Pharmaceutical Business

Off-label Drug Use: Fact vs. Fiction

Posted by cdavenport on Friday Aug 17, 2012 Under Drug Promotion, Drug Safety, FDA

The authors – CM Wittich, CM Burkle, and WL Lanier – offer a concise review of the topic of off-label drug use including its definition, prevalence, and implications for drug safety.   The article format addresses 10 common questions and their answers about off-label drug use.  The breadth of application, its acceptance, and the liabilities of off-label use are explored.  A history of FDA regulations surrounding the practice is presented, which helps to put its evolution into proper perspective.  Off-label use, which occurs in every medical specialty, is more common in patient populations not likely to be included in clinical trials (e.g., pediatric, pregnant, or psychiatric patients).  Once a medication is marketed, the FDA does not limit or control how the medication is prescribed by physicians. The pros and cons of the distribution of information regarding the off-label use of medications by pharmaceutical companies, the use of informed consent, and the liability of prescribing physicians are discussed.

SourceMayo Clinic Proceedings  – pdf of full article.

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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, 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

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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

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In the next 2-5 years, large pharmaceutical companies plan to increase outsourcing of preclinical work, with emphasis on Discovery and non-GLP Toxicology.  This trend is driven by the reductions in internal preclinical capability within Big Pharma.  In an apparent reversal of the current trend towards use of a limited number of preferred providers, capacity will necessitate increasing the number of contract research organizations (CRO) involved.  An offshore trend is anticipated despite the rapidly narrowing price differentials between Chinese and Western CROs for nonclinical work.  A survey suggested that the offshore CROs best positioned to secure the early-stage drug development business from large pharmaceutical companies are Covance, WuXi, BioDuro, and ShangPharma.   As an example, ShangPharma recently opened a new facility to accommodate a multi-year contract with Eli Lilly, with emphasis on in vivo pharmacology, oncology, and metabolic disease work.

Sources: 11 Jan 201217 Apr 2012, 19 Apr 2012

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Growth in demand for nonclinical toxicology services will be weak for the foreseeable future analysts said after the Society of Toxicology (SOT) annual meeting in San Francisco this past week.  “Most agree that the industry is not merely going through a prolonged cyclical slowdown, but has also structurally changed, with less of an emphasis by clients on maximizing the number of drug candidates flowing into preclinical testing,” stated John Kreger, equity analyst at William Blair.  In addition, chronic toxicity testing is being delayed until the later stages of compound development; this reduces preclinical development costs for compounds that fail.  Among other factors, this has led to excess capacity at contract research organizations (CRO), price restrictions, and site closures.  Tim Evans, senior analyst at Wells Fargo, expects the overall nonclinical toxicology market to grow by 2% in 2012 due to higher outsourcing penetration.  In their selection of preferred service providers, global bio/pharmaceutical companies generally favor large CROs with broad capabilities.  These “strategic partnership” deals, which are the cornerstones of global bio/pharmaceutical companies’ current outsourcing strategies, seek to leverage their massive buying power, reduce the cost of overhead, and improve coordination with the CRO.  Sourcing models will continue to evolve, however, and will eventually threaten the business model upon which the recent megadeals are based.


On a related note due in part to ongoing capacity cuts, large pharmaceutical companies are seeking co-development deals with CROs and biotechnology firms to handle excess intellectual property.   Shared risk and reward features are found in some of the more creative models.   CROs that have made major acquisitions in order to leverage capacity, however, could be outmaneuvered by evolving sourcing models.

Sources: 12-Mar-2012, 15-Mar-2012; BioPharm International

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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.



About the Author:

Grace Furman, Ph.D.

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With the rise of combination therapy – the use drugs with different mechanisms of action to combat a specific disease state – comes the need to address medical costs and reimbursement issues.  Joint negotiation of package deals with government and health insurers may prove useful, particularly for companion diagnostics and treatment of chronic conditions.  Companies that share drug development risks and costs (preclinical, clinical trials, sales and marketing, etc.) with each other are not only better positioned to negotiate for reimbursement but are also better poised to defend against competition.   Multiple collaborations, however, increase the risk of legal complexity for all concerned.

Source: Reuters

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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

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Why is naming a drug so difficult?

Posted by cdavenport on Friday Oct 22, 2010 Under Drug Safety, FDA, Pharmaceutical Business

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

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