http://www.raredr.com/contributor/jennifer-payne/2015/11/fda-post-desi-changing-culture-emerging-science
FDA Post DESI: Changing Culture, Emerging Science


Our DESI Roots                                                          

 In gauging the modern-day sense of public-spiritedness and heightened fevers for FDA flexibility as a regulatory imperative, it is my observation that culture makes for a great barometer and arbiter of change.  In fact, according to the Institute for Safe Medication Practices (ISMP), “one of the most significant predictors of success with keeping patients safe is the state of the organization’s culture.1
 
In governance as a science,2 it is argued that the most compelling case in the history of drug regulation in the quest for balancing safety and technocracy surrounds the Drug Efficacy Study Implementation (DESI) Project.  According to project head, Dr. Paul A. Bryan, DESI “is one of the most important projects – perhaps THE most important one – ever undertaken to improve the quality of prescription drugs in the United States.3
 
DESI was launched under provisions to the 1962 Drug Amendments to the Food, Drug and Cosmetic Act (FDCA of 1938) which required a more formal drug approval process in response to Europe’s thalidomide tragedy.  And, with enlisted help of the National Academy of Sciences – National Research Council (NAS-NRC), the FDA conducted the most comprehensive audit ever on the prescription drug marketplace and associated concerns on effectiveness, safety, quality labeling, combination use, therapeutic equivalence, biological availability and quality control.
 
In 1966, the scope of tightened controls on 7,100 NDA drugs (New Drug Applications 1938-1962) was quite impressive. DESI spanned both approved and unapproved drugs, including: 16,573 drug claims (averaging about 5 purported uses for each drug remaining on the market); 15,000 “me-too” drugs; a half-million over-the-counter drugs; and fixed drug combinations.3
 
FDA enforcement posture under the Drug Amendments proved a successful mission in assuring effectiveness and safety, as well as helping to promulgate one of the greatest cost-containment strategies - through birth of the generics industry and rise of the Abbreviated New Drug Application (ANDA). 
 
At the conclusion of DESI circa 1969, Duke C. Trexler, Executive Director, NAS-NRC reported “90% of the drugs that were reviewed by the 30 panels involved in the Study had been formally transmitted to the Food and Drug Administration, and the remainder will shortly be ready for transmittal.4” Completion of this monumental task was a huge feat – executed in record time, with limited resources, and absolutely no compromise in standards.
 
The integrity of the FDA has stood the test of time since the inception of DESI.  The modernized drug approval process is much attributed to the pioneering efforts of Dr. Frances Oldham Kelsey, recipient to most distinguished honors for her role in “preventing a major tragedy of birth deformities5” as per President Kennedy and coined a “20th century American heroine6” today by the New York Times.  Holding true to the conviction of safety, (denying thalidomide approval in the US despite external pressures), Dr. Kelsey set the frontier for the agency’s drug approval process; or in the words of Douglas Throckmorton, “the gold standard to which other countries aspire.7
 
At the conclusion of the DESI project, a revolutionary era had begun with this historical antecedent to the changing face of today’s modern FDA.  In the 1969 NAS-NRC DESI Final Report to the Commissioner, DESI panelists envisioned “the FDA should change from a philosophy of an enforcement agency to that of a partner in drug development.8
 
Today, the echoes of DESI still reverberate and not only invoke the concept of regulatory convergence, but embrace the new and emerging science of advancing patient input in adaptive drug development paradigms and progressive licensure. According to FDA Historian, Dr. John Swann, enactment of the 1962 Drug Amendments "changed the way the public looks at the federal government.  FDA was not an unknown entity but after 1962, members of the public really started taking notice and having expectations that the government will protect them. And, FDA rose to that challenge 50 years ago.9

Reaffirmation of DESI: “We’re in this together.” – Dr. Ostroff

At the October 2015 Orphan Products Breakthrough Summit hosted by the National Organization for Rare Disorders (NORD), Dr. Stephen Ostroff, FDA Acting Commissioner gave recognition to the patient-centric role as an invaluable resource to driving results with meaningful outcomes. The most progressive steps towards speeding innovation and making treatments available to patients faster fall under the Congressionally mandated responsibility known as the FDA Safety and Innovation Act (FDASIA). Signature provisions for patient-focused drug development have translated to what Dr. Ostroff defines as “strength in numbers…and, the numbers do not lie.10
 
Among the hallmark deliverables of relevance to rare disease highlighted at the NORD Summit included the rise in breakthrough therapy designations, expedited development through priority review, fast track and accelerated approval, and over 3500 orphan drug designations granted (as of October 18, 2015).11  Dr. Ostroff expressed much optimism in the rewards that can accrue through unparalleled scientific innovation and real world application of that science with integration of patient-centered initiatives. And, with completion on more than 70% of FDASIA deliverables12 – what does the future hold?

Convergence is Common Sense

DESI is not an institutional memory, it is a living legacy that continues to grow with the convergence of pharma, researchers and patients as partners in defining 21st century regulatory excellence.  And, the DESI philosophy makes sense. History has shown the rise of the Scientific
 
Revolution coincided with the Enlightenment Era, bringing progressive change and societal reform across many institutions just by simply thinking outside of the box. Responsive regulation today is driven by a new science, moving stakeholders together with focus on patient outcomes and repurposing traditional regulatory processes. Success cannot be achieved unless value is given to patient needs and the desired outcomes which only patients can define for themselves. Finding convergence on commonalities to rare disease problems is the essence of human nature, and personal for me - as an adult living with the rare disorder, phenylketonuria (PKU), an inborn error of amino acid metabolism. I appreciate the Commissioner’s approach and concept of duty to “not leave any disease behind.” (NORD Summit, 2015) The tasks are daunting and complex, and more challenging for rare disorders, especially in the case of PKU - where treatment takes the form of a severely restricted diet with provision of medical food. 
 
Problems in orphan therapies (drugs, devices and medical foods) surround the complexity and understanding of the natural disease states, defining appropriate clinical trials designs (for low patient numbers, lengthy approvals processes), the need to demonstrate a standard of evidence, insufficient flexibility of the processes, lack of incentives, commercial development challenges, and reimbursement.13
 
Despite the increasing pressure tendency on the barometer of public spiritedness, the forecast looks favorable for rare diseases due to the transitioning of progressive licensure back to the people where it belongs in crafting their own treatment regimens.  Optimistic signs include the following: FDA’s patient-focused drug development initiative, the first ever Patient Engagement Advisory Committee on medical devices, critical path innovation meetings (in response to request for clinical outcomes assessments communications on biomarkers, natural history studies and others), and the proposed  guidance from Parent Project Muscular Dystrophy to FDA, which was most instrumental in giving rise to the FDA June 2015 issuance of Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment.14  
 
The perception of patients as a partner is critical to fostering a culture of collaboration, defined by the FDA as “the most efficient game in town.15” Dr. Shuren of the Center for Devices and Radiological Health could not have summed it up better in saying, “smart regulation when you need it, no regulation when you don’t.16” How far have we come, and can we keep the momentum going?  In his keynote address, Dr. Ostroff spelled out the recipe for success by defining the three R’s: Recognition, Resources, and Results.10 And, the LAM Foundation served as an epic model for progress in rare lung disease with reiterating the first and foremost ingredient responsible for this success, “capturing the hearts and trust of (LAM) patients.17
 
In setting a new recourse on regulatory processes, the lessons from DESI must not be forgotten because the ultimate beneficiary was, is, and always will be the American patient.

References

  1. Institute for Safe Medication Practices, “If Safety Is Your Yardstick, Measuring Culture From The Top Down Must Be A Priority,” Acute Care-ISMP Medication Safety Alert! March 22, 2007 Newsletter, www.ismp.org, http://www.ismp.org/Newsletters/acutecare/articles/20070322.asp quoted in Smetzer J, Navarra MB. Measuring change: a key component of building a culture of safety. Nursing Economics 2007; 25(1):49-51      
  2. Mark Wahlgren Summers, Party Games Getting, Keeping, and Using Power in Gilded Age Politics, 2004 University of North Carolina Press, US, p48
  3. Paul A. Bryan, Desi Who? Reprint from FDA Consumer, October 1972, DHEW Publication No. (FDA) 73-3013
  4. Division of Medical Sciences, National Research Council, National Academy of Sciences,   DRUG EFFICACY STUDY, Final Report to the Commissioner of Food and Drugs, Food and Drug Administration, Washington DC, 1969, p59 distributed by: National Association of Pharmaceutical Manufacturers, study was prepared under FDA contract 66-197 (neg), sponsored by the Public Health Service Consumer Protection and Environmental Health Service, Food and Drug Administration, Department of Health, Education and Welfare
  5. Robert D. McFadden, “Frances Oldham Kelsey, Who Saved U.S. Babies From Thalidomide, Dies at 101,” New York Times, August 7, 2015, http://nyti.ms/1MaPxKm
  6. Robert D. McFadden, “Frances Oldham Kelsey, Who Saved U.S. Babies From Thalidomide, Dies at 101,” New York Times, August 7, 2015, http://nyti.ms/1MaPxKm      
  7. FDA Consumer Health Information / U.S. Food and Drug Administration, “Kefauver-Harris Amendments Revolutionized Drug Development,” October 2012, http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm
  8. Division of Medical Sciences, National Research Council, National Academy of Sciences,  DRUG EFFICACY STUDY, Final Report to the Commissioner of Food and Drugs, Food and Drug Administration, Washington DC, 1969, p92
  9. FDA Consumer Health Information / U.S. Food and Drug Administration, “Kefauver-Harris Amendments Revolutionized Drug Development,” October 2012, http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm
  10. Stephen Ostroff, keynote address, NORD Rare Diseases and Orphan Products Breakthrough Summit October 22, 2015, Arlington VA
  11. Gayatri Rao, “The Path to Progress: Rise in Orphan Drug Approvals and Breakthrough Designations,” NORD Rare Diseases and Orphan Products Breakthrough Summit October 22, 2015, Arlington VA
  12. Stephen M. Ostroff, “Celebrating the 3rd Anniversary of the FDA Safety and Innovation Act,” posted July 9, 2015 by FDA Voice, http://blogs.fda.gov/fdavoice/index.php/2015/07/celebrating-the-3rd-anniversary-of-the-fda-safety-and-innovation-act/  accessed 7/10/2015
  13. US Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, February 1989 Report of the National Commission on Orphan Diseases
  14. Elektra J. Papadopoulos, “Current Topics in Rare Diseases: A Roadmap to Patient-Focused Outcome Assessment,” NORD Rare Diseases and Orphan Products Breakthrough Summit October 22, 2015, Arlington VA
  15. Douglas C. Throckmorton, Overview of FDA Support for Innovation, presentation February 2, 2015, CDER presentations library, http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm074833.htm
  16. Jeff Shuren, Medical Device Session, NORD Rare Diseases and Orphan Products Breakthrough Summit October 22, 2015, Arlington VA
  17. Sue Sherman, NORD Panel Discussion: Integrating the Patient Voice, LAM as a Model for Progress in Rare Lung Disease, NORD Rare Diseases and Orphan Products Breakthrough Summit October 2015, Arlington VA

image courtesy of the FDA http://www.fda.gov/AboutFDA/WhatWeDo/History/ThisWeek/ucm117831.htm
 

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