or for which the sponsor has not obtained a right of reference
  3. 505(j) – generics: application provides proof that the product is identical to a previously approved product

Pathways at a glance

Now to the questions asked by Ken’s audience:

Q1      Can you change the indication and dosage form at the same time for an approved drug with 505(b)(2)?

Yes. A product that is appropriate for approval via the 505(b)(2) pathway may differ from approved products in multiple attributes, including dosage form, strength, route of administration, formulation, dosage regimen, indication, or even active ingredient. Changes to any of these attributes will usually affect the safety or efficacy of the proposed product. Therefore, the 505(b)(2) application for the proposed product will need to demonstrate adequate safety and efficacy for the indication.

In addition, recall from an earlier blog that a 505(b)(2) application need not refer to any approved product, or listed drug. As described in the earlier post, if the information in the literature is appropriate and of a standard acceptable to the FDA, it is possible to leverage this information for approval of a new product.

Q2      Do “Pre-DESI” products fall under 505(b)(2) or a new (molecular entity) NDA?

Many products that are marketed unapproved (so-called “DESI” or “pre-DESI”), are suitable for approval via the 505(b)(2) pathway. This is because there is often existing information on these products that can be used to support their safety and efficacy. This information may include studies reported in the literature or information retained in the manufacturer’s own database. In many cases, this information can be used to reduce the size or scope of the development program required to get the product approved.

See our previous blogs on unapproved or so-called “DESI” products, including a description here, and notes on approval here and here.

Q3      Does a 505(b)(2) require a proprietary name?

Drug products, including those approved via the 505(b)(2) pathway, do not require a proprietary name. However, if a Sponsor would like to include a proprietary name in the labeling, the proposed name must be assessed for appropriateness by the FDA’s Office of Medication Error Prevention and Risk Management before the final labeling can be approved. Conditional approval of the name may be obtained earlier in the process. Until the proprietary name is approved, the product may be referred to in submissions and studies by any name or number that the Sponsor chooses.

Once approved, a proprietary name is important in distinguishing and promoting a product approved via the 505(b)(2) pathway, similar to that of a 505(b)(1), or new molecular entity.

Q4      Is the 505(b)(2) pathway available for approval of biologics that are similar?

No. Products that are similar to biologics approved via a Biologics License Application (BLA), known as a “biosimilars,” are approved via Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). Whereas a 505(b)(2) product requires an NDA submission to the FDA’s Center for Drug Evaluation and Research (CDER), biosimilars require submission of a 351(k) BLA to the Center for Biologics Evaluation and Research (CBER).


Products that are suitable for approval via the 505(b)(2) regulatory pathway include drug products for which existing information can be leveraged to reduce the time and cost for approval. For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways Camargo’s multi-disciplinary team can help you get your product approved with a minimal development program, read more here or contact us.

Further topics of FAQs in upcoming blogs include:

  • Pharmaceutical Quality (CMC)
  • Nonclinical Data
  • Pharmacokinetic Studies
  • Clinical Studies
  • Patent Certification
  • Marketing Exclusivity and Generic Competition
  • OTC or NDA?


Author: Angela Drew, Ph.D., Product Ideation Consultant, Camargo Pharmaceutical Services

The Regulation of Follow-On Biological Products via 505(b)(2)…Strike While the Iron is Hot

Strike While the Iron is Hot

In December 2015, the U.S. FDA granted approval for Eli Lilly and Company’s Basaglar (insulin glargine injection), a long-acting human insulin product indicated for glycemic control in patients with diabetes mellitus. Basaglar marked the first “follow-on” insulin therapy to be approved in the U.S. through a truncated review pathway based on similar safety and efficacy findings to that of an existing drug, Lantus (insulin glargine injection). Basaglar possesses an identical amino acid sequence to Lantus, and thus Lilly successfully submitted a new drug application through the abbreviated 505(b)(2) pathway that relied, in part, on the FDA’s finding of safety and effectiveness for Lantus to support approval. Ultimately, Basaglar not only proved sufficiently similar to Lantus to scientifically justify reliance, but Basaglar-specific data (including two clinical trials enrolling 534 and 744 patients with type 1 and 2 diabetes mellitus respectively) firmly established the drug’s safety and efficacy for its approved uses.

Notably, Basaglar is considered a biosimilar of Lantus in other regions such as Europe (branded under the name Abrasia) where it received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP, a division of the European Medicines Agency) in 2014, however it was technically approved as a “follow-on” product in the United States. This may come as a surprise to many, however the reasoning behind the FDA’s decision is fairly straightforward, and is largely due to historical regulation of similar (animal- and human- derived) protein-based biopharmaceuticals (like Lantus) as drugs.

Existing Legal Basis for Regulation of Biological Products

In the U.S., two statutes currently have regulatory jurisdiction over therapeutic biological products: The Federal Food, Drug, and Cosmetic Act (21 USC § 301, FD&C), and the Public Health Services (PHS) Act (42 USC § 262; PHS). Generally, the FDA’s Center for Biologics Evaluation and Research (CBER) regulates the majority of biologics and associated biosimilar products under section 351 of the PHS Act, however a select handful of biologics that were traditionally derived from natural sources (i.e. insulin, human growth hormones,) as well as associated follow-on products are actually still regulated as drugs by the Center for Drug Evaluation and Research (CDER) under section 505 of the FD&C Act. FDA generally refers to follow-on protein products as those subsequent-generation proteins and peptides deemed to be sufficiently similar to a product already approved under the FD&C Act.

Why aren’t all biologics reviewed and regulated by CBER? At least in terms of abbreviated approval, the answer may have more to do with familiarity than anything else. Whereas the FDA asserts there already exists sufficient authority and infrastructure for follow-on protein products to be developed under section 505(b)(2) where scientifically appropriate, the infrastructure for accelerated biosimilar approval that currently exists for Section 351(k) of PHS is still somewhat nebulous. In 2010, the PHS Act was amended to create an abbreviated approval pathway for biosimilars, or biologics deemed highly similar to or interchangeable with existing approved reference biological products. This pathway, commonly referred to as the Biologics Price Competition and Innovation Act (BPCIA) of 2010, is similar in concept to that of the Hatch-Waxman Act of 1984 in that it allows reliance on previously established scientific knowledge about a drug, thereby saving time and avoiding unnecessary duplication of clinical or nonclinical testing. According to the FDA, under section 351(i) of this amendment, biological products are approved as biosimilar if a sponsor can demonstrate “high similarity” to a reference product notwithstanding minor differences in clinically inactive components and there are no “clinically meaningful” differences between the biological product and the reference product in terms of safety, purity and potency. However, many have found this concept confusing, especially what constitutes clinically meaningful, and what level of nonclinical and clinical evidence is necessary to establish “high similarity”. Consequently, the BPICA has been riddled with a host of regulatory and scientific issues, which may be why only a small handful of products have been approved since its implementation.

Choosing the Appropriate Developmental Pathway for Biologic Products

When deciding which developmental pathway to pursue for a biologic product, consider these fundamental differences that exist between the 505(b)(2) and 351(k) regulatory pathways (Table 1):

Table 1Differences Between 505(b)(2) and 351(k) Regulatory Pathways

Table 1 Differences Between 505(b)(2) and 351(k) Regulatory Pathways

Going, Going, Gone?

The BPCIA recently changed the authority under which follow-on protein products will soon be regulated by amending the definition of a ‘biological product’ in the PHS Act to include a ‘protein (except any chemically synthesized polypeptide). On March 11, 2016, the FDA released a draft guidance on its interpretation of the “deemed to be a license” provision of the BPICA 2010. This provision (Section 7002(e)(4)) states that “An approved application for a biological product under section 505 of the Food, Drug, and Cosmetic Act (21 U.S.C. 355) shall be deemed to be a license for the biological product under such 351 [of the PHS Act] on the date that is 10 years after the date of enactment of [the BPCI Act]”. The FDA interprets this provision to mean that as of March 23, 2020, the 505(b)(2) pathway will no longer be available for biosimilar approval. Furthermore, NDA applications for biological products that have already been approved under 505(b)(2) will become Biologics License Applications (BLAs) under section 351(k). Regarding pending applications, the statute is interpreted rather conservatively: the FDA states that the BPCIA “does not provide a mechanism to transition an approved application under section 505 to an approved BLA under the PHS Act prior to March 23, 2020, or after March 23, 2020. Unfortunately, the upcoming changes will undoubtedly slow down the developmental process for new follow-on products like Basaglar that are simple enough for submission under 505(b)(2), so it may be advisable for those development programs that are 505(b)(2)-applicable to take advantage of the pathway while the opportunity is still available.

For many, the 505(b)(2) pathway may present a more streamlined regulatory option for certain follow-on protein products, but only for a limited time.  In addition to a more established and predictable regulatory pathway, 505(b)(2) offers up to 5 years of market exclusivity for products where statutory requirements are met. Camargo is the global regulatory authority on 505(b)(2) submissions; for more information on how we can meet your regulatory needs, please contact us.

Author: Marcoita Gilbert, Ph.D., Research Scientist, Camargo Pharmaceutical Services


*Table 1 reference to http://www.biologicsblog.com/blog/biosimilars-under-505-b-2-pathway-2/

Taking the Uncertainty out of Drug Development: Statistical Bootstrapping Method Using a Bias-Corrected Acceleration Approach for Highly Variable Dissolution Data

Statistical Bootstrapping Method Using a Bias-Corrected Acceleration Approach

Well-reasoned and properly conducted statistical analyses can be essential to successful drug development, particularly in the context of manufacturing scale-up, process and component changes, and in comparisons with a reference product. Similarity tests between dissolution profiles steer the development path forward based on the quality and interpretation of the results. When the wrong statistical analysis method is applied, it can lead a development program completely off its rails. But does the choice of statistical analysis method for highly variable dissolution data have to lead to uncertainty?

The Challenge

Dissolution datasets are commonly used to compare manufactured drug products from different lots or from different manufacturers. Because in vitro dissolution analytical methods can serve as a proxy for in vivo product disintegration, dissolution, active ingredient release, and availability for uptake into the systemic circulation, statistical comparisons between lots or drug products’ dissolution data are common. In the context of drug development and regulatory approvals, comparisons are most often used to show similarities or differences between a reference listed drug and a newly manufactured generic version (e.g., as in an ANDA); a different formulation of a solid oral dosage form (e.g., as in a 505(b)(2) NDA); and comparisons between lots of the same drug product manufactured before and after scale increases, or after component, manufacturing scale, and process changes that may occur (or be considered) before and after product approval.

Camargo is deeply familiar with the challenges of performing FDA-acceptable calculations for the similarity factor (f2) when highly variable dissolution data is present. Our experience with more than 200 FDA approvals has driven our team to develop a statistical methodology and associated programming that performs consistent analysis to calculate the similarity factor (f2) using the bias-corrected and accelerated (BCA) bootstrapping method approach.

Statistical methodologies are complex when dissolution datasets are highly variable. This variability can cause a great deal of uncertainty, which can have a significant impact on the clarity of the statistical output and the regulatory conclusions that can be drawn from it. Ultimately, the success of a product-development program and a drug’s FDA approval—particularly for 505(b)(2) and ANDA programs—can rest on the statistical approach used and whether it is reliable or not.

The Road to the BCA Method

The Camargo team meets with the FDA on average 3 – 6 times per month, which helps our regulatory scientists understand FDA’s current thinking on the preferred technical and strategic approaches to drug development. From our many interactions with the FDA, we have confirmed that the FDA prefers the bootstrap method with BCA to evaluate the similarity factor, f2, for highly variable dissolution data.

One of the regulatory requirements is to estimate the similarity factor (f2) to determine the similarity between the dissolution profiles of the test (post-change) and reference (pre-change) products (12 units each). The f2 calculation uses mean dissolution values. However, when the variability of dissolution data is high (more than 20 percent (%) coefficient of variation (CV), at earlier time points (e.g., 15 minutes) or more than 10% at other time points) other statistical models should be considered.

Q&A with Camargo Biopharmaceutical Scientists

In order to best convey the background and substance of this complex topic, we have conducted this discussion as a question and answer with Camargo co-founder and Chief Scientific Officer at Camargo, Dr. Ruth Stevens, and Dr. Loan Pham, Specialist in Pharmacokinetics and Statistics at Camargo, moderated by Jennifer King, Director of Marketing.

How did you become interested in this topic?

Dr. Pham: I like to follow the latest trends for acceptable testing for biopharmaceutics. In this case, I discovered many questions in European and US regulatory forums regarding highly variable dissolution data. I wanted to develop statistical programming that would consistently provide the most reliable results for highly variable dissolution datasets.

Dr. Stevens: Part of the journey is based on previous discussions and research on Scientific and Regulatory Standards for Assessing Product Performance Using the Similarity Factor, f2, and on a scientific roundtable at American Association of Pharmaceutical Scientists Annual Meeting. In 2013, the FDA invited me to write a commentary article from the scientific roundtable (here).

Why is the bootstrap method with BCA important?

Dr. Pham: For NDAs, many applicants don’t fully understand which test is acceptable to the FDA for highly variable dissolution data. There is no clear published guidance for specific tests that the FDA recommends an applicant to use, so Camargo has developed expertise in this matter.

This opens up conversations with the FDA on which statistical approach, given the particular circumstances of a specific drug product, is most relevant for approval.

When is this method most important to be used?

Dr. Stevens: If the assumptions of the statistical tests are met there will be very little difference in the results, thus various methods of statistical analysis can be used. However, the bootstrap method with BCA doesn’t need to assume the data is normally distributed, giving it a wider versatility in calculation to produce reliable results.

What are the top two advantages associated with the bootstrap method with BCA?

Dr. Pham: The top two advantages are: 1) it enables a reliable result even when highly variable dissolution data sets are being compared and analyzed. 2) FDA has concluded that this methodology can be very useful for regulatory decision-making in this context. The SAS code that Camargo developed for the bootstrap method are used to calculate the 90% CIs using bias-corrected and accelerated (BCA) approaches.

What is the basic approach to this bootstrap method?

Dr. Stevens: Often with highly variable dissolution data, a few tablets are considered “outliers” which would have more impact on the mean dissolution time point result than others (an outlier is commonly defined as a point that falls more than 1.5 times the interquartile range above the third quartile or below the first quartile). The BCA bootstrap method is used to gain a more reliable result that limits the impact of any outliers. If the 90% CI lower limit of BCA bootstrapped f2 is equal to or greater than 50, the similarity between the test and reference products is demonstrated, even considering the high variability and outliers.

Bootstrap method with bca

Figure 1, above: f2 histogram obtained from the bootstrapping method (n = 10000)

Is this method easy to implement?

Dr. Pham: For a statistician familiar with the SAS program and formulation sciences [or biopharmaceutics] in drug development, it may be. When the audience is familiar with highly variable dissolution data sets and is looking for an FDA-approved method, the bootstrap method with BCA is one.

You mention the FDA chooses to use the bootstrap method with BCA in the review process. Can you explain that? 

Dr. Stevens: We’ve learned the FDA has used the bootstrap method with BCA to reevaluate an applicant’s highly variable dissolution data set which did not demonstrate similarity (f2 < 50). After reevaluating the data set, the applicant passed based on the FDA’s recalculation using the bootstrap method with BCA. The applicant in that case was very lucky because they weren’t asked to reevaluate the dissolution dataset and resubmit the statistical method for dissolution data.

In the drug development process, the developer needs a very good method in place to make required comparisons, as the tests are being conducted to support drug development decisions and product approval, which ultimately can determine the viability and success of the of the product and its likelihood of reaching the market and the patients it is intended to treat.

Our expertise and experience with the statistical application of the bootstrap method with BCA in industry and with the FDA:

1) Scientific roundtable at AAPS, 2013

2) AAPS journal articles, 2015

3) Presentation at AAPS on bootstrap with BCA, 2015

To learn more about this topic, mark your calendars to attend a session at AAPS 2016, where Dr. Ruth Stevens, Dr. Loan Pham, and reviewers from the FDA will explore this topic further:

Dialogue and Debates Session: (#200) “Statistical Tests Applied To The Comparison Of Highly Variable Dissolution Profiles With Focus On Multivariate Statistical Distance (Msd) Vs. Bootstrap F2 Methods And Their Regulatory Application” for the 2016 AAPS Annual Meeting and Exposition. This session will be held on Wednesday, November 16, 2016 from 01:40 pm – 03:40 pm.

Using the Camargo preferred statistical bootstrapping method with BCA, we can help our clients get their statistics straight and their products approved. Learn more about the turnkey drug development services Camargo can provide or contact us today.


About the Authors:

Dr. Ruth Stevens: In addition to Ruth’s more than 20 years as a senior executive and regulatory scientist and strategist in the pharmaceutical industry, she was also a pharmacokinetics team leader and reviewer at FDA. She has a great deal of expertise in a wide range of biopharmaceutics-related issues crucial to drug approval.


Dr. Loan Pham is a pharmacokinetic scientist with a background in regulatory and pharmaceutical sciences. She performs analyses and review of biopharmaceutics and clinical pharmacology activities including protocol development, analysis plans, PK/PD modeling and simulation. In addition, she designs PK/PD studies and prepares and reviews regulatory documents and submissions.

Fixed-Combination Drug Products: Are Phase 2 and 3 Studies Really Necessary?

Many fixed-dose drug-drug combination products arise from an observation that a synergistic effect occurs when two drugs are administered together, or that both drugs are frequently taken together for convenience. As one or both drugs are typically already approved, the 505(b)(2) pathway is the obvious choice for approval of many drug-drug combination products. We have previously blogged about the appeal of the 505(b)(2) pathway for combination products here. Now to expand the discussion, we want to discuss a question that we are frequently asked by Sponsors: are Phase 2 and 3 studies necessary for fixed-combination drug products seeking approval via the 505(b)(2) pathway?

It would make sense to think that with two drug products already approved by the FDA that fewer Phase 2 and 3 studies should be required when applied in combination. But this is not always the case. In fact, fixed-combination drug-drug products sometimes require more studies than single component products.

Fixed-Combination Drug-Drug Products

Take the example of Allergan Inc. and AstraZeneca PLC working together to develop a combination aztreonam and avibactam product. The double-antibiotic product makes sense. Aztreonam is unique amongst β-lactam antibiotics in that it is resistant to hydrolysis by some metallo-β-lactamases (Amber Class B), yet it is inactive against isolates that produce other serine β-lactamases (Amber Class A and C). Avibactrim, a non-β-lactam β-lactamase inhibitor, restores aztreonam’s activity against isolates expressing multiple β-lactamases. As most Enterobacteriaceae isolates that produce metallo-β-lactamases increasingly coproduce class A or class C β-lactamases, the aztreonam and -avibactam products are already being employed to combat these antibiotic resistant pathogens. Funding support for the Phase 2 and 3 studies will be provided by the US government’s Biomedical Advanced Research and Development Authority and the European Union’s Innovative Medicines Initiative.

Another example is the combination of naltrexone HCl and bupropion HCl (Contrave® NDA205777, Purdue Pharma LP) for weight management. In this case, the constituent’s drugs come from 2 different pharmacological classes: naltrexone is an opioid antagonist, and bupropion is an inhibitor of the neuronal reuptake of dopamine and norepinephrine. Together they are believed to affect the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system). The combination of both products results in a synergistic effect on weight loss.

In both of these examples, each of the constituent drugs had already been approved by the FDA, but the combination of the two drugs had not. However, in both cases, the FDA required at least one Phase 2 and one Phase 3 study. In fact, for the approval of Contrave, the development program required 4 x Phase 2 studies, and 4 x Phase 3 studies in 4,500 subjects, in addition to a nonclinical safety pharmacology study.

Of the 93 drug-drug combination products in Camargo’s proprietary 505(b)(2) database for which approval data are available, two-thirds (63/93) required at least one Phase 2 or 3 study, and 28 required more than 4 Phase 2/3 studies. Of the remaining 30 studies, a further 6 studies required nonclinical studies leaving a total of 69/93 (68%) requiring studies for approval.

Why are so many studies required if both drugs are already approved?

The Combination Rule

In many cases, additional studies beyond those required for the original approvals of the 2 component drugs are required because the FDA must apply what is commonly referred to as the combination rule (21 CFR Section 300.50: Fixed-combination Prescription Drugs for Humans). This regulation states that “Two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.” Two ‘special cases’ of the rule are listed: for the addition of a component that enhances the safety and efficacy of the principal active, and to minimize the potential for abuse of the active.

Recent proposed changes to the regulation include:

  1. a clarification that the Combination Rule will apply to co-packaged and over-the-counter monograph drugs as well as prescription. (The FDA currently applies a similar standard under 21CFR 330.10(a)(4)(iv) in the development of OTC monographs, and has already been applying the Combination Rule to co-packaged products)
  2. a provision for the FDA to grant a waiver of some or all of the requirements in cases where it would be infeasible or medically unreasonable or unethical to meet the requirements, or for natural-sourced drugs/products in which the components make up the combination product, and
  3. removal of the exception for DESI1 drugs that are awaiting the results of safety and efficacy evaluations

These changes are more about harmonizing the existing language between product classes, and won’t make much difference to most Sponsors. In fact, the FDA has determined that this proposed rule is not a significant regulatory action.

What Are the Practical Implications of the Combination Rule?

In order to fulfill the requirements of the Combination Rule, a combination must demonstrate that each component contributes to the safety or efficacy of the product. This typically requires a multi-factorial study in which each component is compared separately and in combination to a placebo control. For example, if the product aims to combine Drug A and Drug B, 2 clinical studies with the following treatment arms may be required to demonstrate that each component contributes to the overall effect of the drug:

  1. Placebo
  2. Drug A
  3. Drug B
  4. Drug A and Drug B combined

Developing a triple drug combination product may require 8 treatment arms! However, the complexity increases even more when one considers that the dose of each drug must be justified in terms of dosing frequency, amount of each drug, and duration of each effect. If the dosage requires clinical justification, the required studies may be so numerous or large they may not be logistically or financially feasible.

Which Studies Should Your Development Plan Include?

When planning a development program for a combination product, it pays to have a 505(b)(2) expert on your side to minimize the size and scope of studies required and to apply 505(b)(2) pathway-specific strategic knowledge for FDA feedback at the Pre-IND stage and beyond.

Prior experience in working with the 505(b)(2) regulatory pathway facilitates the use of appropriate data from the literature, product labels, and OTC monographs to reduce the clinical requirements for approval of the final combination product.

To learn more about ways Camargo’s multi-disciplinary team can help you get your product approved with a minimal development program, read more here or contact us.

1DESI = Drug Efficacy Study Implementation. ‘DESI drugs’ approved between 1938 and 1962 were only evaluated for safety under the FD&C Act. In response to the Kefauver-Harris Drug Amendments to the FD&C Act, FDA initiated DESI reviews to assess the efficacy of these drugs. The National Academy of Sciences-National Research Council produced the reports for evaluation by the FDA. A significant number of the drugs undergoing DESI review were fixed-combination drugs.

Author: Angela Drew, Ph.D., Product Ideation Consultant, Camargo Pharmaceutical Services

Faster Approval of Combination Drug Products Via the 505(b)(2) Pathway

On April 11 and 12, 2016, Ken Phelps, President and CEO of Camargo Pharmaceutical Services, spoke at the 505(b)(2) Forum and CTrials Conference in Tel Aviv, Israel, on the topic of 505(b)(2) Combination Drug Products. What is attractive about the 505(b)(2) regulatory pathway, and specifically, why is it so beneficial for approval of combination products? We’d like to open up and share a part of Ken’s recent discussion here.

What Is Special About the 505(b)(2) Approval Pathway?

Under United States law, “a 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval ‘were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted’” (21 U.S.C. 355(b)(2)). This means the 505(b)(2) regulatory pathway can be used to leverage information that already exists in order to reduce the number and size of studies required for approval.

505b2 NDAs Historical Data

The graphic above shows that over the past ten years, the rate of 505(b)(2) submissions have been increasing such that between the period of 2004 – 2014, more than 350 new drugs have been approved by the FDA through the 505(b)(2) pathway. As they utilize existing information on a drug, 505(b)(2) products typically have a lower risk, lower cost, and faster time to market than traditional new drug approvals.

Examples of combination products for which the 505(b)(2) pathway may be appropriate include new combinations, new dosage forms of approved combinations, and new molecular entities (one or both drugs has not been approved). Two examples of products approved via the 505(b)(2) pathway include:

  • Aripiprazole lauroxil (new molecular entity and drug-device combination)
    • RLD = aripiprazole (Abilify®, Otsuka NDA 021436), oral tablets/solution for daily dosing
    • New molecular entity: aripiprazole lauroxil (Aristada™, Alkermes Inc.; prodrug of the prodrug of aripiprazole), extended-release suspension in prefilled syringes for monthly or 6-weekly dosing, approved 2015.
  • Lidocaine and tetracaine (new combination)
    • Previous approvals: Lidocaine- approved prior to 1982; Tetracaine – not approved
    • New combination: Lidocaine + Tetracaine (Synera, Galen Specialty, NDA 021623) approved 2005.

Which Types of Combination Drug Products are Eligible for Approval via the 505(b)(2) Pathway?

  • A drug plus a device
  • Two drugs and a device
  • A drug plus a biologic
  • A drug-drug combination

In each of the first 3 cases, the products are only appropriate for the 505(b)(2) pathway if the FDA agrees that the Primary Mode of Action (PMOA) of the entire product is the drug.

Examples of 505(b)(2)-appropriate combination drug products include:

  • Monoclonal antibody combined with a therapeutic drug (if drug is PMOA)
  • Pre-filled syringes
  • Insulin injector pens
  • Metered-dose inhalers
  • Transdermal patches
  • Drug packaged with a delivery device
  • Two drugs combined in a fixed-dosage form

505b2 combination drugs

The figure above shows the 505(b)(2) approvals by type. Note the blue slice, 24%, which represents products registered as new drug-drug combination products. When we include drug-device combinations and products for which one component was a new molecular entity, the figure rises to 29.7% of all approved 505(b)(2) products that are some type of combination product.

Here at Camargo, we believe combination products are a growing area filled with potential. Learn more about 505(b)(2) combination products through previous articles and posts, or contact us to find out more about how Camargo can help you and your business reach your drug development goals.



Jennifer King, Director of Marketing, Camargo Pharmaceutical Services

Angela Drew, Ph.D., Product Ideation Consultant, Camargo Pharmaceutical Services

Call 1.888.451.5708 | Visit www.camargopharma.com | Email services@camargopharma.com