Has Pharma finally found its 'skunk'?

Welcome to part 2 of 2 of this blog covering some topics around developing new products quickly.

'In part one, I posited that reconfiguring a problem so that you could fail often, fail rapidly and fail at little cost was a means to rapid success – the so called “fail early fail fast” motto. I certainly have examples within my career where this has proven correct.

With the unprecedented speed of the development and roll out of Covid19 vaccines, in this second part I ask the question “has the pharma industry finally found its “Skunk””?

Confused? Let me explain!

Having worked in and around the development of pharmaceutical and MedTech products for several decades, I came to the view that the industry needed a “skunk works” mentality, especially during early phase development. By any industry standards, the heavily regulated pharmaceutical industry traditionally takes significant time to make any changes. The industry has long accepted this as the norm. Indeed, during the early 2000’s, when a significant “patent cliff” threatened years of enviable big pharma profits, there was a lot of talk of “agile”. This didn’t, however, appear to generate much in the way of tangible change. Having come from an agile SME engineering automation background, I was struck by how much could be achieved by a small highly focused and highly skilled team of engineers, and how little was often achieved by large corporate teams in our big pharma client base. Many clients (only the ones known well) have heard me remark “so you want me to significantly improve this process and you don’t want me to change anything!”. Wasn’t it Einstein that is quoted as saying “Insanity is doing the same thing over and over again and expecting different results”?

Rewind to around 1990, and I had my team described as a “Skunk Works” by a senior exec within a multinational food company. At the time I had never heard of “Skunk Works”. Sometimes an event or a book (in this case both), have a material impact.

I highly recommended the Ben Rich’s seminal book “Skunk Works: A Personal Memoir of My Years at Lockheed” for anyone bringing highly engineered products to market.

For several years, I carried copies and gave them away to pharmaceutical executives in the hope of catalysing change. Like many ideas, it is not unique. Indeed, in 2017 I noticed a short article by Pharmacology academic, Krzysztof Palczewski had very similar thoughts for the pharmaceutical sector. It was entitled “Skunkworks project for Big pharma”

So, what was the “Skunk works”? It was actually a military jet development centre run by Lockheed Martin based in California. It was officially known as their Advanced Development Program (ADP), and was where they developed some of the iconic US military aircraft from the 1940’s to 1980’s.

Originally formed and run by Kelly Johnson. Kelly ran a hand-picked team of the best Lockhead engineers in a purposeful separate facility. Kelly ensured his team weren’t bogged down by corporate systems so they could focus on the technical task in hand. He often demanded and received long hours from his loyal team. His legacy was continued when he handed over to Ben Rich in 1975 (the author of the book). The team in the ADP took on seemingly impossible challenges until they achieved them. A spy plane that could take high-definition pictures of the ground from 70,000 feet and outrun missiles at Mach-3 was the thing of science fiction until Kelly Johnson put his best people around the problem.

The US Airforce Lockheed P-80A Shooting Star (USAF – Wikimedia commons)

The ADP and its team of highly motivated and talented engineers was originally formed in 1943 to develop the first jet fighter for the US military. This was at a time when the Luftwaffe was about to take its jet fighters operational over Europe in WWII. British engineer Frank Whittle is widely credited with the invention of the jet engine, which he patented in 1930, and yet in 1935 he couldn’t afford the £5 to renew his patent so it lapsed. It wasn’t until 1941 that the first British jet-engined plane, the Gloster E.28/39, flew using Whittle’s technology. Despite his post war fame, this was actually the fourth jet to fly after the German Heinkel He 178 (1939), the Italian Caproni Campini N.1 motorjet (1940), and the German Heinkel He 280 (1941). One can only assume that Whittle had a team around him that were the opposite of a skunk works – roughly 4000 days from idea to flight.

Kelly Johnson offered the Pentagon a flying fighter jet prototype within 150 days. It actually took him and his talented team 147 days (and long nights) to have the P-80 Shooting Star in the air.

The ADP was reportedly nicknamed the 'Skunk works' after a moonshine factory in a famous US newspaper comic strip called Li’l Abner. "Skunkworks" is now a term widely used to describe a highly skilled and focused group of experts who are provided with a high degree of autonomy and unhampered by bureaucracy to “get things done”. Skunkworks have a reputation for getting, oftentimes seemingly impossible, tasks done quickly. 

The influence of the ADP now goes far beyond military aircraft. There are many books written about the original skunk works and management texts often quote their achievements.

Steve Jobs was heavily influenced by the stories and mythology surrounding the skunk works. So much so that he arranged to visit the site. During his involvement with Pixar he even styled Pixar’s 1990’s building on Skunkworks. Pixar co-founder and president of Walt Disney Animation Ed Catmull was also a devotee. He famously “flipped” the Skunkworks methodology to the impact of low performing teams by saying, “If you give a good idea to a mediocre team, they will screw it up. If you give a mediocre idea to a brilliant team, they will either fix it or throw it away and come up with something better.” I guess that Steve Jobs was clearly a “cup half full” person whereas Ed Catmull was a “cup half empty” person.

Let’s jump forward to today and consider the pandemic and vaccines. Firstly, consider the complexity of producing a vaccine and I will quote from a 2017 paper (Plotkin S, et al, “The complexity and cost of vaccine manufacturing – An overview”):

“Vaccine manufacture is one of the most challenging industries. Even the most basic manufacturing steps necessary to produce vaccines in a manner that is safe, effective, and consistent over the life cycle of a vaccine are difficult to execute. Outcomes can vary widely due to the nearly infinite combinations of biological variability in basic starting materials, the microorganism itself, the environmental condition of the microbial culture, the knowledge and experience of the manufacturing technician, and the steps involved in the purification processes. To add to the complexity, the methods used to analyze the biological processes and antigens resulting from vaccine production often have high inherent variability. Failure to manage these risks can result in costly product recalls, and suspensions and penalties may be assessed if a manufacturer fails to fulfil supply agreements. In addition, lack of supply can disrupt routine immunization programs and negatively impact national public health outcomes.”

This may all sound too familiar with press stories about scrapped or delayed Covid vaccine batches.

Vaccine development is an even more complex process than the manufacture that is described above. 10-15 years is often quoted as a typical time to bring a new vaccine to market. These heavily regulated products usually start as some basic laboratory research over several years typically using University laboratories and governmental funding. This will involve animal models to investigate likely effectiveness and likely safety in humans. Once something looks like it might work and it appears to be safe, the development expands into what is often described as the pre-clinical phase. This phase typically takes 1-2 years. Most novel vaccines actually fail before the end of pre-clinical because they don’t work or they have an issue with safety. We could now be at 6 years and the new vaccine hasn’t been injected into a human yet. Industry typically now get involved and apply to the regulator (EMA in Europe or FDA in the US) to proceed with an agreed clinical trial in 3 phases.

A phase I vaccine trial will typical involve less than 100 healthy subjects to check the immune response and also check the basic safety profile. Assuming success, phase II proceeds. This is a randomised trial of several hundred subjects, half of whom will receive a placebo. This is where the dose size, delivery method and timing are tested. Again, assuming success, Phase III can occur. Now we have a large randomised and double-blind test. This can run into many 10’s of thousands of subjects half of which receive the placebo. Significant time may be needed to recruit the subjects. Finally, a successful vaccine can be now be approved by the regulator and deployed.

This isn’t the end of the story for the manufacturer. They have the complexity of robust commercial scale production to deal with. The regulator can and will inspect facilities. The regulator also has the power to inspect batches for potency, and safety etc. The manufacturer also has to carry out what is known as post licensing monitoring. This is looking out for rare adverse events (like the recent low levels of blood clots observed with some Covid 19 vaccines). Often the vaccine is only initially authorised for a particular group within the population. Phase IV studies are carried out to ensure efficacy and safety in other population groups, such as children and the elderly.

Given the difficulty of developing and producing vaccines how is it that “a cluster of cases of pneumonia” was identified in Wuhan China in late December 2019 and the UK medicines regulator, MHRA, provided regulatory approval for the Pfizer Biontech vaccine on 2 December 2020, in just under one year?

On the 8^th December 2020, 90-year-old grandmother, Margaret Keenan received the first deployed shot of vaccine (Pfizer). This historic moment happened in University Hospital Coventry, UK, just a few miles from 3P’s offices. (BTW: the second person was William Shakespeare, 81, from Stratford-upon-Avon. You really cannot make this stuff up!).

Within 4 weeks, the Oxford -AstraZeneca and the Moderna vaccines were also deployed.

How was this achieved without cutting corners?

All the successful vaccine producers have similar stories.

• Platform technologies that have been on the shelf for some time almost waiting for a pandemic.
• Small highly focused teams of experts who knew how to configure the platform technologies.
• A lot of long hours and hard work from these experts
• Taking some early financial risks in the hope that it would “come good”
• Having a large “big pharma” organisation available to aid with the large phase III clinical trials and with access to production biopharma and vial fill/finish lines.
• Big pharma taking risk ($100m’s) to get manufacturing assets in-place before success was certain.

The Oxford AstraZeneca story is typical. In truth the work started long before the Covid outbreak in response to the Ebola outbreak. Science readied itself for “disease X”, a mythical disease that could spring up at any moment to become a pandemic. The name of Oxford University with the iconic towers drew in the world’s best vaccine scientists to work at their Jenner Institute (named after the scientist who performed the first ever attempt at vaccination in 1796). The Skunkworks team had therefore already been assembled. They also had some useful platform technologies ready to go. In particular they had a denatured chimpanzee adenovirus cold virus that had been genetically modified to avoid infection in humans. It was specifically designed to be adaptable by delivering proteins to the body for the immune system to recognise. A further disease specific genetic modification is made so that the adenovirus includes what is known as the antigen (in this case to produce the Covid19 spike protein).  Our immune system attacks the spike protein and it is then “trained” against a pathogen like Covid19. Before Covid19, only 330 people had received phase I clinical trials of this modified adenovirus. This was for diseases such as the common cold and Zika virus. Another stroke of luck and Covid19 happens to be related to the Mers and Sars viruses. The scientists at the Jenner Institute, therefore knew that the “key” was going to be the infamous spike protein on the virus surface: they also knew this approach was likely to work as they had already developed a Mers version of their “viral vector” technology which fortunately wasn’t needed.

On January 11^th 2020, the Chinese scientists published the genetic code for the original variant of Covid19. The best scientists working in a “Skunkworks”, which happened to call itself the Jenner institute, were then able to produce the first vaccine within a few days of receiving this crucial genetic code. The world owes a huge debt of gratitude to the Chinese Scientists who shared this genetic code so early on within the outbreak.

Once they had the genetic code, then the really hard work started with around the clock working for the small group of scientists. They had to step out of their comfort zone to find the funding for clinical trials. Animal trials had to continue at pace. St George’s day (23^rd April) is a significant date for anywhere as English as Oxford University. This date turned out to be the day which coincided with the first injection into a human. Phase I had started within 4 months of the genetic code being shared. This is simply unheard of within the pharmaceutical industry.

The focused team were able to carry out back-to-back phase I, II and III trials including 30,000 subjects for phase III. Note: short cuts were not taken but traditional administrative delays were removed. During this time AstraZeneca, one of the world’s largest pharmaceutical companies, had joined the effort to provide expertise and crucially manufacturing capacity from their existing manufacturing network.

The Moderna and BioNTech stories are very similar to the Oxford one. A novel platform technology was on the shelf waiting for “disease X”. The inventor endured academic rejections and even a demotion for constantly pushing this “dead-end” technology during the 1990’s. Fortunately for humanity, Katalin Karikó didn’t give up and in 2005 she published papers describing how to make the technology work in humans. She understood how to genetically modify messenger RNA (mRNA) to con the body’s own cells into producing proteins similar to the Covid19 spike protein and crucially she worked out how to protect it within the body so it could take effect (a problem early on). These proteins would train the body’s immune system ahead of seeing the real thing. Both Moderna and BioNTech were sat at the outbreak with a really cool mousetrap but without any mice until Covid struck. BioNTech husband and wife team of scientists behind BioNTech, Dr Ugur Sahin and Dr Özlem Türeci, were the smallest of skunkworks. They tell of working through the night to get the technology adapted for Covid. Pharmaceutical giant, Pfizer committed hundreds of millions of dollars to build the global manufacturing network before the vaccine was approved. Moderna used the same core technology and their “skunkworks” was led by 35-year-old scientist Hamilton Bennett. At the time they were a small relatively unknown biotech company based, like many MedTech start-ups, in and around Cambridge… in this case it was Cambridge, Massachusetts, not Cambridge UK. At the time, she had 10 years research experience including 4 years in vaccines including mRNA for MERS-Cov and Zika Virus. Just like the Oxford team, as soon as the Chinese released the Covid19 genetic code her team sprang to life. Despite the commercial risks, she persuaded Moderna’s management team that they had a moral duty to run to risk and develop the vaccine (at that time a pandemic wasn’t certain). Her team were then working double shifts and only returning home to sleep. Like the other teams, they then ran all the necessary clinical trials and were rewarded with a very efficacious vaccine. Like the other development teams, Moderna needed a commercial partner and in this case, they turned to some of the world’s largest CMO’s. In the pharmaceutical world, work is often contracted to Contract Manufacturing Organisations (CMO’s). In this case they used Lonza in the US and Switzerland. The crucial lipid raw material needed to protect the mRNA came for CordenPharma whilst the fill-finish was provided by Catalent in the US and Laboratorios Farmacéuticos Rovi in Spain. It is inappropriate to say which ones of these have significant amounts of 3P equipment… but you know who you are!

So finally, to Johnson and Johnson. Let’s start with Paul Stoffels, their Chief Scientific officer, and an interview he gave to “The Philadelphia Inquirer” in January 2020 – note the date - January 2020. In this he stated that J&J had started a “skunkworks” to develop seven constructs for a vaccine as the Wuhan virus threatened to become a global crisis. It is interesting that right at the start of the journey he mentioned “skunkworks”. I am not, however, aware that he ever knew someone in big pharma that I gave a book to, but I can dream!

He turned to their Janssen subsidiary in the Netherlands. Stoffels said the research effort, which began with about 15 people, “didn’t wait for [dedicated financial] support to kick it off. We’ll see as we go and find partners to collaborate to make that happen.” They, like the Oxford team, had an adenovirus viral vector on the shelf, and ready to go.

Their best scientists focused on getting the job done. In the same way that Kelly Johnson said he would deliver a prototype jetplane in 150 days, Stoffels suggested 8-12 months to deploy a vaccine. This optimism was based on the fact that they already had multiple vaccine platform technologies, and they had also recently deployed 2 million Ebola vaccine doses to West Africa. J&J are reported to have pumped US$1billion into readying the supply chain, including deals with Catalent in the US and Italy. The US facility did become embroiled in controversy during early 2021, when the FDA blocked production because of a mix-up in ingredients as the same site also had a contract with AZ for the Oxford vaccine. J&J responded by this almost inexcusable lack of quality control by sending in a “Skunkworks” team of their best aseptic engineers to take control of Catalent’s facility.

So hopefully, you can see some common themes from 4 vaccine development journeys.

There are also similar stories circulating around the response to the shortage of PPE and ventilators around the globe, with manufacturers pivoting their design teams and production facilities. Ford and Jaguar Land Rover both started making visors (as did we at 3P, with our firstly 3D printed and then injection moulded CE marked visors – 40,000 donated in the UK, including a very special custom made one for Her Majesty the Queen!).

Many of the great medical device consultancies around Cambridge (Cambridge in the UK this time), put their competitive nature to one side to come together to develop a new ventilator. One such story from fellow Employee Owned company Team, that 3P know well, can be read on their website here . Just six weeks to develop a ventilator from a standing start – Wow – just Wow! Again, a really talented and focused team of engineers and scientists working very long hours to make it happen.

When you dig into these stories, as I have, you find that there is a small team of highly focused experts working long hours that simply make things happen – It is clear that the pandemic caused “Skunkworks” to spring up all over the planet.

It is also clear that the Covid19 pandemic forced the pharmaceutical and medical technology industries to find their inner “skunkworks”. Small and highly skilled teams of scientists achieved what many said was impossible – this has to be the true measure of any Skunkworks?

A “skunkworks” mentality was built into the DNA of 3P innovation from the business’ inception. Being described as a Skunkworks early within my career and then reading Ben Rich’s book had a profound impact on the rest of my career (which resulted in possibly one too many grey hairs!). The big question that I will now leave hanging is this……. Will the status quo and long timelines return after the pandemic, or has Pharma finally found its “Skunk”?'

 

Skunk photo credit: This is Montreal via 'https://thisismontreal.com/three-skunks-visits-in-one-month/'

The US Airforce Lockheed P-80A Shooting Star photo credit: Wikipedia via: 'https://en.wikipedia.org/wiki/Lockheed_P-80_Shooting_Star)

RNA vaccine photo credit: Wikimedia via 'https://commons.wikimedia.org/w/index.php?curid=97537433'