Camargo 505(b)(2) Blog

Shionogi to Buy Sciele Pharma

Shionogi, a Japan-based pharmaceutical company, announced yesterday (9/1/2008) that it would buy Atlanta-based Sciele Pharma for $1.42 billion –  57% premium to the current share price.  Shionogi’s analysis of the purchase is here.  Sciele’s business strategy relies on 505(b)(2) drug development.  Sciele in-licenses products in a wide range of therapeutic categories. Products include fenofibrate (lower doses), […]
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Transcept and Novacea to Merge

Transcept Pharmaceuticals (formerly TransOral) announced today (9/2/2008) that it is merging with Novacea.  Transcept is a privately held company while Novacea is NASDQ-listed, so the merged company will be a public company.  Novacea had 2 cancer therapies that didn’t meet expectations.  Transcept has a 505(b)(2) strategy which we have reviewed in this blog before.  The […]
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Modeling using Dissolution Data

Not only pharmacokineticists get to have fun in the modeling sandbox.  Chemists and formulators get to have their fun synthesizing data.  Let’s use an example of how dissolution data can be used for modeling.  The example is taken from a project to develop a oral modified release drug where the RLD is an immediate release […]
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Pk Modeling, not just any pretty face

We recently changed the navigation and look of our website to show that we are a full-service drug development company.  505(b)(2) drug development is so much more than just regulatory submissions!  I was asked to explain what the chart is on the pharmacokinetics services ‘page’: The chart is a result of pharmacokinetic modeling.  Note the […]
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Residual Solvents – New FDA Draft Guidance

The USP established a new test requirement for control of residual solvents in finished dosage forms. The new test is in the General Chapter <467> “Residual Solvents”  [Sorry no link – password protected].  The test became official July 1, 2008.  In turn, on August 5, 2008 the FDA issued a draft guidance stating that all NDA and […]
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KV’s DESI Guaifenesin Trumped by Adam’s 505(b)(2) Product

Last week (7/30/2008) , FDA announced that it seized timed-release guaifenesin products from KV Pharmaceutical.  In 2002 the FDA determined this DESI product to be a safety hazard to children.  The manufacturers, including KV Pharmaceutical (Warning Letters: see page 23)  were told to stop manufacturing by November 2003 unless they received NDA approval.  Adams Respiratory Therapeutics obtained NDA […]
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$1,247,200 PDUFA Fees for FY 2009

FDA announced on August 1, 2008 the user fees for fiscal year 2009 (the U.S. government 2009 fiscal year start on October 1, 2008).  The fees are based on PDUFA IV approved last year.  The application fee for an application requiring clinical data is $1,247,200, for an application not requiring clinical data or a supplement […]
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Current versus RLD approval requirements

A 505(b)(2) NDA has the same approval requirements as a 505(b)(1) NDA, the only difference is where the pivotal data comes from .  505(b)(2) is not a shortcut in the sense that you can get by with less information.  Clients are often amazed (the polite word) when they learn about the studies need to get […]
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PREA and 505(b)(2)

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 claimed indication(s) in pediatric patients unless this requirement in waived, […]
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Hospira expands into 505(b)(2) development

Hospira, best known as a generic injectable pharmaceutical company, is going to start developing a transdermal product.  Yesterday (7/2/2008), Altea Therapeutics announced a partnership with Hospira for the development and commercialization of an undisclosed product.  Altea is best known for its transdermal delivery system.  You can see where this business deal is going.  Hospira many injectables, many […]
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505(b)(2) – No patent, just exclusivity

We have all been confronted with the issue of patents and exclusivity for 505(b)(2) product development projects.  Financial backers, VC’s, private equity are fixated on the ruggedness of patents – no patent  = no money.  Biomarin Pharmaceuticals made a presentation at the 2008 BIO conference to encourage others that patents are not always needed.  The […]
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BIO – User’s Manual

I attended the 2008 BIO Annual convention, my first.  More than 20,000 registrants.  There were the usual plenary sessions with lots of wonderful, flowery, well-meaning platitudes and well-deserved awards.  The luncheons had the current governors of Massachusetts and California and Jeb Bush, the former governor of Florida (unabashedly representing John McCain), Colin Powell and other […]
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Orphan’s turn 25

I attended a session at the 2008 BIO convention in San Diego celebrating the 25th anniversary of the Orphan Drug Act.  Before the Act, there were almost no orphan drugs.  The exemption from the PDUFA user fees (running $1.175MM today), 50% tax credit for clinical studies and a 7 year marketing exclusivity are powerful incentives […]
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Creating a safer NSAID

Many companies are attempting to reduce the GI bleeding, ulcers and perforations caused by administration of NSAIDS (e.g., ibuprofen, naproxen, aspirin).  Since Vioxx was removed from the market (and it was a safer NSAID with respect to GI), there has been an surge of NSAID activity around these existing actives.  We understand that the FDA’s […]
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Raptor announces Orphan designation for cysteamine bitartate

Raptor Pharmaceuticals announced that the FDA has granted orphan drug designation for cysteamine bitartrate for the treatment of Huntington’s disease. Cysteamine is currently approved by the FDA and European Medicines Agency to treat nephropathic cystinosis*, also an orphan designation. In addition to the targeted orphan designation, it appears that Raptor is also trying to improve on the […]
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Indevus’ Stock drops 70% on FDA’s request for more safety data

On June 4, Indevus Pharmaceuticals reported that the FDA is likely to request additional safety data before approving NEBIDO®, its depot testosterone product for the treatment of male hypogonadism.  The news sent the stock on a  tumble – losing $2.46 to $1.26/share (a 70% decline) in the subsequent trading period (it has since recovered a bit, Friday’s […]
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Suicidal behavior: Ignore therapeutic area at your own risk

We hope a common theme emerges from this blog and our public interactions: it is vital when planning 505(b)(2) drug development to look at the entire therapeutic class to learn what studies are needed for approval of the drug .  Not including the class in your background of public information can be suicidal. FDA regulates […]
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Fenofibrate in the news (again)

I recently used the saga of Abbott’s TriCor (fenofibrate) product life extension tactics for an FDA citation to support the use of multiple RLD’s in a 505(b)(2) application.  I also think the story is instructive to the 505(b)(2) industry as to how even slight changes can be used to develop your own strategy. Recall that […]
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What’s the competition?

In speaking with prospective clients, 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. Some thoughts on a couple of categories: Existing Products – What other drugs are available for the same therapeutic indication(s)?  Why would the medical profession select yours? Generic […]
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Multiple RLD’s under 505(b)(2)

I enjoy eating Chinese food with a group, because I can get a sample from each person’s plate.  Such as in 505(b)(2) submissions, you can pick and choose parts of different RLD’s for your submission. A reader was surprised when I previously commented that a 505(b)(2) submission can have more than one RLD.  As long as the information is supprortive of […]
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RLD – Born in the USA

You have a global perspective and drug development program.  You want to conduct studies in the US and an international location.  You’re going to use an RLD from Big Pharma – you know, the global giants.  The RLD bought in the US and Europe looks the same, even has the same marking.  But are they same?  […]
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Paragraph IV Certifications under 505(b)(2)

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 submit a patent certification, regardless of the submission route, generic […]
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Fospropofol turned down or approved by FDA Advisory Committee?

MGI Pharma’s Aquavan(R) (fospropofol) is a phosphate prodrug of the anesthetic propofol.  Propofol  must be administered by an anesthesiologist because of its rapid onset. The phosphate prodrug’s time to onset is delayed due to the conversion to the active moiety.   A slow onset of sedation would reduce the likelihood of sudden and unexpected general anesthesia.  […]
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Biovail to reduce 505(b)(2) development

Biovail joined the increasing list of pharma companies that are downsizing or eliminating their 505(b)(2) development programs.  As reported in the Wall Street Journal* Biovail CEO William Wells, in a conference call announcing a  change in company focus,  said “Focusing on the development of products that primarily provide convenience and compliance benefits is not a […]
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505(b)(2) Orphan Drug Approval with only a BE study?

A reader recently inquired about Orphan drugs and asked me if I thought an Orphan drug developed under 505(b)(2) could be approved based on just a Phase 1 study – a pharmacokinetic or pharmacodynamic comparison to the RLD. At first I thought I couldn’t think of an example.  Generally, an Orphan drug fulfills an unmet […]
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Racemate > Isomer Approval under 505(b)(2)

The 505(b)(2) process is used to obtain approval of an isomer of an already approved racemate.  An example is cetirizine.  The original product approved (Zyrtec)  is a racemate.  In May 2007, UCB, Inc. obtained approval for levocetirizine dihydrochloride 5 mg tablets, using the 505(b)(2) process.  That approval was based on replicate clinical studies.  On 1/28/2008 UCB obtained […]
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Trade secrets

According to some observers, the US Patent system is undermining innovation.   In KSR International versus Teleflex Inc., the US Supreme Court ruled that  patents must be “more than the predictable use of prior art elements according to their established functions” or  in my layman’s words, you can’t patent something that should have been obvious.  The drug […]
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505(b)(2) RLD Patent Certification

In our webinar last week on Patent & Marketing Exclusivity we received an interesting question that I would like to pass along to readers of this blog. Q: If there are two RLDs, one with IP and one without IP, does a Sponsor have to certify against both RLDs? A: If you reference a RLD, […]
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505(b)(2) with Orphan Indication

I was recently asked how you can have a 505(b)(2) application for an Orphan drug.  The reasoning behind the query was that Orphan drugs are new chemical entities (NCE).  This perpetuates the misconception that 505(b)(2) cannot be used for NCEs, which by now readers of this blog know is wrong.  We have discussed the use […]
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505(b)(2) Patent & Marketing Exclusivity

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 specifically about patents and exclusivity, many of which I couldn’t […]
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NanoNews – Beads deliver drug to site of action

In another fine example of a formulation change, Biocompatibles International reported that its very small beads were used to sequester Doxorubicin (adriamycin).  The resulting beads were delivered via a catheter directly into the liver of patients with liver tumors.  The tumor growth was suppressed for long enough in 12 of 18 patients to receive a […]
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505(b)(2) Pre-IND Meetings Denied

Yikes!  For the first time, Camargo has two (yes, 2!) pre-IND meetings denied. Same week.  Not cancelled, not postponed, not re-scheduled – denied!  In both cases, the review divisions said we were on the right track, no controversy exists and that we should simply file the IND. Wow.  The purpose of the pre-IND meeting is much […]
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Is your drug project a 505(b)(2), ANDA or OTC?

I get a lot of requests to assure people that their project is, or is not, a 505(b)(2).  A few questions about whether it is an OTC candidate. The question about whether the proposed drug is a 505(b)(1) or 505 (b)(2) is readily answered by the question: is any data essential for approval being obtained […]
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505(b)(2) Patent & Exclusivity

We gets lots of questions about how the patent system works for 505(b)(2)’s and how it relates (or not) to exclusivity provisions.  A good friend and colleague who is an expert in patent law is going to join me on  a webinar sponsored by DIA.  It will be held April 22 from 11:00 to 12:30.  […]
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Approval delays at FDA

One of the expected benefits of the new drug approval process under PDUFA is that drugs get approved within a certain timeframe, today about 10 months after submission. This often cited as a reason why generic companies are looking at 505(b)(2) – generic approval times are now stretching to 20+ months.  Now comes the news […]
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Metabolites: New safety testing requirements – impact on 505(b)(2)

For Valentine’s Day, FDA issued a new guidance on metabolite safety testing.  Essentially, it outlines the non-clinical testing that may be required when the metabolism in humans produces significantly higher amounts of the same metabolites in the animal species where the toxicology was assessed. As the guidance points out, recent advances in analytical technology have […]
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A single Phase 3 trial needed for 505(b)(2) approval of a combination drug

Alchemia Ltd., an Australian pharmaceutical company, announced that it had gained agreement with FDA that a single Phase 3 trial would suffice for approval of its chemotherapeutic drug HA-irinotecan (a new drug containing irinotecan (Pfizer’s Camptosar®) formulated with hyaluronic acid (HA).   Alchemia has conducted phase 1 and 2 studies outside the U.S.  It presented the results […]
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Another “unapproved” drug needs a 505(b)(2) approval

FDA is continuing to act on its promise made in January 2007 to remove products from the market that it considers unapproved.  These products, some stemming from the DESI process, have been with us many years. The latest casualty is Colchicine for Injection.  On February 6, FDA announced it was taking enforcement action because the […]
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505(b)(2) – Part 3: Pre-IND submission & meeting

Before filing an IND, it is desirable (we counsel imperative) to have a pre-IND meeting with the FDA.  The goal is to get FDA’s concurrence with the proposed development plan and regulatory submission pathway.  The steps for this meeting (known as a Type B meeting) include: Prepare a pre-IND submission package. This package outlines where we […]
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505(b)(2) with Only Phase 1 Study

We are often asked if a 505(b)(2) application always requires a clinical study (i.e., Phase 2 or 3 in patients).  The answer is a resounding NO. On January 14, 2008 ADVENTRX Pharmaceuticals announced the successful completion of a bioequivalence study that demonstrated similar blood levels and a “statistically significant reduction in injection site reactions”.  The company further […]
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505(b)(2) – Part 2: The Assessment: Timeline, Cash Flows

Once the clinical development plan is established, the CMC, regulatory and medical communication plans can be matched up. We use MS Project to develop a high-level overall plan.  MS Project then can be used to generate cash flows and Gantt charts.  This information can be used by the sponsor to determine if the project is financially feasible. […]
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PDUFA 2008 – New Submisison Fees for 505(b)(2) Applications

FDA announced that for 2008 the full application fee for a 505(b)(2) that requires a clinical study will be $1,178,000.  In addition, the establishment fee is $392,700 and the product fee is $65,030.  Small  businesses (defined as entities, including affiliates, with less than 500 employees) may request a  waiver of the PDUFA review fee for […]
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FDA takes action against compounding pharmacies’ estriol-containing hormone products

On January 7, 2008, the FDA issued warning letters to several compounding pharmacies (example) advising them stop compounding hormone products contain estriol, an unapproved new drug.  This activity has been going on since the mid-1990’s, popularized by the actress Suzanne Somer’s books. The general term used by this industry is bio-identical hormone replacement therapy – BHRT. […]
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New Safety Reporting Requirements for Unapproved OTC products

We’ve been observing the FDA crackdown on unapproved DESI and OTC drugs.  The reason that Congress and FDA have made these moves is a concern for safety.  Industry counters that these drugs have been used safely for years.  Frankly, there is a lack of data to support either side.  Approved drugs have always been subject […]
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505(b)(2) – Part 2: The Assessment: CMC Development Plan

CMC Development Plan All too often we see plans that don’t integrate the clinical trial materials with the clinical development plan.  This is usually because the people and organizations responsible for each area don’t interact well and there is a lack of overall project management.  Most often, the focus of the company is the clinical […]
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505(b)(2) – Part 2: The Assessment: Clinical Marketing Assessment

Competitive Products Review/Clinical Marketing Assessment      This section includes an assessment of the existence of a medical need and the ability of the proposed drug to compete with existing and pipeline agents.  At Camargo we deeply believe that good science = good business.  In practice, this means that simply getting FDA approval isn’t enough.  The drug […]
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505(b)(2) – Part 2: The Assessment: Regulatory Strategy

Regulatory Strategy This section provides analysis of pertinent regulatory information to produce a recommended regulatory pathway.  A thorough search of regulatory documents supports the regulatory recommendations (e.g., Dockets Management; HeinOnline[1]). The 505(b)(2) regulatory pathway may be appropriate if part of the NDA application requirements can be supplied using information from published literature and/or the Agency’s […]
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505(b)(2) – Part 2: The Assessment: Clinical Development Plan

Clinical Development PlanThe proposed Clinical Development Plan is dependent on the selected regulatory pathway.  The Clinical Development Plan is based on available Agency study recommendations provided in the FDA Guidance for Industry documents, information in the public domain (e.g., PubMed), and information obtained from SBA documents as applicable. The plan consists of the outline of […]
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505(b)(2) – Part 2: The Assessment: Clinical Pharmacology

Clinical Pharmacology An overview of the proposed product’s absorption, distribution, metabolism, and excretion (ADME) is detailed in this section obtained from various resources.  An important source of information for this and other sections is the FDA reviewer summaries (Summary Basis of Approval – SBA) for the reference listed drug (RLD) as well as other drugs […]
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505(b)(2) – Part 2: The Assessment: Pharmacokinetic Review

A comprehensive search of the literature is performed to obtain published pharmacokinetic (PK) data for the proposed product (dependent on selected regulatory pathway). This review compares the PK profiles for all available routes and conditions of administration and dose strengths. This review includes studies assessing: Single- and multiple-dose administration Dose proportionality Bioavailability Dose-ranging studies Drug-drug interaction studies […]
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New MAPP for FDA Accepting Alternate Compendia for CMC standards

On 11/3/2007 FDA issued a new MAPP* entitled “Acceptability of Standards from Alternative Compendia (BP/EP/JP)”.  Although directed at new drugs, one can probably argue that the policy should also apply to the Office of Generic Drugs.  Up to now, reviewers seemed arbitrarily accepting or denying the use of BP, EP and JP grade excipients and […]
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505(b)(2) Combo Plavix/Prilosec

Cogentus Pharmaceuticals is working on a combination tablet that combines clopidogrel, the active ingredient in Plavix, with omeprazole, the API in Prilosec. Cogentus’s business strategy is to: “… improv[e] the therapeutic profiles of existing, proven drugs in ways that take full advantage of their strengths while overcoming their well understood limitations. By combining complementary characteristics of […]
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505(b)(2) – Part 2: The Assessment: Preclinical Review/Preclinical Plan

Rats, mice, dogs, pigs – ANDA folks don’t have to deal with testing generic products in animals.  As long as the excipients are previously approved, generic drugs don’t have to conduct any preclinical studies. 505(b)(2) development programs may need to include some preclinical studies depending mainly on whether the route of administration changes or FDA […]
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505(b)(2) – Part 2: The Assessment: Safety Review

Of course my product is safe! – the RLD was shown to be safe. Perhaps so.  The FDA approves products based on a risk/benefit; is the risk of taking the drug outweighed by the benefit?  Would FDA approve the RLD using today’s standards?  What changes from the RLD are we proposing to make in this development […]
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P&G Drops out of a 505(b)(2) Development

Nastech announced on 11/7/2007 that P&G had dropped out of their co-development of a nasally delivered version of Lilly’s osteoporosis drug Forteo (teriparatide).  As reported, the Nastech CEO speculated that the reason for P&G’s termination of its participation was that original timescales for product development have had to be extended, meaning that the product may […]
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505(b)(2) – Part 2: The Assessment: Efficacy Review

One of the key attractions to the 505(b)(2) route is the potential of gaining approval with only one Phase 3 study.  Moreover, this Phase 3 study is often small, at least compared to the thousands of patients in 505(b)(1) submissions.  There are exceptions, to be sure.  For example, 2 or more trials may be needed […]
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Foreign Inspections by FDA

The US General Accounting Office (GAO) criticised what it concluded is a lack of FDA inspection of foreign API and finished dosage form manufacturers.  This has received a lot of coverage in the lay and professional press, especially since a huge increase in API’s is coming from China; FDA has only 13 inspections scheduled in China, a country […]
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505(b)(2) – Part 2: The Assessment: Competitive Product(s) Review

We investigate major factors that influence the potential clinical evidence required and the likelihood of a product’s acceptance in the market.  Having established a working draft of our labeled indication(s), we look at the therapeutic category.  What drugs have been used, are currently used and what drugs are being studied for eventual marketing? This comparative review […]
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505(b)(2) – Part 1: The overall process

Our process for developing a drug product to be submitted to the US FDA under the 505(b)(2) process has been validated during many meetings with FDA.  I want to share important aspects of this process with the community. This is the first post of several parts.  I will use the following flow diagram as our road […]
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Adams “DESI” Product Approvable

Adams Respiratory Therapeutics announced that it received an Approvable letter from FDA on 10/29/07 for its guaifenesin 600/1200 mg and codeine phosphate 30/60 mg extended-release bi-layer tablets.  The release indicates that the FDA needed additional data to support the use of the product with food. The proposed product is one of several currently on the market […]
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505(b)(2) – Freedom from Generic Competition – Exclusivity Issues

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 to obtain a market free from a duplicate: patent protection and […]
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Drug Repositioning: 2 Flavors

Last week’s Drug Repositioning Summit was attended by more than 150 people.  The Summit started with my 3-hour workshop on 505(b)(2) drug development.  Several attendees were seemingly confused about what “drug repositioning” means.  There are two distinct ‘flavors’ of drug repositioning: Take a currently US-approved drug and make significant changes to it (formulation, dose, route […]
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First Generic FDA Review Time to Drop

Maybe the title should have a question mark after it – will the review time for a first generic drop?  FDA plans to do so – it announced the Generic Initiative for Value and Efficiency (GIVE). Basically, the Office of Generic Drugs will try to review within 6 months an application for a first generic […]
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FDA moving against unapproved Hydrocodone products

FDA is announcing that it intends to remove all unapproved products containing hydrocodone from the market. The FDA intends to swiftly move against products labeled for use in children under 6 years of age and allow 90-180 days for products not labeled for use in children under 6 years of age. Manufacturers wishing to market these […]
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CNN Story on “Unapproved Drugs”

CNN ran a story today to  increase public awareness that there are hundreds of drugs consumed in the U.S. that have never been formally approved by the FDA. For professionals, the FDA has a web page devoted to this topic.  Some of these products were subject to the DESI review process, but it is well known that […]
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PDUFA 2007 – New Submisison Fees for 505(b)(2) Applications

Congress just passed the Food and Drug Administration Amendments Act of 2007.  Most of us in 505(b)(2) drug development will think of it as the PDUFA 2007 (Prescription Drug User Fee Amendments of 2007).  This amendment covers the period from 2008-2012 (plus, to circumvent the rush experienced with this re-authorization, provisions for an extra 3 […]
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505(b)(2) of Withdrawn Product

A source of 505(b)(2) opportunities comes from products that have been discontinued.  One of the first things that must be done is to determine why it was discontinued – by law, the product must not have been discontinued for reasons of safety or efficacy.  You can check to see if the FDA has made this […]
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Use CMO’s Labs or Outside Labs

Why does Camargo recommend not to use a CMO’s testing lab for development?  CMO labs are tailored for commercial production, characterized by many SOP’s and schedules. During early drug development we need answers quickly, sometimes even approximate answers.  We’re not bound at this stage by GMPs.  We have several outside labs, so we can select one that is […]
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Inactive ingredients exposed

You’re choosing excipients and determining amounts, so you go to the IAG (Inactive Ingredient Guide) look up the approved amounts and you’re good to go.  Right? Maybe not…  You need to consider EXPOSURE.  Exposure is amount over time.  Look at the IAG and determine what products have this excipient/inactive ingredient and compute the potential exposure […]
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MDS Bioanalytical Audits

MDS Pharma is back to profitability after shedding its bioanalytical facility in Montreal. This lab conducted analyses of 100’s of bioequivalence studies. FDA audited the lab several times, effectively shut down the lab and called into question the acceptability of the BE study conclusions that were used to approve many ANDA’s. FDA required the ANDA […]
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