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.


GPhA/FDA Fall Technical Conference 2013

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 2013 Sampling Mouse CSF; Simple Dry Eye Model in Mice

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.


MDR1-MDCK Cells: Consider the Source!

It’s important to assess potential drug disposition in the central nervous system (CNS) to understand desired or undesired pharmacological effects. One of the most commonly used tools for screening penetration of the blood-brain-barrier (BBB) is the immortalized cell line, MDR1-MDCK. These cells, which form polarized monolayers, overexpress human P-gp (MDR1), the most well-characterized efflux transporter on the luminal side of the BBB. Most MDR1-MDCK cells lines are derived from one of two origins: 1) the National Institutes of Health (NIH) or 2) the Netherlands Cancer Institute (NKI; Borst cell line).

Kikuchi et al., recently conducted an extensive literature review to compare the P-gp efflux ratio (ER) obtained in vitro (from the MDR1-MDCK cell lines) to in vivo ER. They found a strong correlation between in vivo and in vitro ER, even though the data were obtained from various literature sources from multiple labs. Of note, the ER of the NIH MDR1-MDCK cell line was found to be a better predictor of in vivo ER compared to the NKI MDR1-MDCK cell line, with r2 values of 0.813 vs. 0.531, respectively (Kikuchi et al, 2013).

Absorption Systems has worked with and characterized the NIH MDR1-MDCK cell line for more than a decade. It is a key component of our integrated BBB package. In fact, much of the data referenced in the Kikuchi publication (Broaccatelli et al) was sourced from Absorption Systems original data (Summerfield et al)


Blog - DMDG transporter interactions starts with test system

As the field of drug transporters continues to evolve and additional transporters are deemed ‘clinically relevant’ with regard to drug-drug interactions, drug innovators are faced with selecting in vitro test systems that can not only demonstrate transporter functionality but also generate data that is more quantitative as well as translatable to human outcomes. This is a far cry from where the field was in 2006, when transporters first officially appeared on the FDA’s radar screen in the form of a draft guidance. At the recent DMDG open meeting in Cambridge, UK , there were several subjects at the forefront of the discussion; one of them being transporters and the how to approach in vitro studies. Dr. Agnes Poirier of Hoffman-La Roche AG in Basel presented on the application of FDA-defined thresholds for transporter inhibition assessment. Using a training set of compounds, she and her colleagues applied the FDA’s [I]/IC50 thresholds [I]1/IC50 ≥0.1 and [I]2/IC50 ≥10 (where [I]1 is defined as the mean steady-state total Cmax and [I]2 is an estimate of the gut concentration, equal to dose/250 mL) to determine the accuracy of these cutoffs. These values have been defined based on clinical data and results from a variety of in vitro assays (based on different cell-based and vesicle-based test systems). Based on the assessment by Dr. Poirier, et al. (due for publication in the fall of 2013), [I]2/IC50 resulted in fewer false negatives when using the FDA-defined cutoff but still had some false negatives. However, Roche did not stop there; they moved forward to define their own internal thresholds based on clinical data and results from their in vitro test systems. Ultimately, through the calibration of their test systems to the clinical data, they have defined thresholds that are accurate for their test systems and most translatable to clinical outcomes and will apply these values moving forward. I look forward to this publication very much.

The data presented by Dr. Poirer got me thinking; often, we are more concerned with the outcome of a study involving an in vitro test system (e.g., is my compound an inhibitor or a substrate?) than the characterization and calibration of the test system itself. True translatability of a test system begins with the choice and definition of parameters for use of the test system, before moving forward with assessment of novel compounds. And this is not only limited to the in vitro assessment of a transporter interaction, but also to in silico predictions. Developing in silico models for transporter interactions, highlighted at the DMDG meeting by Dr. Rob Elsby of AstraZeneca, also relies heavily on access to good-quality in vitro data. A model is only as good as the data used to build it – this concept and the different types of models available were recently highlighted in a publication by the International Transporter Consortium (ITC). In additional to this publication, I would also recommend a recent AAPS webinar entitled “The Role of Transporters on Unbound Intracellular Concentrations: Experimental and Modeling Considerations.” These are great resources for the basics on available models and modeling.

As the drug transporter field evolves, so do the available tools. While there are a number of systems available (in vitro, in vivo, and in silico), the road to translatability always begins with thorough characterization and calibration. Although the importance of this step is frequently underestimated (but not by Absorption Systems), confidence in the test system leads to confidence in actionable conclusions for assessment of transporter DDI risks.


DVDMDG symposium on pediatric drug development

The theme of this symposium was that, from an ADME perspective, children are not just small adults and should not be approached as such with regard to drug development.

In the course of describing pre-clinical juvenile toxicology studies to support pediatric clinical trials, Jennifer Ingram-Ross of J&J mentioned that acetaminophen is less hepatotoxic to children than adults. That’s probably a good thing, since there are so many OTC products for children and it would be easy to overdose them with acetaminophen. But it made me wonder why it is less toxic to children: do they express lower levels of CYP2E1 (perhaps as a consequence of consuming no alcohol)? Do they have higher levels of GSH? Not sure, but while discussing the question with Steve Leeder (Children’s Mercy Hospital, Kansas City, MO) he turned me on to some work that I was previously unaware of on a circulating protein adduct that appears to be a biomarker of acetaminophen hepatotoxicity.

Lauren Aleksunes (Rutgers) is studying the global down-regulation of maternal drug transporters during pregnancy and lactation, which may be responsible for intracellular cholestasis of pregnancy (2% prevalence in humans). In vitro, at least, placental lactogen down-regulates uptake and efflux transporters in primary human hepatocytes. I found it particularly interesting that not only the fetal liver, but also the mother’s liver, expresses CYP3A7 during this time.

Steve Leeder discussed the ontogeny of CYPs in humans, particularly enzymes with a polymorphic phenotype determined by genetic variation. For CYP2D6, genetic variation is more important than ontogeny at all ages, since its expression is turned on (except in poor metabolizers) by two weeks of age. Not so for CYP2C19, where ontogeny is more important early and genetic variation more important later. He was followed by Amin Rostami-Hodjegan (Simcyp, University of Manchester, UK), who drove home the point that drug-drug interaction risk may be very different in young children vs. adults due to the importance of the fraction of a victim drug metabolized by a given CYP. In an adult, a drug that is metabolized equally by two different CYPs, inhibition of one or the other will have little effect on exposure.  But if the expression of one of those enzymes is absent or very low at birth and increases gradually during development, inhibition of the other enzyme in an infant could have dire consequences.

In discussing the pharmacogenetics of mycophenolic acid (MPA), Tristan Sissung (NCI) made one observation that, to me, pointed out the complexity of drug transporters and the difficulty of predicting what will happen when a transporter is blockd. Inhibition of MRP2 (for which MPA is a substrate), for example by cyclosporine A (which is frequently co-administered with MPA following an organ transplant), decreases the AUC of MPA by 30% due to interference with enterohepatic recirculation. In general, I would expect to see an increase in exposure when an efflux transporter such as MRP2 is blocked because of an increase in absorption and slower elimination.

Rest assured that Absorption Systems remains on the cutting edge of ADME research and is ever ready to characterize your new drug candidates. Check out our recent peer-reviewed publications here and here.


Medical Device DeviceFest

 

On August 27th, Biocom held its 7th annual DeviceFest Conference at the Sheraton Carlsbad Resort and Spa. The day-long conference delved into a multitude of current issues for both emerging and established biotech companies. With a heavy emphasis on federal regulations and connected health, the FDA’s tight-leashed behavior towards 510k and PMA approval highly contrasted discussions on future personalized patient care. Dr. Shuren’s talk, “FDA’s Medical Device Program 2013: Looking Back and Looking Ahead” kicked the conference off and was ultimately the session I found most elucidating. Through webcast, Dr. Shuren presented the audience with data on the % of PMAs and 510Ks being accepted to the FDA. Between 2000 and 2013, the percentage of PMAs with a Major Deficiency Letter (MAJR) on 1st FDA review cycle has slowly risen from 40% in 2000 to 100% in 2013. The percentage of 510(k)s with an additional information request (AI) on the first FDA cycle has dropped slightly since 2012, but with an initial 37% in 2000 and ending at 69% in 2013, the FDA’s leash-tightening trend looks like it is here to stay. “One of the major reasons 510(k)s are rejected or stalled is due to lack of information,” said Dr. Shuren, “Use the checklist.” With an already hostile economic environment, pushing device approval through the FDA seems like an unattainable feat. However, Shuren’s recommendation to abide by the books and deliver every minute detail recommended in Draft Guidance’s published by the FDA seemed to supply at least one helpful guidepost. This piece of advice was reminiscent of my report-writing days in school, with teachers tossing any assignment that didn’t have the initial requirements. Emphasis was also placed on having adequate information for biocompatibility. Both of these points further solidified my belief that navigating the regulatory environment for medical devices is no small feat and more and more should the individual decide what he/she is willing to risk-(Dr. Shuren)“If patients are willing to accept a higher risk for a device, we should abide by their preferences if the data stands.”

Moving into personalized patient care, Donald Jones provided an enlightening talk titled “A Look Ahead, The future of Connected Health”. While the FDA is becoming more and more strict with pre and post-market approval requirements, the health care industry is continually finding ways to put the patient’s health in the person’s hands who value it the most- themselves. Using cloud computing and cell phone interface technology (apps), companies are now moving towards providing accurate and instant health data to the patient so that first-response and action is immediate. Blood glucose levels, heart rate, and blood pressure are only a few of the many variables which can be readily accessed through an application. According to data provided by Jones, patients are diagnosed correctly only 55% of the time by their doctor. However, if they can diagnose themselves, relying on the “check engine” paradigm immediately, more power will be given to the patient.

The dichotomy between the FDA’s hands-on approach and the future of our “disconnected” impersonal method of self-diagnosis left me wondering how soon I would need to get an upgrade for my phone- or maybe in a few years- for my heart.


Living in “The Transporter Era”

The San Francisco Bay Area chapter of CACO-PBSS recently hosted a minisymposium entitled “DMPK/ADME Problem-Solving Case Studies.” It was an opportunity for scientists to share their thoughts on some significant DMPK/ADME challenges. Although each of the presentations was enlightening, I found the talk by Pfizer’s Kevin Beaumont to be the most intriguing.

Dr. Beaumont’s talk, “The current state of the art for in vivo clearance prediction using in vitro data: causes for under-prediction,” took us through the history of in vitro-in vivo correlation (IVIVC) in ADME. Prior to 1990, the most common for failure of drugs in clinical trials was poor human pharmacokinetics (PK), due in part to incomplete understanding of drug metabolism. In the late 80s and early 90s, two in vitro ADME models were characterized and became readily available, which eventually led to improvement in the ability to predict in vivo outcomes based on in vitro data. One was a drug absorption model, the Caco-2 cell monolayer; the other was human liver microsomes. Use of the latter was driven by necessity, i.e., the need to explain the often-fatal drug-drug interaction between terfenadine and  CYP3A4 inhibitors such as antifungals and antibiotics. Once the value of microsomal metabolism assays was proven, DMPK scientists began using them routinely to anticipate, proactively, such interactions rather than react to them after patients started dying. The pharmaceutical industry was several years ahead of FDA regulatory guidance in this regard.

By the mid-90s, the industry had entered what Dr. Beaumont termed “The Metabolism Era.” The commercial availability of research tools such as recombinant CYPs and cryopreserved human hepatocytes, coupled with advances in predictive software, enabled medicinal chemists to avoid problematic pathways such as CYP3A4. Eventually, they were largely able to tune out oxidative metabolism altogether, propelling the pharmaceutical industry into “The Transporter Era.”  

In general, drug candidates today are more potent and less permeable than in the past; as a result, they often require an uptake transporter in order to reach their target, which is often inside a cell. Efflux transporters are also becoming more significant for drug clearance, as oxidative metabolism has declined (as discussed above). The problem we are currently facing is an inability to predict human PK due to a lack of IVIVC tools for transporter interactions. Plenty of work is ongoing to develop, improve, and understand such tools as well as the computer models that depend on them. Make no mistake: “The Transporter Era” is far from over.

Two questions still remain in my mind. Once transporter interactions are tuned out, which era will we enter next? Or will we take advantage of our improved understanding of transporters to utilize them as portals for entry into specific target tissues?


GDUFA Regulatory Science Meeting June 2013

Every time I visit the Nation’s capital, I’m flooded with feelings of patriotism and memories of political rallies, spirited debates, backyard barbeques, and fireworks.

But this trip was different. As an attendee of the Generic Drug User Fee Amendments (GDUFA) Regulatory Science Initiatives Meeting on June 21st at the FDA, I witnessed democracy in action.

GDUFA is part of the 2012 renewal of the Prescription Drug User Fee Act (PDUFA), originally enacted in 1992 and renewed every five years thereafter. Both authorize the FDA to collect user fees from drug sponsors at the time of submission of a marketing application. In exchange, a time limit is imposed on the agency's review of each application. GDUFA is expected to help reduce the current backlog of generic drug reviews, which is due to the increase in the number of generic drug applications, their growing complexity, and the need to inspect the growing number of generic drug facilities located overseas. As a provider of BCS biowaiver testing (a surrogate for clinical bioequivalence testing), Absorption Systems is a registered generic drug facility under GDUFA.

As part of GDUFA legislation, FDA seeks input from a variety of stakeholders including industry, academia, patient advocates, and professional societies, to develop an annual list of regulatory science initiatives to be used in the Regulatory Science Plan for the following fiscal year.

Admittedly, I hadn’t considered research priorities under the same category as “life, liberty, and the pursuit of happiness”. But I’m undoubtedly passionate about regulatory science initiatives like BCS biowaivers and predictive formulation testing, and have a newfound appreciation for the importance of exhanging related knowledge in a forum with government officials. As the Declaration of Independence states, “governments are instituted among Men, deriving their just powers from the consent of the governed”. Public efforts (and $20M of public funding) should certainly be directed according to the will of the people - a fundamental tenet in preserving “unalienable rights”.

During the public meeting, speakers were allowed to present to an FDA panel for 15 minutes and share their recommendations. General themes included access to generic drugs (particularly inhaled and topical products), therapeutic equivalence of approved generics (with focus on the bupropion case), and quality of generic drugs (including perceived ‘switchability’ issues by consumers).

There was clear demand for research in the development of generic opthalmic drugs, narrow therapeutic index (NTI) drugs, topical dermatological formulations, abuse-deterrent mechanisms, and other ‘complex generics’.  The proposed solution for addressing the unmet research needs was focus on predictive, non-clinical tools such as in vitro release testing (IVRT), dissolution-based bioequivalence, and absorption modeling/clinical trial simulation via IVIVC, all encompassed under the umbrella of quality by design (QbD).

Two years after the publication of FDA’s related guidance, QbD has been embraced in 75% of generic drug submissions. But despite its adaptation, there remains some confusion around QbD, and the vague concepts which define it (design of experiments (DoE), quality target product profile, design space, etc.). The public requested FDA to provide examples and demonstrations of QbD for added clarity, and also update QbD recommendations (“QbD v2.0”) for more complex scenarios like modified release products. Dr. Jim Polli (University of Maryland) called for research efforts to improve predictive dissolution and absorption testing to enhance QbD.

Polli also called for reduced regulatory burden for BCS Class III compounds. He described an ongoing clinical trial at the University of Maryland to investigate the impact of excipients on BCS III drugs. As clinical results support, formulation changes have little impact on bioequivalence for Class III drugs, supporting their eligibility for BCS biowaivers.

Just as GDUFA is intended to accelerate the approval of generic drugs, so BCS biowaivers can reduce the time and cost of generic drug approval, expanding access to generic medications.


Hot Topics in DMPK

David Rodrigues (BMS) led off the 2013 Rozman Symposium of the Delaware Valley Drug Metabolism Discussion Group by outlining a number of present and future drug transporter topics that scientists in the DMPK field should pay attention to.

Alfred Schinkel and colleagues (Netherlands Cancer Institute) published two papers last year on a phenomenon they call “hepatocyte hopping.” Using bilirubin as a model compound, the concept is that the parent compound is taken up by hepatocytes (a transporter-mediated process), metabolized and conjugated (or directly conjugated in the case of bilirubin), and pumped out of the cell into the bile by MRP2 and/or BCRP. But what if the efflux transporters are blocked by a co-administered inhibitor or have reduced activity due to expression of a less active variant? An alternative pathway exists, via efflux back into the blood by MRP3, followed by repetitive cycles of uptake and efflux down the line of hepatocytes until the conjugate finds its way into the bile. It reminds me of the absorption of digoxin in the gut in spite of the fact that it is a P-gp substrate: absorbed apically/effluxed, absorbed apically/effluxed, etc. down the line until it finally gets through the gut mucosa.

Physiologically based pharmacokinetic (PBPK) models are becoming more and more complicated, due in part to the complexities of transporters.

During clinical testing, some drugs appear to give a renal toxicity signal due to elevation of serum creatinine. But in the case of a drug such as vandetanib, originally thought to be an OCT2 inhibitor but actually a more potent inhibitor of MATEs, this is a false positive resulting from interference with MATE-mediated excretion of creatinine rather than kidney damage. Knowing this, we may have to find a more appropriate biomarker of renal toxicity.

In the future, metabolites in excreta, in addition to major circulating metabolites, may have to be phenotyped for transporters.

Finally, cholestasis can be much more complicated than BSEP inhibition by a parent compound. In the first place, bile acids are complicated and their profile dynamic; we need to take into account a patient’s bile acid signature, which can reflect adaptation of the liver. For example, elevation of SULT2A1 (an inducible enzyme) activity would result in more sulfated bile acids; sulfation makes a lipophilic bile acid more hydrophilic, effectively shunting bile acids from BSEP to MRP2 and salvage pathways such as MRP4. Additional complexity comes from the fact that any of these transporters can be inhibited by metabolites (formed right there in the hepatocyte) as well as the parent drug.

Food for thought…and future research.


Importance of Experimental Design and Interpretation for Understanding Efflux Transporter Kinetics and IVIVE

At the Rozman Symposium of the Delaware Valley Drug Metabolism Discussion Group on June 3rd, Harma Ellens of GlaxoSmithKline discussed the implications of some in vitro P-glycoprotein (P-gp) inhibition data. She presented a thorough analysis of in vitro P-gp time course data from both cell-based models (bidirectional transport across monolayers of polarized epithelial cells) and uptake into inside-out plasma membrane vesicles from P-gp-expressing cells. The data (some of which was generated by Absorption Systems) was fitted to mathematical models to derive on-, off-, and efflux rates for the P-gp probe substrate digoxin, as well as P-gp surface density. The latter parameter was 7.7-fold higher in MDR1-MDCK cells than in Caco-2 cells.

IC50 data can vary with P-gp surface density because, in the absence of inhibitor, the intracellular substrate concentration is lower (theoretically, efflux more readily inhibited) in a cell line with higher expression of P-gp. At high inhibitor concentration, on the other hand, the intracellular substrate concentration is similar and high under both conditions.

The most compelling conclusion that came out of the analysis was that fitting the digoxin cell-based transport data, and inhibition by GF120918, requires postulating heretofore unidentified apical and basolateral uptake transporters for digoxin, in addition to efflux by apical P-gp. In other words, digoxin is not a P-gp-specific probe substrate. This is also the case for loperamide and vinblastine. On the other hand, amprenavir, quinidine, verapamil, and ketoconazole, all of which have higher passive permeability, do not require incorporation of uptake transporters to model the data.

Harma also discussed the results of the PhRMA-supported in vitro P-gp IC50 consortium, which was led by Caroline Lee. Using a common protocol and a set of sixteen P-gp inhibitors, there was a high degree of variability in IC50 values across labs, even when using the same test system (Caco-2 cell monolayers, MDR1-MDCK cell monolayers, or vesicles). Using consortium data to refine the criteria for a P-gp inhibitor resulted in only a marginal increase in accuracy of prediction, from 70% to 74%.

Maciej Zamek-Gliszczynski (Lilly) commented that he appreciated Harma’s analysis because efflux transporters should not be approached as “an enzyme in a beaker;” it is more appropriate to analyze them using a multi-compartment model. He also said that, based on a survey of data in the UCSF-FDA TransPortal, IC50 and Ki values are generally lower (for a given inhibitor) in vesicles than in cells. However, according to Harma’s systematic study of compounds across systems, that was not the case.

In addition to contributing to the work presented by Harma, Absorption Systems scientists also presented two posters, one on the intestinal uptake transporter PepT1 and the other on novel, sequence-specific inhibitors of OATPs.


Clinical Implications of Transporter Inhibition at the BBB: Not to Worry

In his presentation at the Delaware Valley Drug Metabolism Discussion Group’s Rozman Symposium last week, Maciej Zamek-Glisczcynski of Eli Lilly discussed the clinical impact of P-gp inhibition at the blood-brain barrier (BBB). Whereas there are many examples, in preclinical species, of large increases in brain exposure to P-gp substrates as a result of pharmacologic inhibition or genetic knockout (KO), such effects are not observed in humans. The question is why.

The main point of Maciej’s talk was that there is nothing intrinsically different about the BBB in different species…the lack of effect in humans is due solely to the limited degree to which P-gp can be inhibited. To illustrate, homozygous KO of mouse Mdr1 (P-gp) results in 60-fold higher levels of loperamide (P-gp substrate) in the brain compared with wild-type mice; in heterozygotes, the increase is only 2-fold, not 50% of the maximal effect. In humans, the plasma Cmax values of P-gp inhibitors approach the Ki, no more. Thus, one should expect less than a doubling of brain exposure in the clinic. In animal models, much higher concentrations of inhibitors can be achieved by IV infusion and tolerated due to the short duration of exposure (10 to 60 minutes).

It has been suggested that the lack of effect in humans could be due to saturation of P gp at the BBB in some cases. On the contrary, the highest plasma concentrations of P gp substrates approach the Km. And BBB expression of P-gp and BCRP are similar in the mouse (P-gp ~2-fold higher) and human (BCRP ~2-fold higher), not enough to explain the differences in CNS pharmacokinetics (PK). So the focus goes back on the inhibitor.

Another factor is the fraction of a substrate effluxed by a particular transporter, sometimes referred to as fT. This concept accounts for the apparently synergistic effect of Bcrp and Mdr1 KO on brain exposure to the drug lapatinib in mice. Bcrp KO has little effect, consistent with the fact that its fT is 0.23, and lapatinib brain levels are ~3-fold higher in Mdr1 KO mice (fT 0.77). When both are knocked out (fT 1.0), there is a huge increase in lapatinib in the brain. But it’s simple PK, not synergism.

I was interested to learn that, although none of the compounds that were designed for clinical use as P-gp inhibitors are approved for therapeutic use, they are available for use in clinical drug-drug interaction (DDI) studies. I’m not sure, but this might be a unique feature of this class of drugs; as far as I know, any other probes that are used in clinical DDI studies must be approved drugs.


Permeability Testing for Highly Variable Drugs

The combination of dissolution testing with permeability and solubility testing provides a way to obtain biowaivers for generic drugs and bypass expensive and time-consuming human bioequivalence (BE) studies. The recent Disso India 2013 conference held in Mumbai, India on May 3rd and 4th attracted over 500 delegates and renowned speakers from all over the world. The success of this conference was testimony to the growing importance of in vitro tests that often serve as a better way to establish therapeutic equivalence, especially for cytotoxic and highly variable drugs.

The Biopharmaceutics Classification System (BCS) provides the scientific basis that supports in vivo bioavailability and bioequivalence waivers for immediate-release solid dosage form drugs that have high solubility, high intestinal permeability, and rapid dissolution. In vitro permeability assays provide direct assessment of absorption potential, whereas in vivo BE studies assess drug absorption indirectly via evaluation of a pharmacokinetic profile. With the latter, post-absorption events such as metabolism and enterohepatic recycling can result in increased variability and make it difficult to quantify the fraction absorbed. Highly variable drugs (HVDs) often require a greater number of subjects to minimize the chance of an erroneous conclusion of inequivalence when, in fact, two drug products are therapeutically equivalent. For an HVD that exhibits consistently inconsistent PK due to extensive first-pass metabolism, human mass balance and bioavailability studies may result in ambiguous or incorrect BCS classification because the variability inherent in human studies is compounded by the intrinsic properties of the drug substance. In such cases, in vitro testing provides consistent and accurate classification as the variability associated with permeability and solubility measurements is less dependent on the factors that magnify the variability of human testing.

In a conference filled with talks on dissolution, Absorption Systems provided the only presentation on permeability testing. As the world leader in BCS, our participation in this conference highlights our commitment to work with companies in India and other emerging markets around the globe. Our focus is to apply the BCS and BCS-based biowaivers to avoid clinical bioequivalence testing through more ethical and definitive in vitro tests whenever possible. Many patients go untreated or are undertreated because bioequivalence for highly variable drugs can be challenging to establish, resulting in many medicines being unavailable. While there is much institutional knowledge and expertise in the areas of formulation development and dissolution technologies in a country like India which is well accepted as the generic hub of the world, an improved awareness and understanding of the in vitro approach will help Indian pharmaceutical companies bring better-quality, lower-cost generic medicines to the Indian market and the world.

The path forward requires a global effort, since most major products are registered worldwide. While the FDA has been clear about their acceptance of the BCS-based biowaiver approach through their BCS Guidance (2000), multiple publications, and webinars, drug regulatory agencies in other countries have yet to follow suit. As long as there is a lack of harmonized acceptance, in vivo testing will always be performed, even if in vitro tests are the better and more ethical option. The universal acceptance and utility of in vitro permeability, solubility, and dissolution testing is therefore necessary and needs to become an integral part of quality-by-design (QbD) efforts during product development.

The combination of dissolution testing with permeability and solubility testing provides a way to obtain biowaivers for generic drugs and bypass expensive and time-consuming human bioequivalence (BE) studies. The recent Disso India 2013 conference held in Mumbai, India on May 3rd and 4th attracted over 500 delegates and renowned speakers from all over the world. The success of this conference was testimony to the growing importance of in vitro tests that often serve as a better way to establish therapeutic equivalence, especially for cytotoxic and highly variable drugs.

 

The Biopharmaceutics Classification System (BCS) provides the scientific basis that supports in vivo bioavailability and bioequivalence waivers for immediate-release solid dosage form drugs that have high solubility, high intestinal permeability, and rapid dissolution. In vitro permeability assays provide direct assessment of absorption potential, whereas in vivo BE studies assess drug absorption indirectly via evaluation of a pharmacokinetic profile. With the latter, post-absorption events such as metabolism and enterohepatic recycling can result in increased variability and make it difficult to quantify the fraction absorbed. Highly variable drugs (HVDs) often require a greater number of subjects to minimize the chance of an erroneous conclusion of inequivalence when, in fact, two drug products are therapeutically equivalent. For an HVD that exhibits consistently inconsistent PK due to extensive first-pass metabolism, human mass balance and bioavailability studies may result in ambiguous or incorrect BCS classification because the variability inherent in human studies is compounded by the intrinsic properties of the drug substance. In such cases, in vitro testing provides consistent and accurate classification as the variability associated with permeability and solubility measurements is less dependent on the factors that magnify the variability of human testing.

 

In a conference filled with talks on dissolution, Absorption Systems provided the only presentation on permeability testing. As the world leader in BCS, our participation in this conference highlights our commitment to work with companies in India and other emerging markets around the globe. Our focus is to apply the BCS and BCS-based biowaivers to avoid clinical bioequivalence testing through more ethical and definitive in vitro tests whenever possible. Many patients go untreated or are undertreated because bioequivalence for highly variable drugs can be challenging to establish, resulting in many medicines being unavailable. While there is much institutional knowledge and expertise in the areas of formulation development and dissolution technologies in a country like India which is well accepted as the generic hub of the world, an improved awareness and understanding of the in vitro approach will help Indian pharmaceutical companies bring better-quality, lower-cost generic medicines to the Indian market and the world.

The path forward requires a global effort, since most major products are registered worldwide. While the FDA has been clear about their acceptance of the BCS-based biowaiver approach through their BCS Guidance (2000), multiple publications, and webinars, drug regulatory agencies in other countries have yet to follow suit. As long as there is a lack of harmonized acceptance, in vivo testing will always be performed, even if in vitro tests are the better and more ethical option. The universal acceptance and utility of in vitro permeability, solubility, and dissolution testing is therefore necessary and needs to become an integral part of quality-by-design (QbD) efforts during product developmen

The combination of dissolution testing with permeability and solubility testing provides a way to obtain biowaivers for generic drugs and bypass expensive and time-consuming human bioequivalence (BE) studies. The recent Disso India 2013 conference held in Mumbai, India on May 3rd and 4th attracted over 500 delegates and renowned speakers from all over the world. The success of this conference was testimony to the growing importance of in vitro tests that often serve as a better way to establish therapeutic equivalence, especially for cytotoxic and highly variable drugs.

The Biopharmaceutics Classification System (BCS) provides the scientific basis that supports in vivo bioavailability and bioequivalence waivers for immediate-release solid dosage form drugs that have high solubility, high intestinal permeability, and rapid dissolution. In vitro permeability assays provide direct assessment of absorption potential, whereas in vivo BE studies assess drug absorption indirectly via evaluation of a pharmacokinetic profile. With the latter, post-absorption events such as metabolism and enterohepatic recycling can result in increased variability and make it difficult to quantify the fraction absorbed. Highly variable drugs (HVDs) often require a greater number of subjects to minimize the chance of an erroneous conclusion of inequivalence when, in fact, two drug products are therapeutically equivalent. For an HVD that exhibits consistently inconsistent PK due to extensive first-pass metabolism, human mass balance and bioavailability studies may result in ambiguous or incorrect BCS classification because the variability inherent in human studies is compounded by the intrinsic properties of the drug substance. In such cases, in vitro testing provides consistent and accurate classification as the variability associated with permeability and solubility measurements is less dependent on the factors that magnify the variability of human testing.

In a conference filled with talks on dissolution, Absorption Systems provided the only presentation on permeability testing. As the world leader in BCS, our participation in this conference highlights our commitment to work with companies in India and other emerging markets around the globe. Our focus is to apply the BCS and BCS-based biowaivers to avoid clinical bioequivalence testing through more ethical and definitive in vitro tests whenever possible. Many patients go untreated or are undertreated because bioequivalence for highly variable drugs can be challenging to establish, resulting in many medicines being unavailable. While there is much institutional knowledge and expertise in the areas of formulation development and dissolution technologies in a country like India which is well accepted as the generic hub of the world, an improved awareness and understanding of the in vitro approach will help Indian pharmaceutical companies bring better-quality, lower-cost generic medicines to the Indian market and the world.

The path forward requires a global effort, since most major products are registered worldwide. While the FDA has been clear about their acceptance of the BCS-based biowaiver approach through their BCS Guidance (2000), multiple publications, and webinars, drug regulatory agencies in other countries have yet to follow suit. As long as there is a lack of harmonized acceptance, in vivo testing will always be performed, even if in vitro tests are the better and more ethical option. The universal acceptance and utility of in vitro permeability, solubility, and dissolution testing is therefore necessary and needs to become an integral part of quality-by-design (QbD) efforts during product development.

Biosimilars? Biobetters? BLAs? FDA Pathway to Biosimilars Still Hazy

As part of the Affordable Care Act of 2010, the impetus for the FDA to set up a defined pathway for biosimilars was set forth, and followed up with a trio of draft guidances first available in early 2012. However, the pathway is still not nearly as clear as it is for small molecules. Many generic companies want to get into the game as they have for small molecules. However, to prove similarity, all in vitro and in vivo studies of the approved reference molecule and the biosimilar candidate must be run in parallel. Additionally, the realization that the set-up and manufacturing costs can be 10 to 20 times more than that of small molecules may lead to many companies deciding to drop biosimilar projects due to lack of both adequate funding and a clear path forward.

There is a need for good quality biosimilars for the developed and developing world. Currently, in the EU, several biosimilar products have made it to market and are routinely used in lieu of the respective innovator molecules. This is true for many other regions of the world as well. However, currently in the US, the pathway is not clear. For biologics, “the process is the product,” so how similar do biosimilars need to be? How easy will it be for a pharmacist to switch out the biosimilar for the innovator? According to innovator companies, it shouldn’t be that simple. To them, if “the process is the product,” then “similar” is not ”identical”; even the current, vague FDA draft guidances acknowledge “biosimilarity” does not equate to “interchangeability.” Beyond the federal position on testing and approval, state governments have been and are being lobbied on behalf of innovator companies, and state laws have been penned requiring that the pharmacist, prescriber, and patient all be made aware of the differences.

While it is clear that extensive biochemical and biophysical characterization and comparison are necessary and that similarity can be demonstrated empirically at the molecular level, there can still be differences at the level of the bioassay or clinical results. Can all of these aspects be proven to be similar? Or is the new product superior, based on structural properties, efficacy, potency, safety, or manufacturing procedure? Several companies eyeing the biosimilar market in the US market have opted to file a BLA (i.e., as an innovator product) and/or target approval as a biobetter, as opposed to a biosimilar. And why not, when the cost of developing a biosimilar could be nearly as high as that of a new product, with the additional risk of an uncertain regulatory pathway.

With several biosimilars currently approved and on the market in the EU, one would assume the filing process would be streamlined for the US market. However, this is not the case. It is important to note that for potential biosimilars, the reference comparator for all in vitro and in vivo studies must be the relevant approved product in that country or region. That is to say, there may be subtle differences between the same innovator molecule approved in the two regions. This may be the case even if they are produced by the same company (e.g., due to different manufacturing  sites). Thus, a company wishing to apply for a biosimilar in the US, even if it has one approved in the EU, may be required to repeat all in vitro and in vivo studies to demonstrate biosimilarity. This is another factor that will tend to push companies toward filing a BLA rather than taking the biosimilar route.

Biologics have grown and will continue to grow in importance in the pharmaceutical market. Biosimilars are expected to contribute to that growth. Though the pathway to biosimilars is not currently clear for the US, defined processes have been established in other markets and, as the field matures, the FDA will further define these processes as they have done with small molecules. With governmental, payer, and patient pressures mounting, it is only a matter of time before the first biosimilar is approved in the US. The path to a biosimilar for the US market may currently be hazy, but the clouds are beginning to lift.

As part of the Affordable Care Act of 2010, the impetus for the FDA to set up a defined pathway for biosimilars was set forth, and followed up with a trio of draft guidances[CB1] first available in early 2012. However, the pathway is still not nearly as clear as it is for small molecules. Many generic companies want to get into the game as they have for small molecules. However, to prove similarity, all in vitro and in vivo studies of the approved reference molecule and the biosimilar candidate must be run in parallel. Additionally, the realization that the set-up and manufacturing costs can be 10 to 20 times more than that of small molecules may lead to many companies deciding to drop biosimilar projects due to lack of both adequate funding and a clear path forward.

There is a need for good quality biosimilars for the developed and developing world. Currently, in the EU, several biosimilar products have made it to market and are routinely used in lieu of the respective innovator molecules. This is true for many other regions of the world as well. However, currently in the US, the pathway is not clear. For biologics, “the process is the product,” so how similar do biosimilars need to be? How easy will it be for a pharmacist to switch out the biosimilar for the innovator? According to innovator companies, it shouldn’t be that simple. To them, if “the process is the product,” then “similar” is not ”identical”; even the current, vague FDA draft guidances acknowledge “biosimilarity” does not equate to “interchangeability.” Beyond the federal position on testing and approval, state governments have been and are being lobbied on behalf of innovator companies, and state laws have been penned requiring that the pharmacist, prescriber, and patient all be made aware of the differences.

While it is clear that extensive biochemical and biophysical characterization[ASL2] and comparison are necessary and that similarity can be demonstrated empirically at the molecular level, there can still be differences at the level of the bioassay or clinical results. Can all of these aspects be proven to be similar? Or is the new product superior, based on structural properties, efficacy, potency, safety, or manufacturing procedure? Several companies eyeing the biosimilar market in the US market have opted to file a BLA (i.e., as an innovator product) and/or target approval as a biobetter, as opposed to a biosimilar. And why not, when the cost of developing a biosimilar could be nearly as high as that of a new product, with the additional risk of an uncertain regulatory pathway.

With several biosimilars currently approved and on the market in the EU, one would assume the filing process would be streamlined for the US market. However, this is not the case. It is important to note that for potential biosimilars, the reference comparator for all in vitro and in vivo studies must be the relevant approved product in that country or region. That is to say, there may be subtle differences between the same innovator molecule approved in the two regions. This may be the case even if they are produced by the same company (e.g., due to different manufacturing sites). Thus, a company wishing to apply for a biosimilar in the US, even if it has one approved in the EU, may be required to repeat all in vitro and in vivo studies to demonstrate biosimilarity. This is another factor that will tend to push companies toward filing a BLA rather than taking the biosimilar route.

Biologics have grown and will continue to grow in importance in the pharmaceutical market. Biosimilars are expected to contribute to that growth. Though the pathway to biosimilars is not currently clear for the US, defined processes have been established in other markets and, as the field matures, the FDA will further define these processes as they have done with small molecules. With governmental, payer, and patient pressures mounting, it is only a matter of time before the first biosimilar is approved in the US. The path to a biosimilar for the US market may currently be hazy, but the clouds are beginning to lift.


[CB1]Not sure how to link to multiple documents

[ASL2]Link to biologics page

As part of the Affordable Care Act of 2010, the impetus for the FDA to set up a defined pathway for biosimilars was set forth, and followed up with a trio of draft guidances first available in early 2012. However, the pathway is still not nearly as clear as it is for small molecules. Many generic companies want to get into the game as they have for small molecules. However, to prove similarity, all in vitro and in vivo studies of the approved reference molecule and the biosimilar candidate must be run in parallel. Additionally, the realization that the set-up and manufacturing costs can be 10 to 20 times more than that of small molecules may lead to many companies deciding to drop biosimilar projects due to lack of both adequate funding and a clear path forward.

There is a need for good quality biosimilars for the developed and developing world. Currently, in the EU, several biosimilar products have made it to market and are routinely used in lieu of the respective innovator molecules. This is true for many other regions of the world as well. However, currently in the US, the pathway is not clear. For biologics, “the process is the product,” so how similar do biosimilars need to be? How easy will it be for a pharmacist to switch out the biosimilar for the innovator? According to innovator companies, it shouldn’t be that simple. To them, if “the process is the product,” then “similar” is not ”identical”; even the current, vague FDA draft guidances acknowledge “biosimilarity” does not equate to “interchangeability.” Beyond the federal position on testing and approval, state governments have been and are being lobbied on behalf of innovator companies, and state laws have been penned requiring that the pharmacist, prescriber, and patient all be made aware of the differences.

While it is clear that extensive biochemical and biophysical characterization and comparison are necessary and that similarity can be demonstrated empirically at the molecular level, there can still be differences at the level of the bioassay or clinical results. Can all of these aspects be proven to be similar? Or is the new product superior, based on structural properties, efficacy, potency, safety, or manufacturing procedure? Several companies eyeing the biosimilar market in the US market have opted to file a BLA (i.e., as an innovator product) and/or target approval as a biobetter, as opposed to a biosimilar. And why not, when the cost of developing a biosimilar could be nearly as high as that of a new product, with the additional risk of an uncertain regulatory pathway.

With several biosimilars currently approved and on the market in the EU, one would assume the filing process would be streamlined for the US market. However, this is not the case. It is important to note that for potential biosimilars, the reference comparator for all in vitro and in vivo studies must be the relevant approved product in that country or region. That is to say, there may be subtle differences between the same innovator molecule approved in the two regions. This may be the case even if they are produced by the same company (e.g., due to different manufacturing  sites). Thus, a company wishing to apply for a biosimilar in the US, even


Importance of MATEs in Drug-Drug Interaction (DDI)

At AAPS Workshop on Drug Transporters in ADME: From the Bench to the Bedside, held on March 17th to 20th, 2013, the latest information on transporter-mediated drug-drug interactions (DDI) was presented and discussed.

One of the hottest topics was still the “new” transporter family, Multidrug and Toxin Extrusion (MATE) including MATE1 and MATE2-K, which have not been officially listed on the 2012 FDA Guidance for Industry[1] and 2012 EMA Guideline on the Investigation of Drug Interactions[2]. Back in 2012, at the second International Transporter Consortium Workshop (ITCW2), Dr. Shiew-Mei Huang, Deputy Director of the Office of Clinical Pharmacology (OCP) in the U.S. Food and Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) stated that OCP reviewers would expect sponsors to evaluate proactively new drug candidates as substrates and/or inhibitors of MATE1 and MATE2-K. During this workshop, Dr. Lei Zhang, Special Assistant to Office Director in the Office of Clinical Pharmacology, Office of Translational Sciences, the Center for Drug Evaluation and Research, FDA (OCP/OTS/CDER/FDA) stated that 1.4% of FDA approved New Molecular Entities (NMEs) from 2003 to 2011 has MATE information on their labeling.

As the first presenter, Prof. Steven Wright, talked about the role of MATE transporters in renal function. He emphasized their “multispecificity” which makes them principal sites for unwanted DDIs and makes them a focus of efforts to develop models capable of predicting and ideally, pre-empting unwanted DDIs (italic statements cited from the speaker abstract). Further, the impact of the interplay of the uptake transporter (e.g., Organic Cation Transporter, OCT2) and the coupled efflux transporter (e.g. MATE1 and/or MATE2-K) and the rated-limit step in the drug elimination across both basolateral and apical membrane barriers has also been widely discussed.  Take a newly published paper as an example, Sugiyama and his colleagues reported that the inhibition potency of cimetidine towards OCT2 (Ki = 124 µM) is much lower than that towards MATE2-K (Ki = 6.9 µM)[3]. Considering the clinically reported plasma unbound concentrations (3.6-7.8 µM) of cimetidine, the competitive inhibition of MATE2-K appears to be the mechanism underlying the DDI caused by cimetidine in the renal elimination of cationic drugs. Please note that this phenomenon is also applicable for other coupled transporters, for instance, if the drug elimination is involved in both uptake transporter Na+-taurocholate Cotransporting Polypeptide (NTCP) and efflux transporter Bile Salt Export Pump (BSEP) in the hepatocyte.

Currently, the regulatory agencies, the pharmaceutical industry and the academic world have recognized the importance of MATE transporters, which indicates that they are likely to be incorporated in the transporter list in the future versions of FDA guidance and/or EMA guideline.  Absorption Systems had the vision to proactively develop test systems for these “new” transporters, including MATE1 and MATE2-K. We can now help our customers investigate the substrate and inhibitor potential of the drug candidates towards MATEs. In doing so, our mission is to work closely with our customers just like their internal R&D group. We utlilize our knowledge and expertise in analyzing the in vitro data and related other information to accurately predict the in vivo outcome.

[1] FDA Guidance for Industry, Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, 2012
[2] EMA Guideline on the Investigation of Drug Interaction, 2012
[3] Sumito Ito, et al. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug-drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther 340:393-403. 2012


BCS: Its Simple and Should Be Universal, Part 4 of 4

In the first three parts of this series, I have covered the basic principles of the BCS, the fact that it remains under-utilized even in the U.S., and some ethical and geopolitical implications. Now we will discuss the simple fact that the in vitro approach to the BCS, when performed correctly, is a reliable, scientifically proven approach and has been utilized for over thirteen years.

  1. It eliminates unnecessary human testing
  2. It shortens development time and therefore overall product costs
  3. It is an inherently conservative, scientific approach
  4. When applicable, it is the BEST approach

Jim Polli of the University of Maryland argues that in vitro BCS testing is actually better than a clinical bioequivalence (BE) study (Polli JE, AAPS J 2008 Jun;10(2):289-299). Besides lower drug development costs and ethical considerations (addressed in prior posts in this series), there are two other important points. In vitro permeability studies assess drug absorption more directly than human BE studies, for which the approach is indirect (one needs to find and account for metabolites as well as the parent drug) and the interpretation is often complicated (e.g., did that compound in feces result from biliary excretion of absorbed drug, or was it never absorbed?). Furthermore, in vitro permeability data is inherently more precise than clinical data due to intra- and inter-individual variability in the latter, particularly for highly variable drugs.

Three simple laboratory tests, two on the active pharmaceutical ingredient (API) − solubility and permeability − and a third on the finished dosage form − dissolution. If the API and the finished dosage form meet the established criteria as outlined in the FDA Guidance, then we know unequivocally that the test product will be bioequivalent to the marketed (“approved” or “reference”) product. This has been proven scientifically over the past 13 years. And, should any of the in vitro test results be ambiguous or fail to meet the Guidance criteria, the manufacturer can simply proceed to human BE testing.

So why has adoption of the BCS been slow in many countries outside the US? To quote Harry Truman, “The only thing new is the history we do not know.” For artisans in the field of in vitro BCS measurements, the history is known and is being told, slowly, from a grassroots perspective. Our challenge is for governments and regulatory authorities around the world to take advantage of what we already know, what makes sense scientifically, and what works. What are your thoughts on the BCS?


2013 AAPS Workshop on Drug Transporters in ADME

As the daughter of two avid Rolling Stones fans (and subsequently a fan in my own right), I’ve enjoyed some of my most memorable moments at rock ’n roll concerts. Yes – this blog is about drug transporters.

Quite unexpectedly, last week’s AAPS Transporter Workshop in ADME: From the Bench to the Bedside brought me back to the front row at Madison Square Garden, anticipating the moment when the Stones would take the stage - starting, of course, with one of Keith Richards’ unmistakable riffs.

Maybe it’s because I woke up early in the morning, hopped in a minivan with my colleagues, and headed toward a nearby city. Maybe it’s because everyone was wearing a lanyard, reminiscent of concert VIP passes. But the main commonality was throngs of people from around the world – people with a similar passion, gathering to share their experiences. The crowd consisted of both newcomers (including a large showing of students) and ‘diehard fans’ (those well-versed and immersed in the still-emerging transporter field).

Before the transporter ‘rock stars’ took the stage, there was palpable excitement and anticipation. Much has transpired in transporter research in recent months, and this group was ready to share and learn. The ‘set list’ included both ‘classic tunes’ (a comprehensive review of transporters and their role in ADME) and ‘new hits’ (including special focus on renal transporters of emerging importance).

Speaking of renal transporters, Steve Wright (University of Arizona) started the workshop with a great review of these, highlighting the increasing importance of MATE transporters in renal function. More specifically, MATE1 and MATE2-K possess ‘multispecificity’ (resulting from a large receptor surface with multiple binding sites, similar to the multidrug resistance transporters such as P-gp), making them principal sites for unwanted drug-drug interactions (DDIs). Substrate-dependent ligand interactions (and differential selectivity vs. OCT2) will influence prediction of such DDIs, necessitating more advanced models.

There is also a need for better understanding of renal transporters in the clinical setting. Alex Sparreboom (St. Jude Children’s Research Hospital) delineated how inhibition of the renal secretion of OCT2 substrates may potentially impair the usefulness of creatinine as a marker for glomerular filtration rate. Daniel Antoine (University of Liverpool) described the current panel of seven urinary biomarkers (including KIM-1) used to assess renal injury, in addition to more classic markers like serum creatinine and blood urea nitrogen, and limitations related to sensitivity and specificity. The ‘next generation’ for evaluating drug-induced acute kidney injury will likely include microRNA biomarkers.

Following the discussion on kidney transporters, the focus shifted to the liver. Curt Klaassen (Kansas University) and Gian Camensich (Novartis) delivered interesting presentations on prediction of hepatotoxicity and hepatic clearance from in vitro metabolism and transporter data. It was fitting to connect this information to the Biopharmaceutics Drug Disposition Classification System (BDDCS). As one may expect, in vitro metabolism data is most predictive for highly permeable compounds (BDDCS 1 and 2), where metabolism is rate-limiting. For poorly permeable compounds (BDDCS 3 and 4), hepatic uptake is most predictive, as cellular uptake is rate-limiting in overall organ clearance. This approach of incorporating BCS or BDDCS classification in early assessment of DDI potential enables clearance estimates based on an established hepatobiliary model, allowing for more predictive PK, PK/PD, and DDI models.

Extending the clinical implications, the impact of transporter expression and function in disease states was reviewed, with focus on Alzheimer’s disease and non-alcoholic fatty liver disease. Jash Unadkat (University of Washington) commented on the role of P-gp in the pathophysiology of neurological diseases, while Mikko Niemi delivered an interesting presentation on pharmacogenetics and clinical applications. I enjoyed Cuiping Chen’s (Depomed) case study, which highlighted the importance of intestinal transporters in the development of a gastroretentive formulation. Coupling site-specific absorption data from an in situ intestinal perfusion model with information on L-amino acid transporters enabled development of a mucoadhesive formulation to overcome the physiological turnover of mucus in the GI tract, exploiting gabapentin’s preferential absorption in the upper GI tract.

The session which resonated the most with me featured the ‘current state of the art’ of transporter assays. Matt Soars (Bristol-Myers Squibb) commented on the progress with development of transporter tools and their applications, highlighting the importance of robust characterization and understanding test system limitations. He also described a practical approach to utilize current analytical techniques in order to produce high-throughput transporter inhibition screens.

Donna Volpe of the FDA provided a survey of transporter studies, noting that 74 of the 183 package inserts from 2003-2011 included the names of specific transporter(s). We have performed a similar review of the approved labels from 2012: 18 of the 24 small-molecule oral/IV drugs included transporter information on their labels and Absorption Systems contributed to 6 of the 18 labels. Donna also highlighted common assay issues, including solubility, stability, choice of cell line, transporter expression, substrate/inhibitor specificity, interspecies differences, and data analysis. Absorption Systems similarly recognizes the importance of these factors, and incorporates appropriate suitability testing to ensure maximum translatability. See our companion guides related to test system selection and test compound characteristics.

Absorption Systems’ Chief Operating Officer, Dr. Sid Bhoopathy, discussed a novel and nuanced approach to in vitro test system selection for substrate assays. We’ve always understood that you can obtain different results with different test systems – but we now appreciate that these differences may be complementary and not necessarily conflicting. Using decision trees related to intrinsic membrane permeability and clearance pathways, Sid highlighted a rational approach to guide substrate evaluation for maximum clinical relevance. Test systems that are relevant to the site of interaction may provide relevant information on both intestinal absorption and systemic drug disposition, for example. This, of course, embodies the Stones’ words of wisdom: “You can’t always get what you want. But if you try sometimes, you’ll find, you get what you need.”

But, like a rock concert, the experience consists not only of the show itself, but the common bond shared amongst the audience members. During the break sessions, I participated in great discussions on common experimental issues in transporter assays. There was also great discussion around measurement of intracellular concentrations of drug and metabolites. Kim Brouwer (University of North Carolina) discussed an elegantly simple technique employing subcellular fractionation and equilibrium dialysis to quantify unbound drug concentration in sandwich-cultured hepatocytes. It is generally accepted that systemic concentrations may not reflect hepatocellular drug concentrations and that hepatocyte distribution and intracellular unbound drug concentrations may be important determinants of hepatic efflux, DDIs, and drug–induced liver injury (DILI). Absorption Systems’ current collaboration with Temple University addresses some of these important questions.

The ‘grand finale’ of the workshop included presentations from Lei Zhang (FDA) and Eva Gil Berglund (EMA), reviewing current regulatory perspectives. Highlights were:

  • the inclusion of MATE1 and MATE2-K on the FDA’s recommended list of transporters for prospective evaluation (as well as BSEP and MRP2 retrospectively, depending on liver toxicity data)
  • the importance of test system calibration and in vitro ‘benchmarking’
  • the FDA’s addition of a ‘methodology’ appendix to its draft DDI guidance in coming months
  • the EMA’s emphasis on including rationale for experimental design choices to assist with identification of sources of variability and standardization of systems
  • the importance of evaluating multiple test systems (depending on the site of interaction, e.g., cell line with endogenous expression, knockdown (CellPort Technologies), over-expression, vesicles, or hepatocytes)
  • selection of appropriate probes/inhibitors and relevant concentrations (e.g., P-gp and BCRP should be evaluated at both systemic and intestinal concentrations).

Overall, the worskhop provided a great forum for information exchange and discussion. As Mick Jagger might say, had he attended the AAPS workshop – “I know it’s only transporters – but I like it.”


MATE Drug Transporters Added to the FDA List

It’s no surprise the list of testing requirements for drug transporters continues to grow. I learned at the ASCPT (clinical pharmacology) conference in Indianapolis last week that there are officially two new transporters of interest to the FDA with regard to in vitro drug-drug interaction (DDI) testing.

According to Shiew-Mei Huang, Deputy Director of the Office of Clinical Pharmacology (OCP) in the FDA’s Center for Drug Evaluation and Research (CDER), OCP reviewers will now expect sponsors to evaluate proactively new drug candidates as substrates and/or inhibitors of the multidrug and toxin extrusion protein (MATE) family of renal efflux transporters (MATE1 and MATE2-K). The change was recommended during the International Transporter Consortium Second Workshop in March 2012, as summarized by Zamek-Gliszczynski et al., Clin. Pharmacol. Ther. 2012 Nov;92(5):553-556. This is in addition to the seven drug transporters already on the FDA’s list: P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, and OCT2.

Also according to Shiew-Mei, the FDA is seeing fewer in vivo digoxin studies in submissions, as they are being replaced by in vitro digoxin studies. If an in vitro study indicates no significant risk of a P-gp-mediated DDI at clinically relevant concentrations, an in vivo study becomes unnecessary. Another strategy the agency uses to avoid unnecessary clinical trials is, increasingly, to rely on computer modeling. If an in vitro study indicates a risk of a DDI but a validated computer model says that the magnitude of the effect is likely to be clinically insignificant, a clinical study may be unnecessary.

The good news is that Absorption Systems is in the forefront of drug transporter research with innovative test systems that enable our clients to utilize in vitro data, predictive modeling, and clinical relevance to maximize their ability to predict human outcomes. We anticipated the need for comprehensive MATE assays, among others that are likely to be added as well, including BSEP, MRP2, and NTCP. Absorption Systems has in vitro assays for all of the drug transporters the major drug regulatory agencies are looking for. Give us a call to discuss the best test system for your drug candidate.


Ethical and Geopolitical Implications of the BCS: Part 3 of 4

Ethical implications of the BCS? Well, yes: considering that (i) it is unethical to perform unnecessary drug testing in humans and (ii) a BCS biowaiver is a science-based, well-validated in vitro alternative to human in vivo bioequivalence (BE) testing, a case can be made that, for Class 1 drugs, the BCS is more ethical than traditional clinical BE testing. Furthermore, some drugs (i.e., those known to have serious side effects such as many anticancer drugs) cannot be tested ethically in healthy human volunteers. The clinical alternative, finding enough subjects for BE testing in the right patient population, who are not already taking a drug that might interfere with the one whose BE you intend to test, can be problematic. On the “Individual Product Recommendation” portion of its website, the FDA recommends a biowaiver for some of these drugs.

The BCS has geopolitical implications? Yes, and they are tied in with additional ethical considerations. One of many ethical landmines for the pharmaceutical industry in recent years has been the high price of medicines (understandable, in light of the high cost of drug development and failed attempts along the way), which makes them unaffordable for most patients in developing countries. To improve access to many medications for these patients, the World Health Organization (WHO) has pushed strongly for the use of BCS-based criteria to classify a long list of drugs whose patents have expired, thereby making them eligible for manufacture by generic companies. Lower-cost versions of Class 1 (and some Class 2 and 3) drugs would then be available in short order without the need for clinical BE studies (which would add to the cost and delay their availability). For its part, Absorption Systems is using in vitro BCS testing to classify the potentially life-saving anti-malarial drug mefloquine, whose BCS class has heretofore been uncertain.

Additional geopolitical considerations follow from the economic crisis that continues to plague many countries, most notably Greece, Portugal, Spain, and Ireland. One way the governments of these and other countries are trying to save money is by encouraging or requiring the use of generic drugs by their publicly funded prescription drug programs. By accelerating the approval of Class 1 generic drugs, the BCS pathway is in line with government cost-saving initiatives.

The fourth and final installment of this series will discuss the Absorption Systems plan for expanding the implementation of the BCS globally.


BCS, The Underutilized Pathway: Part 2 of 4

Given the obvious benefits of a BCS biowaiver in terms of speed and cost of drug development outlined in Part 1, it is reasonable to ask why even more companies and countries don’t take advantage of it. The answer is complicated.

It’s important to realize that the U.S. Food and Drug Administration (FDA) took a leading edge approach when it published the BCS guidance in 2000. Remember, the upshot of this Guidance is that, under certain circumstances, in vitro data on permeability, solubility, and dissolution can be a surrogate for clinical bioequivalence data…the ultimate in translational medicine. As far as I can tell, this was one of the first applications of translational science to be applied to pharmaceutical development by any regulatory agency in the world.