It was a Thursday evening in the fall of 2014, the end of one of those hectic days in the clinic at Bellevue Hospital — hardly a moment between patients and the computer system having epileptic fits. When I finally made my way out of the hospital’s atrium, my head was still swimming in all my patients’ issues. Suddenly I found myself up against a phalanx of news trucks parked in front of the hospital. There was a cackle of urgency in the air, with reporters and camera crews shooting live broadcasts up and down the block.
And then I realized: Ebola had arrived at Bellevue.
At the start of the Ebola outbreak in West Africa, there was chatter among staff — half-joking, half-serious — that if Ebola was going to come to the U.S., it would surely come to Bellevue. But as the epidemic crescendoed in Africa, the chatter became serious and planning began in earnest. A high-tech isolation ward was created, with its own laboratory and waste-removal system. A specialized medical team underwent exhaustive training.
We need to acknowledge our fears — the rational and the irrational — and then tuck them away in one of the many pockets of our white coats. There’s work to be done.
Advanced Therapy Manufacturing Trends:
In pharmaceutical manufacturing, Chain of Identity and Chain of Custody may not be new, but in advanced therapy manufacturing, they take on a whole new significance. Why? Because in personalized therapies, a person is a key part of the process.
With any pharmaceutical product, a key aspect of regulatory compliance is generating and maintaining a complete record of the lot genealogy, which includes the Chain of Identity (COI) and Chain of Custody (COC). This is true for cell therapies, gene therapies, and personalized cancer vaccines as well, and due to the unique and complex nature of these products, the requirements are even more stringent and detailed.
This commentary presents an overview of COI and COC, what lot genealogy looks like in traditional pharmaceuticals, and then highlights the major differences for personalized therapies.
Pharmaceutical Cold Chain Expertise:
Pharmaceutical supply chains continue to reach new levels of complexity that challenge even the most seasoned logistics and supply chain professionals. These complexities include:
⦁ Innovative, advanced therapies;
⦁ Emerging new temperature requirements for products;
⦁ Expanding global supply chain to naïve patient populations; and
⦁ Additional regulatory scrutiny over good distribution practices throughout the supply chain.
Within this evolving world of biopharma, it is estimated that two-thirds of biopharmaceutical manufacturing is outsourced. Therefore, the supply chain is not only complex but also largely virtual for pharmaceutical companies bringing their therapies through clinical development and ultimately to market. As a result of the increasing trend of virtual pharma supply chains, pharmaceutical sponsors view relationships with their contract manufacturing partners as not only critical but vital to the success of their therapies.
To make advanced therapies, we need to industrialize personalization:
What’s the best way to measure the real rate of progress in personalized cell therapies, gene therapies, and other advanced therapies?
I’ve been tracking the ever-growing flow of reports about these therapies in scientific journals and press releases for 15 years, ever since I co-led the passage of California’s $3 billion Stem Cell Research and Cures Act in 2004.
But to truly gauge who will benefit from today’s innovations, I’ve learned I also need to study the stream of business and technology announcements that run in parallel. That might seem more mundane — but to veterans of advanced therapies, making the science “work” actually signals success for these gene-, tissue-, and cell-based advanced therapies.
The reason is simple. My experience working with advanced therapies has taught me, time and again, that true next-generation medicine requires the industrialization of personalization. That sounds like an oxymoron, but it isn’t. To create individualized therapeutics in a sustainable way, we need to deliver — even if it seems counterintuitive — mass customization.
Breakthroughs such as CAR-T cell therapies are inspiring. They are also unsustainably expensive, difficult to manufacture, and complicated to deliver. We can change this by creating a more focused cross-collaborative production and delivery ecosystem.
Latest Updates on Good Clinical Practice for Advanced Therapies in the EU
All sponsors of clinical trials involving an investigational medicinal product, including an ATMP, are required to comply with the GCP.
The general GCP requirements developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (“ICH”) apply also to clinical trials conducted with ATMPs. There is, however, a need for the specific Guidelines that reflect the specificities of ATMPS. This is also recognized in Article 4 of the ATMP Regulation which requires the European Commission to develop these Guidelines.
The Guidelines do not seek to replace or supersede the ICH GCP but serve to complement the basic requirement with certain adaption specific to ATMPs. The Guidelines state explicitly that to the extent there is a difference in the requirements imposed by the ICH GCP and the Guidelines, the content of the Guidelines prevails.
The objective of the Guidelines is to address areas of GCP compliance in which there is a need to take into account the specificities of ATMPs. These areas include:
⦁ the specific manufacturing constraints and the short shelf-life of the ATMPs;
⦁ the specific mode of administration, the need for related training of the clinical trial team and the challenges surrounding the use of placebo;
⦁ the need for long-term follow-up of the patients and monitoring of the effect of the ATMPs;
⦁ specific requirements for retention of samples;
⦁ traceability of ATMPs that contain cell or tissues of human origin;
⦁ Challenges around the feasibility of blinding of the investigator, the investigator’s team or the patients.
⦁ Challenges around the generation of relevant non-clinical data before the conduct of the clinical trial.