During the development of new small molecule drug products, developers must conduct impurity and degradant evaluation at several points in the program and to varying degrees. These evaluations include the active pharmaceutical ingredient (API), also known as the drug substance, and the drug product (formulated
Premier Consulting’s regulatory strategists specializing in the US FDA’s 505(b)(2) approval pathway are often asked how a sponsor can recover from a pre-IND meeting that doesn’t go as planned. While we firmly believe that setbacks can be turned into opportunities for growth and success, conducting
President Biden of the United States (US) has recently signed into law the Fiscal Year 2023 Omnibus Appropriations Bill, which included the FDA Modernization Act 2.0. This act amends the Federal Food, Drug, and Cosmetic Act (FFDCA), which applies to new drugs, and the Public
On November 1, 2022, the U.S. Food and Drug Administration (FDA) adopted an addendum to the guidance titled “S1B(R1) Testing for Carcinogenicity of Pharmaceuticals,” which had previously been finalized by the International Council for Harmonization (ICH). The guidance document and integrated addendum detail an integrative,
One of the most common formulation issues that sponsors of new drug or biologic products face is the qualification of novel excipients. Although novel excipients can be a part of any new drug application (NDA) or biologics license application (BLA) development program, they seem to
There are numerous reasons why a sponsor may wish to market a new dosage form of an approved product. Aside from the obvious financial benefits to the sponsor, providing a more convenient and/or faster-acting dosage form of a well-chosen drug provides significant benefits for patients.
The number of approvals for combination products and 505(b)(2) applications has risen in recent years. Combination products consist of at least two constituent parts, each subject to its own statutory and regulatory requirements. Unlike fixed-dose combination therapies, which consist of drug-drug combinations, combination products can
For developers seeking to obtain approval for previously approved drug products in the United States, the U.S. Food and Drug Administration offers two abbreviated approval pathways — an abbreviated new drug application (ANDA) and a 505(b)(2) application. Both of these applications rely on the agency’s
In 2020, CDER approved 68 NDAs that used the 505(b)(2) pathway, representing important advances in patient care across a wide range of therapeutic areas. 505(b)(2) Drug Improvement Approvals by Year In spite of an unusual year due to the COVID-19 pandemic, NDA approvals via the
Rare Disease Clinical Trials Most Often Terminated Due to Regulatory and Recruitment Issues The difficulty associated with successfully completing rare disease clinical trials is well-known. Most people believe that recruitment is the primary reason because, by definition, the number of potential trial participants is extremely
Drug development is an extremely cumbersome process, requiring the testing of an agent from in vitro studies to in vivo studies to in silico modeling. Given that it can take up to 20 years for a final product to be approved, it is unsurprising that
In an era of pandemic urgency, repurposed drugs may be our first, best hope to finding effective treatments for COVID-19. Dozens of sponsors are now seeking efficient, streamlined processes to test and establish the safety and efficacy of existing products for the treatment of the novel
Hydroxychloroquine. The world rallied around this old drug as a potential treatment of COVID-19 patients. The pharma industry, independent researchers, and governments rushed to conduct trials to see if hydroxychloroquine is safe and effective at any stage of this invasive virus. Though it has now
Updated on: April 19, 2021 Asking the appropriate questions during a pre-IND meeting with the FDA is a critical step in planning a development program. A Pre-Investigational New Drug Application (pre-IND) meeting can be a valuable component in planning a development program. For companies that
In 2019, CDER approved 64 NDAs that used the 505(b)(2) pathway, representing important advances in patient care across a wide range of therapeutic areas. The number of 2019 NDA approvals that used the 505(b)(2) pathway fell from 75 in 2018 to 64 in 2019 (Figure 1), in
To succeed in today’s highly competitive pharmaceutical landscape, differentiation is key. In recent years, many generics companies have turned their focus to niche products, complex generics, or biosimilars to achieve this differentiation. During the 3rd Annual Portfolio Management Strategies for Biosimilars and Generics in Barcelona
As part of nationwide efforts to address the opioid crisis, FDA is taking a closer look at the development of critical medications that combat overdose deaths. Most recently, FDA announced its intention to prioritize review of ANDAs for drug products indicated for emergency use in
Last week, FDA published new guidance, Determining Whether to Submit an ANDA or a 505(b)(2) Application (CDER, 2019), to help Sponsors select the best abbreviated approval pathway for their product. While the guidance does not provide any monumental new initiatives, policies or approaches, here are four key
To get a successful return on investment (ROI) for your product, it is essential to establish early in the process: Is there an unmet need for the product? Which attributes will the product need to access the market? Will providers and patients be receptive to
The 505(b)(2) new drug application (NDA) pathway can provide unique advantages from the nonclinical development perspective that can save significant time, money, and resources. Compared to the 505(b)(1) NDA pathway, which is more standardized and follows the general guidance provided by the International Conference on
It is clear the FDA recognizes the range of development possibilities made possible by the 505(b)(2) pathway, as illustrated by the recently released draft guidance for the development of depot buprenorphine products for treatment of opioid-use disorder. What is striking about this guidance is that
Updated on: March 9, 2021 Emerging biopharma companies play a big role in overall drug development—the percentage of new therapies both originated and launched by these companies has increased over the last decade, in an industry that is growing at the same time. As drivers
From recent news, we know that the FDA has been under increasing pressure to reduce the timing of its reviews while maintaining the highest possible standards for safety and efficacy of the products it approves. This is the reason for the PDUFA and now the
As discussed in a previous blog post (here), the 505(b)(2) development pathway provides a flexible path for developers of new abuse-deterrent formulations. The FDA has shown significant motivation and flexibility in its drive to work with innovators to address the ongoing opioid crisis in the
Several states in the US have already passed laws that remove state restrictions on the medical use of marijuana and its derivatives, and more states are considering such action. The market for medical marijuana in the US is expected to surpass $20 billion by 2020.
The Approval Time for 505(b)(2) and 505(b)(1) NME Products Is Similar A recent article by the Tufts Center for the Study of Drug Development (summarized here) reported that approval times for New Molecular Entities (NMEs) approved via the 505(b)(2) pathway are nearly 5 months longer
Since its first appearance in 1980, the Approved Drug Products With Therapeutic Equivalence Evaluations publication (commonly referred to as the Orange Book) has served as a gateway for the emergence of generic drug products via the 505(j) drug approval pathway (and some new drug products
Section 505(b)(2) of the Food, Drug, and Cosmetic Act describes a 505(b)(2) new drug application (NDA) as an application where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has
Dramatically Decrease Drug Development Costs Through Literature-Only 505(b)(2) NDA Submissions How would you like to get an NDA approved without conducting any clinical studies? Premier Consulting presented a poster on literature-only 505(b)(2) New Drug Application (NDA) approvals at the recent 2016 AAPS annual meeting and
Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) of 2003 was enacted in order to address concerns that had potential to delay access to more affordable drugs. The FDA has been implementing the MMA via the statute since it was enacted
Time to Pick the Low-Hanging Fruit: Improving Drug Development ROI in 2017 With forecasts of decreasing peak sales for late pipeline drugs, a logical way to increase the return on investment (ROI) for pharmaceutical companies is to develop products with lower research and development (R&D)
A significant part of the FDA’s charge is ensuring the safety of drugs available to the public. While a substantial part of the FDA’s efforts in guaranteeing public safety go into the safety assessment process during drug development, the process does not end with NDA
While the United States market for drugs and biologics targeting tropical or rare pediatric diseases is very small, developing novel therapies for patients in these underrepresented groups can be advantageous for both patients and Sponsors. A number of incentives exist to encourage companies to apply
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
As the 505(b)(2) expert, Premier Consulting 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
As the 505(b)(2) expert, Premier Consulting 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,
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
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
On April 11 and 12, 2016, Ken Phelps, Strategic Advisor at Premier Consulting, 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’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
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
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
As new generic product options become more scarce and the competition more fierce, generic manufacturers have recently become very interested in the 505(b)(2) regulatory pathway. The benefits of the 505(b)(2) pathway are well known, such as a potentially lower cost and accelerated path to market.
It is a widely held tenet that market exclusivity is essential for the successful launch of a new drug. But is this always the case? For products approved through the FDA 505(b)(2) pathway, is pursuing the 3-year period of exclusivity available through Hatch-Waxman always necessary?
Earlier this month FDA (CDER and CBER) issued a new draft guidance, Best Practices for Communication Between IND Sponsors and FDA During Drug Development. Based on Premier Consulting’s frequent communications with the Agency during product development, the guidance does not present any profound or significant
On October 15, 2015, the United States Food and Drug Administration (FDA) issued a new guidance for industry and review staff with more uniform recommendations for the nonclinical safety evaluation of approved drug substances that are reformulated or in which a new route of administration
For years FDA has threatened to remove unapproved products (so-called DESI products) from the marketplace. Recently, the FDA took enforcement action against several unapproved prescription ear drops. What products will be next? DESI producers can use the 505(b)(2) pathway to avoid such actions on their products. Let’s take a
The headlines and newscasts reported Amarin’s success in wining off-label promotion, but behind the scenes, another noteworthy action took place – in a very rare action, the FDA rescinded a special protocol assessment (SPA) that would have enabled Amarin to promote the new indication. In
Shifting views on the safety of drug substances at FDA are not uncommon with the advent of new scientific findings or upon better understanding of physiological processes or disease states. With time, these shifting views may manifest as differences in policies or requirements for drug
Extrusion-enabled pharmaceutical processing (E2P2) has long been employed in pharmaceutical development (Drug Development and Industrial Pharmacy. 33:909-926,1043-1057 (2007)). Reasons for utilizing E2P2 include: Enhancing physico-chemical properties of APIs such as solubility and stability Modifying in vivo release of a drug to enhance bioavailability and clinical
Drug shortages can have serious and immediate effects on providing needed therapies to patients, and preventing shortages is a current priority for FDA. FDA has taken a variety of actions to eliminate, mitigate, and prevent shortages (Executive Order 13588; Interim Final Rule; and Draft Guidance
Recently a federal district court spotlighted FDA’s apparently inconsistent definitions of what constitutes an “active ingredient (AI)” in rejecting the Agency’s rationale for denying Amarin Pharmaceuticals Inc.’s fish oil capsule Vascepa (icosapent ethyl) (NDA 202057 approved July 26, 2012), request for 5 years of market
A 505(b)(2) may rely on the FDA’s previous findings of safety and efficacy of an approved drug product. It is possible to rely on more than one approved drug product. It is also possible that a 505(b)(2) applicant does not have to rely on any approved
As we have noted in this blog previously, under the Pediatric Research Equity Act (PREA), all new drug applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration are required to contain an assessment of the
The “cliff” has passed for pharma but has just begun for generics companies that have benefited from the high number of drugs going off patent. CEOs of generics companies report they are considering a spectrum of solutions to bridge the revenue gap, but perhaps none
Priority review vouchers (PRVs), which are fast-becoming a powerful incentive for drug companies, were originally based on a publication (Ridley et al. 2006) from a group at Fuqua School of Business at Duke University in NC. The idea behind PRVs was that developers of treatments
Orphan drugs, defined in the Orphan Drug Act as drugs developed to treat rare diseases that affect fewer than 200,000 people in the U.S., have begun to make their mark for patients and drug companies. As the number of orphan drugs has increased over the
A type of FDA document which sometimes slides past under the radar is MAPP, that is, Manual of Policies and Procedures. These are actually internal FDA documents which are generally analogous to the SOPs FDA requires that industry have and follow. However, by virtue of
Last week at the Generic Pharmaceutical Association (GPhA) Annual Meeting, the 21st Century Cures Act, a proposed bill with bipartisan support, was a topic of discussion. Specifically, subtitle L—Dormant Therapies, which would offer 15 years of exclusivity for drugs and biologics approved as dormant therapies.
Last week the “Dormant Therapies Act” (DTA), a companion piece to the Modernizing our Drug & Diagnostics Evaluation and Regulatory Network Cures Act (also known as the MODDERN Cures Act of 2013), was introduced in the U.S. Senate. The Act would provide a drug maker
In November, this author participated in an open forum at the AAPS Annual Meeting focused on streamlining manufacturing and scale up to support ‘breakthrough therapy’ designation for solid oral dosage forms. The goal was to provide clarity for breakthrough therapies and chemistry, manufacturing and controls (CMC) challenges
The FDA listing of therapeutic equivalence (TE) ratings can be a murky area for products approved under 505(b)(2) applications. The concept of TE ratings emerged from FDA regulations for generics and revolve around the announcement that the FDA would publish a current listing of all
Until now, if a Sponsor intended to request orphan designation with 7 years of marketing exclusivity for a drug that has already been granted orphan designation, FDA has followed the Code of Federal Regulations (CFR), including the condition described in 21CFR §316.34(c): “If a drug
The FDA recently posted new guidance on its website awarding certain fixed-combination drug products (fixed-combinations) 5-year new chemical entity (NCE) exclusivity. While the Agency held previously that these products were ineligible for NCE exclusivity (5 years) if one component is already approved, with this new
The Food and Drug Administration (FDA) began requiring drug efficacy, in addition to safety, for approval in 1962 based on the Kefauver-Harris Amendment. Despite this requirement, many drugs that have been approved by FDA have limited efficacy (eg, drugs that treat cancer or Alzheimer’s disease).
In order to fulfill a requirement specified in Section 745A(a) of the Food and Drug Administration Safety and Innovation Act (aka FDASIA), FDA recently issued a draft guidance directing mandatory use of electronic filing and formatting for most regulatory submissions which currently can still be submitted
The goal of drug product development is commercial success. If this statement wasn’t true, how would patients access the life-saving or life-enhancing drugs we are developing? Yet, all too many companies focus just on FDA approval, which in our view should be just a very
Readers of this blog and Premier Consulting clients know that a 505(b)(2) does not have to reference a listed drug (LD) but may do so. Also, we have submitted many applications that do not reference the ‘obvious’ LD because doing so would trigger patent challenges
Premier Consulting participates in multiple pre-IND (PIND) meetings each month and one thing we notice in the FDA minutes is that the boilerplate answer to ‘does the Agency agree this ….. is appropriate for filing under 505(b)(2)?’ keeps getting longer. Recently, the Agency (or, at
The Food and Drug Administration Safety and Innovation Act (FDASIA; also known as PDUFA V), signed into law on July 9, 2012, contains amendments to the Pediatric Research Equity Act (PREA) that specifically detail the timing of the submission of a Pediatric Study Plan (PSP). In
In this blog post, we will examine a case study that illustrates various factors that should be considered during development. The example is the development of gabapentin enacarbil by XenoPort/GSK for restless leg syndrome. Gabapentin enacarbil is a prodrug of Pfizer’s gabapentin, approved in 1993,
PDUFA V ushered in new industry and FDA commitments. Among these are changes in meeting timelines. A significant change from PDUFA IV is the timeline for Type A meetings. Under PDUFA IV the meeting package was due 30 days in advance of the meeting. Now,
When Premier Consulting was young, products approved under 505j were called “generics” and 505(b)(1) “new drugs.” There was no consensus name for products approved via 505(b)(2). Of course, at the time there had been very few 505(b)(2) products approved. By now, we have seen an
One anomaly to the exclusivity rules is that a combination drug product containing a new chemical entity (NCE) and one or more previously approved drugs does not receive the 5-year exclusivity that a single-component NCE drug would receive. Thus, Ferring Pharmaceuticals Prepopik (sodium picosulfate, citric
Yesterday, Depomed filed suit against the FDA requesting the Court to order FDA to grant their product Gralise (gabapentin) seven years of exclusivity since it was granted Orphan status; upon approval, Gralise was granted three years of exclusivity. Depomed licensed the product to Solvay which became
It’s happened in most generic product development programs: A likely looking drug product candidate is selected and the due diligence begins. A review of the Orange Book shows one or more “use code” patents listed for the RLD. A review of the actual patent reveals
ViroPharma has pulled out all stops to prevent generic copies of its off-patent Vancocin® capsule (vancomycin hydrochloride) including the use of the Citizen Petition process. Recently, FDA denied most of the requests in their Citizen Petition and simultaneously approved generics from 3 companies. ViroPharma immediately
How many drug development companies leave it up to the CMO to design or execute their formulation and manufacturing without oversight? Like those who boarded the Titantic 100 years ago, they seem to trust the mantra that their contractor’s work is unsinkable. MAP Pharmaceuticals seemed
A recent editorial (may need subscription) in the New York Times opined that a recent Supreme Court decision – a “bizarre outcome” – “makes it virtually impossible to sue generic manufacturers for failing to provide adequate warning of a prescription drug’s dangers.” The court case the
At Premier Consulting, we believe that the 505(b)(2) drug development pathway is best used when we can improve the safety and/or efficacy of an existing drug product. We see many opportunities to improve clinical effectiveness, but before trying to prove this in a clinical setting
As part of the PDUFA V reauthorization discussions, the FDA and industry are talking about better approaches to rare disease drug development and orphan drugs. Public interests and Congress have mandated that the FDA develop new guidances on the required studies needed for NDA approval.
Most of us know that a BA/BE study of a generic can be done without an IND (the exception, called a Bio-IND, is when the drug being studied is cytotoxic or a radioactive labeled drug). In 505(b)(2) drug development we often are studying the BA/BE
From a technological standpoint, it is understood that the goal of developing 505(b)(2) abuse-deterrent products is to make changes to the API or formulation of a drug that has abuse potential in such a way that it dissuades the abuser from wanting to use the
In any project development program an understanding of the program goal is critical to finding the shortest path to the final result. Generation of a Target Product Profile early in a development program facilitates reaching the goal of a marketed drug product. It provides a
Some define repositioning as the process of examining alternate indications for drugs that have failed in the clinic. Others say that repurposing (with or without the hyphen; re-purposing) is interchangeable with repositioning. When many people think of repositioning drugs, they expect the outcome to be
On March 4, 2010 the U.S. District Court for the District of Columbia agreed that FDA was within its rights to grant Shire’s Vyvanse (lisdexamfetamine dimesylate) NME status and thus, 5-years exclusivity. New Rivers Pharmaceuticals (NRP) was the original sponsor of the lisdexamfetamine NDA. During the
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all new drug applications for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration are required to contain an assessment of the safety and effectiveness of the
Awareness of current FDA standards and those of its various divisions is important when preparing a new submission. A basic premise for a 505(b)(2) submission to the Agency is that the application contains full reports of investigations of safety and effectiveness. However, for 505(b)(2) applications, at least
As readers of this blog will know, a 505(b)(2) application is a US NDA where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of
Can a 505(b)(2) NDA have more than one RLD? In a word, the answer is “yes.” When using the 505(b)(2) regulatory pathway, sponsors may rely on the agency’s previous findings of safety and/or efficacy of an already approved product which is termed the reference listed
On 30 September 2009, the FDA issued a new draft guidance for industry: Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications. The guidance describes the content and format of a REMS, which the FDA was authorized
What do you need to do when you need to change suppliers or manufacturing sites? Among the many choices is a formal FDA comparability protocol. Advance planning can improve the possibility that the FDA accepts your proposed change. One alternative that can streamline the process
The FDA is moving against DESI drugs and DESI producers are wondering if their products are next on the chopping block. Here are a few commonly asked questions about how that will affect DESI producers. Will a 505(b)(2) of a DESI receive exclusivity? Yes, the
Pivotal stability programs that are used to generate stability data for NDA submissions are different than research stability programs used to design the drug product, explore packaging configurations, etc. This is common sense, but we have seen instances of pivotal stability programs that have been
Any meeting with the FDA is critically important to sponsors. We all know that a tremendous amount of time and effort goes into planning for these meetings. But even before this step the decision to ask for a meeting and the contents of the meeting
I was honored to be invited to speak at the FDA-OCRA 12th Annual Educational Conference in Irvine California on June 10, 2009. I was asked to discuss and compare the 505(b)(2) and ANDA Suitability Petition. I thought I should share this topic with the readers
The Food and Drug Administration (FDA) heard testimony on May 27 and 28, 2009, regarding the effort to develop a class-wide Risk Evaluation Mitigation Strategy (REMS) for long-acting opioids products that contain fentanyl, hydromorphone, methadone, morphine, oxycodone or oxymorphone. The public hearing was held to
DESI drugs are a great source for 505(b)(2) development since many will qualify for 5 years data exclusivity. In this post, we will define what they are. Once upon a time…. In 1938 the FD&C Act was established that required that drugs be proven safe
Developing a product with multiple strengths? How do you go about filing multiple strengths in an IND? How and when do you draft one CMC section covering multiple drug strengths for the same dosage form? Long-term drug development goals may include multiple strengths of a
Two major factors drive clients to consider running trials in foreign countries – cost and recruitment. The question we often get is: can we use the data from such trials in a US submission? The answer is: quite possibly. I won’t address the conduct of
A draft label be included with all NDA submissions. For a 505(b)(2) NDA, where do you get the information for this label? What labeling is required? What is labeling? Well, the “label” is what is on the immediate container of the drug product and can
A 505(b)(2) submission relies on information in the public domain to fulfill some of the information required in an NDA for approval. This information comes from more than the reference drug’s NDA review documents. In fact, for older drugs, the amount of information can be
Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the
In speaking with sponsors, we often discuss the potential competition to their proposed drug product. In order to have success in the market, the proposed product needs market differentiation. Existing products What other drugs are available for the same therapeutic indication(s)? Why would the medical
What is the difference between a Paragraph IV certification between the 505j (ANDA, generic) and 505(b)(2)? None. The difference is the exclusivity outcome – 505(b)(2) never gets any exclusivity based on patent certification. In a U.S. drug application, in Module 1, Administrative Documents, you must
IP attorney Stephen Albainy-Jenai and I just concluded a webinar hosted by DIA entitled 505(b)(2) Patent & Exclusivity. 23 different companies attended, showing the increasing interest in 505(b)(2) issues. Earlier this year, DIA hosted my overview of the 505(b)(2) drug development process where the attendees had many questions asking
Well, freedom from generic competition for a while at least. Generally, most companies’ business plans specify some means to keep the competition at bay until the product can make a profit – when revenues start to exceed investments. There are two ways for 505(b)(2) applications
