Both pharmaceutical industry and regulatory professionals acknowledge the importance of balancing timely access to new medicines with the need for thorough review of drug safety and efficacy data.  A new study, funded by the Pew Charitable Trusts (to be published in the New England Journal of Medicine), reviewed drug approval decisions of the Food and Drug Administration (FDA), the Canadian drug regulator -Health Canada, and the European Medicines Agency (EMA) between 2001 and 2010.  Yale and Mayo Clinic researchers studied each regulator’s database of drug approvals to identify novel therapeutics and timing of key regulatory events, thereby allowing regulatory review speed to be calculated.  The study found that the FDA approves 80% of all the applications it receives.  The median time for novel drug reviews by the FDA was 322 days (10.5 months).  That was 45 to 70 days ahead of Europe and Canada, which typically completed their novel drug reviews after 12 and 13 months, respectively.  Over the same 10-year time frame, the FDA reviewed 225 novel drug applications, 40 more than Europe and nearly 125 more than Canada.  Among novel drugs approved in both the U.S. and Europe, 64% were first approved by the FDA.  For novel drugs approved in both the U.S. and Canada, 86% were first approved by the FDA.

Release of study results may be too late to impact upcoming drug user fee Congressional legislation.  This legislation will reauthorize user fees the FDA collects from companies that make prescription drugs and medical devices.   In return for a 6% increase in user fees, the FDA has already agreed to accelerate novel drug approvals even further.  The standing Senate bill (approved by the White House) supports a new user fee for the review of generic drugs and adds provisions that address some challenges of globalization by enhancing the safety of the drug supply chain, increase incentives for the development of new antibiotics, renew and enhance mechanisms to ensure that children’s medicines are appropriately tested and labeled, and that expedite the development and review of certain drugs for treatment of serious or life-threatening diseases and conditions (e.g., by allowing conduct of smaller, shorter clinical trials).

SourcesHuffPost Health, Modern Healthcare.com, R&D Magazine, and The Hill.

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To make best use of its limited resources, the Institute of Medicine (IOM) concludes that the US Food and Drug Administration (FDA) should direct resources to improve the regulatory systems of developing nations to better ensure the safety of the global pharmaceutical supply chain.  Rather than try to inspect all foreign establishments itself, the FDA and its technologically advanced counterparts in the European Union, Canada, Japan, Norway, Iceland, Switzerland, Australia, and New Zealand are encouraged to plan a system for mutual recognition of inspections, which would eliminate the wasteful duplication of effort.  Along these lines, an active pharmaceutical ingredient (API) inspection program involving many of the world’s premiere global regulatory bodies (FDA, the European Medicines Agency (EMA), Australia’s Therapeutic Goods Administration (TGA), the World Health Organization (WHO), the European Directorate for the Quality of Medicines & Healthcare (EDQM), and the Council of Europe (CE)) has formed to facilitate international collaboration and information sharing to enhance inspection capacity.   Since data review and interpretation is already being shared between some global regulatory authorities in the nonclinical safety arena, it will be interesting to see if such global harmonization efforts extend to nonclinical safety inspections in the near future.



RAPS – Regulatory Focus:  IOM – Boost Foreign Regulatory Capacity and  Global API Inspection Scheme

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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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Dried Blood Spot Analysis: Preclinical Pros and Cons

Posted by cdavenport on Tuesday Jan 25, 2011 Under ADME, EMA, FDA, Techniques

Both advantages and challenges exist for use of dried blood spots during preclinical drug development.   Advantages include small sample volumes coupled with easy shipment and storage.  The amount of blood per spot varies (10 to 100 μL), but use of 15 to 20 μL seems to be most common.  With larger blood spots, although multiple analyses are possible from each spot, the spots are less homogeneous.  For this reason, it is suggested to have 3-4 smaller spots (of 20 μL or less) which are more homogeneous, thus increasing inherent sample quality.

The small sample volumes required for dried blood spot analysis mean that fewer animals – and therefore less drug – are needed during preclinical studies relative to conventional blood analysis (milliliters of blood often required).  Blood samples spotted and dried on cards don’t need to be frozen, thereby simplifying the procedures for both sampling and shipping, with subsequent cost savings.  Provided a compound is stable in blood, which must be demonstrated for each compound, dried blood spot samples can be shipped in an envelope at room temperature.

In addition to the ethical and financial benefits, use of dried blood spot analysis can also improve preclinical data quality.  Typically, use of multiple small animals is necessary to generate drug concentration-time curves in typical pharmacokinetic and toxicology studies, due to insufficient blood volume per animal, thus introducing a potential source of undesirable variation in the data.  That source of variability can be eliminated with dried blood spot analysis.  The smaller volumes associated with the technique mean that serial sampling can be performed with each animal, thereby enhancing preclinical data quality.  In addition, some researchers have found that the relatively high stability of compounds in dried blood spots, especially prodrugs and their metabolites, is a key advantage of the technology.

Dried blood sample analysis has some drawbacks in that analysis is more time-consuming than that required for liquid samples, but still includes liquid chromatography and tandem mass spectrometry.  The limit of resolution is not yet adequate for low-exposure drugs (e.g., pg/mL), and components of the cards on which spots are collected can interfere with some analyses.  Some researchers have determined that the additional time necessary for analysis is a detriment to the speed required in discovery-phase research.  In some organizations, the decision to use dried blood spots is currently being made on a program-by-program basis as drug candidates move from discovery into early-stage development.  One holdup has been the impracticality of switching late-stage compounds with a long history of analyses in plasma over to dried blood spot analysis.  The pharmacokinetic values obtained from liquid plasma and from dried blood are not directly comparable, and “bridging” studies are required to switch between matrices.  “Even though you can generate an in vitro number for converting between blood and plasma, it doesn’t always work,” Neil Spooner, director of bioanalytical science and development at GlaxoSmithKline in Ware, England said.

Perhaps the most pressing detriment to use of dried blood spots is the need for improved automation, although some automation is available.  Fully automated techniques are generally available for fluid samples, thus enabling high throughput analysis of thousands of samples.  Direct analysis methods for dried blood spots, which bypass the need to create a paper punch, are under development.

To date, it is undetermined how global regulatory bodies will respond to data obtained from dried blood spot analysis.  Some feel that the European Union may be more accepting than the Federal Drug Administration (FDA).  The FDA declined to comment citing “insufficient experience with the technology.”  Although international guidelines state that kinetics can be measured in blood, plasma, or serum, specific US guidelines for use of dried blood spot analyses are absent.  Richard M. LeLacheur, vice president at PharmaNet USA, a contract research organization in Princeton, N.J., says “As the comfort level, regulatory experience, and infrastructure grow, people will realize it’s not a big leap to go into dried blood spots, and the benefits are worth it.”

Source: Chemical & Engineering News

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New Comprehensive Website for European Medicines Agency

Posted by cdavenport on Sunday Jul 25, 2010 Under EMA, Regulatory

On 15 July 2010 the European Medicines Agency (EMA) launched a new comprehensive website to address the regulation and safety of drugs (human, veterinary, and herbal) in the European Union.  The site has been completely redesigned to optimize usability for the Agency’s key online audiences and built on existing activities to improve openness and transparency.  Note that previously saved URLs may not be redirected to the new site.  If you are looking for a particular document or piece of information, contact info@ema.europa.eu or use the document library search to locate the documents.

Sources:Drug Injury Watch and EMA .

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