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32 posts from March 2011

March 30, 2011

FDA Regulations Doubles Review Time and Quadruples Trial Size for Diabetes Therapies

FDA Green 
Cardiovascular safety issues with a number of drugs led the Food and Drug Administration (FDA) in late 2008 to introduce new regulatory guidelines for type 2 diabetes drugs and more recently to recommend a risk assessment and mitigation strategy for rosiglitazone. Consequently, as a recent article in the Journal of Contemporary Clinical Trials noted, the “immediate effect of the guidelines was a pathway to approval fraught with greater challenges.”

Accordingly, the authors of the study, Viereck and Boudes, examined the impact of FDA's 2008 guidelines for addressing cardiovascular risks of new therapies for type 2 diabetes on clinical trials.  They focused on the new class of incretin-modulating drugs, exenatide, sitagliptin, saxagliptin and liraglutide, which were approved in 2005–2010.

They then contrasted these findings with those from 2 different groups: 1) diabetes drugs approved in the same timeframe but with a non-incretin mechanism of action (colesevelam HCl and bromocriptine mesylate) and 2) diabetes drugs with NDAs delayed and not yet approved within the same timeframe (vildagliptin, alogliptin, insulin inhalation powder, and exenatide long acting release).

Based on their study, the authors concluded that, “the new guidelines have had an important impact on clinical development.”  Specifically, they found that the drug “review time has increased over 2-fold,” and “the increase is seen even if a drug with the same mechanism of action has been already approved.”  In addition, “the number of randomized patients and patient-years in NDAs increased more than 2.5 and 4 fold, respectively since the guidelines.”

Ultimately, through rigorous methodology, Viereck and Boudes quantitate for type 2 diabetes drugs what many have intuitively thought: huge increases in clinical trial size, NDA  and review times as a result of new cardiovascular guidelines for drugs in type 2 diabetes.  The increased regulatory burden relative to the EU is stifling innovation in the US.  Accordingly, the authors concluded that, “the significant cost increases and negative publicity because of rare adverse reactions will adversely affect future clinical research in type 2 diabetes and not address its burgeoning health care impact.”


IOM Clinical Practice Guidelines We Can Trust -- But What About the IOM?

Clinical Guidelines 
The Institute of Medicine (IOM) issued two reports last week “that it said will provide an objective and consistent framework for clinical practice guidelines, and standardize systematic reviews of comparative effectiveness”—also known as comparative effectiveness research (CER). The studies were requested by Congress and sponsored by the Department of Health and Human Services (HHS).

The first report, entitled Clinical Practice Guidelines We Can Trust, includes eight standards and recommendations.

IOM's second report, “Finding What Works in Health Care: Standards for Systematic Reviews,” addresses the “myriad and often competing guidelines for clinical recommendations by offering what it said are 21 standards to ensure objective, transparent, and scientifically valid reviews.”


According to IOM’s press release, “clinical practice guidelines and systematic reviews of the evidence base for health care services are supposed to offer health care providers, patients, and organizations authoritative guidance on the comparable pros and cons of various care options, but too often they are of uncertain or poor quality.  There are no universally accepted standards for developing systematic reviews and clinical practice guidelines, leading to variability in the handling of conflicts of interest, appraisals of evidence, and the rigor of the evaluations.” 

IOM Clinical Practice Guidelines

1. Establishing transparency: The processes by which a clinical practice guideline (CPG) is developed and funded should be detailed explicitly and publicly accessible.

2. Management of conflict of interest (COI): Prior to selection of the Guideline Development Group (GDG), individuals being considered for membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG.

Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, institutional, and patient/public activities pertinent to the potential scope of the CPG. Disclosure of COIs within GDG:

  • All COI of each GDG member should be reported and discussed by the prospective development group prior to the onset of their work.
  • Each panel member should explain how their COI could influence the CPG development process or specific recommendations.

IOM also recommend that members of the GDG should divest themselves of financial investments they or their family members have in, and not participate in marketing activities or advisory boards of, entities whose interests could be affected by CPG recommendations. Additionally, IOM noted that:

  • Whenever possible GDG members should not have COI.
  • In some circumstances, a GDG may not be able to perform its work without members who have COIs, such as relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the CPG.
  • Members with COIs should represent not more than a minority of the GDG.
  • The chair or co-chairs should not be a person(s) with COI.
  • Funders should have no role in CPG development.

3. Guideline development group composition: The GDG should be multidisciplinary and balanced, comprising a variety of methodological experts and clinicians, and populations expected to be affected by the CPG. Patient and public involvement should be facilitated by including (at least at the time of clinical question formulation and draft CPG review) a current or former patient and a patient advocate or patient/consumer organization representative in the GDG.

4. Clinical practice guideline–systematic review intersection: CPG developers should use systematic reviews that meet standards set by the IOM’s Committee on Standards for Systematic Reviews of Comparative Effectiveness Research. When systematic reviews are conducted specifically to inform particular guidelines, the GDG and systematic review team should interact regarding the scope, approach, and output of both processes.

5. Establishing evidence foundations for and rating strength of recommendations: For each recommendation, the following should be provided:

  • An explanation of the reasoning underlying the recommendation, including:
  • A clear description of potential benefits and harms.
  • A summary of relevant available evidence(and evidentiary gaps), description of the quality (including applicability), quantity (including completeness), and consistency of the aggregate available evidence.
  • An explanation of the part played by values, opinion, theory, and clinical experience in deriving the recommendation.
  • A rating of the level of confidence in (certainty regarding) the evidence underpinning the recommendation.
  • A rating of the strength of the recommendation in light of the preceding bullets.
  • A description and explanation of any differences of opinion regarding the recommendation

6. Articulation of recommendations: Recommendations should be articulated in a standardized form detailing precisely what the recommended action is and under what circumstances it should be performed. Strong recommendations should be worded so that compliance with the recommendation(s) can be evaluated.

7. External review:

  • External reviewers should comprise a full spectrum of relevant stakeholders, including scientific and clinical experts, organizations (e.g., health care, specialty societies), agencies (e.g., federal government), patients, and representatives of the public.
  • The authorship of external reviews submitted by individuals and/or organizations should be kept confidential unless that protection has been waived by the reviewer(s).
  • The GDG should consider all external reviewer comments and keep a written record of the rationale for modifying or not modifying a CPG in response to reviewers’ comments.
  • A draft of the CPG at the external review stage or immediately following it (i.e., prior to the final draft) should be made available to the general public for comment. Reasonable notice of impending publication should be provided to interested public stakeholders

8. Updating:

  • The CPG publication date, date of pertinent systematic evidence review, and proposed date for future CPG review should be documented in the CPG.
  • Literature should be monitored regularly following CPG publication to identify the emergence of new, potentially relevant evidence and to evaluate the continued validity of the CPG.
  • CPGs should be updated when new evidence suggests the need for modification of clinically important recommendations. For example, a CPG should be updated if new evidence shows that a recommended intervention causes previously unknown substantial harm, that a new intervention is significantly superior to a previously recommended intervention from an efficacy or harms perspective, or that a recommendation can be applied to new populations.

IOM Standards for Systematic Reviews

In the Medicare Improvement for Patients and Providers Act of 2008, Congress directed the IOM to develop standards for conducting systematic reviews. The recommendations from the second report emphasized similar standards and principles including:

  • Manage bias and conflict of interest (COI) of the team conducting the systematic review; and
  •  Manage bias and COI for individuals providing input into the systematic review


After announcing the two IOM reports, Sheldon Greenfield, MD, executive director, Health Policy Research Institute, University of California, Irvine, and chair of the IOM committee on guidelines, asserted that, “These standards are necessary given that there is little documentation to judge the quality and reliability of many of the existing clinical practice guidelines.”

Dr. Greenfield emphasized that the “Practice guidelines provide valuable data and guidance that not only inform individual decisions about care but ultimately could also improve overall healthcare quality and outcomes.” 

Alfred O. Berg, MD, professor of family medicine, University of Washington School of Medicine, Seattle, and chair of the committee that wrote the report on systematic reviews, noted that, “this report presents the ‘gold standard’ to which those who conduct systematic reviews should aspire to achieve the most reliable and useful products.”

Dr. Berg recommended that the standards in the IOM reports be adopted to “minimize the chances that important health decisions are based on information that may be biased or erroneous.” He did however recognize that doing so, will “take an investment of resources and time to achieve such high standards.”


The problem with this report and others like it is the underlining belief system that working with industry to develop and commercialize new therapies is somehow inherently bad and should be managed or eliminated.

The problem with this philosophy is that it fails to recognize expertise and value.  In all other industries working with industry by academicians is considered valuable experience.  But in medicine the ivory tower has decided that they can determine clinical guidelines alone without the input of those who design and work on randomized controlled clinical trials, the backbone of industry-academia collaboration.  

The problem with this is that it is the equivalent of setting a rule that NASCAR drivers should not have any relationships with industry therefore lack the expertise of the latest and best science and drive slower cars but they would be pure.

No patient and I literally mean no patient wants a physician who only has knowledge of old therapies setting “guidelines” for other physicians.     These recommendations if adopted will put us one step closer to “government controlled” healthcare.

Rather than spending all our energy determining eligibility based on relationships with product developers. Would not our time and resources be better spent in finding cures for diseases and coming up with guidelines that implement those therapies?    We have had guidelines for 50+ years and almost all have been out of date within weeks of their release.

March 29, 2011

FDA Budget: Trying to Do Everything on Less Money

Hanburg Congressional Hearing 
Recently, the Senate Committee on Appropriations, Subcommittee on Agriculture, Rural Development, Food and Drug Administration (FDA), and Related Agencies, held a hearing on the Fiscal Year 2012 budget for the FDA.

Prior to the hearing, the Committee noted in a press release that under the Continuing Resolution, the Agriculture Subcommittee reduces the budgets of the USDA and the FDA by $1.1 billion (5%) below the President’s FY 11 budget request.  In comparison, HR 1 reduces the budgets of the USDA and FDA by $4.8 billion (22%) below the President’s FY 11 budget request. Specific amounts are provided below:

  • FY 11 President’s Budget: $22.851 billion
  • Senate CR: $21.700 billion
  • HR 1 (House CR): $18.008 billion

The Senate CR provides $2.504 billion for the FDA, which is the same as the President’s request but $400 million (16%) above HR 1. However, HR 1cuts the FDA budget  “far more drastically than the Senate proposal, and would result in large-scale reductions of important food and drug inspections, and could result in furloughs of inspectors.”

Consequently, the Subcommittee then heard testimony from Dr. Margaret Hamburg, Commissioner of the FDA, regarding the 2012 budget request. She used her testimony to outline the important initiatives in FDA’s FY 2012 budget request to Congress. Dr. Hamburg also highlighted FDA’s unique role in protecting public health and the value that FDA delivers for American taxpayers.

FDA Commissioner Dr. Hamburg’s Testimony

At the beginning of her testimony, Dr. Hamburg asserted that she and her “colleagues at the FDA are deeply committed to the health of American patients and consumers – and they recognize that innovation is essential to progress in public health.”

She noted that, “innovation is the foundation of the successful industries FDA regulates, and innovation is responsible for remarkable advances across all of the product areas within FDA’s jurisdiction – which is why FDA must work proactively to foster the scientific innovation that will lead to tomorrow’s breakthrough products.” Dr. Hamburg also recognized that “innovation is critical to maintaining U.S. global leadership in many areas, including medical product development.” However, she noted FDA’s support for the generic drug industry, which markets drugs that save American patients and taxpayers $140 billion per year.

Accordingly, she noted the importance of FDA as an agency innovating and becoming more efficient. She noted that in FDA highlighted in its FY 2012 budget more than 100 examples in which FDA centers and offices are improving the efficiency of FDA programs, and, in many of these examples, FDA is also supporting industry efforts to develop new products.

Examples of FDA innovation include the recent launch of the Innovation Pathway, a program to stimulate new, breakthrough technology and advances for medical device manufacturers as well as a scientific collaboration with industry to develop novel technologies. Dr. Hamburg asserted that, “these efforts reduce the risk and expense of recalling products that fail to meet safety standards.”

She also noted FDA-TRACK, an agency-wide system to monitor key performance measures for more than 90 FDA programs. Dr. Hamburg asserted that FDA-TRACK has helped FDA achieve its performance measures and allowed stakeholders and the public to witness FDA’s progress through quarterly reports posted on Additionally, Dr. Hamburg listed a number of ways FDA has improved the health of Americans in the past year, including:

  • Approved new drugs to treat diabetes, hypertension, osteoporosis, bacterial infections, chronic pain, rheumatoid arthritis, preterm birth, gout, immune deficiencies, schizophrenia, major depressive disorder and pulmonary disease
  • Approved five new therapies to treat rare diseases
  • Conducted four workshops to stimulate new orphan drug development

Consequently, Dr. Hamburg told the committee that FDA’s FY 2012 budget is an investment in health – in the health of individuals and the public health of our nation. As a result, the budget includes $4.4 billion in budget authority and user fees to protect and promote the health of the American public every day, and through every stage of life.

She noted that, “although FDA’s FY 2012 budget is an overall increase for FDA, it also contains savings that contribute to the Administration’s deficit reduction goals. FDA is proposing $29.7 million in contract and administrative savings designed to achieve reductions and cut costs across all FDA program areas.”

To achieve these savings, Dr. Hamburg noted that, “FDA will reduce administrative staff by 46 FTE, lower contract costs by increasing competition, and expand the use of blanket purchase agreements and other agency-wide approaches to reduce contract costs.” She also noted reducing costs by using technology to improve how FDA manages its contracts and the contracting process and by using online training to reduce the cost of employee training.

FDA FY 2012 Budget

For FY 2012, FDA proposed $70 million for the Advancing Medical Countermeasures (MCM) Initiative. Medical countermeasures include drugs, vaccines, diagnostic tests, and medical equipment and supplies to respond to deliberate biological, chemical, radiological and nuclear (CBRN) threats and emerging infectious diseases, such as pandemic influenza. Dr. Hamburg noted that FDA is “critical to the success of the MCM Enterprise, primarily because FDA evaluation of product safety and efficacy can significantly affect the course of product development." The report further recognized that robust FDA engagement from the earliest stages of product development can substantially increase the odds of successful approval. In other words, increased support for FDA’s MCM activities is one of the most critical steps the federal government could take to transform the larger MCM Enterprise.

FDA also proposed an increase of $123.6 million for the Protecting Patients Initiative. This increase includes $64.8 million in budget authority and $58.8 million from three new user fees. FDA is proposing new fees for reviewing generic drug applications, paying the cost of medical product reinspections, and inspecting imports that arrive by international courier.

Dr. Hamburg also noted that with the FY 2012 increase in budget authority, FDA will establish a pathway for approving generic biologics, which are biological drugs shown to be highly similar to an FDA-approved biological product. She noted that,

“approving biosimilar versions of these products offers the potential for substantial savings for the federal government and private sector health plans. However, these savings will not materialize unless FDA has the resources to implement a clear regulatory pathway for approving generic biologics.

The Protecting Patients Initiative will also invest in new scientific tools and partnerships to enhance the safety of increasingly complex drugs, medical devices, vaccines and other biological products. For example, the Protecting Patients Initiative will strengthen FDA efforts to modernize and improve safety throughout the supply chain of medical products at a time when the number of medical products manufactured abroad is increasing dramatically, which presents real challenges for medical product and manufacturing safety. The initiative will also expand FDA’s capacity to conduct medical product safety assessments and strengthen the safety of vaccines and the blood supply.

For FY 2012, FDA also proposed an increase of $48.7 million for the FDA Regulatory Science and Facilities Initiative, to strengthen the core regulatory scientific capacity that supports all elements of the FDA mission. Regulatory science focuses on developing the knowledge and tools to properly assess the safety, effectiveness and quality of products that are being developed or are already on the market. Specifically, this initiative will help modernize and streamline the regulatory pathways that industry relies on to bring new, innovative products to market.

It will also modernize the FDA review and approval process for products that rely on new and emerging technologies. The result will be promising new opportunities to diagnose, treat, cure and prevent disease. Dr. Hamburg also noted how the budget will allow FDA to finish the new laboratory for CBER-CDER. She noted that FDA must make this investment in FY 2012 to ensure that the laboratory is operational and ready for occupancy in FY 2014.

Finally, FDA proposed an increase of $634.5 million for 12 current law user fee programs. FDA user fee programs support safety and effectiveness reviews of human and animal drugs, biological products, medical devices, and other FDA-regulated products. Fees also allow FDA programs to achieve timely and enhanced premarket review performance. Finally, fees support the programs and operations of the FDA Center for Tobacco Products.

Existing user fee laws authorize fee increases for many FDA user fee programs. The increases expand the available options for treating and curing diseases and addressing other important public health needs.


As Dr. Hamburg noted, the FDA budget for FY 2012 contains important investments for critical public health priorities and it will help support the development of urgently needed medical countermeasures; protect patients by assuring that the drugs and other medical products they rely on are safe; and advance regulatory science, which serves as the foundation for all science-based decisions at FDA.”

Funding for FDA is crucial, especially with respect to new drug, device, and medical technology approval. Industry is developing medicines and devices at a fast rate, requiring FDA to provide constant feedback and testing. To ensure that the medical device and pharmaceutical industry remain strong in America, at a time when health care reform is being implemented, Congress must ensure the agency is adequately supported and funded.


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