Clinical Studies, Phases I-IV Resources

Seamless Clinical Trials: Why Didn’t We Think of That?

Seamless clinical trials have become the new buzz word in drug development since FDA Commissioner Scott Gottlieb promoted their use this month. But are they new, and which products are best suited to this style of clinical trial? Oncology drugs are the obvious examples of products that are well suited to the adaptive design of […]
Read More

Special Protocol Assessment: Is It Important for Your Drug Development Program?

The overarching goal of the Special Protocol Assessment Draft Guidance for Industry May 2016 (HHS, FDA, CDER, & CBER) is to improve the quality of new drug applications (NDAs) and biologic license applications (BLAs) by providing more certainty in the clinical protocol design process. Among its several purposes, the Special Protocol Assessment (SPA) affords an […]
Read More

Clinical Trials With Multiple Endpoints: Pitfalls and Management

Randomized controlled Phase 3 (and some Phase 2) studies are clinical trials that are designed to answer specific questions, such as whether the proposed drug is effective in treatment or prevention of a particular disease. As such, the primary endpoint is the most important one that will demonstrate the primary effects being sought by the […]
Read More

Real-World Evidence: Can it Really Be Used For Drug Approvals?

With the signing of the 21st Century Cures Act, the US Congress tasked the FDA with developing a framework to evaluate how the use of data from sources other than traditional clinical trials may be used to support drug approvals. This framework will apply to post-market commitments and to new indications for approved drugs. This […]
Read More

Extrapolation of Clinical Data for Pediatric Uses: Application for Medical Devices and Drug Products

Extrapolation of Clinical Data for Pediatric Uses: Application for Medical Devices and for Drug Products Extrapolation of Clinical Data for Medical Devices1 The Food and Drug Administration released the revised draft guidance entitled ‘‘Leveraging Existing Clinical Data for Extrapolation to Pediatric Uses of Medical Devices” on June 21, 2016 (Docket No. FDA–2015–D–1376). This guidance explains […]
Read More

Alkermes Prodrug for Treatment of Multiple Sclerosis: NCE?

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 many cases, some portion of the limited efficacy is […]
Read More

MannKind Breathes Easier – Inhaled Insulin Finally Approved

MannKind’s Afrezza Receives FDA Approval In June of this year, MannKind Corporation announced that they received FDA approval for Afrezza®, their rapid-acting inhaled insulin product. MannKind is currently working to identify a pharma partner to manufacture and distribute Afrezza, and the product could be available as soon as January 2015. This approval has been a […]
Read More

The Road to Commercial Success – The Target Product Profile

The goal of drug product development is commercial success.  If this statement wasn’t true, how would patients access the live-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 important milestone. When embarking on the drug development journey, it is […]
Read More

505(b)(2) Prodrug Fails Phase III Study

Development of drugs for new indications entails more risk of failure than simply changing formulations.  Just ask XenoPort, which announced May 19th that its prodrug of R-baclofen, arbaclofen placarbil,   failed to show efficacy in a Phase III clinical trial. Arbaclofen placarbil was being studied for multiple sclerosis-related spasticity. Racemic baclofen,  now generic, is indicated for treating muscle […]
Read More

KV Appeals Makena Decision

We have followed the saga of KV’s Makena for two reasons.  The most important reason is that the submission, review and approval of Makena is perhaps the best example of using a publicly funded clinical study for NDA approval, despite the clinical trial material not being sourced by the sponsor of the NDA.  The other reason is […]
Read More

Drug Development Planned Like the Titanic

How many drug development companies leave it up to the CRO or CMO to design or execute their studies or formulation/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 to do just that – the approval of their […]
Read More

KV’s Makena Part 4: Statistical versus Clinical Significance

In previous postings (Intro, Part 1, Part 2, Part 3), I have provided background on KV’s Makena (17a-hydroxyprogesterone caproate injection aka 17P).  The development and regulatory history contains many lessons. In this posting I’d like to examine the difference between statistical and clinical significance.  Please note that this is not meant as a rigorous statistics […]
Read More

KV’s Makena: Part 3: Use of Public Information for 505(b)(2) approvals

In previous postings (Intro, Part 1, Part 2), I provided background on KV’s Makena (17a-hydroxyprogesterone caproate injection aka 17P). The development and regulatory history contains many lessons. In this posting I’d like to examine the use of public information to substitute for sponsors’ studies. By definition, the 505(b)(2) application must contain information to which the […]
Read More

KV’s Makena Part 2: Accelerated Approval Subpart H

In a previous posting, I provided background on KV’s Makena (17a-hydroprogesterone caproate injection aka 17P). The development and regulatory history contains many lessons. In this posting I’d like to examine the accelerated approval process. Makena was approved under 505(b)(2) as seen from the approval letter (at this writing the approval documents are not posted at […]
Read More

Revised Safety Reporting for BE/BA Studies Effective March 28, 2011

On September 29, 2010 FDA published a Final Rule revising the requirements for safety reporting for INDs and other BE/BA studies. At the same time FDA issued an accompanying draft guidance to assist in interpreting the new rule. The Final Rule, revising 21 CFR §§ 312.32, 312.64 and 320.31, becomes effective March 28, 2011. The […]
Read More

Contrave® Rejection: The Long and the (Too) Short of it

On February 1st Orexigen(R) Therapeutics, Inc. and Takeda Pharmaceutical Company Limited (Takeda) announced that the FDA issued a complete response letter dated January 31, 2011 regarding the New Drug Application for Contrave® (naltrexone HCl/bupropion HCl) extended-release tablets for the treatment of obesity, including weight loss and maintenance of weight loss (http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1522207&highlight=). In the letter, FDA […]
Read More

Nuedexta® – Smart Pharmacology to Treat a Unique Disorder

The FDA has approved NuedextaÃ’ (Avanir Pharmaceuticals Inc.), a drug that curbs involuntary and uncontrolled crying and laughing episodes (known as pseudobulbar affect (PBA)) that are experienced by patients with some neurological disorders. Nuedexta is the first drug to be approved to treat patients with these symptoms. Nuedexta is a combination product containing dextromethorphan hydrobromide […]
Read More

505(b)(2)s with Minimal Sponsor Studies

The power of the 505(b)(2) process is realized when the sponsor has to conduct few, if any, studies to get their drug product approved. For many drugs there is wealth of data available in the public domain. The challenge is locating the data and then preparing it for the FDA in such a way that […]
Read More

Failed 505(b)(2)?: Vivus™ Qnexa

I am often asked about 505(b)(2) drug development failures. After all, 505(b)(2) is a regulatory pathway that is chosen because it is lower cost and has lower risk than a 505(b)(1). The lower risk is attributable to the reliance on the known safety and efficacy of the reference drug product. Indeed, one of the strategies […]
Read More

New User Fees for 2011

FDA announced the new PDUFA user fees for fiscal year 2011 (starts October 1, 2010). The fee for a full application containing clinical data is $1,542,000.   For a supplement or an NDA not requiring clinical data, the fee is $771,000. A clinical study is generally Phase 2 or Phase 3, so a 505(b)(2) approved based […]
Read More

Pro-Drug Denied

I am frequently asked if 505(b)(2) projects fail or whether any NDA submissions are rejected. My answer is that the vast majority succeeds and are eventually approved. Those that fail more often are due to money or design issues, not execution risks. Today I discuss an example of a failure based, in large part, on […]
Read More

Generic or 505(b)(2)?

Is an opioid product that has abuse resistant characteristics but otherwise the same as the RLD a generic or 505(b)(2)? Readers will know that Camargo has been involved in many opioid-related projects. We have been to FDA’s DAARP 13 times this past year alone. What is the objective of most of these meetings? For the […]
Read More

GTx Needs a 2nd Phase III Trial and More Safety Data

GTx announced 11/2/2009 that it has received a Complete Response Letter from the FDA concerning its NDA for TOREMIFENE CITRATE 80 mg (ACAPODENE®). The NDA, filed in late December 2008, sought approval for use of toremifene 80 mg to reduce fractures in men with prostate cancer receiving androgen deprivation therapy (ADT). The NDA was based on […]
Read More

A Treatment IND is NOT the same as an IND

In this blog I seldom quote or provide hyperlinks to press reports because they too often contain misleading information.  Yet, today’s DIA web summary contained an article that I just have to correct.  The article was a  summary of a report on Medpage’s website.  The report’s heading is inadvertently correct: “FDA Finds Oral Insulin Spray […]
Read More

AstraZeneca ends collaboration with MAP Pharmaceuticals

MAP Pharmaceuticals announced yesterday (7/9/09) that AstraZeneca has ended its collaboration on unit dose budesonide (UDB).  This past February, MAP reported that the Phase 3 study had failed to reach its primary endpoints.  Apparently, further analysis failed to support continued development of UDB. We seldom see failed 505(b)(2) development projects.  This case is interesting because […]
Read More

Quick-release bromocriptine mesylate approved

The FDA approved VeroScience’s Cycloset (bromocriptine mesylate) 0.8mg tablets on May 5 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The NDA was first submitted in 1997 – before the 505(b)(2) guidance.  The API, bromocriptine mesylate was approved under NDA 017962 in 1978 as Parlodel […]
Read More

505(b)(2) IV Acetaminophen

Cadence Pharmaceuticals announced yesterday 5/14/2009 that it had submitted an NDA for Acetavance(TM) – intravenous acetaminophen.  It is instructive to look at the clinical development plan for this 505(b)(2) product.  According to the company, the FDA required 2 pivotal Phase 3 trials: one clinical trial for the treatment of acute pain in patients following orthopedic surgery […]
Read More

505(b)(2) Program: BTG’s Paxclitaxel Gel for Oesophageal Cancer

Media is reporting that BTG’s Phase IIa study of a novel gel formulation of paxclitaxel showed tumor reduction in 70% of patients.  In effect, BTG is taking a known agent and directly targeting the affected tissues;  BTG is also reportedly in later phase trials looking at this gel product in brain cancer – placing the […]
Read More

One vs. Two batches for single-dose and multiple dose studies

Today’s posting stems from a client question.  The client’s product candidate is an oral product that requires both single- and multiple dose pharmacokinetic studies. Question:  Do companies ever use one pivotal batch for single-dose (SD) study and another batch for the multi-dose (MD) study?  What are the pros and cons of doing this? See the […]
Read More

Dexlansoprazole approved for the treatment of GERD

This past Friday, 1/30/2009, the FDA approved Takeda Pharmaceuticals North America Kapidex (dexlansoprazole) for the treatment of gastroesophageal reflux disease (GERD).  Kapidex is an enantiomer of lansoprazole (Prevacid).  In addition to the change in enantiomer, Kapidex is formulated with two type of enteric-coated granules to provide two separate releases of medication.  According to the Takeda […]
Read More

Watson’s 505(b)(2) Overactive Bladder Gel Approved by FDA

On 1/27/2009 Watson Pharmaceuticals announced that the FDA had approved its GELNIQUE(tm) (oxybutynin chloride) Gel 10% for the treatment of overactive bladder.  The gel product supplements a transdermal patch made by Watson (Oxytrol) which has not had the marketing success one might expect, perhaps due to the acceptance of the patch form by patients. So […]
Read More

505(b)(2) Combination Meets Phase 3 Goals

Horizon Therapeutics announced yesterday that its “fixed-dose combination product containing ibuprofen and famotidine, demonstrated a statistically significant reduction in the incidence of non-steroidal anti-inflammatory drug (NSAID)-induced upper gastrointestinal (gastric and/or duodenal) ulcers in patients with mild-to-moderate pain when compared to ibuprofen alone.”  Note that the drug development program contained two Phase 3 trials, one examining gastric […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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. […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More

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 […]
Read More