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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Analysis and overview of new drug reviews from 1993 through present by an over 20-year-active FDA veteran of drug approvals, Dr. John Jenkins (Director, Office of New Drugs, Center for Drug Evaluation and Research).  The presentation includes review times and comparison to global approvals.  Of note, median approval times for New Molecular Entities (NME) applications are 10 months, a 47% reduction from calendar year 1993.  A status update on CDER compliance with past PDUFA goals is given, with information on forward planning to comply with PDUFA V goals.  In accordance with the enhanced emphasis on benefit-risk analysis in PDUFA V, discussion of the anticipated framework and balance of stakeholder concerns is detailed.   The PDUFA V program for NME review is presented, with key elements and projected timelines detailed.

This slide presentation gives excellent perspective of past and future trends for the global pharmaceutical market, with emphasis on FDA approvals of NME.

Source Slide Show (pdf hyperlink):  FDA

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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:  Outsourcing-Pharma.com 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:  Outsourcing-Pharma.com 12-Mar-2012, 15-Mar-2012; BioPharm International

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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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For pharmaceutical companies, is personalized medicine more of a threat than an opportunity?  In addition to the development of new drugs, genetic information can also help target the use of current medications (e.g., Plavix).  The use of genetic (or other) information to target patient population subsets is expected to increase drug safety and render cost savings to both insurer and patient, but can it also be expected to limit the potential market and lower pharmaceutical sales?  By potentially enhancing drug safety, personalized medicine is expected to elicit fewer adverse drug reactions, thereby leading to fewer liability claims against drug companies.  Drug development costs rise, however, if preclinical scientists also must isolate a genetic trigger and develop a companion test for a treatment, even if the size of clinical trials can potentially be reduced and additional income can be expected through purchase of both medication and companion diagnostic.  Even when a drug is utilized in target populations, how much risk will be deemed acceptable?   Whether personalized medicine stimulates or inhibits pharmaceutical drug development remains to be determined.

Source: Wall Street Journal

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Ideally, every new drug would represent an unprecedented breakthrough and lead to the creation of a
completely novel treatment. This, however, is not the reality of the pharmaceutical industry, or of any other
development-based industry. Creating drugs based on incremental innovations provides pharmaceutical
companies with a secure stream of revenue, which can be directed to higher-risk, potential blockbuster-yielding
research. Policies aimed at reducing the industry’s ability to obtain revenues from incremental innovations
could be self-defeating, as those industries will then have less revenue to reinvest in R&D for new drugs. Put
simply, limiting incremental drug innovation is analogous to limiting competition. The ultimate result could
have devastating consequences for the future of the pharmaceutical industry and for the millions of patients
who depend on it.

Ideally, every new drug would represent an unprecedented breakthrough and lead to the creation of a completely novel treatment.  This, however, is not the reality of the pharmaceutical industry, or of any other development-based industry.  Most new drugs represent the combined weight of seemingly small improvements achieved over time.  Creating drugs based on incremental innovations provides pharmaceutical companies with a secure stream of revenue, which can then be directed to higher-risk, more innovative research.  Many critics contend that “Me-too” drugs — drugs within the same chemical class as one or more already on the market — add little or no therapeutic value to existing formularies.   Conversely, advocates claim that new drugs based on incremental improvements generally represent advances in safety, efficacy, selectivity, and ultimately increase the utility of drugs within a specific therapeutic class.  Innovations may also include new formulations and dosing options.  Changes in one or more of these parameters generally increase patient compliance and improve health outcomes.  Furthermore, patients can respond differentially to drugs within a single class, thus having multiple drug options within a therapeutic class enables optimization of medical treatment to best fit a patient’s needs.  From an economic standpoint, while it is unrealistic to presume that every incremental innovation leads to cost savings, the sum of all drug innovations can reduce overall treatment costs, shorten or eliminate hospitalization, increase worker productivity and reduce absenteeism, and eventually lower drug costs through increased competition among manufacturers.

In conclusion, policies aimed at reducing an industry’s ability to obtain revenue from incremental innovations could be self-defeating, as less revenue will be available to reinvest in research and development.  In pharmaceutical terms, limiting incremental drug innovation is analogous to limiting competition.  The result could have devastating consequences for the future of the pharmaceutical industry and ultimately for patients.

Source:  Competitve Enterprise Institute

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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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Rare diseases can be described in terms of incidence, etiology, morbidity, and survival.  Incidence can vary, however, from rare (e.g., Gaucher disease, cystic fibrosis) to epidemic proportions (e.g., HIV, malaria, cholera).  The incidence of less frequently occurring cancers (e.g., pancreatic and renal cell carcinoma, myeloma, and glioma), although more common in relation to other rare diseases, meet most regulatory requirements for orphan designation.

In a report of the top 200 brand drugs by retail dollars in 2007, 17 top brands (retailing from $144.7 million to $1.837 billion) had an approved orphan use.  Six of these 17 top drugs, in terms of retail dollars, were indicated solely (USA) for an orphan use: opioid dependence, organ transplant rejection, relapsing multiple sclerosis, and cystic fibrosis.  Eleven of the top 17 brands had an additional 2-9 approved uses, which likely factored favorably into their retail sales volume.

Blockbusters can get their start in rare diseases.  Botox (botulinum toxin type A) was first approved in 1989 as an orphan drug for a rare eye movement disorder (blepharospasm) associated with dystonia before seeking approval for cosmetic use.   ClinicalTrials.gov and the Pharmaceutical Research and Manufacturers of America (PhRMA) reported that over 80% of clinical research trials for rare diseases were not industry sponsored.

In regard to the misuse of the Orphan Drug Act, attempts to further subdivide diseases to achieve questionable subsets small enough to qualify for orphan designation seem unlikely to succeed given the requirement to provide support that a condition is a recognized disease with documented incidence.  There are valid and appropriate ways to target subset populations (e.g., pediatrics, refractory patients, severe forms of a more common disease, specific genotype).

The 2007 FDA Amendments Act (FDAAA) priority review (transferable) voucher incentive program and the 2008 common application form agreement between the USA and EU regulatory bodies demonstrate further global  support for rare diseases.  The outlook going forward is that orphan indication exclusivity can be one aspect of a profitable drug’s overall product life cycle, including non-orphan uses, and can contribute to its profitability.

Source:  Drug Information Journal

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