orphan disease

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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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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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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Orphan Diseases… a new pharmaceutical strategy?

Posted by cdavenport on Friday Dec 4, 2009 Under Pharmaceutical Business

As the old “blockbuster” mentality  fades in the wake of relatively weak pipelines, increased emphasis on drug safety, slow sales growth, and the loss of patent protection on older blockbusters, it would appear that the orphan-disease niche (i.e., low volume: high cost) has become an increasingly attractive lure to major pharmaceutical companies.   While there may be few patients with each disease, David Simmons – president of Pfizer’s established product’s business unit- said “collectively, it’s a very large patient population with a great unmet medical need.”  In addition to Pfizer, other major pharmaceutical companies entering this space include GlaxoSmithKline and Novartis.   Source:  New York Times.

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