EMEA

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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Evolving FDA and EMEA Collaborations

Posted by cdavenport on Monday Jan 11, 2010 Under Drug Safety, EMEA, FDA

Collaboration between the 2 of the world’s premier pharmaceutical regulatory bodies (FDA and EMEA) has increased markedly in the last few years, a process which has come largely in response to the rapid globalization of drug development, manufacturing, and production.  Distillation of an interview with Murray Lumpkin, the FDA’s Deputy Commissioner for International Programs who is spearheading the FDA’s efforts in this field, gave several succinct insights relative to the history and context of the collaboration and drug safety (preclinical and clinical) initiatives, among others.

Over the past 10-15 years, the FDA and EMEA initially focused on understanding each other’s regulatory systems.  This initiative evolved to  sharing  information (managerial and technical) since pharmaceutical companies were  submitting largely similar information to both Agencies.  The “Transatlantic Administrative Simplification Action Plan,”  a centerpiece of this relationship,  covers 4 primary areas of potential convergence: 1) quality and inspections, 2) pharmacovigilance, 3) scientific collaboration, and 4) guidelines, format harmonization,  and electronic submission.  Information is shared about applications,  questions and answers, and pre-decisional information.  Drafts of guidance and policy documents are also shared prior to publication.  We try to give each other a heads up on newsworthy items and/or something that is likely to generate questions for them.  We don’t want to blindside each other, particularly in regard to issues with a public health or safety impact.  This cooperation has led to the permanent placement of an executive in each other’s organization:  Janice Soreth (from FDA) and Hilde Boone (from EMEA).

FDA/EMEA “clusters”  in pediatrics and oncology have been particularly active, with periodic teleconferences detailing current applications and upcoming actions, challenges and difficult questions, and various meeting updates (sometimes with joint participation).  Although resolutions may differ between Agencies, there is a mutual understanding of how decisions were formulated, and an acknowledgment that similar data was evaluated by both.  Other examples of joint clusters include:  vaccines, pharmacogenomics, orphan medicines, and cardiovascular.

The potential for joint acceptance of each other’s drug approvals was discussed.  It was acknowledged that although regulatory decisions are largely science based, there are also jurisdictional componenets, such as risk tolerance, which remain largely cultural.  For this reason, mutual acceptance of drug approvals was not seen as likely in the near term.

Upcoming prospects for convergence may involve leveraging each other’s resources (e.g., GMP and GCP inspections) to reduce audit duplication.  The distinction was made that this effort would enable the Agencies to rely on each other’s information, but not necessarily on each other’s decisions.  Other areas of possible harmonization may include biomarkers (e.g., the recent joint validation of renal toxicity biomarkers), as well as trial design and comparators.  In regard to drug safety, the pharmaceutical industry has been invited to conduct a study to compare the EU and US approaches to risk management formats (e.g., E2E, Volume 9a RMP Guidance, REMS, etc.) and to identify opportunities for convergence.  In addition, other areas for possible convergence were discussed.

Source:  InPharm

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