Newsletter Spring 2020


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Note from Kinexum CEO


Thomas Seoh

Thomas Seoh
President and CEO

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Dear Friends of Kinexum,

This Spring 2020 issue of Kinexions features terrific content:

(1) Our Brian Harvey on a pithy yet profound update on development of agents for NASH;

(2) Our Albert Yehaskel’s advice on the Target Product Profile for product and regulatory development;

(3) Our Jennifer Zhao’s summary of our January Wow or Yeow!? webcast, with a link to the full transcript, jam-packed with prognostications on FDA from our all-star panel of David Fox (Hogan Lovells), Frank Sasinowski (Hyman Phelps & McNamara), and Steven Grossman (HPS Group);

(4) Plus this issue’s autobiographical vignette by an individual Kinexer, a teasing reminiscence of decades in public service in Washington, DC, by Steven Grossman...





NASH Update—March 2020


Brian Harvey, MD, PhD

Brian Harvey, MD, PhD
Clinical Development

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As most of you already know, NonAlcoholic Fatty Liver Disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world [1].

The phenotypes of the disease extend from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH), which can progress to liver fibrosis and end-stage cirrhosis [
2]. NASH is also associated with an increased risk of cardiovascular (CV) morbidity and mortality, as well as type 2 diabetes mellitus (T2DM) [3]...





FDA's 2019 Review and 2020 Outlook Webinar Highlights


Jennifer Zhao

Jennifer Zhao
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On January 24, 2020, Kinexum and Hogan Lovells, an international law firm with a prominent food and drug law practice, co-hosted the webinar, “Wow or Yeow!? FDA's 2019 Review and 2020 Outlook.” It was the third edition of an annual roundtable discussing whether the coming year promised exciting (“wow”) or painful (“yeow”) things with respect to medicinal product development regulation at FDA.

The webinar panelists were of distinguished authority...


From Kinexum Founder


Zan Fleming, MD

Zan Fleming, MD
Executive Chairman

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Dear Kinexum friends and family,


The Pandemic is upon us. No more need to be said except: besides being well informed, responsible, and charitable in response to this cataclysm, it is just as important for us to not abandon our posts in the fight against chronic diseases, nor to forsake the day-to-day toil of advancing preventions and treatments. We

should discipline ourselves to “keep calm and carry on” and not be cowered or obsessed by the bombs that are falling around us.

We at Kinexum are honored to be supporting several COVID-19-related projects and to be making the connection between chronic disease prevention and preserving immune function—the subject of Kinexum’s webinar this Friday. But, we are not slacking up on any of the dozens of projects that we lead or support.





The Target Product Profile (TPP)


Albert Yehaskel, MS, MBA

Albert Yehaskel, MS, MBA
Regulatory Affairs & Project Management

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It’s often been said that when one purchases a prescription product, the consumer is not paying for the medication but for the package insert or label attached to the product.

This package insert or leaflet, packed with clinical, nonclinical, and quality information, is the product of years and years of hard work—clinical and nonclinical data generated, discussed, and pored over; several FDA meetings and negotiations; and countless numbers of internal company meetings to arrive at a cogent document.





Potomac Fever and a Life of Stories


Steven Grossman, JD
Regulatory & Government Affairs

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Political legend tells of those who come to DC to serve a President or a member of Congress, expecting to stay a few years before “returning home.” It is said that they catch “Potomac fever” and 30 years later have never left.
I try to be truthful in this regard. I have always wanted be at the seat of government and the source of broad national policy…a place where important things could be accomplished. All of that is to say: I arrived with Potomac fever, and it is no great surprise that I have stayed a long time...




Save the Date: Targeting Metabesity 2020



Targeting Metabesity 2020 is scheduled to take place from 5:00 PM EDT on Monday, October 12, 2020 to 5:00 PM EDT on Wednesday, October 14, 2020 at the Carnegie Institution for Science in Washington, DC.

Amidst uncertainties surrounding the COVID-19 pandemic, the organizers continue to plan and are actively monitoring updates from health organizations responsible for tracking and responding to the virus, including the Centers for Disease Control and Prevention and World Health Organization. 

For more information, please see Given the uncertainty, the conference organizers are not taking commitments and payments yet. More information will follow in due course.




Upcoming Webcasts


The Coronavirus Meets Metabesity Webcast


COVID-19 has been reported to be particularly dangerous to the elderly and to those suffering comorbidities, such as chronic diseases of aging. Early detection, rapid development of vaccines and therapies, and vigilant public health measures are all in the early lines of defense. 
However, for the longer term, we want to reduce health risks—whether from the flu, coronavirus, or other infections—to the elderly and to reduce the incidence of chronic diseases that can render patients more vulnerable to such infections. 
Join this webinar to learn how researchers and clinicians are working to enhance weakened immune function in the elderly and to protect those advancing in biological age from a number of chronic diseases by targeting “metabesity” and other hallmarks of aging.   
Moderated by Adriane Berg (Director of the Metabesity Initiative and Host of Generation Bold Radio), and featuring Joan Mannick, MD (CMO of resTORbio), Nir Barzilai, MD (Albert Einstein College of Medicine), Lawrence Steinman, MD (Stanford University), Cynthia Stuen, PhD (Chair of the NGO Committee on Ageing/NY), and Kathryn Hyer, PhD (President of GSA). 

Click here to RSVP




New Kinexum Team Members



Albert Yehaskel, MS, MBA

Albert Yehaskel, MS, MBA

Regulatory Affairs and
Project Management




Karen McCormack, PhD

Karen McCormack, PhD

Medical Writing




Adriane Berg

Adriane Berg

Director of the Metabesity Initiative




Jonca Bull, MD

Jonca Bull, MD

Clinical Development




Upcoming Conferences

Kinexum executives and leading experts will attend the following conferences. If you are interested in meeting with a Kinexum representative at these conferences, please contact  This email address is being protected from spambots. You need JavaScript enabled to view it. .







DIA 2020




EASD 2020




Targeting Metabesity 2020




GSA 2020 Annual Scientific Meeting




Recent Publications

The Digitisation of Diabetes: Opportunities and Challenges for Industry
Contributions by Alexander Fleming, MD, Athena Philis-Tsimikas, MD, Heidi Soto, and Professor Mike Trenell 
FirstWorld Reports (March 2020)

The Need for Precision Medicine to be Applied to Diabetes
David C. Klonoff, Jose C. Florez, Michael German, and Alexander Fleming
Journal of Diabetes Science and Technology (January 2020)

Diabetes digital app technology: benefits, challenges, and recommendations. A consensus report by the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) diabetes technology working group
G. Alexander Fleming, John R. Petrie, Richard M. Bergenstal, Reinhard W. Holl, Anne L. Peters, and Lutz Heinemann
Diabetologia and Diabetes Care (December 2019)




Next ADA-EASD diabetes technology working group topic announced:
"Automated Insulin Delivery: benefits, challenges, and recommendations"

For current Kinexum resources on automatic insulin delivery, please see previously published Kinexions newsletter articles: 

  1. Artificial Pancreas Device Systems, Part 1: An Evolving Approach and Research Pathway, M. Prasad Palthur, PhD
  2. Part 2: General Product Development and Regulatory Pathways, M. Prasad Palthur, PhD
  3. Part 3: Directions for Future Development, M. Prasad Palthur, PhD




Continuation of Previous Articles


Note from Kinexum CEO (cont.)

But what a new world has emerged in recent weeks! The first case of COVID-19 to present in Northern Italy occurred just about February 20. Here we are now in the US, as if snowed in from a month-long blizzard, hunkered down, with no school, no sporting events, no conferences, concerts, or mass, or all but quite small gatherings in places of work, worship, or alimentation.

Will it be enough, so that we track China, roughly 2 months ahead of us in one possible future of nearly eliminated new coronavirus infections? Or will we more track Italy, with continued scaling of deaths and a national lockdown still in our future? Or even successive waves of lockdowns (cf. the Imperial College London report, “Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand” and a review of the report by the New England Complex Systems Institute)?

Part of the uncertainty is that the pre-symptomatic incubation and infectivity period of SARS-CoV-2 confuses and panics us—daily infection and death numbers are like looking at an astronomical object 10 or 14 light-days away; steps we take now will impact the curve only a week or two later. In the meanwhile, we don’t know how lax fellow residents may be—apparently some groups of college students on spring break continue to party in mass gatherings, while other folks shelter in place.

The laws of viral transmission necessitate that if every individual or family distances themselves from others for a cycle of infection and recovery or death, R-nought and new infections will collapse toward 0. To the extent that folks are more lax about contacts, or re-infections enter from other hot or incubation spots, we risk re-escalation…but as we flatten the curve, we win time for the emergence of repurposed antivirals and support medication, and eventually, vaccines.

But pandemics certainly have the world’s attention now, with the prospect of trillions of dollars in losses. As we rightly focus on state-of-the-art surveillance, quick identification, sequencing, diagnoses, and repurposing of therapies and vaccines, rapid containment policies, proactive logistics, and other steps in our armamentarium, surely “metabesic” approaches to enhance immune response in the elderly and reduce the incidence of comorbidities from chronic diseases have a strategic role in our response to future natural and artificial (e.g., bioterrorist) pandemics.

Indeed, our next Kinexum webcast is precisely on this topic: “The Coronavirus Meets Metabesity: the Nexus between Pandemics and Age-Related Diseases” on Friday, March 27, 2020 at 11 a.m. EDT, features another all-star panel of Nir Barzilai (Albert Einstein), Joan Mannick (resTORbio), and Larry Steinman (Stanford) from Targeting Metabesity 2019, and Cynthia Stuen (NGO Committee on Ageing/NY) and Kathy Hyer (The Gerontological Society of America), moderated by Adriane Berg (the Metabesity Initiative). You can RSVP here.

We also continue to plan under conditions of uncertainty: please reserve your calendar for Targeting Metabesity 2020, scheduled for 5 p.m. EDT Monday, October 12, 2020 to 5 p.m. EDT Wednesday, October 14, 2010, at the repeat venue of the Carnegie Institution for Science in Washington, DC.

Finally, I close on a fun and hopeful note: competitive high school swimmer Norah Kolb, daughter of Kinexer Eric Kolb and Gloria Kolb, CEO of medical device startup Elidah (which is commercializing a women’s urinary incontinence device), is raising funds on a kickstarter campaign for an ergonomic swim kickboard­—really, check out this cool story. We wish Norah success in her drive to train stronger, less injury-prone swimmers, and expect great entrepreneurial things, perhaps in medical products, in her future.



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From Kinexum Founder (cont.)

Understandably, important recent developments in our field have not received the attention that they otherwise would. One example is FDA’s release of its draft guidance, “Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control Guidance for Industry.” The 2020 draft guidance will replace the FDA guidances for industry, “Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” published in December 2008, and “Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention,” published in February 2008.
The new single guidance is said to replace both guidances, but, essentially, it leaves us without a general guidance for diabetes therapies. The new guidance does take away the requirement for cardiovascular outcome trials of new type 2 diabetes (T2D) therapies, but it substitutes some requirements for overall patient exposure and renal impairment studies, which are onerous and will have some negative impact on attracting investment in addressing the unmet needs of people with diabetes. The basis for the requirement to expose 500 subjects with Stage 3/4 renal disease has not been explained, and I don’t believe it can be justified. This exposure requirement is both excessive for approval purposes and inadequate to provide the larger real-world clinical exposure necessary to support a definitive statement of that risk.
The 2008 CV safety guidance was a fit-for-purpose, clear, and executable directive that ultimately not only led to confirmation of safety of virtually all tested products, but also it provided evidence of clear clinical benefits for some of these. The new guidance is very thin and undoubtedly will be supplemented. Importantly, we need guidance for many topics related to both T2D and T1D therapeutic development.
The good news is that FDA has
invited our constructive feedback. It is due by June 6, 2020. In the meantime, so much remains to be said and done in the world of diabetes therapeutic development. I will be back with more proposals and questions.
We begin now. We keep calm and carry on.
To your continued health!



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NASH Update—March 2020 (cont.)

Cirrhosis associated with NASH increases the risk of hepatocellular carcinoma. Despite promising research, liver biopsy is still the only generally acceptable method for the diagnosis of NASH and to accurately assess progression to cirrhosis [4]. However, this clinical trial regulatory endpoint is rarely used in routine clinical practice and can be viewed as a relic of the original NIH-published guidelines [5]. Numerous NASH drug sponsors have used secondary and exploratory endpoints to generate data, which are currently being reviewed by FDA staff, and advance regulatory science to support the use of non-biopsy measures in future FDA approvals of NASH drugs.

The first Agency NASH Advisory Committee Meeting (AdComm) is scheduled for this April 2020. Despite the anticipated product-specific nature of the AdComm agenda, the discussions of the panel experts and statements of FDA staff will be informative for any NASH drug sponsor [
6]. I will be looking for insights into which FDA staff will drive the agenda, including who will sit at the main AdComm table versus the Agency section, and which FDA staff will be in the back of the room.  

The NASH regulatory environment may also be influenced by the addition of a “new” FDA Medical Officer, Dr. Frank Anania, who trained in hepatology at Johns Hopkins University. He left Emory University to join FDA, and after approximately 2 years working as a Medical Reviewer, he is emerging as the Agency’s thought leader regarding NASH [

FDA currently has two draft guidance documents in the NASH therapeutic area on its website: “Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment” (December 2018) [
8] and “Nonalcoholic Steatohepatitis with Compensated Cirrhosis” (June 2019) [9].

Structural transformations at FDA may also impact the practical regulatory climate for the development, review, and approval of NASH drug treatments. The CDER Office of New Drugs (OND) is currently undergoing a reorganization of the review divisions as announced by Director Janet Woodcock [
10], with the goal of increased efficacy and increased focus on functional therapeutic areas, as well as the understanding that some diseases transcend any specific review division and a collaborative Agency approach is needed to speed the clinical trial process and minimize regulatory barriers.

“The new restructuring of OND, approved in September 2019, creates offices that align interrelated disease areas and divisions with clearer and more focused areas of expertise. The changes increase the number of offices that oversee our review divisions from six to eight, and increases the number of clinical divisions from our current 19 divisions to 27 plus six non-clinical review divisions. In addition to enabling greater efficiency, these envisioned changes will help us to better understand the diseases intended to be treated by the drugs we evaluate for approval—another way we aim to enhance our knowledge management and scientific leadership” [

Of special interest to development programs that may involve more than one review division, such as NASH, T2DM, and hyperlipidemia, are proposed changes to IND review management. FDA stated that it will be “implementing initiatives to streamline our scientific review and processes for INDs throughout their life cycle, while maintaining our high standards. The first initiatives focus on the 30-day review of the initial IND application and on review of select clinical protocols with new processes and issue-based templates. The new processes and templates include enhancements to:

  • Promote consistency across divisions and increase effectiveness of documentation practices
  • Foster collaboration and enable better knowledge management
  • Establish procedures that standardize the review process, clearly define roles and responsibilities, and improve our ability to provide high-quality feedback to sponsors in a timely manner
  • Develop a risk-based approach to categorize incoming information from sponsors and identify protocols that should follow a more expeditious review process” [12].

Below are schematics of the overall OND structure and division review reorganization.

Overall OND Structure

Overall OND Structure (

Clinical and Pharm/Tox Structure
Clinical and Pharm/Tox Structure (

Written by Brian Harvey, MD, PhD, Kinexum Clinical Development


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The Target Product Profile (TPP) (cont.)

The genesis of the package insert (or labeling) is the Target Product Profile (TPP). It begins early in the drug development process and delineates the aspirations of the profile the company would like to see of its drug and target for a specific disease. It embodies the concept of “beginning with the end in mind and working backwards to identify the requirements and needs within the company’s drug development program to accomplish its goals.
Function of a Target Product Profile (TPP)
The TPP facilitates the drug development program by initially identifying a “wish list” of what the ultimate and ideal labeling would look like. For example, consideration may be given to the safety profile, absence of drug-drug interactions, the type of dosage form (such as tablet versus capsule), and even the color of the dosage form. Examples of questions a Sponsor may ask include: Are the dyes compendial or not? Can they be used in the US and Europe, or will the Sponsor encounter challenges? Are the primary and secondary (and exploratory) endpoints accurate and compatible for a US and/or European submission? What will the safety database look like, and will it be acceptable? Beginning with the end in mind, the Sponsor works backwards to identify what needs to be done in order to achieve the ideal labeling.
A TPP is a planning tool for an emerging drug candidate, and serious consideration should be given to using it throughout the drug development process for INDs, meetings with FDA, and post-marketing programs to pursue new indications or other substantial changes in labeling. The information contained in a TPP captures the data that have been generated, current plans, and future studies for consideration that will achieve the endgame.
Pursuant to FDA’s guidance document on the TPP,
Guidance for Industry and Review Staff: Target Product Profile—A Strategic Development Process Tool, a TPP is a format for a summary of a drug development program described in terms of labeling concepts. A TPP can be prepared by a Sponsor and then shared with the appropriate FDA review staff to facilitate communication regarding a particular drug development program.
Although there is no obligation or mandate to submit a TPP to FDA, providing a TPP in a Sponsor’s briefing package can oftentimes facilitate Agency interactions, engage FDA in constructive dialogue, streamline receipt of practical and useful advice from FDA by presentation of all the relevant medical and scientific information for the Sponsor’s drug development program, and maximize the efficiency of the development program.
The TPP is a “living document”; it is dynamic and subject to change as new data and information present itself. Because the TPP is subject to change as the company’s development program evolves and matures, it is prudent to label the document with a version number and date (pursuant to the company’s SOP). A library of TPPs should be established for each new project and versions adequately maintained in the company’s regulatory files.
Both FDA and Sponsors have seen the advantages of using a TPP at meetings early in the drug development process. Use of a TPP can facilitate the efficiency of Sponsor-FDA interactions and communications. A Sponsor may find it valuable to develop a practice of asking to discuss the TPP with FDA as early as possible (e.g., at a pre-pre-IND meeting/interaction to discuss IND-enabling studies or design of a Phase 1 clinical trial) and as often as possible to accelerate Agency guidance on later-stage clinical development. The TPP is a valuable means of communicating internally (e.g., project meetings), as well as in Agency interactions.
As the development program of a new drug nears the end and the NDA/BLA is being prepared, the TPP will serve as the basis for producing the annotated package insert that will be submitted with the application and negotiated with FDA after review of the NDA/BLA. The production of the annotated package insert will be considerably facilitated with an updated and robust TPP.
Structure of a TPP
The TPP briefly summarizes the specific studies (both planned and completed) that will provide evidence for each conclusion that is a labeling concept. The TPP should be organized according to key sections in the drug’s labeling. A Sponsor should endeavor to populate all the items below, though it may also depend on the nature of the meeting. Typical key sections from which a Sponsor can choose comprise the following:

  • Indications and Usage
  • Dosage and Administration
  • Dosage Forms and Strengths
  • Contraindications
  • Warnings and Precautions
  • Adverse Reactions
  • Drug Interactions
  • Use in Specific Populations
  • Drug Abuse and Dependence
  • Overdosage
  • Description
  • Clinical Pharmacology
  • Nonclinical Toxicology
  • Clinical Studies
  • References
  • How Supplied/Storage and Handling
  • Patient Counseling Information

A copy of FDA’s proposed template can be found at the following link:
The TPP is used to clarify data that support a given indication and facilitate FDA-Sponsor discussions for a drug (or biologic) development program. It is also a valuable tool for preparing the final draft label that will be submitted in an NDA or BLA at the very end of the drug development process. Whether your company is looking for regulatory, clinical, nonclinical, or other guidance on the TPP process, Kinexum’s subject matter experts are here to help.

Written by Albert Yehaskel, MS, MBA, Kinexum Regulatory Affairs & Project Management

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FDA's 2019 Review and 2020 Outlook Webinar Highlights (cont.)


...David Fox (Partner, Hogan Lovells) is a former FDA senior lawyer and leader on the regulation of prescription and over-the-counter drugs, biological products, combination products, and controlled substances. Frank Sasinowski (Director, Hyman, Phelps & McNamara) is former Deputy Director of health policy staff in the FDA Commissioner’s office and a specialist in product development and authorization of new drugs for sponsors and patient organizations. Steven Grossman (President, HPS Group) is former Health Staff Director of what is now the Senate HELP (Health, Education, Labor, and Pensions) Committee and an expert on health policy, orphan applications, and pediatric vouchers. The webinar was co-moderated by Zan Fleming (Founder and Executive Chairman, Kinexum), endocrinologist and former senior FDA reviewer, and Thomas Seoh (President and CEO, Kinexum), former senior executive in private and public emerging biotechnology and medical device companies.
This article outlines topics discussed and key highlights made by the panelists.
Has FDA been approving more drugs with less data?
Fleming presented the JAMA article, “
FDA Approval and Regulation of Pharmaceuticals, 1983-2018,” which highlights the difficulties for FDA to help the public understand its mission and its challenges. The article describes legislation and processes at FDA over the past several decades aimed at speeding the review of therapeutic products. However, as Fleming described, it inaccurately concludes that FDA has done more with less data.
In response to headlines about FDA approving drugs faster with weaker evidence, Sasinowski commented that these approvals need to be viewed in light of other factors. For example, statistics on expedited approval programs, such as RMAT (Regenerative Medicine Advanced Therapy) Designation, can be misleading because some of these programs did not exist for the same portion of the period of analysis (for instance, RMAT was born when the 21st Century Cures Act became law in December 2016). Additionally, advances in science have led to more targeted therapies for diseases, such as type 1 spinal muscular atrophy, and, therefore, the quantum of evidence needed to prove substantial efficacy may have lessened over time.
Fox remarked that these approvals depend on signal from the data and context in which products are being developed. Although more drugs are seemingly being approved based on a single pivotal study, a closer analysis shows that the total number of patients being studied—apart from the extremes of ultra-orphan cases—has increased. Meanwhile, development times of 8 years have remained the same. Fox also commented that approvals depend on the ability of FDA reviewers to pick up these data signals.
Grossman opined that 1980s approvals cannot be compared to 2010 approvals because regulators’ understanding of science has evolved over time. Deeper analysis of the 8-year periods to approval is needed. For example, could different classes of drugs have been approved at different speeds due to differing quality of scientific analysis?
Review of FDA approvals in 2019
Fox summarized that 2019 saw 48 NME (new molecular entity) approvals. Compared to the historical average of less than 30 approvals a year, the past decade has seen an average of about 40 approvals a year due to faster approval times by expedited programs. Whereas approvals now take about 10-10.6 months, the average NDA review time before enactment of the PDUFA (Prescription Drug User Fee Act) in 1992 was about 2.5 years.
Among the 48 approvals, 16 were from single-product companies, 5 from Novartis, and 8 for monoclonal antibody products. There was a diversity of clinical datasets accepted and clinical indications. Noteworthy approvals included treatment for lupus, post-partum depression, sickle cell anemia, and bladder cancer.
For infectious diseases, Fox noted 2 new Gram-negative approvals. However, with the bankruptcies of Achaogen in April 2019 and Melinta Therapeutics in January 2020, Fox stressed that incentives for developing antibiotics, including more exclusivity under the GAIN (Generating Antibiotic Incentives Now) Act, are not working. Fox believed there should be some form of transferrable exclusivity, in which exclusivity is transferred from drugs that should be used sparingly to drugs more frequently used.
In other disease areas, Fox commented that 2019 was another strong year for oncologic approvals. FDA reviewers have become comfortable with the concept of tissue-agnostic therapies that treat tumors with certain genetic biomarkers. There has also been a rise in neurology and psychiatry approvals, including the approval of CAPLYTA® (lumateperone) for schizophrenia.
Of note, FDA approved air (air polymer-type A) as an NME. Fox raised the question of how much longer FDA will regulate products that have neither a true chemical action nor metabolic activity in the body as drugs—as opposed to an adjunct to imaging equipment as a medical device.
Can FDA maintain approval parity?
Fox asked whether FDA can maintain an “approval parity,” defined as parity in the application of the basic approval standards across all the applications that FDA sees. As an example, Fox mentioned Vyondys 53 (golodirsen, Sarepta Therapeutics). Vyondys 53 was approved for treatment of Duchenne muscular dystrophy after receiving a complete response letter and going through a brief appeal process. Understanding that some cases are extreme and have unmet medical need, Fox wondered how much longer FDA can continue such a practice.
Sasinowski pointed out that not all cases can be looked at in the same way when considering whether FDA is maintaining approval parity. In his analyses of orphan drug approvals from 1983–2010, Sasinowski found that two-thirds of approvals demonstrated FDA's flexibility. However, he noted that orphan drugs that were rejected and not approved are missing from every analysis. Some of these rejections may have been based on narrow interpretations of regulatory statutes and requirements, but they are not capable of being considered in these analyses.
Another question Fox raised was whether approvals are subjective to FDA reviewers. FDA builds up a body of precedent with approvals every year and needs to be able to reasonably align them. Sasinowski believed that FDA has the ability to distinguish each precedent in its judgement.
As for whether exercise of judgement varies from FDA review divisions to division, Sasinowski answered that it may be more granular—that it varies from individual reviewer to reviewer. Fox believed FDA should conform to clarity in expectations and reasonable consistency in the application of a universal approval standard, though flexibility in certain cases is important.
Outlook to 2020: Dr. Stephen Hahn as FDA Commissioner
Although Dr. Hahn has not yet articulated priorities that will shape his legacy, Grossman said that Dr. Hahn is interested in the use of data collection in FDA decision making and workplace development issues. These two issues are important and need to be addressed at FDA. For example, CBER is currently managing 900 INDs in gene therapy, 243 of which were received last year. Additionally, FDA has about 30 data systems, most of which are siloed. Integration of information, not to mention digital health, adverse event information, and real-word evidence, commented Grossman, would be useful.
FDA’s role in presidential year dynamics
Grossman discussed how little political interference FDA runs in any given year. Even though former FDA commissioners have implied otherwise, Grossman clarified that the same examples are used year after year. Apart from tobacco, opioids, CBD, and vaping, there is not much else FDA can do in the political environment, apart from drug prices.
Sasinowski agreed; in contrast to popular opinion, FDA is insulated from influence of the White House. This allows FDA to truly achieve its mission to protect and advance the public health. Fox also agreed, adding that Janet Woodcock and Peter Marks remain the most important people in driving policy and decision in drug and biologicals approvals.
However, Fox commented there are at least three areas in which FDA intersects with the political environment: 1) drug importation, 2) drug compounding, and 3) supply chain. There has been more push by political means for FDA to loosen its hold on the drug approval environment. A large percentage of the US’s API (active pharmaceutical ingredient)—especially for generic drugs—comes from China. Given the fact that the US has no meaningful contract manufacturing capability for sterile injectable drugs, as well as the ever-looming possibility for shortages of key drugs, there is potential for politics to interfere.
Is drug pricing at the heart of these issues?
Grossman answered yes. Grossman clarified, however, that the issue of FDA getting involved in drug pricing politics is overblown. There is a lack of general understanding of the boundaries of FDA’s responsibilities. Grossman explained that FDA can prioritize review of products that make the market more competitive, such as generics and biosimilars. Although this can affect drug pricing, FDA is not the lead agency on drug pricing. Grossman stated, “The reality is that the Agency has no expertise on drug pricing.” Although the FDA could hire people to work on that, that is not FDA’s main role.
The reason why people are confused whether FDA plays a role in drug pricing is due to former FDA Commissioner Dr. Scott Gottlieb. Dr. Gottlieb was uniquely the administration spokesperson on drug pricing, since he was at both CMS and FDA. In contrast, other FDA commissioners, such as Dr. Robert Califf and Dr. Margaret Hamburg—and now Dr. Hahn—do not have such credentials to talk about the marketplace for drugs once approved.
Effect of the opioid crisis at FDA
Seoh asked whether the opioid crisis had any effect at FDA. For example, does it raise awareness or affect FDA’s standards or urgency in looking at applications for non-opioid drug/pain relief?
Sasinowski did not see a way for FDA to exert any influence on addressing the opioid crisis. Abuse-deterrent formulations have been largely ineffective and do not sell because generic opioids are cheap. The opioid crisis seems to be an issue largely outside FDA’s area. Grossman agreed, adding that although FDA has some responsibility to address opioids as part of its public health mission, it is not the lead agency on the problem.
Fox agreed and made the interesting point that FDA’s regulation of opioids has been for on-label use, but there is no label on how to stop taking the product, which he calls “an enormous blind spot.” Sasinowski agreed that clear label instructions on how to withdraw from opioids would be an advancement.
Orphan Drug Act: “Wow” or “yeow”?
The Orphan Drug Act has been successful in increasing the number of drugs that have addressed rare diseases, but Seoh asked the panel whether the effect is helping the maximum number of people or only small populations.
Sasinowski viewed the Orphan Drug Act as a “wow.” As part of his
2012 paper on orphan drugs, one-third of orphan drug approvals were based on two adequate and well-controlled studies; one-third were approved based on other guidances, such as Accelerated Approval in the May 1998 guidance; and one-third were approved on a case-by-case basis. In short, two-thirds of orphan drug approvals were not required to provide the conventional level of proof of effectiveness. This highlights FDA’s flexibility in its review of certain applications of orphan drugs.
Fleming asked whether public policy will infringe on the approval and availability of orphan drugs. Grossman answered that the heart of the issue depends on drug pricing concerns. More effective policies that address pricing issues would ease pressure on orphan drug development and approval. Nonetheless, he remarked, threats to the Orphan Drug Act are not new.
FDA guidance on demonstrating substantial evidence of effectiveness for human drug and biological products
Sasinowski lauded FDA’s “
Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products” guidance issued in December 2019, an update to the original issued in May 1998. The December 2019 guidance embraces FDAMA 115, a law passed in 1997 that allowed a single, adequate, well-controlled study with confirmatory evidence to meet the statutory standard for proving benefit to patients. The guidance also explains how FDA will allow additional flexibility for cases beyond FDAMA 115, such as where there is unmet medical need for a rare condition. Sasinowski was excited for the implications in demonstrating patient benefit, but he said there is more to be articulated. For example, he asked whether FDA will accept an aggregate of confirmatory evidence from different types of confirmatory evidence to supply the amount of certainty equivalent to substituting for the second positive adequate and well-controlled study.
In contrast to Sasinowski, Fox believed the new December 2019 guidance to be a “yeow.” Although the guidance was elegantly drafted, Fox found it too broad to be of great use. Given the body of precedent developed since the enactment of FDAMA in 1997, he believed FDA would have several factors prioritized by now, but that prioritization is not clearly understood in the guidance. To Fox’s point, Sasinowski agreed. FDA has struggled to be able to come up with an effective policy statement or a catalog that describes all the precedents.
Orphan exclusivity to cellular therapies and gene therapy products
Looking ahead, Fox believed the orphan drug field will be chaotic when the time comes to apply orphan exclusivity to cellular therapies and gene therapy products indicated for the same orphan use. Comparing products based on viral vectors, delivery modes, cellular composition, or bacteria clusters could be a gray area. How would FDA fix that?
Even though there is a 12-year exclusivity period for biologics, Fox believed that today’s biosimilars are of mature therapeutic proteins with little-to-no residual 12-year exclusivity. If a new, commercially attractive biological product that will have a full 12 years of exclusivity were developed, Fox believed that biosimilars companies may opt not to wait 12 years but instead file a full application to be on the market in 8 years.
Implications of the “Deemed to be a License” Provision of the BPCI (Biologics Price Competition and Innovation) Act
Fox explained that March 23, 2020 will be the 10-year anniversary of the enactment of the ACA (Affordable Care Act) that included the biosimilar statute. As part of the enactment, “legacy proteins,” which are protein products that have been historically regulated as drugs, will be regulated as biologics. Over 20 categories of drugs, including insulin, will be licensed as biologics. By regulating these protein products as biologics, they will become more available for competition under the biosimilar statute.
Fox noted that Congress amended the definition of a biological product at the end of 2019. Although the 2010 bill stated that all proteins except those made by chemical synthesis will be biologics, the 2019 bill struck that exclusion. Chemically synthesized polypeptides will be treated as biologics as well. This change will impact what products will qualify as both legacy products and biologics and will impact interchangeability. Fox stated, “When you regulate as a drug and you're approved as a generic, you're automatically therapeutically equivalent and interchangeable—not so for biologics.”
For sponsors who want to develop a bio-better but do not have existing data to rely on, Fox called the situation “an example of the cognitive dissidence in the biologics field.” The biosimilars law was intended to promote competition, but it does so only for matching biosimilars (i.e., same dosage forums, strains, and route of administration). Developers of bio-betters have “no choice but to go back to square one,” meaning filing a full application and deriving the safety and efficacy data independently and originally. Antibody drug conjugates and new combinations involving biologics also have to be filed anew. Fox suspected that at the time of the next PDUFA reauthorization, which will be after 2022, some attention may be paid to plugging that gap, along with perhaps generic drug reform.
Grossman commented that it is no surprise there are policies and rules missing or wrong with the biosimilars law. He said the law was “put together politically, not rationally” and got tied up with the Obamacare legislation. However, Grossman commented that FDA has done “an excellent job implementing a far-from-perfect law.”
Reorganization of FDA

Reorganization of FDA’s Office of New Drugs
will create a flattened structure, as well as divided divisions. For example, the Division of Metabolism and Endocrinology Products (DMEP) will divide into the Division of Diabetes, Lipid Disorders, and Obesity (DDLO) and the Division of General Endocrinology.
Sasinowski believed that the reorganization will bring benefits. FDA reviewers will be able to exercise their expertise in each discipline, focus on document substance, and hopefully be able to complete more reviews.
Sasinowski noted some lesser-known changes with the reorganization. The Office of New Drug Policy (ONDP) will be established and headed by Keith Flanagan, previously from the Office of Generic Drugs (OGD), and deputy Jim Smith, previously from DMEP. The ONDP demonstrates strong integration of both a clinical policy staff and a regulatory policy staff. Another change is creation of a “virtual Rare Disease Center of Excellence” within the Center for Drugs, which Janet Woodcock announced at the NORD (National Organization for Rare Diseases) Summit in October 2019.
Fleming noted a few things missing in the OND reorganization, such as a division or center that would focus on metabesity, the chronic diseases blanketed by common metabolic roots. Issues related to metabesity, including sarcopenia and frailty, are being addressed by different parts of Center for Drug Evaluation and Research (CDER), but Fleming believed that is “a crying need not in the current reorganization plan.”
Fox offered an interesting observation he found in the trade press, which stated that FDA had completed a contract with outside vendor Booz Allen to place 150 million FDA documents into an AI-like database, with an interface available to all FDA reviewers. The database is alleged to include submission documents. Fox commented that if FDA reviewers were to be able to instantly search across not only their own review documents, but submissions by other Sponsors, that would be an enormously powerful tool.
FDA Personnel Changes
Sasinowski lamented over the retirement of Sharon Hertz, Director of the Division of Anesthesiology, Addiction Medicine, and Pain Medicine (DAAP), and Dragos Roman, Acting Director of the Division of Gastroenterology and Inborn Errors Products (DGIEP). Although Sasinowski believed that their respective successors will be great, he noted that the loss of institutional memory is still a consequence.
Grossman provided an alternative angle. Although FDA suffers losses when people leave, there is a bench of people who have been training to take their place. Furthermore, there is always the opportunity for successors to contact their predecessors. Overall, FDA remains strong on its institutional aspects.
Even so, Sasinowski pointed out that with the flattening of FDA’s structure, there will be a need to bring in more people to staff the newly reorganized divisions. For example, DMEP saw the loss of Director Jean-Marc Guettier and Deputy Director Jim Smith, who will become Deputy Director of ONDP. With the splitting of DMEP, two sets of division directors and deputy directors will be needed.
Questions & Answers
Q: How does the Sarepta example align with the value-based medicine initiative that FDA is supposedly supporting?
David Fox: With the Vyondys decision, FDA probably rightly shielded itself from thinking about drug price and tried to do its best on the science… In the end, FDA culture is, “it's hard enough to figure out if these drugs work. Whether they're actually cost-effective would be way too difficult.”
Steven Grossman: Similar to what I said with regard to drug pricing, there is no expertise at FDA on cost effectiveness… We all have an institutional interest in continuing to say that FDA has a specific role, which they work hard at. In the end, their job is to approve or disapprove medical products, not practice medicine, create formularies, or make broad societal judgments about which safe and effective drugs and devices should be favored.
Q: FDA only needs one drug crisis—for example, the COX-2s—to be in crisis mode. Where do you see some risks?
David Fox: One of the legacies of the COX-2 and the Vioxx issue was that Congress put into the Food, Drug, and Cosmetic (FD&C) Act that all new molecular entities (NMEs) shall go to an advisory committee unless FDA can justify why not. The purpose of that was to make sure there was an additional check on safety.
Now, one of the observations was the decline in advisory committees for NMEs, and FDA is actually excusing NMEs from advisory committees more often. It makes you wonder if at some point that is going to catch up to FDA.
Frank Sasinowski: I agree. Another point is that was not only for Vioxx after COX-2, which was in September 2008, but also Avandia for diabetes. FDA came out with the December 2008 guidance that says every type 2 diabetes drug would have to prove that it won’t increase the rate of MACE or cardiovascular risk by more than 80%.
Looking at it in hindsight, what we've done is that we drove down a lot of interest in developing new drugs for diabetes. And for these crises that get responded to, it’s very difficult to retract them.
Q: How might FDA value companies differently that are developing orphan drugs but are not necessarily looking for “windfall” prices, like value-based and accessibility pricing? Should FDA be motivated by that kind of distinction?
Steven Grossman: If you're going to argue—as I have—that FDA doesn’t have the expertise nor the mission to be concerned about high prices after approval, it stands to reason that you can't make the argument in reverse. In fact, FDA almost always makes decisions without knowing what the pricing decision will be.
That said, do I think that FDA might give a little more attention to somebody who whispered, "We're going to price this differently"? Maybe, but the reality is that no such commitment is binding to the company.
Q: How have patients impacted the therapeutic development process?
Frank Sasinowski: I've been a patient advocate for a long time and have seen FDA paying attention to the rising voice of patients. It has been slowly evolving since the mid-1990s. FDA has held about 30 patient-led, patient-focused drug development meetings since.
Q: What about patient-reported endpoints?
Frank Sasinowski: There's a problem when people talk about PROs (patient-reported outcomes). To develop a brand-new PRO and validate it take years and millions of dollars. It's a terrible idea. There are other ways to get the patient's voice into the drug development paradigm. What you can have is a patient or caregiver global impression. It has face validity.
Steven Grossman: From my perspective, FDA has been incredibly receptive to patients. I think the issue of PROs and face validity goes back to something that FDA needs to do more of—and that we need to support FDA, institutions, and companies to do more of—is regulatory science. When you start getting into the issue of, for example, what patients want and what really reflects improvements on their disease, and you see the number of diseases for whom the marker is the six-minute walk, is it all that accurate or appropriate? We need other measures. Somebody's going to have to invest in that.
Frank Sasinowski: One thing FDA's been good at—at least in the rare disease field—is to modify already-validated instruments for a particular disease. If you have a very rare disease and don't have enough of the population to be able to validate it de novo, FDA will allow a validated instrument to be applied to other situations.
David Fox: A quick plug: a Sanofi researcher published an
article earlier in 2019 surveying FDA approvals and how many approvals take patient input into account. That’s now part of the review checklist.
Additional Resources
Click to view a full recording of the webinar, slides, and a full transcript. For any further questions on this webinar or to the panelists, please email
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Written by Jennifer Zhao, Kinexum Associate

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Potomac Fever and a Life of Stories (cont.)

...Not counting “actings,” I am on my 13th FDA Commissioner.
To me, it has been a life of stories. For example, Dr. Koop was a controversial nominee to be Surgeon General in 1981. In the confirmation hearing, Senator Ted Kennedy tried to show that Koop was far out of the mainstream by reading an excerpt from a speech in which Koop said, more or less, that it wasn’t the worst thing to grow up poor.
Leaving aside that Kennedy had no personal experience of such matters(!), he read Koop the excerpt, and Koop explained what he meant and the context in which his thoughts had been expressed. Unsatisfied with the answer, Kennedy angrily read the excerpt again. Koop, ever patient, responded, “Senator, I think the audience understood what I meant, but sitting here listening to you read those paragraphs, I would have certainly expressed myself differently.”
I have retold this story more often lately…undoubtedly because admitting one’s failings (even minor slips) seems to have gone out of fashion in DC.
Another story took place a few years later, while I still worked in the Senate. It appears elsewhere as “
FDA, Me and Maybe the Mafia.” It is a true story and made me a life-long supporter of FDA inspectors and others who routinely put themselves in harm’s way to protect the American people. It is more apt nowadays because of FDA’s increasingly global responsibilities and society’s greater acceptance of road rage-type behavior that makes every day perilous for government inspectors.
A few years after that, I had moved to HHS to be a Deputy Assistant Secretary for Health. A notorious political figure, Roy Cohen, was secretly admitted to the NIH Clinical Center for treatment. Scores going back more than 30 years, to the 1950s and the Army-McCarthy hearings, were settled when columnist Jack Anderson revealed, via his Washington Merry-Go-Round column, confidential information about Cohn’s diagnosis, experimental treatment, and lifestyle (none of which would be controversial today, although Cohn would still be).
Dr. James Wyngaarden, then Director of NIH, was tasked with identifying who had access to the information and then “plugging the leak.” He tried hard but eventually gave up. He explained at a senior staff meeting that he stopped looking when he had identified more than 1200 people who could have retrieved the information and been the source of the leak!
This is a reminder that computers didn’t invent patient confidentiality problems; they merely magnify them. The story also illustrates that there is no statute of limitation on revenge in politics.    
Some years later, after I left government, I remember taking a call at my office. The woman on the line said, “Please hold for Congressman xxx.” Totally uncertain why I was being called, I waited about 30 seconds. The Congressman came on the line, screaming at me with some profane words thrown in. He finally drew breath (it seemed like an eternity), and I asked if he really meant me. He had wanted Steven Grossman, but the one who had run AIPAC and been a chairman of the DNC. I guess I took one for Team Grossman that day, although I have never met the other Steven.
More recently, my second wife, Barbara, tells the story of how I cost her a job more than 20 years before we met! In the early 1980s, I was the lead Senate staffer in ending a decade-old program that mandated and funded local health planning. At the time, Barbara worked for the health planning agency in Southern Maryland. Not long after the law was repealed, she lost her job.
Although I don’t see how I could be culpable, she holds me personally responsible for her being fired and will grant me no forgiveness. And we joke about it—because she is a good sport, but also because I sort of see her point.
I often get asked: how did you become a subject matter expert on FDA? In Washington parlance—which means abbreviate everything—that makes me a SME. I didn’t necessarily choose FDA so much as my clients decided—by only hiring me for FDA projects. Most people don’t know I can do anything else (hint: I can).
One of my proudest accomplishments is the 2006 co-founding of what is now the
Alliance for a Stronger FDA. The Agency was in a terrible state—multiple recalls, incredibly slow processes, and a funding level that was at least a decade behind its responsibilities. I was approached by patient groups and research advocates—who saw clearly that public, corporate, and foundation funding of biomedical research might fail for lack of FDA resources. They understood that for an underfunded Agency, “no” takes far fewer resources than a well-reasoned and researched “yes.”
Diane Dorman (then of NORD), Nancy Myers (of Catalyst Healthcare), and Wayne Pines (of APCO) demonstrated courage to sign the Alliance’s incorporation papers, which tied them to a highly visible project with a low probability of success. It doesn’t look that way today, but I assure you it was a very brave thing for them to sign. Together with Ladd Wiley and former HHS Secretary Tommy Thompson, both then at Akin Gump, we built a united all-stakeholder alliance that has contributed to a doubling of the FDA’s budget authority (taxpayer paid) appropriations over the last 13 years.
My current favorite books are murder mysteries that fall under the rubric of “Nordic Noir.” These are dark stories that explore the underbelly of life in seemingly well-functioning Scandinavian societies. One of the common themes is that the (mis)deeds of the past live on, never losing their ability to affect current events. This strikes me as very DC. 
Yet, “the past is always prologue” seems less compelling in 2020 with a President with little regard for precedent. Even so, the past keeps poking through. The story I told earlier about Roy Cohn is one I have told for years—because it is about the settling of scores and has a great punchline. The hero of the story—in my view—is Jack Anderson, and it is a revelation that even investigative journalists can thirst for payback.
Yet there is contemporary relevance. Roy Cohn mentored Roger Stone, teaching him all about political dirty tricks. Also, Cohn was Donald Trump’s lawyer for a dozen years and taught him the art of winning by never backing down. A recent
documentary quotes Trump as having asked, “Where is my Roy Cohn?”
Did I mention that I love DC? For those who enjoy these types of local stories, I highly recommend former Washington Post publisher
Katherine Graham’s Pulitzer Prize-winning autobiography, Personal History. To whet your appetite, go see Meryl Streep’s magnificent portrayal of Kay Graham in the 2017 movie The Post. And while I am an émigré to DC, I am very proud to have raised two native Washingtonians: my son, David, and my daughter, Emily.
Want to swap DC stories? Lunch is always a great time to do so. Be sure to ask about my meeting with Armand Hammer (as a result of which there are only two degrees of separation between me and Lenin!) and my memories of negotiations on the Orphan Drug Act. Those (and others) are stories to be told another day.

Written by Steven Grossman, JD, Kinexum Regulatory & Government Affairs

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