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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

Product Ideation: Identifying Your Optimal Drug Development Candidate

It’s a familiar story: Pharmaceutical Company X spends years developing Product Y only to discover at a crucial point in the process that Product Y will not succeed. The result is often millions of dollars and development years wasted. But could drug development failure be prevented?

Oftentimes, drug development failure can be attributed to misalignment with one or more factors crucial for success in medical, regulatory, science and manufacturing, and market. Devoting more time and resources to these areas doesn’t always equal success; drug development failures happen to pharmaceutical giants as well as to small startups. But does failure have to happen so often?

At Camargo, we think drug development failure can be prevented. We’ve proven our experience by working on and gaining approval for more than 200 drugs. With a more than 95% FDA concurrence rate, our team helps clients like you to develop successful drugs, time and again. Our process for selecting viable drug candidates is called Product Ideation.

What is Product Ideation?

Product Ideation is a partnering process in which Camargo works with a client (Sponsor) to identify an optimal drug or drug-device product(s) for the Sponsor to develop for approval via the 505(b)(2) pathway. Over the last decade, Camargo has conducted numerous Product Ideation projects for large, medium, and small pharmaceutical companies. Each project required unique criteria, which has helped us to hone a customized process. Camargo’s drug development experience positions us as the most qualified team in the rapidly expanding field of Product Ideation.

So what is the process and how does it start?

Camargo performs the Product Ideation process with extensive consultation with the Sponsor. The process begins with Camargo’s proprietary Product Selection Criteria Questionnaire in which the Sponsor shares preferences regarding all relevant product attributes that will be important for a commercially successful final product. In most cases, the Sponsor requests that the drug be selected from a particular therapeutic area or from a preselected list of candidates, or that it be suited to a technology that the Sponsor has developed.

Examples of the new technology may include a novel drug delivery device or a new formulation offering superior drug delivery or pharmacokinetics compared with existing products. Camargo then considers the Sponsor’s requirements and designs a custom Process Plan that outlines the intended filtering and prioritization process.

Camargo's Ideation Product Selection Process

Figure 1: Camargo’s Product Ideation Process


Partnering to select an optimal product with a Sponsor involves multiple rounds of prioritizing based on Camargo’s regulatory, CMC, nonclinical, clinical, quality, marketing, and commercialization, and general drug development experience (see Figure above). The Sponsor’s input on strategic priorities is an integral part of the process.

At each step, Camargo generates Target Product Profiles (TPPs) for the remaining candidate products. A dynamic TPP proposes drug product attributes while being continually refined during the entire selection process. The TPP is the critical foundation of a successful drug development program because it forms the basis for the labeling that will distinguish the proposed product in the marketplace.

As the candidate priority list becomes progressively shorter after multiple rounds of consideration and advice, drug development feasibility reports are prepared for the highest priority candidates. These reports provide the Sponsor with in-depth strategic, regulatory, and commercialization information that assist in identifying the final candidate/s for development. After a decision is made, the final step in the product ideation process usually involves a Pre-IND meeting with the FDA to gain agreement on the proposed development program.

What are the Benefits of Product Ideation?

In today’s competitive drug development landscape, the benefits of optimizing your next product according to your company’s capabilities and strategic goals are obvious. Product Ideation allows utilization of Camargo’s databases and regulatory expertise, including ways to reduce your nonclinical and clinical programs by using the 505(b)(2) regulatory pathway. Often, Camargo presents novel solutions to a Sponsor that were not previously considered, including formulation enhancements, and/or changes to the approved indication or dosage form.

A comparison of various development strategies for lead candidates, combined with establishing credibility of the chosen strategy by aligning with the FDA expectations early in a development program, can save time and money on the pathway to the market. In all cases, the benefits of having a Product Ideation partner with experience in creating successful drug development programs and in preparing 505(b)(2) submissions can mean significant reduced costs and/or time to market for a product

What Is the Result?

The final number of drug candidates provided depends on the Sponsor’s initial request, as with all of the requirements laid out at the beginning of Product Ideation. Camargo believes in the process and guarantees that the end result will be a viable candidate(s) that fits your specific requirements, and are appropriate for development via the 505(b)(2) pathway. The extent of Camargo’s involvement and guidance from that point on is up to you.

Learn more about Camargo’s services by visiting our Services page, or Contact Us for more information.


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

Pediatric Applicability or Not–This Revised Guidance Is for You

Since 1994, the statutory and regulatory requirements for drug product labeling for pediatric populations have been evolving. The FDA Modernization Act of 1997 (FDAMA) contained incentives for conducting pediatric studies on drugs that had exclusivity or patent protection. In 2003, the Pediatric Research Equity Act (PREA) was signed into law requiring, for certain drugs, sponsors to conduct studies on pediatric populations for the claimed indications; however, it did not include a proposed timeline and plan for the submission of pediatric studies to the IND. The FDA Safety and Innovation Act of 2012 (FDASIA) required sponsors planning to submit an application for a drug subject to PREA, to submit an Initial Pediatric Study Plan, or iPSP, early in the drug development process.

Currently, a sponsor who plans to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration (i.e., that is subject to PREA) is required (under FDASIA) to submit an iPSP, unless the drug was granted orphan designation for the proposed indication at the time the iPSP is required. Thus, unless you are developing an orphan drug, ALL NDAs must have a pediatric plan, even if your drug is not targeted at this population. If you fail to adhere to the timings presented below, your NDA may be refused.

Pediatric Study Plans: FDA Revised Draft Guidance

On March 8, 2016, the Federal Register (FR DOC# 2016-05223) announced availability of a revised draft guidance, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans, (CDER/CBER, 2016) replacing the July 2013 draft guidance for industry of the same title.

This Procedural Revision 1 is currently distributed for comment purposes only; however, it addresses the FDA’s current thinking regarding implementation of the requirement for sponsors to submit an iPSP to an application. The guidance includes additional clarifications to existing sections, an updated Appendix 1 iPSP template, and the addition of new sections. Highlights are as follows:


  • A sponsor must submit the iPSP before the date on which the sponsor submits the required assessments and not later than 60 calendar days after the date of the end-of-phase 2 meeting. In the absence of an end-of-phase 2 meeting, the sponsor should submit the iPSP as early as practicable but before the initiation of any phase 3 studies, or any combined phase 2 and phase 3 studies.
  • If a phase 3 study or a combined phase 2 and phase 3 study will not be conducted, the sponsor should submit the iPSP no later than 210 calendar days before it submits a marketing application or supplement.
  • A sponsor should submit the iPSP to its IND for the drug.
  • In cases when there is no active IND for the drug, but the sponsor expects upon submission of the IND that the initial studies would include a phase 3 study, the iPSP should be submitted as a pre-IND submission. In this situation, the FDA encourages sponsors to schedule a pre-IND meeting before submission of the iPSP, and, as stated above, the sponsor should submit the iPSP before the initiation of any phase 3 studies or combined phase 2 and phase 3 studies.
  • FDA has 90 days to review and comment on an iPSP. The sponsor then has 90 days to submit an agreed iPSP. FDA has 30 days to issue correspondence confirming agreement or to issue a non-agreed iPSP letter. [total review time = 210 days].
  • Do not submit a marketing application until an agreed-iPSP is reached.

The following sections are added in the revised guidance:

Section V.A. Materially Incomplete iPSPs.

If all pediatric age groups and all indications are not addressed, a sponsor will be contacted and a complete iPSP should be submitted within 30 days. A new 210-day clock starts.

Section VI. Relationship of Agreed iPSP to the Requirement to Submit a Pediatric Plan with an Application.

The sponsor must submit the agreed iPSP in the NDA. Any waivers/deferrals in the agreed iPSP serve as the official requests and a decision is made during review of the application.

Section VII. Contents and Timing of Requested Amendment to an iPSP.

An agreed iPSP may be amended and can include changes that would significantly delay the start and/or completion of pediatric studies, or from changing the plans for deferrals, waivers, or partial waivers arising from safety data generated from nonclinical studies and/or clinical trials. A request for an amendment should include:

  • specifications of the changes with justification,
  • a redline of the agreed-iPSP showing the changes
  • a clean copy of the amended iPSP.

The amendment is not agreed until FDA sends an acceptable letter. If the amendment is submitted within 210 days of the planned NDA submission, include the previously agreed iPSP as part of the application. Changes will be considered during application review. However, if studies were expected to be completed before NDA submission as part of the agreed iPSP, this may result in a refusal-to-file. If that is the case, submit a justification for the delay in completing the studies in the request for an amendment to the agreed iPSP.

Section VIII. Non-Agreed iPSP.

If the sponsor and the FDA are unable to reach an agreed iPSP within the 210 day review period, FDA issues a non-agreed letter. There is no timeline for review and agreement of a non-agreed iPSP. If no agreement is reached for an amended iPSP, a non-agreed amended iPSP letter is issued. The agreed iPSP is considered in force until the amended iPSP agreement is reached. If agreement is not reached before NDA submission when a deferral is requested, submit the agreed iPSP and all correspondence regarding non-agreed amendments.

Section IX. Reaching Agreement on the Non-Agreed iPSP.

There is no statutory timeline to resolve the non-agreement; however, FDA will work to resolve it as quickly as possible. The sponsor can request a meeting with FDA to discuss any disagreement. After resolution, submit the proposed agreed iPSP or amendment for FDA review.

Camargo can provide expert guidance through the process of developing an initial pediatric study plan. For more information about services Camargo can provide, visit our Services page or Contact Us for more information.


Author: Annette Arlinghaus, Associate Director of Submissions, Camargo Pharmaceutical Services

Is a Reference Listed Drug Mandatory in the 505(b)(2) Pathway?

If you are a frequent reader of our blog, you know that the 505(b)(2) pathway can facilitate a cheaper, faster drug approval route. This is accomplished by relying on: 1) safety and efficacy data from published literature and/or 2) the agency’s assessment of safety and efficacy of a FDA-approved product, known as the “reference listed drug”, or RLD*. While many 505(b)(2) applications can and should use an RLD, the necessity of an RLD in a 505(b)(2) application is a common misconception. In fact, there are many situations where using an RLD doesn’t make sense from a scientific or strategic perspective. In this post, we will discuss some considerations involved in choosing a “No RLD” strategy.

In some cases, an RLD is simply not necessary. Active pharmaceutical ingredients (APIs) with a long history of use may have enough publicly available data to “cover all the bases” for safety or efficacy. Camargo recently worked with a sponsor developing a product with an API that was part of a class of drugs with a long history of use. Because of this extensive history, much was known about this API’s of mechanism of action, safety, and side effects. Upon further investigation, all of the information needed to satisfy the FDA’s safety requirements could be found in published literature. This included nonclinical data, drug interaction information, mechanism of action, local effects and safety information. Therefore, the sponsor only needed to provide evidence of efficacy, which was accomplished by a Phase 3 study that was already underway. Since there was no reliance on data previously accepted by the FDA, a “No RLD” strategy could be used.

The twist to this story is that this same product could have cited an RLD in the application. While this would have been a reasonable approach, the RLD under consideration was on patent for many more years. If this RLD had been used in the application, the filing would have been subject to patent infringement litigation and a 30-month stay on approval. Therefore, while an RLD can prevent unnecessary duplication of studies of efficacy and safety, it can also have important legal implications. Clearly, this decision shouldn’t be taken lightly!

With the option of “RLD” vs “No RLD” on the table, of course the sponsor chose the “No RLD” strategy. This is just one of many situations where a “no RLD” strategy can be used. With all the options available in a 505(b)(2) pathway, working with an experienced regulatory team can help save you time and money. So whether your application has an RLD, no RLD, or you need help deciding which is the best strategy, the experts at Camargo can help you plan the best path forward.


*The Orange Book refers to a Reference Listed Drug, or RLD, for a generic and its correlating 505(j) approval pathway. For 505(b)(2) pathway, the Orange Book uses the term Listed Drug. For simplification and the purposes of this article, we are using the term RLD for both 505(j) and 505(b)(2) applications.

Author: Lisa Crose, Ph.D., Camargo Research Scientist

Additional 505(b)(2) Benefits: Selective Safety Data Collection


Last month CDER/CBER released a short, final guidance, “Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations.” (CDER/CBER, 2016)

While brief, the guidance could provide a significant reduction in safety data collection for NDA sponsors. This could be especially true for sponsors using the 505(b)(2) regulatory pathway.

The guidance is “…intended to apply to safety data collection during late-stage premarket and postapproval clinical investigations in all disease settings except rare diseases…” FDA notes that the guidance may differ from recommendations in a specific oncology related guidance (Cancer Drug and Biological Products Clinical Data in Marketing Applications CDER/CBER 2001) and also that the guidance may well conflict with the expectations for safety data collection in other countries.

FDA also points out that: “This guidance is not intended to affect reporting (as opposed to collection) of postmarketing adverse events relevant to an approved drug as required under 21 CFR 314.80 and 600.80 or affect reporting of investigational new drug application (IND) safety information as required under § 312.32 (21 CFR 312.32). Those reporting requirements remain unchanged, and selective safety data collection may only occur in a manner that would permit all regulatory reporting requirements to be fulfilled.” The guidance describes a number of situations in late stage product development and early post-approval where it may be appropriate for the collection of safety data to be reduced in some ongoing trials. This is defined as “Selective Safety Data Collection”. Examples are:

  • No collection of certain safety data
  • Less-frequent collection of certain safety data
  • Collection of certain safety data from only a fraction of the total trial enrollment (e.g., 10 percent of patients in a large trial)

The conditions which may make selective safety data collection appropriate are listed as:

  • The number of patients and their characteristics, the duration of exposure, and the dose range used in previous clinical investigations are sufficient to adequately characterize the safety profile of the drug for common, non-serious adverse events.
  • The occurrence of common, non-serious adverse events has been generally similar across multiple clinical investigations.
  • The drug’s safety profile is established to the extent that it is reasonable to conclude that the occurrence of common, non-serious adverse events in the population to be studied will be similar to rates observed in previously conducted clinical investigations.

The types of clinical investigations that may be considered for selective safety data collection are:

  • Clinical investigations of new indications of approved drugs
  • Postapproval clinical studies and trials conducted to fulfill postmarketing requirements and postmarketing commitments
  • Late-stage premarket and postapproval outcome clinical trials
  • Premarket clinical investigations for some original applications
  • Postapproval clinical investigations in a different patient population or with different doses or other conditions of use

Next, and probably most importantly, what types of safety data are candidates for selective safety data collection?

  • Postapproval clinical investigations in a different patient population or with different doses or other conditions of use
  • Routine laboratory monitoring
  • Information on concomitant medications
  • Patient history and physical exams

The lynchpin to the possibility of selective safety data collection appears to be the existence of a robust safety database for the product in question. That is often the case with a product being developed using the 505(b)(2) regulatory pathway. By definition, an application pursuant to Section 505(b)(2) frequently relies on extensive, pre-existing safety data.

The guidance contains further details and conditions, the most important of which is the requirement to develop a plan and reach agreement on the specifics of a selective safety data collection with the relevant FDA review division or divisions at, e.g., the end-of-phase 2 meeting prior to initiation of a Phase 3 study. Camargo frequently assists in these types of negotiations.

Author: William Stoltman, JD

How Much Is a First Cycle Review ANDA Approval Worth to You?

At the recent GPhA meeting in Orlando, Florida, Dr. Kathleen Uhl from the FDA Office of Generic Drugs (OGD) spoke about the quality of Abbreviated New Drug Application (ANDA) submissions and highlighted the detriments of a poor quality submission. All would agree that a poor quality submission is costly for drug product development. Dr. Uhl discussed the various metrics for a first cycle quality ANDA submission, and presented the following:

  • The number of Refuse to Receive (RTR) letters issued each fiscal year
  • The first cycle review ANDA approval rate
  • The number of ANDA review cycles prior to approval

In 2015 alone, approximately 24% of ANDA submissions resulted in Refuse to Receive letters. These letters were primarily associated with inadequate stability information and / or inadequate dissolution data. Many of these could have been avoided with closer attention given to the basic dissolution and stability requirements in the submission.

Existing ANDA Filing Guidance

The ANDA Filing Checklist is a great place to start when reviewing an ANDA prior to agency submission. The June 2013 Guidance for Industry ANDAs: Stability Testing of Drug Substances and Products and the September 2011 article published in the AAPS journal titled Dissolution Testing for Generic Drugs: An FDA perspective include the following basic recommendations:


  • Conduct comparative dissolution using a minimum of n=12 dosage units each of both test and reference products
  • Generate dissolution data for products with samplings at multiple time points (3-4 time points at a minimum, equally spaced, excluding time zero) to characterize the dissolution profile
  • Develop and communicate rationale for the Dissolution method used
  • Use an FDA-recommended method. If not using an FDA-recommended method, then the agency expects to see both data from the sponsor’s method compared with the data using the FDA-recommended method


  • Submit data from a minimum of three batches which are manufactured and packaged using processes representative of the commercial processes
  • Provide data from a minimum of 2 drug substance lots and additional data if more than one drug substance source
  • Present a minimum of 6 months stability data that includes long-term and accelerated conditions at the time of submission

The Approval Facts

In her presentation, Dr. Uhl highlighted the number of review cycles required to gain ANDA approval, and how that number has changed over the years (Figure 1). What is the average number of CMC review cycles for an ANDA?

Figure 1: the average number of CMC Review Cycles for ANDAs to Approval for 2009 – July 2014

Figure 1: the average number of CMC Review Cycles for ANDAs to Approval for 2009 – July 2014

Since 2009, it reportedly takes an average of 4 CMC review cycles prior to an ANDA approval, as shown in Figure 1. Fixing the above CMC metrics is a sure way to reduce the number of review cycles.

In contrast, an NDA is now approved on the first cycle review 95% of the time (Figure 2).

Figure 2: the Increasing Rate of First Cycle Approvals under PDUFA for CDER NME NDAs/BLAs by Year

Figure 2: the Increasing Rate of First Cycle Approvals under PDUFA for CDER NME NDAs/BLAs by Year

Additional Requirements

The basic requirements established in the above help guide a submission to filing, but don’t guarantee acceptance. This is where experience in the field helps, in understanding the nuances involved with the many more requirements based on the dosage form, route of administration, and active pharmaceutical ingredient.

Camargo can provide expert guidance through the regulatory maze that leads to a first cycle ANDA approval, saving time and money, therefore improving a product’s return on investment. For more information about services Camargo can provide in an ANDA and NDA application, visit our Services page or Contact Us for more information.


About the Author: Kathy Kemme utilizes more than 18 years of pharmaceutical and CMC experience in her position as Associate Director of CMC at Camargo Pharmaceutical Services. She provides clients with her manufacturing, project management, and regulatory expertise to support human or veterinary pharmaceutical development programs.


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