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Joint Review of New Drug Applications by Regulators and Payers: An Idea Whose Time Has Come

I’m always pleased to read about cooperation among different drug development stakeholders. Thus, I was pleased to read a news piece in a recent (Jan 2014) issue of Nature Reviews Drug Discovery about a European Medicines Agency (EMA) workshop (the first of its kind) that took place in London in November 2013. The theme was the concept of the EMA and various European health technology assessment (HTA) bodies (such as the UK’s National Institute for Health and Care Excellence [NICE]) reviewing drug marketing submissions in parallel and providing joint feedback to sponsors.
These days, there is no excuse for a sponsor to be so focused on approval and launch that it completely disregards the views of payer(s). The importance of payer buy-in is a departure from when I entered the industry 25 years ago, but of course at that time there weren’t any drugs that cost upwards of $100,000 per year. And it’s not hard to understand why the views of regulators and payers sometimes differ. On the one hand, to convince regulators of the safety and efficacy of a new drug, sponsors are forced to conduct longer, larger, and more expensive clinical trials. Longer clinical trials means less patent life available to (i) recoup the ever-increasing investment in the development program, and (ii) build in a profit margin to fund future drug discovery and development. And pharmacogenetics and companion diagnostics, while directing the drugs to the right patients, are drastically shrinking the pool of potential customers.  On the other hand, payers look at cost, effectiveness, the ratio of the two, and existing therapeutic alternatives, if any. Increasingly, payers are refusing reimbursement for new, expensive, unproven drugs, at least until their benefits have been demonstrated in the real world.
If regulators and payers could provide their feedback together, it would enable sponsors to modify their clinical programs accordingly in order to generate data that might satisfy everyone. With that end in mind, both the EMA and EUnetHTA, a network of HTAs across Europe, have been working together since 2010, with each organization launching a pilot program involving parallel review and advice. The results so far, presented at the workshop, are beginning to reveal some of the divergent expectations of the two parties and the most effective and efficient ways for sponsors to approach the parallel advice process.
My hat is off to both organizations for taking steps toward improving the process of reviewing new drug applications from both a regulatory and reimbursement perspective. Success in this endeavor will be a win for everyone involved.
I’m always pleased to read about cooperation among different drug development stakeholders. Thus, I was pleased to read a news piece in a recent (Jan 2014) issue of Nature Reviews Drug Discovery about a European Medicines Agency (EMA) workshop (the first of its kind) that took place in London in November 2013. The theme was the concept of the EMA and various European health technology assessment (HTA) bodies (such as the UK’s National Institute for Health and Care Excellence [NICE]) reviewing drug marketing submissions in parallel and providing joint feedback to sponsors.

These days, there is no excuse for a sponsor to be so focused on approval and launch that it completely disregards the views of payer(s). The importance of payer buy-in is a departure from when I entered the industry 25 years ago, but of course at that time there weren’t any drugs that cost upwards of $100,000 per year. And it’s not hard to understand why the views of regulators and payers sometimes differ. On the one hand, to convince regulators of the safety and efficacy of a new drug, sponsors are forced to conduct longer, larger, and more expensive clinical trials. Longer clinical trials means less patent life available to (i) recoup the ever-increasing investment in the development program, and (ii) build in a profit margin to fund future drug discovery and development. And pharmacogenetics and companion diagnostics, while directing the drugs to the right patients, are drastically shrinking the pool of potential customers.  On the other hand, payers look at cost, effectiveness, the ratio of the two, and existing therapeutic alternatives, if any. Increasingly, payers are refusing reimbursement for new, expensive, unproven drugs, at least until their benefits have been demonstrated in the real world.

If regulators and payers could provide their feedback together, it would enable sponsors to modify their clinical programs accordingly in order to generate data that might satisfy everyone. With that end in mind, both the EMA and EUnetHTA, a network of HTAs across Europe, have been working together since 2010, with each organization launching a pilot program involving parallel review and advice. The results so far, presented at the workshop, are beginning to reveal some of the divergent expectations of the two parties and the most effective and efficient ways for sponsors to approach the parallel advice process.

My hat is off to both organizations for taking steps toward improving the process of reviewing new drug applications from both a regulatory and reimbursement perspective. Success in this endeavor will be a win for everyone involved.

Continuous, real-time in vivo drug monitoring

 

At the present time, clinicians can continuously monitor, in real time, in vivo levels of glucose, lactose, oxygen, and maybe a few other substances; that capability for glucose is revolutionizing medical care for diabetics. Imagine what it would mean to pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and clinical practice if the same thing were possible for drugs and one or more biomarkers relevant to the disease being treated. According to a recent (27 Nov 2013) article in Science Translational Medicine, that future is now.
Ferguson and colleagues (senior author Tom Soh) of the University of California, Santa Barbara report on the development of a microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC). At the heart of the MEDIC device are gold electrodes linked to drug-specific aptamer probes that bind reversibly to their drug target, generating an electrochemical signal proportional to the drug concentration. As a proof of concept, they measured therapeutic concentrations of doxorubicin and kanamycin in blood drawn continuously from live rats, with temporal resolution of less than a minute. And, the authors note, “the modular architecture of MEDIC means that it can be adapted to a wide range of target molecules simply by exchanging the aptamer probes.” Possibly even more exciting is the notion that multiple probes could be integrated into one device, enabling one to simultaneously monitor a drug and one or more disease-specific biomarkers. This would make truly personalized medicine a reality, as you would know if you were giving the right drug at the right dose to the right patient at the right time. As the authors point out, it “could also enable the expanded use of drugs with narrow therapeutic indices.”
Just so you know, Absorption Systems is constantly on the lookout, staying abreast of the latest technological advances in our field.

At the present time, clinicians can continuously monitor, in real time, in vivo levels of glucose, lactose, oxygen, and maybe a few other substances; that capability for glucose is revolutionizing medical care for diabetics. Imagine what it would mean to pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and clinical practice if the same thing were possible for drugs and one or more biomarkers relevant to the disease being treated. According to a recent (27 Nov 2013) article in Science Translational Medicine, that future is now.

Ferguson and colleagues (senior author Tom Soh) of the University of California, Santa Barbara report on the development of a microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC). At the heart of the MEDIC device are gold electrodes linked to drug-specific aptamer probes that bind reversibly to their drug target, generating an electrochemical signal proportional to the drug concentration. As a proof of concept, they measured therapeutic concentrations of doxorubicin and kanamycin in blood drawn continuously from live rats, with temporal resolution of less than a minute. And, the authors note, “the modular architecture of MEDIC means that it can be adapted to a wide range of target molecules simply by exchanging the aptamer probes.” Possibly even more exciting is the notion that multiple probes could be integrated into one device, enabling one to simultaneously monitor a drug and one or more disease-specific biomarkers. This would make truly personalized medicine a reality, as you would know if you were giving the right drug at the right dose to the right patient at the right time. As the authors point out, it “could also enable the expanded use of drugs with narrow therapeutic indices.”

Just so you know, Absorption Systems is constantly on the lookout, staying abreast of the latest technological advances in our field.

Highlights from MD&M West 2014

On February 11th, the largest medical device design and manufacturing conference in the United States took place at the Anaheim Convention Center in California. This three day event, better known as MD&M West, showcased over 2000 exhibiting suppliers demonstrating the latest technical innovations and trends, 80 interactive and educational seminars, several inspirational keynote speakers, and of course an abundance of networking opportunities. The conference allowed visitors the flexibility of following several different tracks, depending on their interest, with the ability to “mix and match” sessions throughout each day. These tracks included:

Design, Prototype & Usability
Risk, Quality & Validation
FDA & Global Regulations in Practice
Material & Supplier Management

Also, for the first time, MD&M hosted a ‘Peer to Peer Speed Networking Event’ that allowed individuals to establish new connections, gain industry knowledge, and create new opportunities by aligning participants with professionals according to their preference. After 90 minutes and a collection of mini-meetings, MD&M-ers could walk away satisfied that they were maximizing their experience.

As an exhibitor, Absorption Systems had the opportunity to directly engage with a span of industry professionals, ranging from medical device engineers and company CEO’s, to FDA consultants and manufacturing specialists. With an event focused on product design and manufacturing, one may ask where a Contract Research Organization (CRO) like ourselves fit into the equation. Given the nature of our company, we place emphasis on the fact that we’re here to provide the support our clients need to help ensure not only the best study designs, but the best outcomes as well. We work diligently with our clients through all stages of device development to support the success of their innovation. With an industry that so heavily relies on regulatory guidance, we also make a point to maintain our education on these concepts so we can guide our customers in the right direction.

With that in mind, we feel the importance of establishing symbiotic relationships with contract manufacturers, material producers, and design specialists (to name a few) so that we can all work toward cohesively ensuring the success of our client’s product. 

MD&M allows Absorption Systems to fully connect and understand each step that goes into a device before it ever reaches our facility. This gives us the opportunity to absorb as much as we can about the industry trends while preparing us for the challenges our customers may face in the developmental stage. With this insight, educational advancement, and team of highly skilled professionals, we can suggest solutions to overcoming these obstacles.

Highlights from the 2013 GPhA/FDA Fall Technical Conference

The 2013 GPhA/FDA Fall Technical Conference placed great emphasis on quality and compliance issues, and how GDUFA addresses these.

In one of my favorite talks, Robert Lionberger (FDA OGD) addressed the growing complexity of generic products and the regulatory science initiatives surrounding such. Complex drugs may include those with complex APIs (e.g. peptides, natural source products), complex formulations (e.g. liposomes), complex routes of delivery (e.g. locally acting), or drug-device combinations (e.g. DPI, MDI, nasal sprays, and transdermal systems) - all controversial topics which have prompted citizen’s petitions.

This year featured a number of unprecedented bioequivalence (BE) guidances for complex products, including the first for an MDI (albuterol sulfate), an ophthalmic emulsion (cyclosporine), and a DPI (fluticasone proprionate/salmeterol xinafoate).

The most interesting, in my opinion, was the FDA’s stance on acyclovir ointment. The BE recommendation for this drug, published in March 2012, permits  an in vitro option in lieu of a clinical endpoint study, assuming the generic formulation and RLD (Zovirax) are quantitatively and qualitatively the same (Q1/Q2), the formulations have similar physiochemical properties (viscosity, rheology, etc.), and comparable in vitro release rates.

This approach was not well-received by the innovator (Valeant) who, in their citizen’s petition to the FDA, claimed that permitting approval based on in vitro data for a locally-acting semisolid is “unprecedented and scientifically unsupportable”. Valeant claimed that such products are multiphasic with complex thermodynamics which could modify the release characteristics of the drug. Prior to the acyclovir BE recommendation, the only exceptions to a clinical endpoint study for locally-acting semisolids were 1) the Stoughton-McKenzie vasoconstriction or ‘skin blanching’ assay for corticosteroids and 2) in vivo microdialysis.

The FDA’s response to Valeant stated that there are two key concerns when determining BE for topical dermal products: 1) Are the test and reference formulated similarly such that release characteristics are the same between the two products, and 2) Will the amount of drug uptake by the skin be the same or will absorption be affected by differences in formulation and/or manufacturing of the two products? Furthermore, Zovirax is a unique product whose characteristics distinguish it from other topical semisolids: 1) The product does not have a multiphasic vehicle, rather it is a single API in a single ingredient vehicle (PEG), 2) the physiochemical characteristics which have potential to impact bioavailability are well-established, and 3) clinical endpoints are difficult given the modest clinical benefit shown for acyclovir.

This “characterization-based equivalence” for formulations with the same concentrations of the same inactive ingredients signifies the trend towards a rational, science-driven approach, relying on trusted in vitro methods (not unlike the notion of BCS biowaivers for solid oral dosage forms). Absorption Systems offers in vitro release tests for topical dermatological products and other semisolid dosage forms.

Lionberger also expressed the need for additional draft guidance on FDA recommendations for complex generics. For submission of complex products, the FDA recommends scheduling a pre-ANDA meeting.

Another interesting session was Johnny’s Young’s talk on ANDA filings and refuse to receive (RTR) issues, underscoring key points from the draft RTR guidance which was mandated by GDUFA. One audience member asked if they would be subject to RTR if they submit a BCS waiver application and the biowaiver option is not specifically listed in the product’s BE recommendation. The panel confirmed our experience that this would not be cause for an RTR. Young also advised applicants to consult the ANDA filing checklist which is updated quarterly (typically March, June, September, and December).

Dr. Susan Rosencrance (FDA OGD) provided a review of the Stability Guidance for ANDAs (finalized on June 20, 2013). This Guidance requests applicants to follow the stability recommendations provided in ICH Q1A-E guidelines, including 1) data from three pilot scale batches, or two pilot batches and one small scale batch, 2) six months accelerated and long-term data, 3) multiple lots of drug substance, 4) principles that are representative of the commercial process, 5) fully packaged primary exhibit batch, 6) three batches when using bracketing and matrixing designs, and 7) statistical analysis of the data as appropriate.

Rosencrance stated that the primary purpose of the Stability Guidance is to provide clarity in the stability expectations and a formal process for generic drugs that aligns with ICH. This is to promote harmonization between new and generic drugs, and an overall enhancement in generic drug quality. On the other hand, industry voiced concerns that that the new stability requirements represent significant changes and the time/resources required to fully implement.  It is projected that the workload in stability labs for the enhanced stability testing will increase by 45% over three years and stability study budgets will increase by 40% over five years.

As the conference highlighted, the generic industry is facing new challenges and opportunities in introducing quality products. Whether in the design of complex products, in new stability provisions, or submission of applications – quality

AALAS National Meeting: Sampling Mouse CSF; Simple Dry Eye Model in Rats

AALAS (American Association for Laboratory Animal Science) held its 2013 national meeting recently in Baltimore. A primary focus of this meeting is technical advances in animal models, including tutorials on technically challenging manipulations and validation of a novel way of simulating a disease condition. I highlight one of each here.

Shaolan Li and Jennifer Scola of Vertex Pharmaceuticals presented a poster demonstrating a technique for sampling cerebrospinal fluid (CSF) via cisterna magna puncture in mice. The key is to obtain a sufficient volume of CSF (5 to 10 μL in this case), free of contamination by blood, to enable quantification of the amount of a test compound that has crossed the blood-brain barrier. The CSF:plasma concentration ratio is an important parameter, both for compounds targeting the central nervous system (CNS) and for non-CNS compounds. With this technique, it is possible to obtain both CSF and plasma concentrations in the same animal, which is generally quite challenging in mice. CSF sampling is performed with anesthetized animals in a stereotaxic apparatus. Key considerations include proper fixation of the head and positioning of the body, gentle dissection of overlying tissues, avoiding blood vessels (which are clearly visible) when penetrating the dura mater at a shallow angle, and limiting the amount of CSF withdrawn and the rate of withdrawal. Although the technique described is currently a terminal procedure, the authors anticipate that it may be possible to perform it as a survival procedure in the future. We are already practicing the technique and look forward to incorporating it into relevant pharmacokinetic study designs soon.

Glen Gum and colleagues from Absorption Systems took third place in the poster competition with their presentation on the development of a novel, economical prototype chamber for inducing dry eye (keratoconjunctivitis sicca, or KCS) in rodents. The novel design, which incorporates two small fans in a standard rodent enclosure, is an alternative to more expensive controlled environmental chambers. Computer-aided design (CAD) was used to simulate and optimize the airflow in the chamber, helping to direct design modifications. Measured airflow in the chamber was stable and consistent, and it produced the desired results: within three days, tear production in mice was less than 50% of control and the corneal epithelial layer was compromised. This is a model that we can now use to test treatments for dry eye.

At the AALAS meeting and in every field in which Absorption Systems is active, we remain on the cutting edge and actively involved in advancing the science.

Authors

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