SiDx Appoints Dr. Caroline Popper to Board of Directors

Heritage Partners is honored to have played a role as the consultants to SiDx in the recruiting of Caroline Popper as a Board Member. SiDx is a Seattle based diagnostics firm pioneering a new rapid diagnostic platform based on silicon photonics.

Dr. Popper is President of Popper and Company, a consultancy she co-founded in 2003 offering strategy and transaction advisory services to healthcare and life science companies. She was a founder of Diversigen, a science-driven microbiome analysis company recently acquired by OraSure Technologies.  She is currently an Advisory Board member to the Johns Hopkins Bloomberg School of Public Health and to Riverside Partners, a private equity firm for healthcare and technology companies.  In addition to SiDx, Dr. Popper also serves as a Board Member to Avance Clinical, Agilex BioLabs, and LBT Innovations.

Dr. Popper’s early career included leadership roles with MDS Proteomics and BDGene, the molecular diagnostics division of Becton Dickinson. She earned a medical degree from University of Witwatersrand and a MPH from The Johns Hopkins University.

The recruiting effort was led by Alan Thomas, Partner with Heritage Partners.

Heritage Partners is a senior level retained executive search firm working in the life sciences and digital healthcare vertical. The firm’s strength is in providing executive leadership to emerging clients at the interface of science and business.

A Bottleneck for COVID-19 Vaccines: Manufacturing and Distribution

 

The Problem

Think about being in your kitchen to make Eggs Benedict for Sunday brunch. It is an unforgiving ballet bringing the poached eggs, bacon, toasted muffin, and notoriously fickle hollandaise sauce to culinary perfection at exactly the critical final moment….exceptionally good when it works, but an ugly mess if it does not.

Now consider pulling off the same magic from the same kitchen with the same lone carton of eggs when 50 hungry neighbors drop in unexpectedly.  How about 7 billion hungry neighbors?  Even using paper plates and plastic forks, you have a problem with scale-up.

What is a Biological?

In the world of medicines, a Biological is a vaccine or therapeutic product whose key ingredients are produced in living organisms.  Biologicals contrast with Synthetic Drugs (typically “pills”) which are manmade (synthesized) from elemental chemical ingredients using the techniques of manufacturing chemistry.  Synthetic drugs are defined by composition of matter, whereas biologicals are uniquely defined by the manufacturing process.  Effectively, for biologicals the process is the product, and each batch must follow the complicated recipe perfectly.

Why are Vaccines biologicals?

Vaccines work by training an immune system to recognize and attack a target pathogen, e.g., virus or bacterium, and thereby prevent infection.  The immune system’s clue for recognition of the pathogen is called an “antigen” – a biochemical fragment uniquely associated with the pathogen.  Years of applied research going back to Louis Pasteur’s cow pox have pointed the way to the use of biological manufacturing processes to produce these antigens…use a thief to catch a thief.

Processes

The U.S. Food and Drug Administration (FDA) publishes manufacturing regulations for drugs and biologicals. Called “Current Good Manufacturing Practices” (cGMPs), they comprise standards for things like materials, cleanliness, security, record keeping, environmental controls, activity logging and quality events. FDA cGMPs also set standards for staff qualifications, training, leadership, and management accountability.  Satisfying cGMP mandates is a legal requirement for the makers of vaccines and ensures that the resulting products are as intended.

Biologicals manufacturing is almost always a batch process. Pilot manufacturing in small batches is conducted to identify the choice of materials inputs, cell lines, oxygenation levels, temperature controls, etc., necessary for making bulk vaccine substances. Pilot production is scaled-up up to larger batches for production volumes.  As with the Eggs Benedict example, production level scale-up encounters practical physical constraints that limit batch size and process methods.

Because a virus is a parasite inhabiting individual cells, “cell culture” in mammalian or other animal host cells is a common method for making human vaccines.  The choice of the appropriate cell “vector” for antigen production depends on genetic similarities to the human cells the virus parasite inhabits, and on the ability to manipulate cellular control processes to obtain satisfactory yields of antigen.

Very promising new vaccine technologies including so called conjugate vaccines and emerging DNA and RNA constructs are in development.  These approaches all incorporate a degree of complexity in manufacture that make production scale-up easier, but still a daunting challenge.

The take-away is that vaccine product safety, efficacy and patient outcomes are directly related, and the common link is the exacting and fragile biologics manufacturing process.

Materials

To enable biological bulk antigen production, many gallons of highly specialized cell culture growth media may be required.  These media are typically biological fluids or synthetic analogs. Growth media availability at scale is one of several potential supply chain choke points.  Next, the cell lines engineered for antigen production need to be curated.  Targeted antigens are separated out from the production broth (or “supernatant”) using specialty materials ranging from filters to highly specialized high purity “affinity” compounds.

So called formulations, fill and finish steps will all come to bear. Necessary specialized materials include stabilization and preservation additives to retard the natural decay of biomolecules; adjuvants – substances that upregulate overall immune system receptivity to vaccination; and medical grade glass vials and stoppers….more potential choke points.

Facilities

Vaccine manufacture is done in purpose-built buildings or suites housing sophisticated purpose-built equipment.  Clean room facilities, environmental controls and high purity water systems are needed.  Facilities and materials must be ‘aseptic’, meaning that the spaces must be protected from the introduction of unwanted viruses and bacteria.  Further, the purpose-built equipment used in the production process must not react with the materials.

In certain cases, vaccine manufacturing facilities require operating licenses that are coupled with approvals for the specific vaccine product being produced at the site.  Multiple sites will share designs, but each must be individually vetted and “validated”.

These are common considerations, but the dedicated engineering, equipment sourcing, construction and validation steps all take time, and scale will be a factor.  Large companies can afford lean forward to develop manufacturing capacity “at risk” when product approval appears likely, but smaller companies cannot.

Distribution Logistics and Priorities

Distribution issues likely to occur include theft, diversion, counterfeit, preferential access, and third-party resale at black market prices.  Of those problems, the most insidious and deeply evil may be counterfeit.  Fraud in COVID-19 testing is a sorry predictor of what is possible with COVID-19 vaccination and drug therapies.  Penalties criminal acts should be prescribed early, be severe and be prosecuted aggressively.

More importantly, there is no publicly disclosed management plan for the allocation of COVID-19 vaccines.  Setting priorities, i.e., triage, is going to be a distasteful but unavoidable necessity.  The ethics of distribution may well eclipse the mechanics of vaccine manufacture as the central issue in managing the pandemic. Setting priorities both nationally and globally seems certain to be a contentious process.  Pricing and ability to pay are also compelling unavoidable issues. These are issues of conscience, ethics, policy, and politics.

One prospective COVID-19 vaccine distribution paradigm for the U.S. is control under the Defense Production Act.  Given the uneven nature of critical PPE and COVID-19 testing supply distributions to date, an early, transparent, and well-understood plan seems essential to operational planning and social equity.

Conclusion

There is every reason to anticipate a COVID-19 vaccine in the mid-term future.  Success in the discovery effort needs to be coupled with a rigorous effort in manufacturing scale-up.  It will take more time and encounter more obstacles than anyone would like.  Meeting global needs will not be instantaneous.

To paraphrase Dr. Tony Fauci: “You can’t just leap over things…”.   And if you are making Eggs Benedict, I’ll be over for brunch.

 

Charles Grebenstein, PhD

May 6, 2020

 

 

 

Charles Grebenstein is a partner with Heritage Partners, a senior-level retained executive search and advisory firm serving the life sciences sector.

Why is Testing for Coronavirus so hard?

The Short Answer

Useful and reliable diagnostic testing is a complex process requiring perfect completion of an unbroken chain of events:

  • Grasp of the medical problem – what to test for, what to collect, and where and how to sample
  • Accurate, timely and useful specimen collection methods
  • Test components and collection supplies available for the right platform at the right locations in the right quantities at the right time
  • Timely sample transport, accession and access to installed automated analytical equipment
  • The ability to process, capture and report the results back to caregivers quickly
  • All of the above at scale

Break the chain at any point and the effort fails. Further, our diagnostic testing systems must work at enormous scale, and scale-up brings its’s own daunting challenges.

A naval analogy may be useful here: “The fleet doesn’t sail any faster than the slowest ship”.  A breakdown or bottleneck at any point, e.g., a shortage of the proper specimen collection swabs, brings the entire effort to a grinding halt.

It’s a hard and inconvenient truth, but adequate testing will still take some time if we want it to be widely available and correct. Wishing it was easier won’t make it so.

Is the FDA the problem?

The U.S. FDA regulatory process for medical diagnostics represents our collected experience on the ways that testing development, manufacture and use can run off the rails.  Taking shortcuts means ignoring known likely failure points.

“Validating” all the components of the system informs the reliability of the results.  Reliability of testing is literally a matter of life or death. The validation process can be accelerated with a concentration of effort and parallel evaluation of component parts, and that is being done.

Recent reports that up to 30% of coronavirus “negative” PCR test reports may be incorrect illustrates the risk of allowing urgency to overrule rigor.  Failure of the initial CDC test kits further illustrates the point. Being wrong quickly is a danger all by itself. Trading speed for validated reliability introduces chaos, not confidence.

State vs. Federal

The U.S. Federal Government has regulatory jurisdiction over diagnostic testing equipment, devices and disposables with nationwide distribution.  Both high-throughput automated “PCR” molecular tests for live virus, and “Antibody” blood tests for post-infection diagnosis (either point-of-care or high-throughput central laboratory versions) require review.  Manufacturing quality standards are absolutely essential. All the test components and protocols must work individually and as a system. Bending the testing effort around automated high-throughput clinical diagnostic systems is the goal of a lot of current effort.  We know how to do it, but we don’t know how to make it instantaneous.

Solutions to the testing challenge at national scale will be assisted and enabled by review systems under the jurisdiction of the FDA.

State governments have regulatory jurisdiction over clinical laboratories performing diagnostic testing in their geographies. State public health, hospital and academic testing laboratories fall in this group. State-licensed laboratories are permitted to conduct testing of “home-brew” tests under the supervision of a qualified clinical pathologist. Individual wet chemistry PCR coronavirus tests, for example, can be performed “under the hood” by trained laboratory technicians in state licensed “CLIA” laboratories.  Rate limiting factors are quality-controlled reagents, trained technicians and laboratory facilities suitable for contagious pathogens.  A significant proportion of initial COVID-19 testing was done this way. Reliability of local testing varies, and throughput rates are limited. It was never going to be the long-term answer, but it got things started.

Equipment

We go to war against COVID-19 with the diagnostic systems and hardware we have in place – what the commercial diagnostic equipment makers refer to as “the installed base”.  The good news is that we have a lot of automated equipment, it is sophisticated, much of it is useful for this purpose, and we know how to use it.  Reliable laboratory robotic systems ease the need for exposing technicians to the virus.  Even so, there are limits to the throughput rates.

The bad news is that it is that there are several manufacturers of high-throughput analytical equipment.  There is no single dominant national diagnostic equipment model.  The equipment systems are not identical, not evenly distributed, and capacity-limited by the other systemic factors.  Slight differences in reagents, disposable accessories, sample collection, accession and preparation protocols all impact progress by resisting standardization. Each testing moiety requires separate validation and quality control efforts.  One size doesn’t fit all which magnifies supply chain and scale-up challenges.

Materials

Key among the materials necessary for testing are chemical or biochemical reagents – the “juice” that processes medical specimens.  Manufacturing using standard biological products methods almost always involves trial-and-error.  The “recipes” employ exacting process-intense manufacturing chemistry, highly technical “separations” technologies with their own materials requirements, and component testing for quality and stability at each step.  The same is true for the plastic disposable components necessary to collect, prepare and process collected samples. Skip a step here with the critical inputs during “scale-up” and the whole house of cards collapses.

Proximity vs. Volume

The Abbott Labs system introduced in early April is designed for local testing and falls in a category known as Point-of-Care. The patient, physician and equipment are all at the same place. It is ideal for quick turn-around and immediately actionable information. The downside is that the platform can perform only one test at a time, manufacturing of disposable supplies is not yet at scale, and test material distribution logistics will be imperfect.

Central or “reference” laboratories can handle multiple tests simultaneously but take longer to produce results due to the intake, batching and reporting logistics.  Reference laboratory testing is easier to scale, but test results are not immediately actionable. Here, too, the supply chain for disposable collection and testing materials has been imperfect.

The Path Forward

News of approval of for a test of the presence of the virus in saliva is a promising recent advance.   Other clever approaches are certain to enter the testing armamentarium. Each advance, though, will still need to be thoroughly vetted and integrated into use. Our technology and logistics resources are enormous and up to the task, but each step in validation is still absolutely essential.

The fleet will get up to speed.  We know how to do this. It will occur as quickly as possible. It just won’t be instantaneous.

 

Charles Grebenstein, Ph.D.

4/17/20

Heritage Partners Expands Executive Search Practice to Atlanta

ATLANTA, GA – May 8, 2019 – Heritage Partners International (HPI), a leading retained executive search firm, announced expansion to the Southeast U.S. with the opening of an office in Atlanta.  Charles Grebenstein will head the new office located in the technology hub in Atlanta’s northern metro.  Grebenstein is a cofounder of the firm.

The new Atlanta office extends the firm’s presence to six major U.S science and technology hubs including Boston, Philadelphia, Chicago, San Francisco and Portland, Oregon.

The office positions Heritage Partners’ retained executive search practice in a vibrant and rapidly growing Atlanta entrepreneurial community.  In addition to the biotech vertical in Atlanta, the new office also serves the life sciences hub in North Carolina, the digital healthcare hub in Nashville, and the agtech sector in the Southeast U.S.

Formed 16 years ago, HPI focuses on C-suite assignments in high-growth life science environments. HPI’s core competence is finding and recruiting executives who understand the business/science interface and growing emerging businesses. Verticals include biotechnology, pharmaceuticals, medical devices, medical diagnostics, digital healthcare and agtech.

“Managing transformative growth has always been a serious leadership challenge,” said Grebenstein. “There is an art to bringing commercial competence to visionary ideas.  The trick is to find leaders who understand the applications, who can develop the team, and who can meet the management challenges without compromising the creativity.”

Glucose Monitoring: Still on the Frontier of Innovation

”…To a large degree, medical care depends on a transfer of information.” †

There is almost no overnight success.  That is why Alphabet subsidiary Verily’s cancelation of work on a glucose-sensing contact lens last fall shouldn’t be a large surprise…nor should it be viewed as the last word on the concept.  The history of glucose monitoring is replete with fits and starts, and with some specular success. ‡

In 2002, Cygnus, Inc., launched The GlucoWatch – the first approved commercial transdermal continuous glucose monitor. The GlucoWatch failed to gain traction, however, because:

  • There was no reimbursement for the device at the time;
  • It was expensive;
  • The technology was novel but not yet bullet-proof; and
  • The data was interesting, but difficult to transmit, store, access, share, analyze and act on.

More recently, advances in glucose monitoring by companies including Dexcom and Medtronic/MiniMed have been life-changing for diabetes patients and their caregivers.

Verily’s project cancellation does point to some relevant truths:

  • The management of complex diseases depends on timely and accurate information;
  • Collecting, transmitting, recording, analyzing and acting on clinical data is intolerant of failure;
  • Despite of the urgency for a better solution, all the links in the solution set must work in concert and “the fleet sails no faster than the slowest ship”; and perhaps most significantly,
  • It was an initiative by an information company.

Things to be considered in glucose monitoring go well beyond new detection technology. For the entire generation of new physiological wearables – including new glucose monitors – to be both useful and competitive, they will need to be information-driven and include:

  • Seamless and user-friendly data collection, transmission, aggregation and analysis methodologies;
  • Integration into existing and evolving medical information systems;
  • integration into the dominant next-gen smart phone and home-assistant tech;
  • Clinically relevant, actionable information presentation;
  • Relevance to the payers, other interested third parties and population health;
  • Data security and data access; and
  • Synergistic data-driven alliances with the relevant device and pharma companies.

Better, cheaper, faster glucose measurement technology will always be welcomed; but in the end it’s all about the data.

 

Charlie Grebenstein

_____________________

† Johns Hopkins’ Barbara Starfield, M.D. from Primary Care: Concept, Evaluation and Policy in 1992

‡Heritage Partners has published a “A History of Digital Healthcare” (http://bit.ly/2u9AIoI) that incorporates advances in glucose monitoring as an allegorical representation of the historical integration of technology and clinical medicine.

Meditations on Early Stage Innovation – The Talent Valley of Death

The Valley of Death is a much-suffered phenomenon in the financing of early-stage science-based start-ups: ideas too late for basic research funding, but too early for venture or industrial financing.  Less talked about, but just as real and painful, is a related Talent Valley of Death.  Critical to the viability of such early-stage ventures is attracting a founding CEO who can articulate a compelling and fundable vision for the concept.

But the difficulty of finding such talent and connecting it to promising early stage ventures is as frequent a failure point as early financing.  Innovation geography obeys cluster economics.  Start-ups, venture backers, entrepreneurs, skilled workers, service providers, and acquirers co-locate around a small number of zip codes.  This creates deep labor markets for skilled workers, ready availability of expertise and resources, and collective learning.  The ability to conceive and execute start-up concepts is significantly enhanced, the perceived and actual risk proportionately lowered.

But what if you are outside an innovation cluster?  The geographical dispersion of basic research funds to research universities does not overlay innovation clusters. Indeed many, if not most, inventions arising from basic research are born outside of them. They are geographically marooned, potentially exciting and viable in the right hands, but much less likely even to get to the starting line.

When I was at the University of Chicago, we managed a portfolio of inventions from Prof. Susan Lindquist which we pitched aggressively to venture in the late nineties and early 2000’s, with consistent feedback that this was too early and too risky.  In 2001 Dr. Lindquist moved to MIT as Director of the Whitehead Institute.   Rapidly thereafter a start-up called FoldRx was founded around the portfolio and venture funded, going on to successfully develop the drug tafamidis, and to be acquired by Pfizer in 2010.  The only thing that changed in this story was the zip code of the inventor.

The lens of executive search is a particularly instructive one with which to look at this founding CEO challenge.  To power an effective search, 200 candidates that meet the spec might be approached, 20 might be qualified, interested, and available, and 5 may be interviewed to result in one successful hire.  Such a search in Chicago might yield 2 qualified candidates.  In Boston or San Francisco: 200 readily: at least a two order-of-magnitude different in talent density.

It’s not practical to use executive search for university start-ups.  Among other factors, there is no money.  But it speaks to a feature of the valley of death: the need for expensive resources when they are least likely to be available.  And it helps quantify just how underpowered the talent search is in this situation, even if there was money and bandwidth for it.

What is the cost of this geographical mismatch?  I’d warrant hundreds if not thousands of lost projects and start-ups, lives not saved or improved; swathes of wasted research dollars, wasted effort and talent, lost opportunity, lost economic value.

Small improvements could make a big difference. Basic research funding into North American universities (including some $35 billion/yr of combined NIH and NSF extramural funding) yields about 25,000 inventions per year, 16,000 patent applications, and 1000 start-ups (here).  Currently enough invention “baby turtles” hatch on the beach and make it to the water to keep the innovation economy humming.  But the number unnecessarily eaten by the “seagulls” of distance and isolation from resources is, I’d observe from experience, shockingly high.

So what are those outside of innovation clusters to do?

  1. Recognize reality. In cluster economics, the rich get richer.  Build the best possible connection to cluster regions, become effective satellite feeders to them and allies with them;
  2. Funds and talent are attracted to critical masses of invention and opportunity: well-curated, well-articulated, accessible;
  3. Look for unserved niches where you can build your own cluster that can compete at a national level.

Alan Thomas

Your Career in “Specialty Pharma”

Med Ad News; October 2011 — Tig Conger, partner at Heritage Partners provides perspective on creating a successful specialty pharma career. Click here to read the article.

New Faces For A New Pharma

Med Ad News; October 2009 — Peter Goossens and Matt Vossler, partners at Heritage Partners interviewed the executives that provided their insights to this article. Click here to read the article.

Launch Success in Specialty Medicine

Med Ad News; August 2009 — Successfully launching specialty medicines requires marketers to adopt a new set of skills and priorities. Tig Conger, partner at Heritage Partners interviewed the participating executives and provides his insights. Click here to read the article.

Leadership: From Big Pharma to Biotech

Med Ad News; October 2008 — Although the skills required to lead in both big pharma and specialty/biotechnology companies are similar, the application of those skills is what determines success. Tig Conger, partner at Heritage Partners interviewed the participating executives and provides his insights. Click here to read the article.