drug development

Adverse Preclinical Events – Now What?

Posted by cdavenport on Thursday Aug 4, 2011 Under Drug Safety, TigerU

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.

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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

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Translational Toxicology: Biomarker Development

Posted by cdavenport on Monday May 16, 2011 Under Drug Safety, Renal, toxicity

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.


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For pharmaceutical companies, is personalized medicine more of a threat than an opportunity?  In addition to the development of new drugs, genetic information can also help target the use of current medications (e.g., Plavix).  The use of genetic (or other) information to target patient population subsets is expected to increase drug safety and render cost savings to both insurer and patient, but can it also be expected to limit the potential market and lower pharmaceutical sales?  By potentially enhancing drug safety, personalized medicine is expected to elicit fewer adverse drug reactions, thereby leading to fewer liability claims against drug companies.  Drug development costs rise, however, if preclinical scientists also must isolate a genetic trigger and develop a companion test for a treatment, even if the size of clinical trials can potentially be reduced and additional income can be expected through purchase of both medication and companion diagnostic.  Even when a drug is utilized in target populations, how much risk will be deemed acceptable?   Whether personalized medicine stimulates or inhibits pharmaceutical drug development remains to be determined.

Source: Wall Street Journal

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Ideally, every new drug would represent an unprecedented breakthrough and lead to the creation of a
completely novel treatment. This, however, is not the reality of the pharmaceutical industry, or of any other
development-based industry. Creating drugs based on incremental innovations provides pharmaceutical
companies with a secure stream of revenue, which can be directed to higher-risk, potential blockbuster-yielding
research. Policies aimed at reducing the industry’s ability to obtain revenues from incremental innovations
could be self-defeating, as those industries will then have less revenue to reinvest in R&D for new drugs. Put
simply, limiting incremental drug innovation is analogous to limiting competition. The ultimate result could
have devastating consequences for the future of the pharmaceutical industry and for the millions of patients
who depend on it.

Ideally, every new drug would represent an unprecedented breakthrough and lead to the creation of a completely novel treatment.  This, however, is not the reality of the pharmaceutical industry, or of any other development-based industry.  Most new drugs represent the combined weight of seemingly small improvements achieved over time.  Creating drugs based on incremental innovations provides pharmaceutical companies with a secure stream of revenue, which can then be directed to higher-risk, more innovative research.  Many critics contend that “Me-too” drugs — drugs within the same chemical class as one or more already on the market — add little or no therapeutic value to existing formularies.   Conversely, advocates claim that new drugs based on incremental improvements generally represent advances in safety, efficacy, selectivity, and ultimately increase the utility of drugs within a specific therapeutic class.  Innovations may also include new formulations and dosing options.  Changes in one or more of these parameters generally increase patient compliance and improve health outcomes.  Furthermore, patients can respond differentially to drugs within a single class, thus having multiple drug options within a therapeutic class enables optimization of medical treatment to best fit a patient’s needs.  From an economic standpoint, while it is unrealistic to presume that every incremental innovation leads to cost savings, the sum of all drug innovations can reduce overall treatment costs, shorten or eliminate hospitalization, increase worker productivity and reduce absenteeism, and eventually lower drug costs through increased competition among manufacturers.

In conclusion, policies aimed at reducing an industry’s ability to obtain revenue from incremental innovations could be self-defeating, as less revenue will be available to reinvest in research and development.  In pharmaceutical terms, limiting incremental drug innovation is analogous to limiting competition.  The result could have devastating consequences for the future of the pharmaceutical industry and ultimately for patients.

Source:  Competitve Enterprise Institute

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Why is naming a drug so difficult?

Posted by cdavenport on Friday Oct 22, 2010 Under Drug Safety, FDA, Pharmaceutical Business

In February 2010 the FDA published “Guidance for Industry on the Contents of a Complete Submission for the Evaluation of Proprietary Names” (Guidance), which describes in detail the FDA’s evaluation methodology for proposed proprietary drug names.  By carefully examining this methodology and incorporating it into name clearance strategies, drug companies can optimize their chances of clearing drug names through the FDA review process.

Source:  Drug Discovery and Development  22 Oct 2010

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Blockbuster Drug Potential: Importance of Risk Management

Posted by cdavenport on Wednesday Oct 13, 2010 Under Drug Safety, FDA

Prior to drug approval, a potential new drug is usually subjected to the scrutiny of an expert advisory panel, selected by the FDA, who recommend whether or not the product should be marketed.   These recommendations are non-binding.  Industry analysts looked at product-specific decisions, a total of 120 votes, made by advisory committees to the FDA from 2007 through 2010.  The FDA followed its committees’ advice 74% of the time.  Significantly, only 3 times did the FDA overrule a “no” vote from the committee: Tarceva (lung cancer), Avastin (breast cancer), and Micardis (hypertension).  In other words, a “no” vote from an advisory panel is likely to meet acceptance, but a “yes” vote does not mean that the product will be approved.  All of the recent hype over obesity drugs aside, it is important to understand current events in light of historical precedence.  It also highlights the importance of risk management, particularly when dealing with drugs that have blockbuster potential.

Source: Forbes

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Historical Overview

During the past 30 years, genetic toxicology testing has evolved technologically to play an important safety assessment role in the progression of chemical candidates through the drug discovery and development process.  Prior to application of the battery of regulatory tests, high-throughput screening assay methods are now used to reduce costs by terminating compounds with undesirable characteristics (mutagenic hazard or potential carcinogen).  With few exceptions, compounds found to be mutagenic in these assays are dropped from development, and clastogenic compounds result in unfavorable labeling, require disclosure in clinical trial consent forms, and can greatly impact the marketability of a new drug.  Furthermore, in vitro clastogenicity responses can delay drug development by requiring additional testing to determine the in vivo relevance, although these assays can at times be integrated into other in vivo toxicity studies to expedite the progression of drugs to clinical trials.  Thus, genetic toxicology testing at the drug discovery and optimization stages serves to quickly identify mutagenic compound so that they can be quickly dropped from development.

Genetic toxicology was the first branch of toxicology to fully embrace in vitro test methods, notably through the visionary work of Bruce Ames and coworkers with the development of the Salmonella typhimurium tester strains.  These prokaryotic assays demonstrated good correlation with rodent carcinogenicity results.  The Ames test is generally used as the first screening method to assess chemical genotoxicity.   Although it provides extensive information on DNA reactivity, the Ames assay is not suitable for detecting nongenotoxic carcinogens.  In time, in vitro assays were developed for the detection of gene mutations, chromosomal aberrations, and micronuclei formation.  The mouse lymphoma assay in particular has been developed to the point that  both gene mutations and chromosomal aberrations can be detected and quantified following exposure to test chemicals, when compared with known direct-acting mutagens and promutagens.

Current Perspectives

Assay Predictivity

The performance of a combination of the 3 most commonly used in vitro genotoxicty tests – the Ames, the mouse lymphoma, and the in vitro micronucleus or chromosomal aberration tests – have been evaluated for their ability to discriminate rodent carcinogens from non-carcinogens using a database of over 700 chemicals (Kirkland et al., 2005).  Based on the relative predictivity  measure (RP; the ratio of real:false positive results), that study demonstrated that positive results in all 3 tests indicated that a chemical is greater than 3 times more likely to be a rodent carcinogen than a non-carcinogen.  Similarly, negative results in all three tests indicated that a chemical is more than two times more likely to be a rodent non-carcinogen than a carcinogen.  But further evaluation of combinations of positive and negative results in this genotoxicity battery using the RP calculations indicated that it is not possible to predict outcome of a rodent carcinogenicity study when only 2/3 of the genotoxicity results are in agreement (Kirkland et al., 2006).

Assay Shortcomings

A basic if not critical shortcoming in all these mammalian in vitro assays is the lack of mammalian absorption, distribution, metabolism, and excretion (ADME) features.  As summarized in a recent European Centre for the Validation of Alternative Methods (ECVAM) workshop (Kirkland et al., 2007), cell lines used for genotoxicity testing have a number of deficiencies that may contribute to a high false-positive rate.  These include a lack of normal metabolism leading to reliance on exogenous metabolic activation systems (e.g., Aroclor-induced S9), impaired tumor protein 53 (p53) transcription factor function, and altered deoxyribonucleic acid (DNA) repair capacity.  Also the use of excessive test chemical concentrations to achieve an empirical correlation between genotoxicity and carcinogenicity can result in “promiscuous activation.”  Because these in vitro assays rely on such artificial activation systems, other enzymes that are relatively unimportant in vivo may take over the activation role, leading to the same or a different metabolite – hence, “promiscuous activation.”  Recently, a risk assessment method has been proposed that is dependent upon the availability of quantitative human and rodent ADME  data such that exposures to a metabolite of genotoxic concern can be estimated at the intended human efficacious dose and the maximum dose used in the 2-year rodent bioassay (Dobo et al., 2009).

Other notable genotoxicity testing methods are available for use in the drug discovery and lead-optimization process.  The comet assay is a microgel electrophoresis technique for detecting DNA damage – in vitro and in vivo- at the level of a single cell.  When used in vivo, DNA lesions can be measured in any organ, regardless of the extent of mitotic activity and under normal ADME conditions.  The conventional mouse micronucleus test in the hematopoietic system is a simple method to assess the in vivo clastogenicity of chemicals if the chemical reaches the hematopoietic system.  When multiple organs in the mouse were analyzed following exposure to 208 chemicals, the comparison of comet assay results and carcinogenicity suggested that the comet assay was more capable than the mouse micronucleus assay of detecting rodent carcinogens (Sasaki et al., 2000).

Regulatory Guidance

At present, the ICH/FDA Guidance Document S2(R1) outlines two GLP genotoxicity testing assay options.  Option 1 requires completion of: (1) a test for gene mutation in bacteria., (2) a cytogenetic test for chromosomal damage (choice of three), and (3) an in vivo test for chromosome damage using rodent hematopoietic cells (either micronuclei or chromosomal aberrations in metaphase cells).  Option 2 combines (1) the highly predictive gene mutation assay in bacteria with (2) an in vivo assessment in 2 tissues (e.g., micronuclei using rodent hematopoietic cells plus a second in vivo assay, such as the liver unscheduled DNA synthesis (UDS) assay, transgenic mouse assay, comet assay, etc.  Thus, the ICH guidance allows  for the registration of pharmaceuticals without the submission of data from in vitro mammalian genotoxicity tests (e.g., the in vitro micronucleus test, chromosomal aberrations, mouse lymphoma assay).  This is important because some authors (Matthews et al., 2006) have indicated that 2 of the tests in the FDA battery show good correlation for carcinogenicity prediction (Ames and in vivo micronucleus) and 2 tests show poor correlation (mouse lymphoma and in vitro chromosomal aberrations).

High-Throughput Screens

With the trend towards the application of early pre-screening, high-throughput methods to eliminate potential mutagens/clastogens prior to application of the more resource-intensive and time-consuming regulatory testing methods, many pharmaceutical companies are using these screening methods early in the discovery/lead optimization process.  Examples of modified or high-throughput methods for early screening include: (1) computer-assisted (in silico) structural activity relationship (SAR) methods for predictive toxicity screening, (2) modified assays such as the in vitro assessment of micronucleus induction in Chinese hamster ovary (CHO) cells, the Ames II assay (TA98 and TA Mix), the in vitro comet assay, or well-based (e.g., 96- or 384-well format) modifications of the yeast deletion (DEL) assay, or (3) proprietary assays such as Vitotox™ (mutagenicity), RadarScreen® (clastogenicity), and GreenScreen® HC (genotoxicity).

About the Author:

David Amacher is a senior investigative and biochemical toxicologist with extensive experience in the safety evaluation of human and animal health products.  Dr. Amacher is a Diplomate of the American Board of Toxicology, a Fellow of the National Academy of Clinical Biochemistry, and serves as an Assistant Research Professor of Toxicology and Adjunct Professor in the Graduate School of the University of Connecticut.  His professional affiliations include memberships in the American Society for Pharmacology and Experimental Therapeutics, Society of Toxicology, American Society of Biochemistry and Molecular Biology, International Society for the Study of Xenobiotics, American Association of Clinical Chemistry, and the American College of Toxicology.


Dobo KL, Obach RS, Luffer-Atlas D, et al.  A strategy for the risk assessment of human genotoxic metabolites.  Chem Res Toxicol. 2009;22(2):348-56.

International Conference for Harmonization Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use.  S2(R1), 6 March 2008.

Kirkland D, Aardema M, Henderson L, et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens: I. Sensitivity, specificity and relative predictivity [published erratum appears in Mutation Research 2005;588(1):70].

Kirkland D; Aardema M; Müller L; et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens II. Further analysis of mammalian cell results, relative predictivity and tumour profiles.  Mutation Research 2006;608(1):29-42.

Kirkland D; Pfuhler S; Tweats D; et al.  How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop.  Mutation Research 2007;628(1):31-55.

Matthews EJ, Kruhlak NL, Cimino MC, et al.  An analysis of genetic toxicity, reproductive and developmental toxicity, and carcinogenicity data: I.  Identification of carcinogens using surrogate endpoints.  Regul. Toxicol. Pharmacol. 2006;44(2):83-96.

Sasaki YF, Sekihashi K, Izumiyama F., et al.  The comet assay with multiple mouse organs: comparison of comet assay results and carcinogenicity with 208 chemicals selected from the IARC Monographs and U.S. NTP Carcinogenicity Database.  CRC Crit. Rev. Toxicol. 2000;30(6):629-799.

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New MHRA pharmaceutical directory resource

Posted by cdavenport on Monday Feb 15, 2010 Under MHRA

The Medicines and Healthcare products Regulatory Agency (MHRA) website now provides a new and easy to use directory for the pharmaceutical industry.  Highlights include:

  1. News and hot topics
  2. Contacting the MHRA
  3. Fees
  4. Legislation, guidance, and policy
  5. Clinical trials
  6. Applying for a marketing authorization
  7. Post-marketing authorization approval
  8. Product information and advertising
  9. Herbal, homeopathic, and borderline medicines
  10. Inspection, manufacturing, and wholesaling
  11. Safety and pharmacovigilance
  12. Over-the-counter medicines
  13. Medicines for children
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Drug Pharmacokinetic Comparison between Humans and Monkeys

Posted by cdavenport on Thursday Jan 21, 2010 Under ADME, Drug Safety

To verify the availability of pharmacokinetic parameters in cynomolgus monkeys, hepatic availability (Fh) and the fraction absorbed (Fa) multiplied by intestinal availability (Fg) were evaluated to determine their contributions to absolute bioavailability (F) after intravenous and oral administrations. These preclinical results were compared with those for humans using 13 commercial drugs for which human pharmacokinetic parameters have been reported.  In addition, in vitro studies of these drugs, including membrane permeability, intrinsic clearance, and p-glycoprotein affinity, were performed to classify the drugs on the basis of their pharmacokinetic properties.

In the present preclinical study, monkeys had a markedly lower F than humans for 8 of 13 drugs.  Although there were no obvious differences in Fh between humans and monkeys, a remarkable species difference in FaFg was observed.  These results suggest that first-pass intestinal metabolism is greater in cynomolgus monkeys than in humans, and that bioavailability in cynomolgus monkeys after oral administration may be unsuitable for predicting pharmacokinetics in humans.  A rough correlation was also observed between in vitro metabolic stability and Fg in humans.

Key: F (bioavailability), Fa (fraction absorbed), Fg (intestinal availability), Fh (hepatic availability).

Drugs examined: amitriptyline, dexamethasone, digoxin,  hydrochlorothiazide, ibuprofen,  lithium carbonate, midazolam, nifedipine,  propranolol, quinidine,  tacrolimus, timolol, and verapamil.

Source: Drug Metabolism and Disposition

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