Episode 10 | How to Write a Strong Specific Aims Page – Part 2.

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Episode Guests

William Bozza, Ph.D.

William Bozza, Ph.D., serves as a Program Director, managing a portfolio of oncology startups (SBIR & STTR awardees) to facilitate small businesses in technology commercialization for cancer diagnosis and treatment.  Dr. Bozza is currently leading the Center’s efforts on the Small Business Concept Award for early-stage high-risk/high-reward technologies that target rare and pediatric cancers.  He is also taking the lead on the program’s Peer Learning and Networking Webinar Series to help SBIR companies learn from peers and facilitate collaboration.

Amanda Schalk, Ph.D.

Amanda Schalk, Ph.D., is the co-founder and COO of Enzyme by Design. Amanda earned her undergrad degree in biochemistry on a full-ride scholarship from Eastern Michigan University and went abroad to Goettingen, Germany to earn her Master's and Doctorate degrees in Molecular Biology from the prestigious International Max Planck Research School for Molecular Biology and the Max Planck Institute for Biophysical Chemistry.  She spent 5 years as a postdoc in the lab of Dr. Lavie at the University of Illinois at Chicago characterizing the structures and enzymatic activities of L-asparaginases, resulting in multiple first-author peer-reviewed publications.  She also has experience as the operations manager at a startup where she also has gained experience as a virtual lab manager.

Ying-Hsiu Su Ph.D.

Ying-Hsiu Su Ph.D., is a co-founder of JBS Science Inc. and a member of the Board of Directors. Dr Su is a Professor of Translational Medical Sciences at The Baruch S. Blumberg Institute. She is one of few pioneers in the field of transrenal DNA for cancer detection. Dr. Su’s research team has developed the technology to preferentially isolate this circulation-derived urine DNA for detection of colon and liver cancers. In addition, a Standard Operating Protocol (SOP) for collection and storage of urine samples for biomarker studies in the EDRN of the NCI has been established by her group. Dr. Su has collaborated with JBS scientists in developing various approaches to bring the transrenal DNA technology to clinical applications in the fields of cancer detection and personalized cancer management. Dr. Su’s office and lab are located in The Baruch S Blumberg Institute. Dr. Su contributes her expertise in urine DNA technology. She serves as a member of the scientific advisory board.

Articles referenced in this episode

• PLAN series: specific aim page
• NCI SBIR/STTR Grants
• Phase IIB Bridge Award

Visit our website, sbir.cancer.gov, for the latest funding opportunities and commercialization resources to support your journey from lab to market.

Episode Transcript

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BILLY BOZZA: Hello and welcome to Innovation Lab, your go to resource for all things biotech startups, brought to you by the National Cancer Institute’s Small Business Innovation Research, SBIR Development Center. 

Our podcast hosts interviews with successful entrepreneurs and provides resources for small businesses looking to take their cutting-edge cancer solutions from lab to market. 

I'm Billy Bozza, a Program Director at NCI SBIR and today's host. In this episode, you will hear advice on how to write a stronger Specific Aims page from a therapeutics company and a diagnostic company funded by the NCI SBIR program. 

The first company, Enzyme by Design, will provide insights on addressing a competitive landscape, application features for therapeutic startups, and considerations for reapplying. 

The second company, JBS Science, will highlight application features for diagnostic startups, differences between an SBIR grant and traditional academic grants, and describing quantitative milestones. Now, without any further ado, here's Amanda Schalk, co-founder and COO of Enzyme by Design. 

AMANDA SCHALK: Hello I am Dr. Amanda Schalk, Co-Founder and COO of Enzyme by Design and I'm here to tell you how to write a good Specific Aims page. So to address the question, how long did it take to write your Specific Aims page? 

I feel like this is a bit of a trick question because the writing of the page itself usually only takes an hour or two, but it involves a lot of homework and brainstorming on the entirety of the grant. 

For us, it's definitely an iterative process. And a Specific Aims page really compiles every component of the grant, and as you flesh each part of it out, you have to make sure that the Specific Aims page really reflects that. So it's really working on a part, making changes, making sure the Specific Aims page is consistent with each section and updating it as necessary. 

And what was really important for us is knowing that the first and last impressions count, so making sure that you really sum up your entire grant in the Specific Aims page. Among that is significance and impact. So really thinking about why? Why are we doing what we're doing? Why should people care? What problem or unmet need are we solving? And why is the problem significant? And really, what is the impact that will be had, if we're successful with our technology? 

Another piece is innovation. Really explaining why our product is uniquely posed to solve this problem. And for the writing of the specific aims, remembering that the point of this is not to do science for science's own sake, but really using this as a way to test our commercialization potential of our product, and setting goals and milestones that clearly enable us to demonstrate feasibility. 

So what highly compelling data do we need to demonstrate viability and reduce risk for investors? 

Avoiding a mistake that I made of making really lofty specific aims and then going to the budget later and realizing that, “Oh, wait, I can't do that with this budget.” So understanding how much approximately it's going to cost and making sure that your specific aims fit within your budget, and thinking about it in terms of what successful product testing of our therapeutic looks like. 

And really, we really stuck to having one to three quantitative milestones for each specific aim and having between one and three specific aims, so keeping it manageable. 

So then there's a question of how did we address the competitive landscape as part of our innovation. And this part is really important. So regarding innovation, explaining why our product is uniquely poised to solve this problem, if we can't answer this question, then we have to go back to the drawing board and think, you know, does this make sense for us to even be doing this? How -- What can we do to show that our product is the one that's going to solve this problem more than anything else out there? 

Part of this is knowing who else is out there, who are our competitors, which products are already on the market? They have the advantage of being known and understood. It also involves us having an awareness of competing products in development and understanding how our technology stacks up. 

If there's something that's super similar, that's already further ahead, does it make sense for us to put our time and energy in developing this product or a different product or having a product that has features that's going to outcompete what's also coming up in the market? 

And understanding the trends for how treatment landscapes might shift in the future. Yes, our product could be significant if it were coming out now, but if the treatment landscape is going to greatly shift, how will our product compare to products in five years, in ten years? And does it make sense to develop what we're trying to develop now and really thinking about it holistically like this? 

Thinking about what features make our technology significantly superior, so having just a slightly different version isn't necessarily going to be enough to get adoption in the clinic. 

So for us, we're going for non-inferior efficacy of our therapeutic and really the, the highlight is a superior safety profile, and it's a superior safety profile that's going to enable more patients to complete their treatments, and for us to be able to treat more patients that normally wouldn't be able to take this kind of therapeutic because of toxicity. 

Thinking about why is my product going to succeed where others have failed? So understanding what's kept other technologies back. In our case, it's toxicity. So we really focus on proving superior safety profile while not having inferior efficacy, that's really important. 

Another question that is important to ask is whether the technology is protectable by IP and what rights does our small business have on that IP? If you can't protect it, it's going to be really difficult to get a share in the market for this. 

And another thing that I've learned is really trying to understand, does my product have a clear path to market? Does it have a way to be easily adopted by physicians, who are our patients going to be that are first trying it? 

You normally don't get first line patients and how is this going to affect what we're bringing to market? And we've actually had to make changes based on knowledge that we've accumulated for hurdles to our path to market. 

So what milestones specific for therapeutic technologies are essential to be included in a Phase 1 application? So efficacy is definitely one. How effective is our therapeutic against our target disease? 

We used our specific aims to demonstrate proof of concept efficacy in vivo and multiple models of the disease using quantitative methods. We've used both well-established models, different CDX models, and PDX models to more closely mimic patient conditions. 

And understanding that the efficacy that we demonstrate is going to support our path to market, so which subset of patients are we planning on doing trials in first and does our drug work for those types of patients that may have been pretreated with other therapeutics or have a certain genetic profile? 

Setting specific milestones and aims for how safe or tolerable is our product. So doing toxicity studies, acute and repeat dose, and for PKPD, understanding how and how often will our therapeutic be dosed? So what is our route of administration? How long has our therapeutic stable in vivo? And how does this compare to competitors? Because it all comes into play in how effective we think our product is going to be adopted into the market and how it compares. 

We made our aims quantitative by using meaningful benchmark metrics to compare our product with our competitors. Understanding how our product will literally measure up in the current and future market and setting up these milestones as feasibility go, no go points. 

What will it take for our technology to demonstrate efficacy, safety, stability that is competitive in the market? Using purity thresholds like 95% as determined by SDS page and schematic thresholds that will give us a clinically effective therapeutic, having certain stability measures, a T1 1/2 of a certain number of hours or days, tumor burden reduction by a certain percentage, overall survival increase by a certain percentage compared to the first line drug, scoring clinical signs of toxicity percent body weight changes, organ changes, percent differences in clinical chemistry compared to first line drug. 

For us to hire a biostatistician in order to make sure we have statistical power, sufficient statistical power for vertebrate animal studies, and understanding what are clear cut-offs our product needs to achieve to make the cut to be successful in the market. 

A critical and unique aspect of our Specific Aims page really has to do with understanding how our therapeutic measures up in the market, and we did this by leveraging head-to-head testing with the current standard of care, first-line asparaginase, to really demonstrate that our technology is going to be able to compete and eventually replace in the market. 

So doing this testing side-by-side is extremely important because that's really what investors have been asking us about and that's what they want to see. 

And we used the Specific Aims page to incorporate suggestions from peer review on a resubmission application. One, by clarifying the path to market challenges that made using a half-life extension other than peculation necessary for a new product to be successfully adopted. 

So there, there were certain path to market hurdles, that were not obvious, that we had to really make clear of why we're doing what we're doing, why we're taking this path, clarifying why our product would have reduced immunogenicity compared to currently available asparaginase drugs. This was something that reviewers really wanted us to demonstrate. 

We also, in our resubmission, showed additional preliminary data and multiple xenograft models of the disease and additional PK data, and had basically achieved our previous Specific Aims 1 and 2 to demonstrate strong proof of concept for further development. 

We also added PDX models, at the suggestion of reviewers. And to address toxicity-related concerns, we incorporated both acute and repeat dose toxicity, and really both the efficacy and the toxicity, we were comparing against the first line drug which was extremely important. 

So thank you so much for listening and I hope this was helpful. Bye. 

BILLY BOZZA: Thanks for the insights, Amanda. Now let's hear from Ying Su, co-founder of JBS Science. 

YING SU: Thank you for the opportunity to share with you my experience in writing Specific Aim pages for SBIR application, more specifically, a Phase 1 application for developing a product in the individual diagnostic space. 

Just a little bit about myself. I've been working as a PI in a few R01s [unclear] and later co-founded a company, JBS science, writing SBIR for product develop. 

The project I was referred to is developing a urine test for early detection of liver cancer. This project is awarded by NCI for one year Phase 1 study, three years Phase 2 study, and another three years Phase 2 Bridge Award. All three awards were founded by first submission, with the score ranging from 22 to 26. 

I will use our Specific Aim page as an example to share with you our experience. 

Since I was asked by a few colleagues who are quite successful getting R01, but happen, have not much luck for SBIR, for, why? So what I'd like to do first is to highlight the unique feature of SBIR that are different from a more traditional academic grants. 

SBIR is a Small Business Innovation Grant, therefore, the application is product development and business-centered. So what is your product for business and is there a good market for it? 

If there is no product, there is really no SBIR. So what is your product? It's really the most important question when you start to think about an SBIR application. 

So this brings us to a significant section. So can your product change medical practice and if it is competitive enough in the market? As we all know, the purpose for Phase 1 is to have the Phase 2 for product development. Therefore, the milestone in Phase 1 is to be used to determine if the project is ready for moving forward to a Phase 2. Therefore, the milestone in the Phase 1 is really need to have quantitative and measurable. 

So with a product in mind, what should be in the Specific Aim page? This is really the most important page of the application, so use the full page, at least 90% of the page. And I see it as the beginning and the end of the entire application preparation. 

We start with the end and we develop the strategy, and end that mature, and we finalize the end. Since this is a page that reviewers get prepared for what to anticipate from the application, so it should have at least the product, and the significance, and the product, if it can change the practice and how is the market competition? And also the backgrounds and importance, also, how we de-risk of the application. 

Of course, there are ends with the timeline, again, with the quantitative milestones. Phase 1 is really to get to Phase 2, so you want to have the Phase 2 in mind. And so I always put a projected ends for Phase 2 in the Phase 1 Specific Aims. And of course, the concluding remarks for what really the impact of the product. 

This is example showing the structure of our Specific Aim page. Of course, a product, significance with some market information, and the background, and also what is the technique and innovation, also how we de-risk the application. 

And of course, we have a Specific Aims timeline and milestone. And what I think is quite important, again, is to have what is projected aims for, for Phase 2, since this is Phase 1 and is trying to move forward to the Phase 2. So it's good to have this or to show reviewer you know what you want to do in Phase 2. 

And the concluding remark, and full page, of course, it's almost full page here. So in the next couple slides, I would like to use this specific aim here to further illustrate how we de-risk the application and also how we work to get the milestone to be quantitative and measurable. 

This is a section for background, including company information, technical innovation, and the risk mitigation, and how they related to the proposed ends. 

I like to highlight the risk mitigation within in this section, such as the preliminary data such -- Our success in developing messaline [phonetic] assays and also successful mapping the HVCC [?] specific CPG methylation signatures for, to propose stream for assay development, and the already completed tests for detection of HVCC [?] specific TP-50 [unclear] mutation. 

One of the three marker assays, that Phase 1 proposed to do, to develop and to evaluate for performance. And finally, availability of the study materials with the sample size. 

All these were provided for risk mitigation in order to increase likelihood of success of the proposed Phase 1 study. So we can increase the likelihood to move forward in the Phase 2 application. 

So what specific milestones for diagnostic technology are essential to be included in Phase 1 application? And myself, I think you want to propose the milestone that is achievable, not the ideal, perfect one, it’s achievable and is measurable, and of course, it has to be justifiable, a better performance. 

So you need to know what are current test performance and how much better the threshold is needed to change the medical, current medical practice or improve the outcome of the disease. 

Ideally, for the diagnostic, you want to have 100% sensitivity and 100% specificity, but this is probably not real. Versus the reality, what are the current test performance? In the HVCC [?] screening, the biomarker, the most used biomarker are serum AP tests, which only has a 50% sensitivity with very high percent of specificity, 95%. 

So if you look at this number, you know you're not going to improve much in specificity, but there is room for sensitivity. So what we did is we propose, we believe it’s achievable, and indeed, it was achieved to detect 20 to 30% more HVCC [?] and earlier HVCC [?] to improve the survival, and that's. pretty significant. 

I mean, you detect 30% more than what can be detected, so this can be a justifiable. And we also emphasize the non-invasive, convenient urine test. 

So again, the really important is the measurable. So we have 20 to 30% more than serum AP and it's achievable, it's not 100%, and it's justifiable because it's significant to detect 30% more HVCC [?] to improve the prognosis of the patient. 

So how to make a milestone quantitatively? The answer is use the numbers, because the number you can measure for the success. As an example here, the M1 in our study is to develop three assays. How good does the assay need to be? 

So we say, well, five copies in here. So five is the number and if that's a justifiable, we say it's sufficient because we use five and we detect the markers previously. So basically, numbers and is it justifiable?

So in M2, the same, we put the sensitivity and specificity, again, achievable and justifiable numbers for the quantitative milestone. 

So in conclusion, Specific Aim page is the one page for reviewer to learn the entire applications. There should be a product and how to de-risk the application and with a quantitative achievable milestone to justify for Phase 2 study. And finally, good luck on your applications.

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BILLY BOZZA: There you have it. Special thanks to Enzyme by Design and JBS Science for speaking with us today. As always, don't forget to check our website, sbir.cancer.gov, for the latest funding opportunities and commercialization resources to support your journey from lab to market. 

This was Billy Bozza from NCI SBIR. Please join us again for the next installment of NCI SBIR Innovation Lab. And subscribe today wherever you listen. 

If you have questions about cancer or comments about this podcast, e-mail us at nciinfo@NIH.gov or call us at 800-422-6237, and please be sure to mention Innovation Lab in your query. 

We are a production of the US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Thanks for listening.