orphan drug

According to a commentary by former Institute of Medicine (IOM) committee members, published this week in the New England Journal of Medicine, increased “fast-tracking” of drug approvals (i.e., for medical conditions with no effective treatment) necessitates a counterbalance of enhanced postmarket surveillance and ethical governance throughout the lifecycle of a drug.  The authors of the report argue that the FDA, when requiring that a postmarked study be initiated, has a unique ethical obligation to research participants, which “cannot be handed off to contractors or the industry sponsor.”  Furthermore, “because some postmarked trials are required specifically to address mounting concerns that the drug’s risks may outweigh its benefits, there are heightened obligations to ensure that potential research participants understand the risks of enrollment.”  Because the volume of postmarked studies is increasing – due not only to FDA-mandated research, but also to increased emphasis on comparative-effectiveness – the benefit-risk balance for comparable study designs can vary depending upon the purpose for which a specific study is being conducted.  The challenges, therefore, for ensuring truly informed consent by study participants can vary widely.

Source:  Science Codex

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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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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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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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FDA Encourages Applications for Orphan-Drug Status

Posted by cdavenport on Friday Mar 12, 2010 Under FDA, Personalized medicine

Getting an orphan-drug designation opens the door to incentives once the FDA approves a medicine for sale in the U.S., including 7 years’ marketing exclusivity and tax breaks.  Last year, just 250 requests for orphan-drug designation were filed, and 160 were successful.  There are roughly 350 orphan drugs approved, covering about 150 rare diseases.  Timothy Coté, director of the FDA’s Office of Orphan Products Development, said that his office is offering 2 workshops with on-the-spot regulatory advice to try to elicit more orphan drug applications.  Over the course of the 2-day workshop, each company met 4 times with FDA staffers who offered advice on 9 critical issues in filling out an application.  Orphan drug applications are 6-7 pages.  At the conclusion of the first workshop, only 14 of the 29 companies submitted applications, although they can still submit at any time.  It usually takes the FDA 60 days to determine whether the designation will be given.  Up to 50 more organizations can attend a second workshop to be held at the University of Minnesota in August 2010.  Dr. Coté said he is considering a workshop in Europe.  Next time, he wants only applicants who can file, without the delay of company approval, at the end of the 2 days to attend.

Source: Wall Street Journal (digital)

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