Clinical Summary Template: Fill & Download for Free

A New Drug Application (NDA) follows the same format as a Biologics Licensing Application (BLA). Nowadays, the applications even go to the same division. The notable difference is that NDAs fall under the Food, Drug, and Cosmetic Act where as the BLAs fall under the Public Health Service Act. The BLA will also have a more extensive emphasis on facilities and process. That said, I can completely see a scenario where the NDA would basically do all of the same steps and reviews as a BLA. Since both a NDA and a BLA follows the same structure outlined in the International Conference on Harmonisation (ICH) for the Common Technical Document (CTD), they have the same flow and the same material will go to other agencies like the Marketing Authorization Application (MAA) to the EMA and the JNDA to the PMDA.For more details I would suggest looking at How is the FDA approval process for New Drug Applications (NDAs) different from Biologic License Applications (BLAs)? The only decent figure about the differences produced by an “expert” that I don’t trust is the followingAnyways the timeline. The answer really depends on how ready the different bodies are and how they’ve been generating their data and how well these different bodies communicate with each other.While the clinical teams are filling out the clinical summary (2.5/2.7) in Mod 2, the PD/PK teams and Tox teams are doing their own studies (2.4/2.6). Many of those studies are determined as the clinical data comes back. It’s further broken into the Quality, Safety, and Efficacy. All of this work operates completely separately from Quality sections which comprises of Module 2.3 and Module 3 associated with the process development and manufacture. Since the process development is linked with the clinical material used for the trials and the data from the clinical trials is necessary to determine what would be considered Critical Quality Attributes that would influence the Target Product Profile of the drug, you really need the two units to communicate with each other all while you’re operating under triple blind conditions.The CTD consists of a huge number of sections from units that have completely different timelines. The “structure” of the application is associated with each individual segment of the above CTD and it’s further broken into smaller subsections that will get updated during the drug lifecycle. Ideally, you have independent minions like me that handle each section.This is a schematic of a subteams for just a Module 3 NDA writing team.Still with me? Let’s assume that all of the data comes back in good shape and there is shockingly no need to redo any studies.If you were smart and forward thinking, a company that probably has gone through several mergers and acquisitions, 10 years of studies performed by hundreds of scientists, written by hundreds of authors, and uncountable number of handoffs, you should have the foresight to have a standard formatting guide using standard templates that makes all of the reports sound like it was written by one person AMIRIGHT?Thus begins the long and arduous process of an army of technical writers trying to find all of the relevant source documents that have been accumulated over the years and copy and pasting them into the relevant sections and copy editing them so that it doesn’t sounds like hundred people wrote individual sentences and then decided to string them together (although that’s probably what just happened).Presumably you’ll probably want to check that they didn’t accidentally delete any numbers or provide too much information. Chances are you’ll have an independent reviewer look over all of those numbers and confirm that they are the same.By this point you’ll have thousands of pages of individual sections. It should just be a simple PDF rendering and then merge! Apparently the “Publishing” of the eCTD process itself takes several days. Part of the challenge is the the individual sections hyperlink to each other and are connected by some XML backbone thing to make sure that it’s all connected or something. IT’S COMPLICATED.All of this happens with a simple premise: if the writing is not good, it means that the reviewers will need more time to review and they will need to ask more questions and that adds time to the review cycle and prevents your drug from getting to the patients that need them.Now for the question. How long does it take? How long does it take for a small team of researchers to write a manuscript? How long does it take for for a long team of scientists to coordinate to write a manuscript? I think that’s the right comparison. ATLAS and CMS are probably the other extreme when it comes to writing 1,000 author manuscripts. There you had hundreds of individual teams ensuring that their sections were accurate all while being coordinated by some master section chiefs. At the same time, if you did all of the writing correctly ahead of time, you should have all of the individual sections ready to go and easily merged.One of the great problems about the completion of Phase 3 trials is that they tend to be unexpected. Companies will schedule “checks” where select people will look at the data and decide whether or not they should unblind the data. Even after the data is unblinded and the company decides to kill the program or shift everyone over to the dose arm, the trial is still “going on” as they monitor the overall survival of the active population.But if I had to imagine writing a NDA from scratch, it sounds like it would take around half a year to ready a submission.But that’s not actually what happens. Under the FDA’s fast track program, they will accept rolling submissions. Thus, if they feel that the prospects of the clinical trial are looking good, OR they have already granted an accelerated approval and they are looking for an expansion of the application, they will take a look at the already completed section. Typically, the FDA will only look at the non-clinical and quality data after efficacy has been shown but if they are feeling good about the power of the efficacy data, they’ll start looking at the other sections early.Thus, companies will start writing these sections ahead of schedule at risk. Likewise, for the clinical data, they’ll probably prepopulate the reports and sections and leave the tables and conclusions empty until the data starts rolling in. Likewise, the non-clinical groups will write what they can in their main sections and fill in the gaps as their final studies come back together. These groups also have the opportunity to go back into the archives and revise all of their older source documents so that they follow the same style guides as the newer sections so that their data is ready for the Tech Writers once they become available. Those teams are then going to sit on their sections until the clinical results are announced and they’ll race to push out the NDA. As the individual reviewers finish their reviews the queries will go back to the companies where they will try to quickly provide a response to minimize the review time. At the end of the review process when all of the inquiries can come back and the FDA is satisfied with the quality of the product, they’ll start to finalize the label and look at the final steps of drug release.Using Merck’s submission strategy, they started writing their filing before they actually qualified their process via their PPQ. [1][1][1][1] Thus, they wrote up their process characterization and stability work before they achieved a process lock and demonstrated process validation. A huge risk if their process didn’t work.So practically speaking, the NDA is being written the entirety of the Phase II/III clinical trials. Since no one knows how long those trials can last, it could be a year, it could be 5. Either way, people are probably going to be locked up in rooms with lots of Red Bull typing away into the night hoping to get their drug to people as quickly as possible.Footnotes[1] http://c.ymcdn.com/sites/casss.site-ym.com/resource/resmgr/WCBP_Speaker_Slides/2015_WCBP_ToblerScott.pdf[1] http://c.ymcdn.com/sites/casss.site-ym.com/resource/resmgr/WCBP_Speaker_Slides/2015_WCBP_ToblerScott.pdf[1] http://c.ymcdn.com/sites/casss.site-ym.com/resource/resmgr/WCBP_Speaker_Slides/2015_WCBP_ToblerScott.pdf[1] http://c.ymcdn.com/sites/casss.site-ym.com/resource/resmgr/WCBP_Speaker_Slides/2015_WCBP_ToblerScott.pdf

The title of the paper in question is: “Gender-Based Cerebral Perfusion Differences in 46,034 Functional Neuroimaging Scans”.That title is a good tl:dr summary of what was actually reported in the paper. The study in question compares the flow of blood to various areas of the brain across two main grouping factors — sex (male vs. female) and diagnosis (healthy vs. a variety of psychiatric conditions). A modest group difference between male and female was shown, but age and specific diagnosis may be interacting factors. The type of imaging study that was done has technical limitations. Data resulting from the study is not specific enough to allow more than speculation on how the results relate to anything about differences in cognition or “thinking”.The blood flow difference is likely real (and has been shown before), but small, possibly more a product of physiology than cognition, affected by other factors, and any speculation coming from this difference about female thinking vs. male thinking should be taken with a ****ton of salt.Specifically:A group which runs community-based clinical imaging centers (Amen Clinics*) collected a very very large number of brain scans over many years. So this is a retrospective study, using a dataset that contained patients and healthy people who came into various clinics and got scanned for a variety of reasons. The group included many diverse psychiatric conditions, ranging from ADHD to cognitive decline to dementia.There was a small to modest (Cohen’s effect sizes d reported ranges from ~0.3 to 0.6 for most brain areas) group difference between males and females.The parameter that was different between the male and female group was a measure of how much blood was flowing to specific areas of the brain. The blood flow was measured “at baseline” and also while doing a “concentration task”. In both men and women, blood flow increased during the task stage, although the task-based increase was only significant in healthy female controls.The paper also reports that they controlled for age, but the age range in their sample was quite large, and there’s no detailed report of the distribution of age. This is potentially important to the interpretation of results, as it is known that there is also age-associated reductions in cerebral blood flow. Thus, a male sample skewed older could affect the group difference.Male/female differences in cerebral blood flow have been reported in the literature since the 1980’s when this was measured with gas inhalation studies.Blood flow is coupled to the activity of neurons, because of Neurovascular coupling. However, this coupling may be affected in various brain disease, like dementia or atrophy (which they didn’t explicitly look at in the paper).The one technical issue that I can see, as someone who has done imaging analysis, is how the group analyzed the images. Normally, a brain imaging study first involves a step called “spatial normalization”, where individual brain scans are warped and transformed into a common space, usually defined by a template brain or brain atlas. In the paper, instead of warping the individual brains to the common space and then making comparisons, they warped the template to the individual brains. That is not the standard, commonly used procedure for the AAL template used in the paper. It might be that the study had to do it that way because the low spatial resolution of the SPECT scans — warping the SPECT scans to a higher resolution template probably didn’t work well enough to produce the statistical maps they needed for the next step of the analysis.*Amen Clinics provides SPECT scans as a means of diagnosing a variety of psychiatric issues. However, using SPECT scans in this manner is very controversial at best, and Amen Clinic’s use of SPECT scans a tool for psychiatric diagnoses has been severely criticized.

In my view, a template is clinical and does not allow for the qualitative aspects that are equally critical in a company, especially in a startup.My suggestion is to provide a short summary of the health of the venture, capturing critical aspects that will be relevant to investors. I would suggest the following:Overview - a one-para summary of what has happened since the last interaction (e.g. on product, customers, people, brand, etc.)A para on how the business is progressing as per the plan (including what is working well, and what is not progressing well - could be on customers, pricing, costs, people, cost of servicing, etc.)Highlight challenges or red flag any thing that you see as issuesOutline what you wish to achieve in the next month (I have noticed that investors may not pay too much attention to this para, as usually it is transactional and mundane. However, if it is not there, it usually creates discomfort. Just having even the regular stuff in this is reassuring that all seems to be well.)If needed, seek assistance in any area that they can helpAnother reason why I think a good, crisp report every month is a good idea is because it allows you to also reflect on the progress and helps you identify red flags for yourself earlier too.In most cases, investors want to help. These type of reports provide investors a good view of where they can help, and allows you to seek out their support when and where required.