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

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.

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.

In order to keep our competitive edge, the Federal Drug Administration (FDA) is placing increased emphasis on strengthening both the field and application of regulatory science relative to pharmaceutical research, development, review, and post-market surveillance.  The FDA also has a mandate to recognize areas of unmet public health need and try to galvanize action to move appropriate new products through the pipeline and into the market.  The FDA has the responsibility, therefore, not just to review and approve products if the data support that decision, but also to follow these products once marketed to answer critical questions about efficacy and safety.  Examination of products across their life cycle enables not only the identification and analysis of emerging safety signals, but also facilitates the continual balancing of risks and benefits.

Research studies, both preclinical and clinical, that form the basis for approval of medical products are increasingly being performed in other countries and often in networks of other countries.   For this reason, international recognition of both the scientific appropriateness and ethical conduct of those studies becomes increasingly important to global regulatory bodies.  A key understanding is that if a safety concern develops for an approved drug, it does not necessarily reflect that a mistake was made.  It may instead reflect new emerging knowledge about that drug in practical use.  Regulatory safety has to be a dynamic process.  The desire is to proactively ensure that the right studies are done so that the best possible decisions result.  However, there isn’t always an absolute, clear decision to be made; resolution, therefore, requires a dynamic balancing of risks and benefits.  Questions need to be asked about whether certain subpopulations of patients may benefit from targeted use of a drug, or whether the safety concerns are sufficient to mean a more active withdrawal of a product from the market.   Advances in science and technology need to be better incorporated into the regulatory process, with a key area being safety science.   To continue to strengthen the science of regulatory safety, the need is to broaden not only the kinds of preclinical and clinical studies that can be done to deepen our understanding of safety, but also to broaden our understanding of how to apply and weight that data to further the science of risk management.

Source: Interview between Dr. Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One-on-One, and Dr. Margaret Hamburg, Commissioner of the US Food and Drug Administration.  MedScape Today.

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