FDA

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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Potential Academic Contributions to Drug Development

Posted by cdavenport on Monday May 14, 2012 Under Drug Safety, FDA, Techniques

Dr. Janet Woodcock (CDER, FDA) stated that for every 10 drugs that enter Phase I clinical trials, only 1 drug is approved.  The cost of bringing an innovative drug to market often requires a decade and a billion dollars of investment.  The paradigm where pharmaceutical companies invest heavily in research and development yet garner few drug approvals is unsustainable.

Woodcock suggests that academic researchers can contribute better methods and technologies to enable faster/better preclinical and clinical decisions to be made during drug development.  Recommendations given include:

  • Development of biomarkers that help identify not only safety risks but also identify patients most likely to benefit from a new, targeted therapy
  • Greater emphasis on applied science (e.g., drug manufacturing and scale-up enhancements)
  • Identification of biochemical pathways causal to disease states
  • Identification of proof-of-concept/surrogate endpoints
  • Enhanced understanding of how the body handles a drug
  • Take a lead on developing orphan drugs, which have historically not been a priority for pharmaceutical companies
  • Develop and implement new ways to conduct clinical trials (e.g., use of early biomarker identification to guide patient selection) with the goal of developing faster, better, smaller clinical studies to gain critical information more quickly ( e.g., work being done at Stanford University)
  • To extend clinical trials into the community and region surrounding academic medical centers to facilitate patient access, recruitment, and to enhance compliance

The public has a decreased tolerance for risk, as evidenced by increased regulatory requirements for premarket evaluation of drug safety and efficacy.  The hope is that academic researchers can drive changes in the required testing paradigms (nonclinical and clinical) to enable faster, better, and cheaper drug approvals.

Sources:  Lecture by Dr. Janet Woodcock at the California Institute for Quantitative Biosciences (qb3), UCSF and HealthCanal.com.

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An Institute of Medicine (IOM) committee report, recommends that the FDA take proactive steps to continue monitoring drug safety after initial approval and throughout the market lifecycle.   Post-market evidence is far greater than what the FDA has when deciding upon initial approval.  The IOM recommendation is that the initial approval is viewed as just one early step in a process that requires continuous, long-term monitoring (the “lifecycle approach”).  The report makes recommendations about how post-market research should be conducted.  The committee found that while randomized controlled trials remain the gold standard for studying drug effectiveness, observational studies have ethical and practical benefits over clinical trials post-approval.  Safety results can be obtained more quickly, therefore regulatory action can be initiated earlier.  One of the key report recommendations is that upon approval, each drug will have a single, publicly available Benefit and Risk Assessment Management Plan (BRAMP) to serve as a central, evolving repository of side effects and other information.  As a centralized comprehensive record, the BRAMP will include a description, a benefit/risk assessment of any safety questions that exist when a drug is approved as well as any that emerge over the course of its market lifecycle, and details on any regulatory actions taken and their results.  Furthermore, it was recommended that the FDA’s drug surveillance systems could be improved through use of various technological and methodological advances (e.g., use of natural language processing for review of electronic medical records).  The possibility was also raised that with a more robust post-approval monitoring process, the more flexible regulatory authorities could be in the pre-approval stage.

SourceMedical News Today, and HealthCanal.com

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High-throughput ADME Screening Technologies

Posted by cdavenport on Monday Apr 16, 2012 Under ADME, Drug Safety, Regulatory

High throughput (HT) Absorption, Distribution, Metabolism, and Excretion (ADME) screening technology is the current push from Big Pharma to be outsourced through contract research organizations (CROs).  Shifting also is the ADME regulatory emphasis; the FDA has released a draft guidance (17 Feb 2012) that includes specific wording around what needs to be done with respect to transporter drug-drug interactions (both efflux and influx).  The guidance will start to drive significant changes in how ADME screening is performed.  Two assays that are routinely being utilized in pharma are the Caco-2 cell-based assay and the PAMPA (parallel artificial-membrane permeation) assay.  As currently practiced, predictive ADME screening is made even more difficult given the variety of transport mechanisms available.  In toxicology screens (ADME-tox), however, one is not looking for altered aspects of the drug, which is generally initially unknown, but changes in known, endogenous parameters.  Thus ADME-tox lends itself more easily to HT platforms.  New platforms for high throughput ADME screening are available, and discussed in this article.

Source:  Drug Discovery and Development

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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.

 

Sources: 

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

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Nonclinical Toxicology: FDA Guidance Agenda for 2012

Posted by cdavenport on Monday Mar 26, 2012 Under Drug Safety, FDA, Preclinical, Regulatory

The Federal Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) has issued a list of planned draft and final guidance documents for release in 2012.  There are about 50 such guidances planned.  Below are a few select highlights relevant to the preclinical safety space, with emphasis on the drug development of small molecules.

Electronic Submissions

  • Providing Regulatory Submissions in Electronic Format – General Considerations
  • Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions.  Using the eCTD Specifications
  • Providing Regulatory Submissions in Electronic Format – Study Data
  • Providing Regulatory Submissions in Electronic Format – Standardized Study Data

Procedural

  • Integrated Summary of Safety
  • Investigational New Drug (IND) Applications prepared and submitted by Clinical Sponsor Investigators

 

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FDA Pre-IND Meetings: Why, When and How

Posted by cdavenport on Friday Feb 24, 2012 Under FDA, Regulatory, TigerU

The pre-IND phase of drug development is the foundation upon which all development-related activities (including registration) depend.  It is, therefore, essential to give proper forethought and attention to this initial, all-important step of the drug-development process.  In the United States, a pre-IND meeting can add considerable value to the overall process and maximize efficient use of both Sponsor and FDA resources.  Although pre-IND meetings require considerable planning and preparation on the part of both the Sponsor and FDA, if warranted and properly conducted, the meeting can provide the Sponsor with valuable insight as to the FDA’s expectations regarding initial- and later-stage development and registration strategies.  This presentation provides a high-level introduction to U.S. FDA pre-IND meetings ─ why and when a Sponsor should consider having a meeting and how the Sponsor approaches the process.

 

Source: Outsourcing4BioPharma

Outsourcing4BioPharma is designed to facilitate business transactions between the clients in health science industries and the contract service providers.

USA · http://www.outsourcing4biopharma.com

 

About the Author:

Grace Furman, Ph.D.

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FDA Changes Expected with PDUFA V

Posted by cdavenport on Monday Oct 24, 2011 Under FDA, Regulatory

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

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Dried Blood Spot Analysis: Preclinical Considerations

Posted by cdavenport on Tuesday Jun 14, 2011 Under FDA, Preclinical, Techniques

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.

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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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