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

All medical products pose risks and postmarketing surveillance is critical to expanding the limited evidence base that exists when new drug products are approved.  Through initiation of the Sentinel Initiative (May 2008), the Food and Drug Administration (FDA) is developing the capacity for actively monitoring the safety/toxicity of approved medical products using the electronic health information in claims systems, inpatient and outpatient medical records, and patient registries.   The pilot program, Mini-Sentinel, uses a distributed data network (rather than a centralized database) of health plans and other organizations to create data files in a standard format while maintaining physical and operational control over their own patient-level data, thus ensuring patient privacy.   Laying the groundwork for that system has required input from both public and private organizations.  These data partners can obtain full-text medical records, when necessary, to confirm diagnoses or exposures and to determine the existence or severity of risk factors.

The initial focus of Mini-Sentinel has been on developing the ability to use medical claims data.  Over the next year, laboratory-test results and vital signs will be added.  The FDA will soon begin to actively monitor the data, seeking answers to specific questions (e.g., frequency of myocardial infarction among users of oral hypoglycemic agents).  Using the Mini-Sentinel system, the FDA will also be able to obtain rapid responses to new questions about medical products and, eventually, to evaluate the health effects of its regulatory actions.

Source: New England Journal of Medicine

FDA approval does not mean that a drug works well; it means only that the Agency deemed its benefits to outweigh its harms.  Comparative efficacy data, other than to placebo, may be missing from the label.  In 2006, the FDA revised the drug label design, adding a “highlights” section to emphasize the drug’s indications and warnings.  It also issued guidance about reporting trial results in the label and emphasized the importance of effectiveness data.  Yet some recent label updates (e.g., for Lunesta and Rozerem) are substantively unchanged.  Use of “Prescription Drug Facts Boxes,” featuring a data table of benefits and toxicities has been proposed.  Recently, the FDA’s Risk Advisory Committee recommended that the FDA adopt these boxes as the standard for their communications.  FDA leadership is deciding whether and how to use the boxes in reviews, labels, or both.  Also proposed is the generation of a standardized executive summary of FDA drug reviews.  These summaries should include data tables of the main results of the phase 3 trials, highlight reviewers’ uncertainties, and note whether drug approval was conditional upon a post-approval study.  While publication of new comparative-effectiveness results is helpful, publications generally occur post approval.  In contrast, much is known about drug effectiveness and drug safety at approval that could better guide physician and patient choice if this information was more widely disseminated.

Source: New England Journal of Medicine

FDA commissioner Dr. Margaret Hamburg launched a new initiative to innovate regulatory science so that it can keep pace with the evolution of biomedical research.  New pilot and feasibility studies are proposed to investigate early drug safety and efficacy.  In addition, use of genetic data and biomarkers may further elucidate disease targets and support efforts to optimize clinical trial design.  A key part of the plan is to set up centers of excellence in regulatory science, which would most likely be housed in academic centers, and would bring academia, FDA, and industry together in collaboration.  A new office, dedicated to regulatory science, will lead strategic development and co-ordination within FDA.  Initial efforts will focus on recruiting key personnel and building senior leadership.

Source: InPharm

In the FDA’s effort to make both its decisions and clinical trial data more transparent to the public, Agency decisions have become more available for public debate.  Sophisticated analyses (increasingly by third parties) of publically available data may present to the FDA a more complex picture of drug safety, as not all posted clinical trials fit standard regulatory paradigms, are sufficiently powered, have similar patient selection criteria,  or collect and analyze similar parameters. Changes made in the interest of public health, therefore, may further complicate regulatory assessment of potential changes to drug status.  For these reasons, among others, drug safety decisions are rarely “black and white.”  To its credit, the “new” FDA seems more open to try a middle path (e.g., the diabetes medicine Avandia will remain on the market under a restricted access program [risk evaluation and mitigation strategy, or REMS]).  Even more unusual, however, was public admission by the FDA of disagreement about Avandia within its own scientific ranks.  Furthermore, 3 top FDA officials co-authored a New England Journal of Medicine article explaining their rationale.  Interpretation of clinical trial data, however, is relatively easy compared to analyses of post-market safety data, where patient populations and indications are even more diverse.  It will be interesting to see how public access to evolving data (e.g., the anticipated FDA post-marketing drug safety (public) website) will affect Agency decisions, the timing of those decisions, and how much influence third-party analyses will have on regulatory outcomes.  The upside to the ensuing debate may be heightened public awareness of the importance of risk management, as all drugs have risk.  With the down-spiral of new drugs both coming to and remaining on the market, an outstanding question is whether the public and subsequently the regulatory environment will become more or less risk adverse as our perception of drug safety and risk management evolves.

Source: The New York Times

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

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

As of 15 June 2010, the new Food and Drug Administration (FDA) Postmarketing Drug Safety Evaluation website was launched.   The FDA posted postmarket safety evaluations for 26 drugs approved between September 2007 and January 2008 and is reviewing an additional 20 or 30 others. To date, no label changes have been recommended.

In accordance with the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA now summarizes information about ongoing and completed postmarketing safety evaluations of serious adverse events (SAE) submitted to the FDA for New Drug Applications (NDAs) and Biologic License Applications (BLAs) that have been approved since 27 September 2007.   These evaluations are completed to determine if there are any new SAE not previously identified during product development, known side effects reported in unusual number, or potential new safety concerns identified post approval.  These postmarketing evaluations will be performed no later than 18 months following approval (i.e., early in the product’s marketed life cycle) or after its use by 10,000 individuals, whichever is later.

To develop these postmarketing safety evaluations the FDA assesses several data sources including:
• The product’s pre-approval safety profile
• The product’s current FDA-approved label
• Reports made to FDA’s Adverse Event Reporting System (AERS)
• Reports made to the Vaccine Adverse Event Reporting System (VAERS)
• Manufacturer-submitted periodic safety reports
• Medical literature
• Drug utilization databases
• Data from post-approval clinical trials and other studies, when applicable

FDA analyses for the safety evaluations include:
• Data mining analysis of all adverse event reports in the AERS or VAERS databases
• Review serious adverse event reports
• Medication error analysis
• Product utilization analysis
• Risk management review
• Analysis of post-approval safety data from clinical trials and other studies, when applicable

Summaries of FDA safety analyses on recently approved products will now be prepared quarterly and posted on FDA’s website along with a brief discussion of the steps FDA is taking to address any identified safety issues.

Related posts:

New On-line Quarterly Drug Safety Summary and REMS are Complimentary Efforts
Postmarket Drug Safety: Institute of Medicine Recommendations to FDA

Sources:

FDA-1,   FDA-2,   Resource Shelf,   USA Today,   World Pharma News

To share this post easily, cut and paste:  New FDA Postmarketing Drug Safety Evaluation Website   http://bit.ly/b79Fqs

On May 24, 2010, the Food and Drug Administration (FDA) and the National Institutes of Health (NIH) launched a new Web site that, when fully developed, will provide a mechanism for the reporting of pre- and post-market safety data to the federal government.  Currently the Web site can be used to report safety problems related to foods, including animal feed, and veterinary drugs, as well as adverse events occurring on human gene transfer trials.  Consumers can also use the site to report problems with pet foods and pet treats.  For the present, however, this safety portal will be of limited use for human pharmaceuticals.

Source: FDA

The Food and Drug Administration (FDA) is responsible for ensuring the safety of prescription drugs.  Though all drugs are tested in clinical trials before they are available to the public, the risks of some drugs may not appear until well after they are approved.  With the passage of the Food and Drug Administration Amendments Act (FDAAA) of 2007, the FDA can now require clinical trials or other studies to assess the safety of approved drugs.  With this new authority, the FDA must decide when it is ethical for the Agency to require or continue to require clinical trials, and how to ensure the safety of trial participants.

The FDA requested that the Institute of Medicine (IOM) examine when and how to conduct clinical trials ethically to evaluate drug safety. The IOM recommended that the FDA should ensure that any randomized, controlled trial to evaluate the efficacy and safety of an approved drug that is suspected of causing serious adverse events is conducted only when a responsible policy decision cannot be made based either on the existing evidence or on evidence from new observational studies.  The IOM suggested that observational studies – often done by reviewing insurance claims and other databases – can yield strong enough evidence to make a decision on a marketed drug.

The Agency should determine that questions about a drug’s possible risks or risk-benefit balance rise to the level of requiring a policy decision, such as whether to revise the product’s label.  In addition, FDA should make sure that trials are appropriately designed to resolve uncertainties about efficacy and safety and to minimize risks to participants.  A conceptual framework broadly applicable to many situations is provided.

This report is part of a larger study of the scientific and ethical issues involved in conducting studies of the safety of approved drugs. A comprehensive report is expected in 2011.

Sources: IOM and Office of News and Public Information.  Free report available from these sites.

Concurrent Information:

Experts urge limits for some drug safety trials;

When is a drug too risky to stay on the market?