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To enhance speed to patient, the FDA had passed the Orphan Drug Act which allowed the personalized and targeted effort to treat orphan diseases. While these conditions are rare, they end up impacting nearly 30 million Americans who have these one of these thousands of rare diseases. Since the approval in 1983, over 600 drugs have been approved.One of results of decades of concentrated work on orphan diseases has been the acceleration on drug development activity around orphan diseases. However, the increased flux of activity has highlighted that the current process is obsolete and unable to keep up with the demand. As a result, the agency is taking proactive measures to support the review of these submissions.The FDA’s 90 in 90 Plan is focused on 2 goals:In 90 days, FDA will complete reviews of all orphan drug designation requests that are older than 120 days (the backlog) while maintaining consistent, scientifically rigorous reviews; andAfter 90 days, 100 percent of all new orphan drug designation requests will receive a response by the agency within 90 days of receipt. FDA will adhere to this 90-day timeline going forward.Goal 1 will be covered via 6 major objectives to complete reviews of all requests older than 120 days.Creation of a Backlog SWAT team of vetaran OOPD reviewers who will be focused on reviewing older requestsCreation of a Designation Review Template to streamline the review process.Reduction of discretionary workSetting up a CDER-CBER Orphan Designation Pilot Project so that CDER and CBER will do preliminary reviewsCollaborate with the Office of Pediatric Therapeutics to do joint reviewsShifting review of FOIA to the FOIA officeGoal 2 to maintain a 90 day review cycle is broken up into 8 objectives.FDA will establish an “FDA Orphan Products Council” to address scientific and regulatory issues related to orphan products to ensure a consistent approach to regulating these productsFDA will work to establish and implement a future state including the below changes. We will report on a full timeline of the progress on these activities within the next two months.Organizational re-structuring to maximize expertise and improve workload efficienciesLeverage the inter-center consult process, involving the medical product centers, that was developed for combination products to develop a streamlined process for consistent and timely orphan consultsDesignation and Exclusivity Programs (Orphan Drug, RPD, Humanitarian Use Device (HUD))Centralize orphan exclusivity review and determinationsContinue to enhance the information technology infrastructure, e.g., automating more of the administrative processes for designation reviewsImprove and implement streamlined “Designation Review Template” across all designation programs to bring more efficiency, consistency, and predictability to these activitiesComplete development of web-based training for sponsors to enhance quality of submissionsGrant Programs: With respect to the Orphan Products (OPD) Grant Program (Clinical Trials + Natural History) and Pediatric Device Consortia (PDC) Grant Program; FDA will:Revise grant monitoring processes by increasing utilization of desk-top and virtual tools and by implementing a new risk-based approach for conducting in-person site visits to grant recipientsModify and modernize reporting requirements so that FDA can continue to give a high assurance related to appropriate monitoring of federal funds and efficiently measures program successContinue to enhance IT infrastructure for continued efficiency and better monitoringReduce OOPD office-wide workloadModify Orphan Cluster meetings with EMA from monthly to quarterly o The impact of the reduction in frequency of meetings with EMA is mitigated by our wellestablished and long-standing relationship with our EMA counterparts, which will allow us to have ad hoc meetings should they become necessary in the intervening months.Modify FDA Rare Disease Council meetings from monthly to quarterly o The RDC was established in 2012 to serve as a forum to communicate and collaborate across the agency on rare disease issues. It is chaired by OOPD and includes representatives CDER, CBER, CDRH, OHCA, OL, and OOPD. Quarterly meetings would ensure continuity of cross-agency communication but would help reduce workload in administering monthly meetings. The implementation of more joint reviews and closer regular, ongoing collaboration should reduce the need for the larger, RDC meetings.Minimize outreach activities and discretionary projects to only those deemed most meaningfulOOPD will create a new “Tracking Dashboard” to monitor and facilitate its efforts to meet the new designation goals and FDA will report on overall workload and progress more regularlyA lot of these changes implement standardization of work and the reduction of bureaucracy by clarifying roles and decision makers in the process. This was a key focus of Trump’s drug regulation agenda and a change that Scott Gottlieb had been advocating for long before getting into office.

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] 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

The electronic medical records in the United States is a sad joke. Hospital electronic records are loaded with cut and paste errors and are replete with electronic templates that fill in everything automatically, to the point that a scan report that shoud be distilled into two sentences is pasted in it’s entirety.So every electronic note is pages and pages of filler before getting to the important part, the impression and plan. But even that is a joke with the problem list expanded to permit for optimal coding to collect payment from insurance and Medicare/Medicaid.The medical records are so long and complicated that no one reads them and that is a very bad thing. Because tucked into those records are the nuggets of very important information for how consultants are assessing a case and how the patient to be managed.I’m often called by hospitalists to help with a patient.Hospitalist: “I wanted to let you know that your patient is in the hospital.”Me: “Thank you, I know, I have been seeing her every day.”Hospitalist: “Oh, I didn’t know. What do you think?”Me: “I put it into my notes.”Hospitalist: “Oh, well maybe you can just tell me.”Whoever programmed EPIC and Cerner should be sent to Siberia for several years to atone. This stuff is awful.As to the question, an emphatic NO. Patients’ comments should not go into the medical record. That is an terrible idea. The medical record is supposed to be for medical care. It’s already too clogged with worthless data points and mind numbing in complexity.The medical records are not the comments section that comes with your restaurant bill. What doctors and nurses don’t need is one more thing to read instead of spending time at the bedside and getting patients better.Electronic Medical Records and the Demise of the Useful Medical NoteElectronic medical records (EMRs) are much on my mind, as last week at Medical Grand Rounds Robert (Bob) Wachter, chief of the medical service at UCSF, gave a brilliant talk on the unanticipated consequences of our move towards what he calls the “Digital Doctor.”Bob has thought a lot about this issue, so much so that he’s about to publish a book on the topic. In his talk, after a brief history of how we got to where the vast majority of U.S. physicians use EMRs, he focused on three main consequences:The fact that doctors now interact as much (if not more) with screens as they do with patients— the “iPatient” phenomenon. The no eye contact problem. The lack of doctors on the medical wards, as we gravitate toward “work rooms” full of computers. You know how pediatricians sometimes get drawings from their school-age patients that include the doctor? He showed a remarkable example, in crayon of course, of a doctor facing away from the artist (the child), the MD staring at a computer screen and typing. From the book: “I’m guessing this one didn’t make it onto the doctor’s Wall of Fame.”The loss of interaction between doctors when the data are digital rather than something you can hold. Remember that brilliant radiologist who used to go over all chest films on your medical team? Now a radiologist may be reviewing films at home overnight, or in India, reports filed digitally and not requiring any human-to-human contact with the ordering doctor. Radiology rounds are slowly disappearing, along with the time for clinicians to pause — and think collectively — about what the images mean.The potential for automated systems to amplify medical errors. We’ve grown increasingly reliant on computers to help with decisions, for better and worse. In a taut, complex story involving a series of increasingly unlikely errors, he described how a child received a massive overdose of medication during hospitalization — all the indirect result of how a poorly designed systems can usurp clinician autonomy.What he didn’t have time to cover (but does so in the book — he shared the excerpt with me), is the powerful effect EMRs have had on clinical notes.It’s a fact that the note as means of communicating how the patient is doing has all but been destroyed. Notes even from the best clinicians routinely have the following features:A massive amount of repetition. Cut/paste phenomenon #1.“Required” elements that serve no clinical purpose. How useful is a lengthy review of systems? And isn’t a history-directed, targeted physical examination of far greater value than a comprehensive one “done” merely to meet higher billing criteria?Giant chunks of computer-generated data. Cut/paste phenomenon #2. It’s mostly lab and imaging results, with no interpretation of what the data mean.Factual errors. Cut/paste phenomenon #3. In the ambulatory record, one of my favorites is that some children never age: “Has three children, a son age 10, daughters ages 8 and 1” — which is then written unchanged in the social history over the next five years. Reminds me of The Simpsons — Bart, Lisa, and Maggie never age either. On the inpatients, we routinely see this: “ID consulted, considering pneumonia, UTI, C diff, disseminated fungal infection as cause for fevers” — then these same words are repeated for many days after some or all of these diagnoses have been ruled out.Sentences whose sole purpose is to avoid getting sued. You know ’em when you see ’em. They sound defensive, are depressing to read, and communicate no useful clinical information.Boilerplate text of highly dubious relevance to the individual case. During a mandatory “compliance” review of my notes (shudder — is there anything in modern medicine more painful?), I had someone suggest I add the following phrase to all of my notes: “More than 50% of this 30-minute visit was spent counseling the patient on the chronic nature of his/her condition, the rationale behind the laboratory tests ordered, the importance of taking medications directed, and the directions for making follow-up visits. Contact information provided, and patient’s questions answered.” The rationale? “You don’t do a procedure, so you need to improve the documentation of what you’re doing with your time.” Lovely.The genesis of this problem, of course, is that the medical note is trying to do too many things at once. Previously a way of summarizing the clinical course of the patient, both for our own individual use and to communicate with other clinicians, it now has other masters with different motivations. Facilitated by EMRs, the note has subsequently evolved into a Jackson Pollock-like canvas of disjointed text, much of it of marginal or no clinical significance, with sections held together only loosely by the name and medical record number at the top of the page or screen.Here’s a solution that will never happen — let’s have the medical note evolve even further, breaking it down into distinct sections based on their primary purpose. Imagine three tabs on the top of the note; you get to read only the one you want or need:Clinicians, here’s your section — it includes the stuff you really want to know, such as the history, exam, and lab/imaging results that matter (not all the labs/imaging, thank you), plus what the clinician writing the note thinks is going on, and what he/she plans to do.Billing compliance folks, read this part — it will have the required review of symptoms (most of them irrelevant), lengthy rubber-stamp documentation of counseling and education, and whatever other parts are required by whatever payor this patient has. And it will be inserted there by someone who’s not a doctor — or even better, by some automated bot — because successfully generating this kind of documentation is not why we went to medical school.Medicolegal guys, this is for you — lots of defensive phrases here, none of them of any clinical relevance, but they’re here just in case something untoward happens and the case ends up in court. Electronic Medical Records and the Demise of the Useful Medical Note - HIV and ID ObservationsEMR Entry Error: Not So BenignCareless copying and pasting could to lead to deadly errors in the healthcare industry, and many errors are flying under the radar.EMR: Physicians read nurses notes less 20% time; while physicians notes read 97-99% - pg.4