As an ex-Alvean and also 15-year industry veteran I can maybe weigh in, particularly because I think this ties in to what was Alvea’s main value proposition: speed for pandemic response. There were some aspects that enabled Alvea to go faster than a “from-scratch”, hypothetical vaccine program: Alvea based its DNA-Omicron vaccine on an existing, approved vaccine platform (ZyCoV-D), and applied to SAPHRA instead of FDA/EMA.
But even trying to account for that, Alvea went faster than any company I’d seen that wasn’t in early COVID pandemic-speed (with the full weight of mid/large pharma, funders, governments, regulators, plus also having based their vaccines on their own existing coronavirus platforms as opposed to someone else’s). I’m sure there are instances of groups going faster (colleagues did an exhaustive ct.gov search and found them) but I still think its notable that a mostly inexperienced team was in the ~0.1% of fastest programs developed in the last 35 years. I attribute this to:
More sophisticated/aggressive risk appetite—Most biotechs are extremely risk averse, often to the point of irrationality. Execs might add months/years to their timeline (and spend $$$) to reduce risk by a tiny percentage since that is what they are optimizing. E.g. more US biotechs should be executing Phase 1s in the Australia (fastest option, cheaper, very safe bet) vs US (safest bet).
First principles thinking—As Kyle referenced, not listening to “conventional wisdom”, always expanding the space of possibilities and stress-testing assumptions (probably assisted by seeing ourselves as “outsiders”) was critical. E.g. nobody thought Alvea could source a comparator vaccine for its trial, the team was able to be one of the few orgs to achieve this.
Operational excellence—At least biotechs (I’m not as familiar with big pharma, but they are a different reference class) have a pretty sufficing perspective on timelines, Alvea had a maximizing approach: existing timelines were almost never satisfactory. Most companies would have stopped calling manufacturers after the first 3-5 vendors had similar timeline estimates, but at Alvea they would be exhaustive in their search to find a timeline that matched the targets. See Max’s post for more details on all all these points btw.
Value alignment—Most biotechs/pharma are not staffed by many people who believe in the mission to the degree that Alveans believed in their mission. This improved coordination, reduced politics and increased personal risk-taking, e.g. picking a smaller, nimbler CRO versus a “nobody gets fired for picking IBM”-type CRO. This belief in the mission also contributed to the operational excellence—you will move faster if you think you are practicing for responding to the GCBR than if you are advancing a dermatology asset for stockholders.
For further evidence on the speed improvement: As part of the pivot towards a partnership/service-based business model that Kyle alluded to, we also conducted pilots that allowed us to analyze other biotech’s development paths and were consistently able to save (on paper at least) 12-15 months off their timelines by applying lessons learned.
It is also important to note that from my perspective this product development speed focus did not contribute to the failure of Alvea, but I wasn’t involved in the preclinical decision-making and the case could be made that jumping from one program to the next too quickly and without proper strategic consideration might have contributed (as Kyle also referenced above). Given all this, I would end by suggesting people run, not walk, to work with ex-Alveans (myself excluded).
Thanks for that additional context Mats. I did want to follow up on US vs ex-US P1 trials.
At this point, Pfizer and Moderna have consistently gotten mRNA vaccines into US trials in ~2 months after receiving a new sequence. Are the timelines to starting a trial in Australia/South Africa/elsewhere considerably shorter?
As a comment, big pharma does perform vaccine trials in the global South, although this is more about seasonality than speed. Pfizer performed a major P1/P2 trial for their RSV vaccine in Australia, because the timing of RSV season in Australia matched well with the development timelines for the drug.
One of the main arguments I see in favor of US or EU P1 trials is that the FDA/EMA are the most sophisticated regulatory agencies, and will provide more useful feedback on your development plan than other agencies. This is particularly relevant if you intend to eventually market a drug in the US, since the FDA only accepts foreign trial data if the study was conducted according to FDA requirements. Since Alvea wasn’t really targeting the US market, this is less of a consideration. Still, what do you make of this argument?
I’d also mention that once you get to the P3/BLA stage, filling in a country with a less sophisticated regulatory agency can be a burden. My own experience is that FDA/EMA/Japan are more willing to let sponsors deviate from official guidelines if there is a good scientific justification. Meanwhile, other agencies lack the expertise to assess drugs on the merits and will fall back to saying that you must follow the guidelines. For instance, I’ve been in the maddening position before of having agencies in small countries repeatedly cite FDA guidance to argue that we need to make some change to our plans, despite the fact that our drug was already approved by the FDA without said change!
Hi Matthew, thanks for engaging and for your thoughtful comments/questions.
In non-pandemic times, yes. Australia has less requirements for a IND-type submission (GMP certificate only needed prior to enrollment, not at submission); you only need the HREC approval (IRB equivalent) and no national regulatory approval (just a rubber stamp); and depending on the indication and competitive pressures you usually get faster enrollment.
Agreed. I was talking more about regulatory speed to get into FIH.
You can still get a pre-IND meeting with US regulators and get their feedback before or in parallel to conducting a AU P1 (I recommend before, but if there are few/no uncertainties you might consider in parallel). So you don’t have to choose. Agreed that FDA has requirements for foreign data, but it is a low bar (GCP, IRBs, ICs), and you could still get a majority of your data from outside the US. Rule of thumb is you need 20% of your data for an NDA/BLA to be from US populations, but even that rule has been broken successfully.
These are great points, I don’t have a lot of experience with NDA/BLA submissions to foreign countries so your insights are valuable. I’ll just note I was specifying people use Australia for P1. Agree that P2s and P3s are another ballgame.
As an ex-Alvean and also 15-year industry veteran I can maybe weigh in, particularly because I think this ties in to what was Alvea’s main value proposition: speed for pandemic response. There were some aspects that enabled Alvea to go faster than a “from-scratch”, hypothetical vaccine program: Alvea based its DNA-Omicron vaccine on an existing, approved vaccine platform (ZyCoV-D), and applied to SAPHRA instead of FDA/EMA.
But even trying to account for that, Alvea went faster than any company I’d seen that wasn’t in early COVID pandemic-speed (with the full weight of mid/large pharma, funders, governments, regulators, plus also having based their vaccines on their own existing coronavirus platforms as opposed to someone else’s). I’m sure there are instances of groups going faster (colleagues did an exhaustive ct.gov search and found them) but I still think its notable that a mostly inexperienced team was in the ~0.1% of fastest programs developed in the last 35 years. I attribute this to:
More sophisticated/aggressive risk appetite—Most biotechs are extremely risk averse, often to the point of irrationality. Execs might add months/years to their timeline (and spend $$$) to reduce risk by a tiny percentage since that is what they are optimizing. E.g. more US biotechs should be executing Phase 1s in the Australia (fastest option, cheaper, very safe bet) vs US (safest bet).
First principles thinking—As Kyle referenced, not listening to “conventional wisdom”, always expanding the space of possibilities and stress-testing assumptions (probably assisted by seeing ourselves as “outsiders”) was critical. E.g. nobody thought Alvea could source a comparator vaccine for its trial, the team was able to be one of the few orgs to achieve this.
Operational excellence—At least biotechs (I’m not as familiar with big pharma, but they are a different reference class) have a pretty sufficing perspective on timelines, Alvea had a maximizing approach: existing timelines were almost never satisfactory. Most companies would have stopped calling manufacturers after the first 3-5 vendors had similar timeline estimates, but at Alvea they would be exhaustive in their search to find a timeline that matched the targets. See Max’s post for more details on all all these points btw.
Value alignment—Most biotechs/pharma are not staffed by many people who believe in the mission to the degree that Alveans believed in their mission. This improved coordination, reduced politics and increased personal risk-taking, e.g. picking a smaller, nimbler CRO versus a “nobody gets fired for picking IBM”-type CRO. This belief in the mission also contributed to the operational excellence—you will move faster if you think you are practicing for responding to the GCBR than if you are advancing a dermatology asset for stockholders.
For further evidence on the speed improvement: As part of the pivot towards a partnership/service-based business model that Kyle alluded to, we also conducted pilots that allowed us to analyze other biotech’s development paths and were consistently able to save (on paper at least) 12-15 months off their timelines by applying lessons learned.
It is also important to note that from my perspective this product development speed focus did not contribute to the failure of Alvea, but I wasn’t involved in the preclinical decision-making and the case could be made that jumping from one program to the next too quickly and without proper strategic consideration might have contributed (as Kyle also referenced above). Given all this, I would end by suggesting people run, not walk, to work with ex-Alveans (myself excluded).
Thanks, that was useful and interesting to read, and makes more sense now!
Thanks for that additional context Mats. I did want to follow up on US vs ex-US P1 trials.
At this point, Pfizer and Moderna have consistently gotten mRNA vaccines into US trials in ~2 months after receiving a new sequence. Are the timelines to starting a trial in Australia/South Africa/elsewhere considerably shorter?
As a comment, big pharma does perform vaccine trials in the global South, although this is more about seasonality than speed. Pfizer performed a major P1/P2 trial for their RSV vaccine in Australia, because the timing of RSV season in Australia matched well with the development timelines for the drug.
One of the main arguments I see in favor of US or EU P1 trials is that the FDA/EMA are the most sophisticated regulatory agencies, and will provide more useful feedback on your development plan than other agencies. This is particularly relevant if you intend to eventually market a drug in the US, since the FDA only accepts foreign trial data if the study was conducted according to FDA requirements. Since Alvea wasn’t really targeting the US market, this is less of a consideration. Still, what do you make of this argument?
I’d also mention that once you get to the P3/BLA stage, filling in a country with a less sophisticated regulatory agency can be a burden. My own experience is that FDA/EMA/Japan are more willing to let sponsors deviate from official guidelines if there is a good scientific justification. Meanwhile, other agencies lack the expertise to assess drugs on the merits and will fall back to saying that you must follow the guidelines. For instance, I’ve been in the maddening position before of having agencies in small countries repeatedly cite FDA guidance to argue that we need to make some change to our plans, despite the fact that our drug was already approved by the FDA without said change!
Hi Matthew, thanks for engaging and for your thoughtful comments/questions.
In non-pandemic times, yes. Australia has less requirements for a IND-type submission (GMP certificate only needed prior to enrollment, not at submission); you only need the HREC approval (IRB equivalent) and no national regulatory approval (just a rubber stamp); and depending on the indication and competitive pressures you usually get faster enrollment.
Agreed. I was talking more about regulatory speed to get into FIH.
You can still get a pre-IND meeting with US regulators and get their feedback before or in parallel to conducting a AU P1 (I recommend before, but if there are few/no uncertainties you might consider in parallel). So you don’t have to choose. Agreed that FDA has requirements for foreign data, but it is a low bar (GCP, IRBs, ICs), and you could still get a majority of your data from outside the US. Rule of thumb is you need 20% of your data for an NDA/BLA to be from US populations, but even that rule has been broken successfully.
These are great points, I don’t have a lot of experience with NDA/BLA submissions to foreign countries so your insights are valuable. I’ll just note I was specifying people use Australia for P1. Agree that P2s and P3s are another ballgame.