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Archive for the ‘Electronic Publishing’ Category
21 CFR Part 11 and Electronic Publishing: the Elephant in the Room?
posted by Kathie Clark @ 8:16 PM
Friday, July 23, 2010
In my document management career, my company provided specialized EDMS solutions for Pharma (for submissions, SOPs, trial master files, etc.). It was a given that these systems needed to be Part 11 compliant, and I authored our position paper on how Part 11 compliance was achieved and demonstrated in our product. If our product had ever been viewed as being noncompliant, no one would buy it – end of story.
For whatever reason, few sponsors seemed to apply that same requirement to their publishing vendors. Back in the days of paper submissions, this didn’t seem too unreasonable. After all, the FDA says in Guidance for Industry: Part 11, Electronic Records; Electronic Signatures — Scope and Application”:
“Under the narrow interpretation of the scope of part 11, with respect to records required to be maintained under predicate rules or submitted to FDA, when persons choose to use records in electronic format in place of paper format, part 11 would apply. On the other hand, when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules and persons rely on the paper records to perform their regulated activities, FDA would generally not consider persons to be “using electronic records in lieu of paper records…”
But eCTDs don’t meet these criteria. By definition, when you submit an eCTD you are asking the government to accept “in electronic format in place of paper”- and as part of the conditions of acceptance, they state that “Electronic documents that bypass the controls for electronic files described in 21 CFR 11 are not considered official documents for review.” (see Guidance for Industry: Providing Regulatory Submissions in Electronic Format — General Considerations.”)
Despite this, I don’t hear a lot of talk about Part 11 and publishing tools. Vendors don’t post much on their websites about Part 11 compliance (and what they have often applies more to document management). Googling Part 11 and electronic publishing doesn’t return anything useful.
So where does that leave sponsors in terms of the need for compliance? Granted that in these days of McNeil plant closures, tainted heparin, accusations of suppressed safety data, and etc., it seems unlikely that the FDA’s risk-based approach to inspections and audits will result in scrutiny of sponsors’ publishing systems. But sponsors certainly don’t intend to entirely flout requirements or fail to follow good practices. It would be interesting to define what the essential elements of compliance and good practices are.
Some areas are straightforward. Most people would agree that their publishing tools should have limited access and operational controls to prevent errors. But other areas aren’t so clear. To add to the ambiguity, in the Scope and Application document, the FDA announced its decision to exercise “enforcement discretion”, specifically lack of intention to take enforcement action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of Part 11.
Audit trail almost always remains one of the most complicated issues for electronic systems – so given the “enforcement discretion” what needs to be audit trailed in a publishing system?
As a reminder, Part 11 applies to “Records that are required to be maintained under predicate rule requirements and that are maintained in electronic format in place of paper format.” In the document management world, almost everyone interprets this as meaning that draft documents do not require an audit trail, as you aren’t required to create or retain them at all in most cases. When you are publishing, everything is a draft, right up until you lock things down and send them through the gateway. When you are working on a sequence, if you add a specification, then remove it, is an audit trail needed? If so, is it because Part 11 requires it, or because the sponsor wants an “electronic watchdog” reporting on who made changes to the submission prior to finalization?
Many other Part 11 requirements should be important to the sponsor regardless of whether they are subject to inspection. I would want my electronic publishing system to be installed in accordance with an IQ protocol and validated with an OQ and PQ protocol regardless of whether they FDA requires this or not, because incorrect installation or operation could have a profound impact on my submission quality or timeliness.
I would be interested in hearing from my readers on this subject. Do you disagree with the assessment that Part 11 applies to publishing software? What do you consider the necessary elements for Part 11 compliance for your publishing tool? Is Part 11 the “elephant in the room” that no one will acknowledge related to publishing software, or addressed by following basic good practices?
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Updated Study Data Specifications and the eCTD Dataset Problem
posted by Kathie Clark @ 12:12 AM
Friday, April 30, 2010
A few months ago, FDA issued version 1.5.1 of Study Data Specifications. Although the changes in the new version were not great, they were significant for eCTD as a new specification for organizing datasets was defined. The change has to do with how the files are organized in the file structure in which an eCTD is delivered and has no effect on the Table of Contents that is visible to a reviewer (created from the eCTD XML backbone).
The specifications for organizing study datasets and their associated files in folders are summarized in the following figure. No additional subfolders are needed; unused folders do not need to be supplied. In the document, an accompanying table provides further definition of the folders.
The problem that this is causing in the short term is that current publishing tools are not set up to produce this structure. Looking at the folder structure required in the previous specification:
You will see an important difference: tabulations must be assigned to a folder based on whether they are STDM datasets or legacy format. The problem is that most publishing tools don’t “know” which of the formats are being used, and aren’t prepared to create and populate the legacy and sdtm folders.
A second difference is that there is now a separate folder for datasets under analysis, where previously analysis datasets were placed directly in the analysis folder.
So where does that leave sponsors? I see three main options:
- Demand an upgrade from your publishing vendor. Of course, that’s easier said than done as the vendor may not be prepared to provide this upgrade for the software version that the sponsor is using. Even if the vendor can provide a hotfix, the sponsor has to undergo all the agony associated with introducing the update into their validated environment.
- Manually update your folders and patch your XML. Ugh – never a great idea. If you do this make sure you update your checksums and have a good validation tool!
- Approach the FDA about a waiver.
I would be interested in hearing about what approach people are taking.
Today’s blog features a guest posting by Dr. Shannon Strom, Senior Regulatory Specialist at Cato Research.
Acceptance of electronic submissions by small to mid-size early-stage pharmaceutical companies has been characterized by a slow, but steady, conversion to the eCTD standard, and nowhere is that fact more evident than in the rate of IND conversions to eCTD format. According to the FDA, 52% of original marketing applications and 83% of efficacy supplements are received in eCTD format, but only 12% of original IND submissions are in eCTD format. However, the FDA’s numbers also offer positive signs for the future. While the percentage of original INDs submitted in eCTD format remained stable from FY 2008 to FY 2009, the number of IND amendments in eCTD format nearly doubled, indicating that companies are beginning to understand the benefits of electronic submissions.
Small to mid-size pharma companies most frequently cite infrastructure requirements as the reason to delay conversion to electronic submissions. For a small or early?stage organization with limited budgets and internal resources, the expense of purchasing electronic submission software, including the implementation and validation effort, can be overwhelming enough to wait until the FDA or other global regulatory authorities require electronic-only submissions. After the software is purchased, installed, and validated, a company must also make another investment in hiring a regulatory submission specialist with experience in electronic submissions or providing training to existing regulatory affairs resources to actually create and review the electronic submissions. Additional infrastructure considerations may include implementation of an electronic document management system, on-going validation requirements for software updates, implementation of standardized document templates, and training of medical authors to write for electronic submissions. It’s no wonder why electronic submissions can be so easily delayed by corporate management until strong convincing data justifies the investment.
But this “wait-and-see” type attitude ignores the very real benefits of electronic submissions for small firms. The FDA has stated repeatedly that the eCTD is their preferred format for both INDs and marketing applications, and that the review process is significantly facilitated by the automatic processing of sequences through the Electronic Submission Gateway. Large pharma companies have, for the most part, already made the transition to, or are actively engaged in, the transition process to electronic submissions. A product portfolio that already contains an electronic regulatory submission can be more attractive to a large pharma company than a paper-based regulatory dossier because the time and effort to convert the submission to electronic format is saved. Therefore, it’s within a smaller company’s best interest to develop electronic dossiers as soon as possible.
Software providers have developed very cost- and time-effective solutions to minimize the impact of electronic submissions on existing corporate infrastructure and business goals. The best solution for some companies may be to outsource some, if not all, of the components of the electronic submission process. One of the more innovative solutions in the last few years has been to utilize Software as a Service. In this business model, the submission software is “rented” as a hosted solution from the software vendor to minimize the internal infrastructure requirements and the validation effort and to maximize the time spent on creation of electronic submissions.
In summary, the transition to electronic submissions for IND-phase submissions can be difficult, but represents a real economic and time-effective choice for innovative early-stage companies.
Cato Research is a full-service CRO with international resources dedicated to helping pharmaceutical and biotechnology companies efficiently and expeditiously navigate the regulatory approval process in order to bring new drugs, biologics, and medical devices to the people who need them. One of Cato’s specialties is outsourced regulatory publishing, and they bring considerable expertise and experience to creating and maintaining NDAs, BLAs and INDs in the eCTD format. For more information about Cato’s services, contact Christine Warrington at 919-368-5995. Also check back for a URL to Cato’s new blog, which will be launched shortly.
EDM Reference Model, eCTD, and the Holy Grail
posted by Kathie Clark @ 11:54 PM
Monday, October 19, 2009
Many of you are no doubt familiar with the EDM Reference Model. This is a cross-SIAC initiative by the DRM (Document and Records Management (DRM) SIAC. [A SIAC is a Special Interest Area Community within DIA.]
As a quick refresher, the goal of this group is to define a minimum set of metadata to enable the context of use of regulatory submission for CTD documents and supporting documents. In other words, what metadata should be used to tag each type of document that is included to or closely related to a CTD submission, in order to fully understand what information it is representing? The problem was broken down into six domain areas: Regulatory administrative, Regulatory labeling, Regulatory Pharmacovigilance, Clinical, Nonclinical, and Quality/CMC.
The taxonomy/metadata reference model could then be used by any company as a starting point for building document management processes and electronic document management systems, shortening the timeline and reducing the expense of implementing EDM systems. It might also enable documents and data to be exchanged between disparate systems in licensing-in or acquisition business scenarios.
This approach is familiar to me as in my former life I was a document management consultant specializing in submission documents. Along with my colleagues, we piloted a similar approach starting around 2000, and constantly refined our “best practice” taxonomy and metadata with feedback from our clients. We also reviewed it with every change in guidance from a regulatory authority. The approach worked really well, cutting down the analysis time for an EDMS for submission documents by an order of magnitude compared to the “blank slate” approach. (However, many big pharma, unless firmly managed by their own project manager, continued to find reasons why the model could not possibly be used out of the box for them because they were “different”.)
Anyway, to get back to the story – the EDM Reference Model appears to be gaining some traction now as I see a number of vendors have made announcements that their products are incorporating the model. On the whole, I think that’s a good thing. While I don’t think it offers much benefit to clients of my former company (which already had a sophisticated best practice model), it offers a major step up for some vendors who, in the past, have been more about the tools than about the best practices and industry knowledge.
While I was back in the document management world, there was one “Holy Grail” that we never reached – using metadata to automatically populate an eCTD table of contents. It was always something that was out there for our next release (since we had almost all the necessary metadata) but something we never quite got to.
Since I have moved out of the document management world and more into the submissions world, I have become skeptical about the true value of that “Holy Grail”. Realistically, I think there are a number of reasons why the auto-population would be a nice to have but in the end not really much of a time-saver. These reasons include:
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Despite the best intentions of eCTD being a “global” submission, documents submitted are substantially different in each region. And it’s not usually workable to tag a document (such as an analytical method or stability document) for the exact regions in which it will be submitted.
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Study components submitted in Europe are often different than in the US, and it’s not just as simple as excluding SAS files and CRFs.
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In the CMC world, you may be submitting documents that are not the current version.
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Again despite best intentions, document management systems often have various documents in them that won’t ever be submitted, multiple documents representing the same content, and other issues it takes a person to resolve.
But in the end, the real reason I don’t think it’s really a signficantly worthwhile exercise is that it really only makes sense for an original application. How would a computer know which documents you wanted to put in an amendment, variation or supplement unless you told it? Which would amount to doing the same work as you do dragging and dropping a document into a submission anyway.
The bottom line is that even the biggest company only produces at most three or four NDAs/MAAs in a year - most work goes into maintaining submissions. When you look at how long it takes to populate the submission TOC, even for an original application, you would not be saving much time. However, you would be increasing coupling between your EDMS and your publishing tool, and significantly increasing the time and complexity to validate (think about what happens if it misses a document).
But I would be interested in the thoughts of others in this area…
Regulatory Software Technology Trends Survey
posted by Kathie Clark @ 6:56 PM
Monday, August 24, 2009
Recently, I caught up with my old friend Steve Gens (of Gens and Associates Inc.) to talk with him about a very interesting global survey he just completed on “Benchmarks of Emerging Technologies and Approaches for Collaboration and Document Management” in the Pharma industry. The 2009 survey was completed in partnership with Steve Scribner of International Life Sciences Solutions, as a follow-up to their well-received 2007 survey. Steve and Steve worked with 37 Pharma companies (including 17 of the top 20, but no very small companies) to understand their collaboration and document management practices, program priorities and challenges, technology landscapes, outsourcing, and total cost of ownership. Some of their findings may surprise you.
Here are a few key points from the Gens & Scribner survey (including both the expected and the surprising):
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Over 90% of respondents feel that their Electronic Document Management (EDM) solution for submission documents is effective, with less than 10% considering their solution ineffective; however 44% will be changing their systems within the next three years. All of the respondents had implemented an EDM solution.
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Top priorities for companies in the EDM area are integration with collaboration systems, enhancing system performance, improving searching, and reducing TCO
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Speaking of collaboration, just over 50% feel that they have an effective solution. The survey also provided insight on specific aspects of collaboration, such as collaboration with partners and regulators, with details available in the figure below.
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Adoption of XML authoring remains rare outside of the obvious areas of labeling, with less than 10% of companies reporting other applications such as clinical and nonclinical reports and protocols. Even in the labeling area, only 25% of companies are doing XML authoring themselves. Many companies are projecting to conduct pilots in 2010 & 2011.
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eCTD adoption was nearly universal, with only a couple of the participants (both Japanese) still researching or unsure about adoption.
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PIM, on the other hand, has been adopted by only about 15% of companies, with another 10% in the process. (and lots researching, probably due to the news that PIM will be mandated in the relatively near future).
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Out of the 37 companies, only 8 are submitting PIM right now – four top 20 and (surprisingly to me) four mid-tier
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Dossier publishing was outsourced to low cost regions at least in part by 15 out of the 37 companies, with India (4) and China (4), with 10 companies planning to expand outsourcing. Although companies are increasingly driven to overseas outsourcing due to economic reasons, they are also very concerned with Intellectual Property issues in many outsourcing regions.
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Twenty-four percent of EU participants outsource NeeS production. Out of that group, 31% were satisfied with their outsourcing arrangements and about 31% actively dissatisfied. Interestingly, satisfaction rates with eCTD outsourcing were significantly higher.
One conclusion that was surprising to Steve was that a great many companies do not yet collect metrics on cycle times and the efficiency and value of their EDM-related programs. Companies are also much slower to implement regulatory tracking than projected, most likely due to issues regarding data cleansing and harmonization/adoption of a global system by stakeholders used to many specialized if less capable local systems.
What’s Next?
Steve and Steve will be conducting individual debriefing sessions with the survey participants in the coming weeks. These sessions help the participating companies understand where they stand with respect to their peers in the industry. In previous years, the extremely detailed information provided to the participants has proven invaluable in confirming their direction and priorities or helping them re-plan. Having seen the detailed information and analysis that will be presented in the debriefing sessions (a subset was presented at the DIA Annual Meeting in June), I can well believe that the participants in the 2009 survey will conclude that the time they spent participating in the survey was a good investment.
If you didn’t participate in the survey, you may still be able to get more detailed information since Steve and Steve will most like make some of it available in a series of articles or presentations in upcoming months. Contact information is as follows: Steve Gens (sgens@comcast.net) and Steve Scribner (SteveScribner@nc.rr.com). They have over 40 years experience in the Life Science industry and both their companies provide consultancy services (Strategy, Implementation Planning, and Program Management).
As promised, the EMEA released Version 1.4 of the EU Module 1 Specification on schedule in August. The new spec has some changes that will impact eCTD assembly, publishing, verification and viewing software tools. The EMEA has reached out to the vendor community to ensure that they are aware of the changes to ensure that they can modify their products in advance of the required implementation timeline. It’s worth reproducing that timeline here – quoting from EU Module 1 Implementation Guidance:
1. Applicants are advised that, from 1st January 2010, when the new variation regulation comes into force, the EU M1 v1.4 must be used for any eCTD submission for any European procedure that contains grouped variations or is subject to a worksharing agreement. Grouped variation or worksharing eCTD submissions provided from this date using any previous version of the EU M1 specification (v1.0. v1.1, v1.2.1 or v1.3) will not be accepted. All European Regulatory Authorities must therefore be able to accept eCTD submissions built using EU M1 v1.4 from 1st January 2010.
2. Applicants are further advised that, from 1st July 2010, the EU M1 v1.4 must be used for all eCTD submissions for all European procedures, and any eCTD submissions provided from this date using any previous version of the EU M1 specification (v1.0. v1.1, v1.2.1 or v1.3) will not be accepted
The nature of this timeline is related to the most significant change in V1.4: the Specification and DTD have been amended so as to support the New Variations Regulation. The envelope has been reviewed so as to support the different modes of submission for variations: single, grouping and worksharing.
A new envelope element, submission ‘mode’ is now provided for use with variations and line extensions. A related change involves the use of a “high-level” submission number for worksharing submissions and certain grouped submissions. Submission publishing tools will require user interface changes to accommodate these requirements, and publishers will need to be aware of their correct usage. EMEA has also provided a number of sample submissions to illustrate the correct use of these elements.
Another significant change is a new limit on folder path length. The Specification has been amended to update the maximum length for file path. The new maximum length has been set to 180 characters. That is, the overall folder and file name path length starting from the sequence number should not exceed 180 characters, for any file in any module. This is an EU regional requirement, and it is acknowledged that this is less than the ICH agreed overall path length. This may cause issues for anyone using attribute-related folder paths (such as drug substance, indication, etc.) of more than a dozen characters or so. Although this won’t affect sequences already submitted, it will mean that some sponsors may have to modify their conventions in this area (keep in mind that the HAs have said that folder names do not have to actually match metadata in the eCTD backbone).
A few more minor changes:
· The ATC number metadata in M1 has been retired
· A few new values have been added for submission type
· A new stylesheet has been supplied
· Naming conventions for the tracking table have been updated
Sponsors need to prepare to accept and validate updated versions of their publishing tools and will need to work with vendors to ensure that updates will be available in advance of the portion of the deadline that applies to them based on their submission plans. They will also need to update some procedures.
It’s worth reviewing the EU Module 1 V1.4 Release Notes to make sure you understand all the changes…
In other EMEA news, a The NeeS validation criteria v1.0 (a set of technical validation criteria to be applied to all non-eCTD electronic submissions has been drafted. Finally, Practical guidelines on the use of the eCTD format for the Plasma Master File (PMF), for the submission of MAAs for plasma derived medicinal products and medical devices that include a PMF certificate, and for 2nd step procedures, has been released by EMEA.
Loads of Great Information from The AAPS Workshop on Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
posted by Kathie Clark @ 7:24 PM
Tuesday, May 12, 2009
*** Update: the links below, which had been working fine between when this was posted and today (May 18), appear to be no longer functional. Possibly the AAPS had not meant them for public consumption; however, I have not been contacted by them so I don’t know this for sure. Apologies that the links no longer work but they are out of my control. - K.C. ***
You could contact the AAPS, or see if you can track down the speakers and ask them for the presentations. The following email addresses were included:
Agencies:
Health Canada: ereview@hc-sc.gc.ca
EMEA: eCTD@emea.europa.eu
PMDA: ectd-helpdesk@pmda.go.jp
MPA: karin.grondahl@mpa.se
FDA: gary.gensinger@fda.hhs.gov
The AAPS Workshop on Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now! was held March 9-11, 2009. There were some great presentations, and best of all they are publically available. The agenda contains links to the presentations.
All the presentations were good but some of the highlights for me appear below. There’s great information on Japan and Health Canada that has been rather hard to locate recently, and lots of discussion about some of the more puzzling and problematic aspects of eCTD as they relate to CMC in particular – so you know there will be discussions about metadata, granularity, and the tradeoffs in structuring M2 and M3.
Updates from the Regulators
Evdokia Korakianiti of EMEA presented eCTD: EMEA Experiences containing FAQs received by the EMEA, concerning CMC metadata, CEPs, ASMF – plus some great key messages for industry.
The presentation eCTD in Japan by Harve Martins has lots of good info on eCTD in Japan that has not been readily available – such as details and examples on lifecycle (handled in an accumulative approach in Japan), Module 1 TOC, cover letter and form information, module 5 unique requirements, validation details, submission instructions, etc. I’ve reproduced the update on the number of sequences received in Japan (keep in mind that a reference application is something like Health Canada’s co-submission – in effect a review aid for a paper submission.) 
Health Canada’s Vianney Caron presented e-Submissions at Health Canada which reviewed HC’s history and future direction with eCTD, challenges and issues with CMC documents, especially the QOS. Health Canada also presented statistics on the number of eCTDs they have been receiving (they now get about 7% of their regulatory activities in eCTD format). 
Regulatory Activities in eCTD format (NDS, SNDS, ANDS, SANDS, NC)
About 8.2% of submissions are currently failing validation, well down from the 31% experienced in early days. Following the lead of FDA and EMEA, they have provided their top 10 list of validation errors:
1. Inactive bookmarks -no link destination
2. Inactive hyperlinks -no link destination
3. External links -pointing to the folder or destination that does not exist in the folder structure on the CD/DVD. The folder or destination would only exist in the sponsor's repository.
4. Incorrect naming of the 3011 form (correct name is hc-sc-3011-en.pdf)
5. Unreferenced files in the index.xml or ca.regional.xml
6. Life cycle management of the document: invalid file reference or no previous ID found
7. Subfolders created in ca regional folder
8. Missing top level folder
9. Missing attestation letter; content as per eCTD Guidance, letter needs to be dated and signed
10.Printed content of MD-5 Checksum does not match the one in the index-md5.txt file
Health Canada strongly recommends electronic submissions in eCTD format, and they plan to expand the existing architecture to support as many application types across product line as possible. Some of their next steps in support of eCTD include:
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Perform assessment of the hybrid pilot
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Widen the scope to more electronic data in eCTD format
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Implement two-way secure electronic communication (secure channel, secure email and gateway)
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Improve tracking system and integrate it with a workflow system
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Strengthen international collaborations
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Announce a date (TBD) for accepting electronic-only submissions
The eCTD Industry Forums –Europe presentation by Phyllis Thomas of AstraZeneca UK summarizes discussions by the CMC eCTD informal industry group and EFPIA eCTD-Q topic team. It has lots of discussion about metadata and repeating section issues, including illustrative examples. It also discusses issues and areas that lack clarity that have been passed on as Q&A and in turn referred to the harmonization taskforce (some of them not yet resolved).
ICH & Regional Guidance and Terminology by Hans van Bruggen provides a comprehensive summary of eCTD status in many regions (including individual EU countries). Again, this is information that is hard to find and nearly impossible to find in one place.
Industry Best Practices
In Points to Consider for Case Studies in Lifecycle-Biologics, Colleen Godshall of Merck addresses some of the issues that have always caused me to hold CMC people in awe: however do they perform impact analysis of change and manage the approvals and notifications requirements that are so different in every region? Concrete examples are provided, such as “Adding a New Air Handler to a Class 100 Area used to manufacture multiple vaccines”. Ms. Godshall also talks about managing 3.2.A.1 for both US applications, which allow cross-applikcation linking, and International Marketing Authorizations, which do not.
A presentation by Pamela Cafiero of Boehringer Ingelheim, Simultaneous eCTD Applications in US and EU: Similarities/Differences and the Reasons Behind them, gives detail on a subject I’ve been asked about many times – what are the real differences in content between US and EU Module 3? She also gives recommendations about document identification (header/footer), Referencing between CMC documents, referencing and linking within Module 3 (her minimalist approach resulted in about two dozen links between Module 3 documents and was the same in US and EU), and recommendations and examples of CMC metadata, leaf titles and the relationships between them.
Phyllis Thomas of AstraZeneca UK also spoke about USING MODULE 3 (FOR INDs). She focused on encouraging the use of granularity in IND M3 (even though it is not required) and some special considerations for INDs such as Placebos, Comparators, and Introductory CMC text.