Saturday, May 19, 2018

FDA's RFA for Stakeholders & Experts in Regulatory Science (May 2018)

Originally posted as:

    Part 2. Full Text of Announcement
    Section I. Funding Opportunity Description
    The FDA Center for Drug Evaluation and Research seeks to support efforts to research, identify key issues, and convene appropriate subject matter experts to help advance regulatory science to promote the increased availability of safe and effective drugs to the public. This effort will inform regulatory science by advancing the scientific discussion of key research topics of interest to both FDA and external stakeholders such as the pharmaceutical industry, healthcare professionals, patients, and academic researchers. FDA seeks support to address research needs identified in the 2018 reauthorization of the Prescription Drug User Fee Act (PDUFA VI) and requirements under the 21st Century Cures Act. The research areas identified in PDUFA and the 21st Century Cures Act represent key scientific priorities identified by FDA, Congress, and stakeholders that, if advanced, will help expedite the development of drugs and improve efforts to assess their safety and effectiveness, thereby increasing the availability of safe and effective drugs to the public.
    More information about the research areas identified under PDUFA VI can be found at the following website:
    In the most recent reauthorization of PDUFA, FDA identified specific areas of research interest in consultation with drug industry representatives, patient and consumer advocates, health care professionals, and other public stakeholders.  These areas represent a wide range of new innovative initiatives related to virtually every aspect of the new drug life cycle. Advancing research, discussion, and understanding on these areas will benefit FDA's stakeholders, expedite drug development, and improve FDA, industry, and researchers' ability to assess drugs' safety and effectiveness.  These initiatives may include, but not be limited to, the following:
    • Enhancing regulatory science and expediting drug development
    • Facilitating rare disease drug development
    • Advancing the use and understanding of innovative statistical methods and trial designs
    • Advancing development of combination product review
    • Enhancing the use of real world evidence for use in regulatory decision-making
    • Enhancing regulatory decision tools to support drug development and review
    • Enhancing the Incorporation of the Patient's Voice in Drug Development and Decision-making
    • Enhancing Benefit-Risk Assessment in Regulatory decision-making
    • Advancing model-informed drug development
    • Enhancing capacity to review complex innovative designs
    • Enhancing capacity to support analysis data standards for product development and Review
    Several key areas of research interest are described in greater detail below:
    Enhancing the Incorporation of the Patient's Voice in Drug Development and decision-making
    In PDUFA V, FDA conducted a series of Patient-Focused Drug Development (PFDD) meetings with the aim to more systematically gather patients' perspectives on their condition and available therapies to treat their condition. Under PDUFA VI, FDA proposes to build on these efforts to bridge from PFDD meetings to fit-for-purpose tools to collect meaningful patient input that can be incorporated into regulatory review and used by all stakeholders to assess drugs' benefit to patients. The field is constantly evolving and this work cannot be done in isolation. Many professional groups and research teams around the world have developed and are developing templates, checklists, and guidelines for different aspects of gathering and interpreting patient experience data, and many such documents already exist for patient reported outcomes. FDA seeks to identify the challenges and opportunities within the current collection and use of patient input.  Advancing research in this area will help ensure that drug development is more responsive to patients' input and needs.
    Structured Approaches to Enhancing FDA’s Assessment of Benefits and Risks in Human Drugs
    FDA’s qualitative Benefit-Risk (B-R) Framework serves as the foundational element of CDER’s and CBER’s structured benefit-risk assessment. With implementation of the B-R Framework gaining solid ground within FDA’s drug review, there is now an opportunity to systematically explore and advance the use of more technical approaches within the qualitative framework to inform benefit-risk assessment in targeted cases. These may include structured techniques to characterize underlying judgments and uncertainties inherent in the assessment, methods to compare and/or weigh benefits and risks, and other qualitative and quantitative approaches aiming to improve the quality of the decision-making process in some cases. FDA recognizes that the agency’s efforts to develop a more structured approach to benefit-risk assessment could be complemented by further engagement of stakeholders and other parties, providing an opportunity to share challenges and lessons learned in applying a more structured approach to benefit-risk decision-making.  Such research would benefit FDA, drug manufacturers, health policy analysts, and others who make decisions about the benefits and risks of drugs.
    Achieving these research objectives requires bringing together input from a wide range of relevant external subject matter experts and other interested public stakeholders. In addition, this input process should be timely, well-informed, candid, thoughtful, thorough, and well-documented.  FDA is therefore seeking to establish a cooperative agreement with a qualified awardee with experience in the conduct of the needed research, workshops and other meetings, and related work.
    The goal of this collaboration is to advance research in several key areas of interest to FDA and external stakeholders by convening stakeholders with diverse expertise, and to inform and support the advancement of regulatory science priorities, particularly those identified in PDUFA VI and the 21st Century Cures Act. Through a series of meetings, workshops, webinars, and/or workgroups, the awardee would provide effective opportunities for engagement of these stakeholders to pursue research on these topics. In addition to gathering input from selected stakeholder groups, the awardee will  conduct background research prior to expert engagement, use input gathered to develop white papers and research reports, and communicate updates on the progress of its regulatory science research to broader audiences. Specific objectives of this collaboration would include:
    • Working collaboratively with FDA to identify and prioritize pressing research issues related to the key areas of interest identified in PDUFA VI and the 21st Century Cures Act
    • Conducting research and reviews of relevant literature to plan the focus of sessions in which experts are convened to provide critical input on regulatory science issues;
    • Convening expert stakeholders in focused, substantive discussions of these issues, and identify and explore potential strategies for resolving them
    • Developing reports that summarize the background research and discussion at each meeting, and posting these reports for public access to promote external interest and advance public understanding of key research issues; and
    • Helping to make research results and reports actionable by FDA, industry, and other stakeholders.
    The timeframe of the project is five years. Conducting this research will require a multi-year effort, involving a variety of topics, stakeholder groups, and issue specific activities. We propose to establish a five-year collaboration, aligned with the reauthorization of the PDUFA agreement, to facilitate the successful, in-depth exploration of key research topics.
    Inherent in the cooperative agreement award is substantive involvement by the awarding agency. Accordingly, FDA will have substantive involvement in the programmatic activities funded by this Cooperative Agreement. Substantive involvement includes, but is not limited, to the following:
    FDA will provide guidance, and assistance in the identification of key research objectives.

Monday, April 23, 2018

Brief Listing of Transgender Healthcare Regulations


In May 2016, HHS released final regulations on healthcare discrimination, including transgender issues.

Trade press here

Detailed FAQ here

Actual 2016 final regulation here

81 FR 31376  (May 18, 2016; effective July 18, 2016)

This rulemaking was undertaken to implement ACA Section 1557; more here and here.  This section of the ACA is written in very brief and dry legalese and merely refers to nondiscrimination (in the ACA) on the grounds of other laws including the Civil Rights Act of 1964, etc.


In April 2018, HHS announced plans to scale back the impact of this regulation, certainly in the context of transgender persons, based on a prior Court Order specific to this regulation.  In stating so, HHS/DOJ were responding to a court order and a judge in Texas.   The NYT doesn't name the court case but attributes it to "eight states, a network of Roman Catholic hospitals, and the Christian Medical & Dental Association."  The CMDA has 19,000 members.

Somewhat ironically, a separate judicial ruling appears to uphold a Texas state law regarding discrimination as it applies to transgender issues (Wittmer v Phillips).

Note that while the scale-back was announced in response to a judicial order, the Administration would have various options in handling the order - compliance, appeal to a higher court, etc.   Both left and right administrations have the option to rapidly comply with an order they find palatable and fight several years against an order they object to.


In July 2016, CMS proposed standalone hospital rulemaking that combined two topics: (a) discrimination in Medicare, including transgender issues; and separately, (b) hospital antibiotic stewardship programs.

Yes, it's a little confusing, because at about the same time HHS released final regulations on transgender and discrimination under ACA Section 1557 (May 2016), and CMS released somewhat similar proposed regulations specific directly to the Medicare program (July 2016).  This July 2016 proposed CMS regulation hasn't been finalized but CMS has 36 months to do so (July 2016 to July 2019), under SSA 1871.


There is also 2018 policymaking regarding transgender status in prisons.


CMS reversed a decades old ban on transgender surgery Medicare coverage in 2014.

CMS formally described transgender surgery as a condition and therapy for local coverage decisions in 2016.


Separately from the administration and court case on the implementation of ACA 1557 discussed above, a "conscience regulation" at HHS is under comment in early 2018.

Friday, April 20, 2018

1971 Nixon Speech to AMA Annual Convention

In 1971, Nixon gave a long speech to the AMA annual convention in Atlantic City.

The topics would be familiar today - health care costs, new health care plan for cost control, and drug addiction crisis and need for new effective interventions.  The speech runs 5000 words (for me, 9pp single spaced).

Topics include:
  • Previously spoke in 1951 and 1966
  • Only 4 sitting Presidents have spoken to AMA; last Ike 1959
  • Disraeli: Health of the people is the foundation of all happiness
  • History of genius and impact; Mayo, Salk
  • Doctors are geographically unbalanced, with shortage areas
  • We need more emphasis on primary care
  • Commercial health insurance leaves Americans without care or without catastrophic coverage
  • We are in a period of productive discussion
  • Your new president was a "boxing commissioner" - good background for health policy
  • Nationalized compulsory health insurance is being discussed, but is a bad idea
    • I said so in 1951 too.
    • 25% of federal budget would be this giant health plan ($77B)
  • I am recommending we increase federal health costs from $405 per year per family to $466.
  • We don't want Feds to set national health policy, budgets, fee schedules.
  • Free the doctor from bureacracy.
  • What we propose is a National Health Insurance Partnership - not nationalized health insurance.
  • American health system needs reform.
  • We all work toward a system of choice, quality, and reduced costs.
  • Now, drug abuse.
  • Drug abuse is US Enemy #1.
  • It is the greatest threat to our social future, and no longer a ghetto problem or black problem.
  • After my proposals and a year of review, Congress has passed new laws - a national drug war.
  • World, nation, and all segments of society.
  • We will cut off the supply of dangerous narcotics, BUT, we will also double funding for rehabilitation.
  • There will be a new "command post" in the Executive Office of the President (Dr. Jerome Jaffe)
  • Nine federal agencies work on drugs, and compete against each other, we'll fix that.
  • Emphasis on education: Preventive education is better than interdictment of supply or rehab or prison.
  • There is a strong link between inappropriate use of drugs in the medical context, and abuse outside the medical context.
  • Production of tranquilizers has doubles, with billions of doses of tranquilizers, amphetamines, barbituates.  50% are diverted into illegal channels.
  • We could give high doses to every citizen for 11 days.  1/3 of people 18-74 used one of these drugs last year.
  • "We have created a culture of drugs."  "A pill for every problem." Masking not fixing problems.
  • Medical profession realizes that doctors prescribe drugs too fast, too easily.
  • Doctors have a critical role in education of patients on the front lines.
  • Arizona has a great new drug control program for Maricopa County, doctor-based.
  • We think AMA for its "Volunteer Physicians for Vietnam" program.
  • "Project USA" under my administration will marshal energy, leadership, of doctors in an all out battle against drug abuse, especially educating younger people.
  • Doctors should have a role in policy and politics. *
  • Closes with several paragraphs on the importance of doctors, leadership, and the grand vision of America in the world.

* A 1935 book, Frustration of Science, talks about whether scientists should go into politics, concluding no, they would simply become subject to the same forces as politicians.  Most of the book is about the decline of the West in the 1930s such as depression and fascism.

Friday, March 30, 2018

Pushing Around ADLT Prices through Appeals in Year 1

Pricing rules for ADLT allow payment at list price in Year 1 (actually for 3 quarters) and then payment at the average price of Year 1 in Year 2.    CMS gets a recoupment when the CMS list payment in Year 1 has proven to be more than 130% higher than the actual observed commercial median payment in Year 1. 

I've made a model system where an ADLT has 900 sales to Medicare and 900 sales to commercial in Year 1, and 6,000 sales to medicare and 6000 sales to commercial in Year 2. 

List price is $4000.   Actual commercial payments in all years are 1/3 $1000, 1/3 $2000, 1/3 $3000.   

In Year 1, the lab accepts payment for all its $3000 commercial cases, but appeals all the $1000 or $2000 payments into Year 2.   Thus, its commercial median payment in Year 1 is $3000, which sets its Medicare rate for Year 2.

Since $4000 CMS paid list price in Year 1 is 133% of the later observed commercial median of $3000 in Year 1, CMS recoups 3% x (900*$4000) = 3% x ($3.6M) = $118,800 in Year 2.

Total CMS payments in Year 1 are 900*$4000 = $3.6M, 6000*$3000 = $18M in Year 2, and with the small clawback, this is net of $21,481,200 in the two years for 6900 cases, giving an average CMS payment of $3,113.

Had CMS paid all cases at the actual commercial median for both years, which was always about $2000, CMS would have paid the ADLT lab 6900*$2000 or $13.8M instead of $21.4M.   Thus, despite the clawback rule, which applies only to Year 1, it is fairly easy to get net payments over 2 years that are 150% or more of the actual commercial medians. 


click to enlarge

click to enlarge

Spreadsheet in cloud here.

Friday, March 23, 2018

Tuesday, March 13, 2018

Modifier 59 and X Modifiers - Saga to 2018

2014 article on creation of X modifiers

2015 article on X modifiers

2018 Update on X modifiers

Thursday, March 8, 2018

HBR Publishes Case Study, Interview about Adaptive Trials

  • Harvard Business School has published a 26-page case study about Adaptive Trials, download for $9, here.    
  • Read an interview with the author, here.

The interview is from Harvard's business school case study podcast series.   The case is about GBM-AGILE, which starting as an ad hoc working group to make a blueprint for adaptive studies in GBM.   The case study is about converting the blueprint from the drawing board to a real world funded study.

For a different perspective on GBM Agile see these two links:


I recently pulled up a few new review articles on umbrella and basket and adaptive trials.

Open Access, see Savoia 2017, Clin Sci 131:2671 [view is general but focus is cardiology], here:

...Not open access, but sound good:

Renfro 2017, Ann Oncol 28:34, Statistical Controversies... [in such trials],  

Simon 2017, Clin Pharm Ther 102:934, Critical review... [of such trial designs], 


See also Simon 2017 in Ann Intern Med, 165:270, Adaptive oncology trials...

See also Renfro 2017, Cancer Lett, 387:121, Precision oncology: new era of trials...

See also Renfro 2016, Cancer Treat Rev 43:74, Clinical trial designs incorporating predictive biomarkers...

See also Beckman et al. 2016, Clin Pharm Ther 100:617, Adaptive dsign for confirmatory basket trial...