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Expand Up @@ -299,8 +299,9 @@ <h2 id="toc-title">Table of contents</h2>
<li><a href="#perceived-fear" id="toc-perceived-fear" class="nav-link" data-scroll-target="#perceived-fear"><span class="header-section-number">6.2</span> (Perceived) Fear</a></li>
<li><a href="#reducing-uncertainty" id="toc-reducing-uncertainty" class="nav-link" data-scroll-target="#reducing-uncertainty"><span class="header-section-number">6.3</span> (Reducing) Uncertainty</a></li>
<li><a href="#avoiding-doubt" id="toc-avoiding-doubt" class="nav-link" data-scroll-target="#avoiding-doubt"><span class="header-section-number">6.4</span> (Avoiding) Doubt</a></li>
<li><a href="#discussion" id="toc-discussion" class="nav-link" data-scroll-target="#discussion"><span class="header-section-number">6.5</span> Discussion</a></li>
<li><a href="#references" id="toc-references" class="nav-link" data-scroll-target="#references"><span class="header-section-number">6.6</span> References</a></li>
<li><a href="#industry-experiences" id="toc-industry-experiences" class="nav-link" data-scroll-target="#industry-experiences"><span class="header-section-number">6.5</span> Industry Experiences</a></li>
<li><a href="#discussion" id="toc-discussion" class="nav-link" data-scroll-target="#discussion"><span class="header-section-number">6.6</span> Discussion</a></li>
<li><a href="#references" id="toc-references" class="nav-link" data-scroll-target="#references"><span class="header-section-number">6.7</span> References</a></li>
</ul>
</nav>
</div>
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<p>Yet still some doubts persist. If a sponsor submits analytical results using Tool X, but the agency reviewer re-analyses the data with Tool Y and sees a different result, who owns reconciling the differences? The sponsor, via a time-bound Information Request from the agency? The agency? The developer of Tool X? When the majority of analysis uses only one tool for analysis, this situation is likely to be a rare occurence. But when the toolset available to both sponsors and agencies becomes wider, then resolving these questions is likely to come up more often.</p>
<p>And what about agencies who typically do not re-analyse sponsor data? How can the industry provide reassurance and proof that analytical environments are validated: accurate, reproducible and traceable? When installation of software into an environment is a one-step process, we can be pretty sure of consistency across analysts. But if there are multiple steps involved, and the software can change almost daily, then how do we ensure this consistency and reproducibility? This is not just the job of IT organisations within sponsor companies, but the responsibility of the individual analyst, to ensure that they are working compliant with organisational processes and in validated environments. Audit trails and traceability helps ensure this, but it is a potential source of doubt for both sponsor and regulatory authority.</p>
</section>
<section id="discussion" class="level2" data-number="6.5">
<h2 data-number="6.5" class="anchored" data-anchor-id="discussion"><span class="header-section-number">6.5</span> Discussion</h2>
<section id="industry-experiences" class="level2" data-number="6.5">
<h2 data-number="6.5" class="anchored" data-anchor-id="industry-experiences"><span class="header-section-number">6.5</span> Industry Experiences</h2>
<p>The industry offers a diverse range of experiences that can significantly enhance your professional growth. Below is an overview of various industry experiences gathered so far:</p>
<table class="caption-top table" data-quarto-postprocess="true">
<colgroup>
<col style="width: 25%">
<col style="width: 25%">
<col style="width: 50%">
</colgroup>
<thead>
<tr class="header">
<th data-quarto-table-cell-role="th">Sponsor</th>
<th data-quarto-table-cell-role="th">Agency</th>
<th data-quarto-table-cell-role="th">Experiences</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><strong>RConsortium Pilot</strong><br>
<a href="https://github.com/RConsortium/submissions-wg">Info</a></td>
<td>FDA</td>
<td>Submitted<br>

<ul>
<li>Accepted</li>
</ul></td>
</tr>
<tr class="even">
<td rowspan="5"><strong>Novo Nordisk</strong><br>
<a href="https://www.youtube.com/watch?v=t33dS17QHuA">Presentation</a></td>
<td>FDA</td>
<td>Submitted<br>

<ul>
<li>Big data ADaM programmed in R and pre-announced this during Type C and B meeting packages</li>
<li>Remaining ADaM in SAS and double programmed in R (where applicable)</li>
<li>All TFL in R</li>
<li>Following requests from FDA all TFL programs and internal R packages submitted. Packages packed using pkglite.</li>
<li><a href="https://github.com/NNaikp/phuse-css-2023/blob/main/submission-files/instructions-to-programs-in-r.pdf">Additional guidance</a> and informal meeting with FDA statisticians on restoring R environment was held</li>
</ul></td>
</tr>
<tr class="odd">
<td>EMA</td>
<td>Submitted content using R</td>
</tr>
<tr class="even">
<td>NMPA</td>
<td>Same as PMDA</td>
</tr>
<tr class="odd">
<td>PMDA</td>
<td>Submitted<br>

<ul>
<li>Big data ADaM programmed in R and pre-announced during additional eSubmission meeting</li>
<li>Remaining ADaM in SAS and double programmed in R (where applicable)</li>
<li>All TFL in R programs submitted</li>
</ul></td>
</tr>
<tr class="even">
<td>Health Canada</td>
<td>Submitted content using R</td>
</tr>
<tr class="odd">
<td rowspan="3"><strong>Roche</strong><br>
<a href="https://www.youtube.com/watch?v=BlJNILSoZlM&amp;t=2187s">Presentation</a></td>
<td>FDA</td>
<td>Submitted content using R<br>

<ul>
<li>Initial pushback from the FDA reviewer to accept R, they wanted SAS instead.</li>
<li>Roche pushed back and submitted in R (based on Technical Conformance Guidance)</li>
<li>Key message - acceptance of R may vary between different agency reviewers</li>
<li>Key message - have the content &amp; format discussions early with the agency</li>
</ul></td>
</tr>
<tr class="even">
<td>EMA</td>
<td>Submitted content using R<br>
(no comments received so far)</td>
</tr>
<tr class="odd">
<td>NMPA</td>
<td>Submitted content using R<br>
(no comments received so far)</td>
</tr>
<tr class="even">
<td><strong>SwissMedic</strong></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Merck</strong></td>
<td>FDA</td>
<td>Submitted<br>

<ul>
<li>Multiple successful submissions</li>
<li>GxP platform available</li>
<li>Reproducible environment</li>
</ul></td>
</tr>
<tr class="even">
<td><strong>Astellas Pharma</strong></td>
<td>FDA</td>
<td>(2021) for using R markdown to submit programs<br>
<a href="https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/212608Orig1s006.pdf">Example</a></td>
</tr>
</tbody>
</table>
</section>
<section id="discussion" class="level2" data-number="6.6">
<h2 data-number="6.6" class="anchored" data-anchor-id="discussion"><span class="header-section-number">6.6</span> Discussion</h2>
<p>Contribute to the discussion here in GitHub Discussions:<br>
<a href="https://github.com/phuse-org/OSTCDA/discussions/6" target="_blank">Will the <strong>FDA</strong> accept data and analyses generated with solutions developed and available as open source?</a></p>
</section>
<section id="references" class="level2" data-number="6.6">
<h2 data-number="6.6" class="anchored" data-anchor-id="references"><span class="header-section-number">6.6</span> References</h2>
<section id="references" class="level2" data-number="6.7">
<h2 data-number="6.7" class="anchored" data-anchor-id="references"><span class="header-section-number">6.7</span> References</h2>
<p>Bell, B “Issues with Open Source Statistical Software in Industry: Validation, Legal Issues, and Regulatory Requirements” ASA JSM 2006.</p>
<p>Sukop, M “Using R: Perspectives of a FDA Statistical RevieweR”. UseR 2007 <a href="https://www.r-project.org/conferences/useR-2007/program/presentations/soukup.pdf" class="uri">https://www.r-project.org/conferences/useR-2007/program/presentations/soukup.pdf</a></p>
<p>U.S. Food &amp; Drug Administration. (2015, May 6).Statistical Software Clarifing Statement. Retrieved from FDA.gov: <a href="https://www.fda.gov/media/109552/download" class="uri">https://www.fda.gov/media/109552/download</a></p>
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18 changes: 14 additions & 4 deletions search.json
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"text": "6.6 References\nBell, B “Issues with Open Source Statistical Software in Industry: Validation, Legal Issues, and Regulatory Requirements” ASA JSM 2006.\nSukop, M “Using R: Perspectives of a FDA Statistical RevieweR”. UseR 2007 https://www.r-project.org/conferences/useR-2007/program/presentations/soukup.pdf\nU.S. Food & Drug Administration. (2015, May 6).Statistical Software Clarifing Statement. Retrieved from FDA.gov: https://www.fda.gov/media/109552/download\n\n\n\n\nBell, B. 2006. “Issues with Open Source Statistical Software in Industry: Validation, Legal Issues, and Regulatory Requirements.” https://ww2.amstat.org/meetings/jsm/2006/onlineprogram/index.cfm?fuseaction=people_index&letter=B.\n\n\nBowsher, P. n.d. “Open-Source-in-New-Drug-Applications-NDAs-FDA.” https://github.com/philbowsher/Open-Source-in-New-Drug-Applications-NDAs-FDA.\n\n\nDrug Administration (FDA), U. S. Food &. 2015. “Statistical Software Clarifying Statement.” https://www.fda.gov/media/161196/download.\n\n\nKnoph, Larsen, A. S. 2023. “Novo Nordisk’s Journey to an r Based FDA Submission.” https://www.youtube.com/watch?v=t33dS17QHuA.\n\n\nNeitman, Martin, T. 2023. “Shifting to an Open-Source Backbone in Clinical Trials with Roche.” https://www.youtube.com/watch?v=nqJsLSLd39A.\n\n\n“R Consortium Submissions Working Group.” 2021. https://rconsortium.github.io/submissions-wg/.\n\n\nSchuette, P. 2018. “Using r in a Regulatory Environment: Some FDA Perspectives.” https://rinpharma.com/publication/rinpharma_7/.\n\n\nSoukup, M. 2007. “Using r: Perspectives of a FDA Statistical RevieweR.” https://www.r-project.org/conferences/useR-2007/program/presentations/soukup.pdf; useR.",
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