The average cost of developing a drug was $1.3 billion as of January 2011.  The average first-cycle approval rate for standard new molecular entities (NME) has increased from an average of 30% in 1992 to 38% this year.  Priority NMEs have fared better with the FDA, with approvals rising from 46% to 68% during this same period.

The Food and Drug Administration Amendments Act (FDAAA) of 2007, which allowed FDA to require post-marketing studies and clinical trials to address outstanding drug safety questions, lowered the percentage of new drugs, biologics, and efficacy supplements approved by the FDA to below 80% in 2Q 2009.  By 1Q 2011, that percentage returned to the mid 90% range, about the same as in 1Q 2005.

The current forth authorization of the Prescription Drug User Fee Act (PDUFA IV) expires at the end of September 2012.  According to the Draft Commitment Letter signed by the Federal Drug Administration (FDA), Biotechnology Industry Organization (BIO), and Pharmaceutical Research and Manufacturers of America (PhRMA),  to increase the chances of successful first-cycle approvals, PDUFA V will delay the start of FDA’s clock for its first review cycle to after its 60-day administrative filing review period.  Once the clock starts, however, FDA is committed to reviewing and acting on 90% of standard NME, New Drug Application (NDA), and original Biologics License Application (BLA) submissions within 10 months —12 months from the date of filing.  FDA has also committed to reviewing 90% of priority NME, NDA, and original BLA submissions within 6 months, or 8 months from the filing date.  Furthermore, once the PDUFA V review clock starts running, drug developers and FDA officials must meet 3 times:

•    A pre-submission meeting at which “the applicant is strongly encouraged to discuss the planned content of the application.”

•    A new mid-cycle meeting, to which the FDA will call an applicant, will generally be held within 2 weeks after the Agency holds its own internal mid-cycle review meeting on an application.

•    A late-cycle meeting at which FDA’s review team will meet with an applicant to discuss the status of Agency review of the application late in the review cycle.

The new mid-cycle review meeting is meant to provide an opportunity for the Sponsor and Agency to discuss what issues have been identified and how to resolve those issues.  It also provides an earlier opportunity for the Agency to alert the Sponsor if additional information is needed related to labeling, Risk Evaluation and Mitigation Strategies (REMS), and post-marketing commitments.

PDUFA V raises to $3 billion the amount of user fees to be collected by the Agency from a Sponsor.  User fees of $2.9 billion are required by PDUFA IV.  This user-fee increase will enable the Agency to hire additional staff to review drug and biologic applications.  PDUFA V also commits the FDA to develop staff capacity to review submissions that involve pharmacogenomics and biomarkers and to fund the FDA regulatory science initiatives.  To this end, target dates for completion of new initiatives have been set.

• Oct. 24, 2011: FDA will hold a public meeting to discuss PDUFA reauthorization.

• Sept. 30, 2013: FDA will develop a dedicated drug development communication and training staff within the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER), and increase the existing manufacturers’ assistance staff at FDA’s Center for Biologics Evaluation and Research (CBER).   The CDER Rare Disease Program within OND will increase the number of staff focused on rare disease drug reviews, which is particularly important due to the increasing emphasis placed by Big Pharma on orphan drugs.

• Sept. 30, 2014: OND drug development and communication staff will provide training to all CDER staff involved in review of Investigational New Drug (IND) applications.

• March 31, 2015: FDA will publish draft guidance for review staff and industry describing best practices for communication between FDA and IND sponsors during drug development.

And finally in regards to drug safety and as an effort to lessen the effect of politically-induced risk aversion by the Agency, PDUFA V also calls for greater integration of patient perspectives into the review criteria.  The Agency has explicit plans over the course of the PDUFA V period to change the way it assesses benefits and risks, as well as the endpoints used to assess safety and efficacy, based on the advice it receives from patients.

Sources: Genetic Engineering and Biotechnology News, BioPortfolio, BioCentury, Legal News Directory, FDA

Prospective identification and potential amelioration of cardiotoxicity is a critical component of contemporary drug development, particularly for targeted therapies (e.g., tyrosine kinases) in oncology that are designed to inhibit critical signaling pathways shared by both the tumor cell and the cardiac myocyte (e.g., HER2 and C-Abl).  Current preclinical approaches to cardiac safety, which often focus primarily on ion channel testing (e.g., hERG), need to broaden the in vitro test menu to assess other cellular functions that are critical to cardiac cell health.  Accordingly, effective nonclinical cardiotoxicity screening programs need to be implemented earlier in the development process.

Stem-cell technologies offer induced pluripotent stem-cell-derived (iPSC) cardiac myocytes that are pure, functionally relevant (exhibit electrical profiles in culture and are amenable to patch-clamp-like studies that monitor electrical potentials and voltage-gated ion channel function), and are human in origin.  The following would comprise an effective preclinical cardiac safety testing program utilizing  iPSC-derived cardiac myocytes:

• Determining influences on key cardiac metabolic pathways focusing on AMPK;
• Evaluating changes in fatty acid beta-oxidation;
• Measuring changes in mitochondrial health , reactive oxygen species production, and ATP levels;
• Assessing drug-induced apoptosis;
• Survey potential off-target effects using a comprehensive kinase profiling platform.

In addition to the above, the preclinical program should identify compounds that demonstrate cardio-protective effects with regard to mitochondrial health and energy homeostasis.

Glossary

ABL1 = a proto-oncogene which encodes a cytoplasmic (C-ABl) and nuclear protein tyrosine kinase.  Implicated in processes of cell differentiation, cell division, cell adhesion, and stress response.

AMPK = a metabolic sensor of cellular ATP.  Controls fatty acid oxidation and glucose uptake in skeletal muscle, heart, and liver.

ATP = adenosine-5′-triphosphate, a multifunctional nucleoside triphosphate used in cells as a coenzyme.  Responsible for intracellular energy transfer.

HER2 = “Human Epidermal growth factor Receptor 2,” a receptor required for healthy heart function.

hERG = the human Ether-à-go-go Related Gene.  Codes for a potassium ion channel protein.

Source – Drug Discovery and Development

Zebrafish offer a nonclinical model for the high-throughput screening of drug compounds, including toxicity assessment, with resolution at the cellular level in living vertebrate organisms.  These small, freshwater, tropical fish share genetic and biochemical similarity to humans, in addition to similar organ system development.  Vertebrate disease models (e.g., Parkinson’s, epilepsy, wound repair) are available , as are 3-D image resolution and data analysis capabilities.  Live-imaging options, unparalleled in other vertebrate organisms, are possible using the transparent larvae.  Furthermore, live-cell microscopy can provide views of the inner complexity and workings at the cellular level.  For purposes of disease modeling, researchers can create and screen genetic mutants in the zebrafish that are linked to human immune diseases.  Neurological assessments using the live, transparent, zebrafish larvae allow visualization of the mechanisms of myelination.  In conclusion, the zebrafish preclinical model owes much of its popularity to the transparent nature and relevant ease of imaging of vertebrate larvae.  Optimization of data analyses for these varied indications is ongoing.

Source:  Genetic Engineering and Biotechnology News

Drug development is a complicated, often convoluted process.  The ability to predict drug toxicity in humans from nonclinical data remains a major challenge.  Since you can’t “erase” an adverse event, optimization of preclinical dose selection is essential.  This presentation outlines the process for dealing with adverse preclinical / nonclinical events in order to 1) optimize the chances of successful drug development, or 2) to create a scientific basis for early termination of drug development.  Conclusion: Experience counts!  There is no single answer for all problems.  Use of sound scientific and business judgement generally yields the best outcome.

With the rise of combination therapy – the use drugs with different mechanisms of action to combat a specific disease state – comes the need to address medical costs and reimbursement issues.  Joint negotiation of package deals with government and health insurers may prove useful, particularly for companion diagnostics and treatment of chronic conditions.  Companies that share drug development risks and costs (preclinical, clinical trials, sales and marketing, etc.) with each other are not only better positioned to negotiate for reimbursement but are also better poised to defend against competition.   Multiple collaborations, however, increase the risk of legal complexity for all concerned.

Source: Reuters

A previous entry detailed Dried Blood Spot Analysis: Preclinical Pros and Cons.  Additional preclinical considerations include the ambiguity of acceptance by global regulatory agencies, none of which have issued definitive rulings on how they’ll handle New Drug Applications (NDA) that use the technique.  Furthermore, although validation standards and regulatory guidance exist for liquid assays, many of the suggested parameters (e.g., reproducibility after freezing and thawing of samples) are not applicable to dried blood spot analyses, where samples are dried and stored at room temperature.

Physical parameters also affect dried matrix spotting.  Blood spot size is partly dependent on hematocrit, the percentage of the blood volume composed of red blood cells.  Hematocrit is not only variable between individuals but also varies daily within a given individual.   Therefore given sample dilution based on variable hematocrit, analyte levels can vary widely between individual samples.   As a further development, the heightened analytical sensitivity used in nonclinical drug development (relative to the more traditional clinical uses) has mandated more stringent standards for blotter paper.

Another preclinical use for this technique is analysis of other limited-volume body fluids (e.g., synovial fluid, tears, and cerebrospinal fluid), some of which have not been routinely sampled preclinically in the past due to inefficient methodology.  For example, arthritis mostly affects biomarkers in synovial fluid.  In rodent preclinical models, however, only a few microliters of synovial fluid exist in each joint.  This has forced preclinical scientists to rely on surrogate markers in the animal’s plasma to monitor drug efficacy/toxicity.  By utilizing dried matrix spotting, rodent joints can now be sampled directly.  Furthermore, due to the generally colorless nature of alternate fluids, proprietary paper treatments have been identified to allow for color changes that facilitate spot identification.  As an additional benefit, alternate fluid analyses lack the inherent variability due to hematocrit.

Dried matrix spotting is quickly overcoming perceived challenges.  It remains to be seen whether the heralded FDA Strategic Priorities for 2011-2015, which include advancing the field of Regulatory Science, will promote advancement/acceptance of dried matrix spotting as part of it’s mandate to develop new tools, standards, and approaches to assess the safety, effectiveness, quality, and performance of FDA-regulated products.  Stay tuned…!

Source: Drug Discovery and Development.

Side effect overload on drug labels has less to do with true toxicity and drug safety than with manufacturer liability.  Examination of more than 5600 drug labels yielded over half a million side effects.  An average drug label and the more commonly prescribed drugs averaged 70 and 100 side effects, respectively.  The upper range in a single label was 525 reactions.  Information overload can overwhelm physicians, who must weigh the risks and benefits when prescribing a medication.  The Food and Drug Administration discourages such ‘over warning,’ but information overload is presently the rule rather than the exception.  Not surprisingly, medications typically used by psychiatrists and neurologists had the most complex labels, while drugs used by dermatologists and ophthalmologists had the least.  Although providing drug safety information more efficiently to both health care providers and the public is warranted, drug manufacturer liability concerns must also be addressed.

Source: Drug Discovery and Development

Biomarker use in translational medicine is predicated upon preclinical qualification and validation – 2 distinct steps in the biomarker development process.  Prior to issue in 2009 (EMA) and 2010 (FDA, PMDA) of the renal-specific DRAFT qualification guidelines, there was no clear direction by the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA) of how companies should qualify new biomarkers for disease progression or clinical trial endpoints.  The trend in biomarker use is multivariant analysis, the tracking of subtle changes in multiple biomarkers simultaneously, often utilizing various tissue types.   While the new guidance addresses biomarker qualification, analytical validation of new biomarkers remains undefined.  This review updates the reader of the status of both qualification and validation of translational biomarkers.

Source: Drug Discovery & Development

Additional Reading:

Predictive Safety Testing Consortium: special issue of Nature Biotechnology (renal biomarkers)  (http://www.c-path.org/PSTCPublications.cfm)

EMA:  Qualification of novel methodologies for drug development guidance to applicants.

Abuse Liability Screening in Animals

Any new drug that penetrates the central nervous system must receive some preclinical analysis of abuse liability potential (Draft Guidance).  Usually, it is determined through prior knowledge of chemistry and/or pharmacology of the candidate’s drug class that compounds have abuse liability.  For example, if a test article stimulates release of dopamine in the nucleus accumbens of the brain, most likely it will be abused by humans (Koob and Volkow, 2010).  Discussion of nonclinical abuse liability testing requirements with regulators prior to submission of any formal materials, however, is always advised.

Behavioral pharmacology is only one facet for determining abuse liability; however, preclinical drug discrimination and self-administration data speak loudly.  As outlined in O’Connor et. al. (2011), several factors can influence nonclinical drug self-administration data.  Animal strain, training regimen, food restriction, duration of access, rate of infusion, and training doses can all influence self-administration data (Baladi et. al., 2010; Banks and Negus, 2010; Caroll, 1985; Kosten et. al., 1997; Lynch et. al., 2010; Woolverton, 1992).  Misleading self-administration data can lead to program-killing false-positives or underestimated abuse liability that will manifest during clinical trials.  Something as “unimportant” as the dose of the training compound can impact drug discrimination.  Too high or too low of a training dose may alter the interoceptive cue of test article and shift dose response curves accordingly when the test article is screened (e.g., Mumford and Holtzman, 1991).  These results would drastically affect interpretation of safety margin.  Unchecked variables can significantly impact analysis and delay submissions.  Although regulators are savvy to these variables, to the classically trained chemist, for example, these variables can seem like smoke and mirrors without the proper experience.

Daily monitoring of behavioral data and animals (weights, response patterns, and general health) is necessary to determine whether preclinical studies are being carried out properly and are subsequently valid.  One must be aware that self-administration and drug discrimination studies usually take several months to complete, with animals generating data daily.  Failure to incorporate appropriate controls such as presenting “inactive” levers and recording inactive lever responses can render a study invalid; this practice serves as an index of accuracy (O’Connor et. al., 2011).   Additionally, catheter patency in rats used for self-administration studies is not a trivial concern.  An impaired catheter can seriously alter response patterns.  The same animal may alter behavior over time due to time-dependent physiological changes (e.g., behavioral tolerance) or a faulty catheter.  Behavioral criteria must be established well in advance in order to accurately track animal response patterns.  Frequent catheter patency tests should regularly occur.

Several nonclinical laboratories (especially academic) combat less than aseptic conditions with daily administration of antibiotics to their experimental animals to maintain catheter patency and animal health for lengthy self-administration experiments.  Body weights must be maintained at certain levels to ensure motivated animals.  If an animal is food restricted for eight months and administered daily antibiotics, will this create problems with your compound?  Concomitant effects can potentially lead to additional toxicology studies if you have unexpected clinical signs or abnormal clinical pathology findings.

Some contract research organizations (CRO) may suggest using their “trained” animals, usually non-human primates, for preclinical drug discrimination and self-administration studies.  Will the drug history of these animals pose a problem?  Should you instead consider use of rats over non-human primates?  At this point in time, if the metabolism and kinetics of your compound are similar in rats and humans, use of non-human primates is not necessary and may not be justified from an animal welfare standpoint (O’Connor et. al., 2011).  Moreover, the behavioral database for rats is just as strong as for non-human primates (O’Connor et. al., 2011).  The benefits of using non-human primates, however, are multiple.  A CRO can maintain a small colony of non-human primates that are trained to self-administer or discriminate drugs of abuse for years.  For this reason, animals are essentially ready for screening at initiation of the study.  One should consider, however, that non-naive animals may have impacted health due to long histories of handling, laboratory conditions, implanted devices (in self-administration animals), and a history of drugs that may impact physiology and/or behavior.  Will this confluence of factors negatively interact with your compound?

In conclusion, behavioral pharmacology studies should not be taken lightly, and possession of the necessary expertise and skills to navigate these challenges is necessary.  Lack of experience in what was once considered a “soft science” can be extremely detrimental in drug development, costing additional time and money.  Just like any scientific assessment, there are “correct” and “incorrect” ways of conducting behavioral pharmacology experiments.  For this reason, many large pharmaceutical companies and CROs now have expert working groups for abuse liability screening.

References Cited

Baladi MG, Newman AH, France CP.  Dopamine D3 receptors mediate the discriminative stimulus effects of quinpirole in free-feeding rats.  J Pharmacol Exp Ther. 2010 Jan; 332(1):308-15.

Banks ML, Negus SS.  Effects of extended cocaine access and cocaine withdrawal on choice between cocaine and food in rhesus monkeys. Neuropsychopharmacology 2010 Jan; 35(2):493-504.

Carroll ME.  The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats.  Drug Alcohol Depend. 1985 Nov; 16(2):95-109.

Draft Guidance for Industry Assessment of Abuse Potential of Drugs (January, 2010) prepared by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.

Koob GF, Volkow ND.  Neurocircuitry of addiction.  Neuropsychopharmacology 2010
Jan; 35(1):217-38. Epub. Review.
Erratum in: Neuropsychopharmacology 2010 Mar; 35(4):1051.

Kosten TA, Miserendino MJ, Haile CN, et. al.   Acquisition and maintenance of intravenous cocaine self-administration in Lewis and Fischer inbred rat strains.  Brain Res. 1997; 778(2):418-29.

Lynch WJ, Nicholson KL, Dance ME, et. al.  Animal models of substance abuse and addiction: implications for science, animal welfare, and society.  Comp Med. 2010; 60(3):177-88.

Mumford GK, Holtzman SG.  Qualitative differences in the discriminative stimulus effects of low and high doses of caffeine in the rat.  J Pharmacol Exp Ther. 1991 Sep; 258(3):857-65.

O’Connor EC, Chapman K, Butler P, Mead AN.  The predictive validity of the rat self-administration model for abuse liability.  Neurosci Biobehav Rev. 2011; 35(3):912-38.

Woolverton WL.  Cocaine self-administration: pharmacology and behavior. NIDA Res Monogr. 1992; 124:189-202.

About the Author:

Paul Kruzich is an experienced abuse liability and safety pharmacology consultant.  He has extensive industrial/CRO experience as a study director and academic experience as a tenure-track faculty member at the Medical College of Georgia.  His professional affiliations include the College on Problems of Drug Dependence, Safety Pharmacology Society, Society of Toxicology, and Society for Neuroscience.  Dr. Kruzich has authored over 23 peer-reviewed articles and 2 book chapters and has served as a reviewer for over 5 scientific journals.

Paul J. Kruzich, PhD
Preclinical Consulting Services, LLC
paul.kruzich@preclinicalconsultingservices.com
http://www.linkedin.com/in/paulkruzich
608.807.7205

By utilizing the basic principles of hemodynamics and hydraulics, research suggests that fluid retention is detrimental for the cardiovascular system because it increases the likelihood of turbulent blood flow, regardless of whether or not blood pressure is raised.  Increased turbulence promotes endothelial dysfunction, thereby contributing to the development of atherosclerotic cardiovascular disease.  Fluid retention induces hypertension in some individuals, increases stroke volume (the amount of blood that is ejected by the heart with each contraction) in others, and causes edema.  Some blood pressure lowering medications also increase stroke volume and cause edema but prevent heart attacks and strokes when used to treat hypertension.  For drugs that increase the risk of adverse cardiovascular events, it may be possible to reduce or neutralize the increased risk by simultaneous diuretic administration.

Source: ScienceBlog

Original Article: Clinical Hemorheology and Microcirculation (free pdf)