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  1. documents/10.1056_nejmoa1801005/protocol.html +18 -29
  2. documents/10.1056_nejmoa1801005/sap.html +18 -29
documents/10.1056_nejmoa1801005/protocol.html CHANGED
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@@ -1509,7 +1509,7 @@ combination arm at the pre-specified FA, an updated analysis may be conducted wi
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  2.2 Trial Diagram</h3>
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  <div>The trial design is depicted in Figure 1.</div>
1511
  <div class="table" number="1">
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- <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-019.jpg?height=929&width=1522&top_left_y=784&top_left_x=330" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 1 Study Schema</div></div>
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  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.0-objective(s)-%5C%26-hypothesis(es)">
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  3.0 OBJECTIVE(S) &amp; HYPOTHESIS(ES)</h3>
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  <div>Pembrolizumab in combination with chemotherapy will be compared with saline placebo in combination with chemotherapy in subjects with advanced or metastatic nonsquamous, nonsmall cell lung cancer (NSCLC) who have not previously received systemic therapy based on the following primary, secondary, and exploratory objectives:</div>
@@ -2880,19 +2880,7 @@ if the subject started new antineoplastic treatment (serious adverse events will
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.023ex" height="1.532ex" role="img" focusable="false" viewBox="0 -677 1778 677"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></svg></mjx-container></span> days</td>
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  </tr>
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  <tr style="border-top: none !important; border-bottom: none !important;">
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- <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="2">Administrative Procedures</td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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  </tr>
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  <tr style="border-top: none !important; border-bottom: none !important;">
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  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Informed Consent</td>
@@ -3045,7 +3033,7 @@ if the subject started new antineoplastic treatment (serious adverse events will
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  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="11"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-052.jpg?height=38&amp;width=1225&amp;top_left_y=1426&amp;top_left_x=1084" alt="" data-align="center"></figure></td>
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
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  </tr>
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  <tr style="border-top: none !important; border-bottom: none !important;">
@@ -3799,7 +3787,7 @@ if the subject started new antineoplastic treatment (serious adverse events will
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  <tr style="border-top: none !important; border-bottom: none !important;">
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  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
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- <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="9"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-055.jpg?height=38&amp;width=1220&amp;top_left_y=1004&amp;top_left_x=1136" alt="" data-align="center"></figure></td>
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
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  </tr>
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  <tr style="border-top: none !important; border-bottom: none !important;">
@@ -4713,8 +4701,9 @@ if the subject started new antineoplastic treatment (serious adverse events will
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">±</td>
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">±</td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-059.jpg?height=60&amp;width=27&amp;top_left_y=605&amp;top_left_x=1388" alt="" data-align="center"></figure></td>
 
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
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  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
@@ -6060,7 +6049,7 @@ The analyses planned, endpoints evaluated and drivers of the timing are summariz
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="1.448ex" height="1.025ex" role="img" focusable="false" viewBox="0 -442 640 453"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D6FC" d="M34 156Q34 270 120 356T309 442Q379 442 421 402T478 304Q484 275 485 237V208Q534 282 560 374Q564 388 566 390T582 393Q603 393 603 385Q603 376 594 346T558 261T497 161L486 147L487 123Q489 67 495 47T514 26Q528 28 540 37T557 60Q559 67 562 68T577 70Q597 70 597 62Q597 56 591 43Q579 19 556 5T512 -10H505Q438 -10 414 62L411 69L400 61Q390 53 370 41T325 18T267 -2T203 -11Q124 -11 79 39T34 156ZM208 26Q257 26 306 47T379 90L403 112Q401 255 396 290Q382 405 304 405Q235 405 183 332Q156 292 139 224T121 120Q121 71 146 49T208 26Z"></path></g></g></g></svg></mjx-container></span>-allocation for each hypothesis in the ellipse representing the hypothesis. The weights for reallocation from each hypothesis to the others are represented in the boxes on the lines connecting hypotheses. This is further explained below.</div>
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  <div>See Figure 2 for the type I error reallocation strategy for endpoints PFS, OS, and ORR.</div>
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  <div class="table" number="2">
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- <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-097.jpg?height=624&width=751&top_left_y=1072&top_left_x=719" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 2 Type I Error Reallocation Strategy</div></div>
6064
  <h2 type="section" data-unnumbered="true" class="section-title" id="pfs">
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  PFS</h2>
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  <div>PFS hypothesis will be tested at <span class="math-inline ">
@@ -6651,7 +6640,7 @@ through appropriate mechanisms (e.g., scientific publications and/or presentatio
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  <h2 type="section" data-unnumbered="true" class="section-title" id="understanding-the-intent%2C-scope-and-public-health-benefits-of-exploratory-biomarker-research">
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  Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research</h2>
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  <div class="table" number="3">
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- <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-119.jpg?height=388&width=1614&top_left_y=859&top_left_x=670" alt="" style="max-width: 100%;"/></div><div class="caption_figure">A Guide for IRBs/IECs and Investigational Site Staff</div></div>
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  <div>This informational brochure is intended for IRBs/IECs and Investigational Site Staff. The brochure addresses issues relevant to specimen collection for biomarker research in the context of pharmaceutical drug and vaccine development.</div>
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  <blockquote>
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  <div>Developed by<br>
@@ -6662,7 +6651,7 @@ The Industry Pharmacogenomics Working Group (I-PWG)<br>
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  1. What is a Biomarker and What is Biomarker Research?</h2>
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  <div>A biomarker is a &quot;characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention&quot;. '</div>
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  <div>Biomarker research, including research on pharmacogenomic biomarkers, is a tool used to improve the development of pharmaceuticals and understanding of disease. It involves the analysis of biomolecules (such as DNA. RNA, proteins, and lipids), or other measurements (such as blood pressure or brain images) in relation to clinical endpoints of interest. Biomarker research can be influential across all phases of drug development, from drug discovery and preclinical evaluations to clinical development and post-marketing studies. This brochure focuses on biomarker research involving analysis of biomolecules from biological samples collected in clinical trials. Please refer to I-PWG Pharmacogenomic Informational Brochure <span class="math-inline " data-overflow="visible">
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- <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> and ICH Guidance E15 <span class="math-inline " data-overflow="visible">
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.885ex" role="img" focusable="false" viewBox="0 -833.2 436.6 833.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></svg></mjx-container></span> for additional information specific to pharmacogenomic biomarkers.</div>
6667
  <h2 type="section" data-unnumbered="true" class="section-title" id="2.-why-is-biomarker-research-important%3F">
6668
  2. Why is Biomarker Research Important?</h2>
@@ -6734,7 +6723,7 @@ While it can be a chailenge to specify the details of the research that will be
6734
  <div>The duration of storage - The permissible duration of storage may vary according to the nature and uses of the samples and may also vary on national, state, and local levels. The intended duration of storage, including indefinite storage, should be specified.</div>
6735
  <h2 type="section" data-unnumbered="true" class="section-title" id="biomarker-research-in-clinical-trials">
6736
  Biomarker Research in Clinical Trials</h2>
6737
- <div><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-124.jpg?height=996&amp;width=1709&amp;top_left_y=502&amp;top_left_x=418" alt="" data-align="center"></figure></div>
6738
  <h2 type="section" data-unnumbered="true" class="section-title" id="8.-biomarker-sample-collection-in-different-countries">
6739
  8. Biomarker Sample Collection in Different Countries</h2>
6740
  <div>Collection of biological samples for biomarker research is straightforward in most jurisdictions. Some countries have specific laws and regulations regarding collection, labeling, storage, export, and/or use of exploratory samples. In addition, some regulations distinguish between DNA and non-DNA samples or between samples used for diagnostic purposes and samples collected for scientific research. Processes for the collection, labeling, storage. export, and/or use of biomarker samples should always adhere to the laws and regulations of the country/region in which those samples are collected.</div>
@@ -6800,11 +6789,11 @@ ities and policy groups to ensure alignment. More information about the I-PWG is
6800
  <li>Frueh FW, Goodsald F, Rudman A, et al. The need for equcation in phamacogenomics: a regulatory perspectve. The Pharmacogenomics Journal, 2005; 5: 218-220. (Accessed at: www.nature comitpHoumaivsina/ abs/6500316a.ntnl)</li>
6801
  <li>Genomic Blomarkers Related to Drug Response: Context, Structure and Format of Quaification Submissions. ICH E16 Step 3 draft. (Accessed at: <a href="http://www.emea.europa.eu/pdis/humanildh38063609endrat.pdr" target="_blank" rel="noopener" style="word-break: break-all">www.emea.europa.eu/pdis/humanildh38063609endrat.pdr</a>)</li>
6802
  <li>Guiding principles Processing Jolnt FDA EMEA Voluntary Genomic Data Submissions (VGDSs) within the framework of the Conndentialty Arrangement. May 19, 2006. (Accessed at:<br>
6803
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=25&amp;width=708&amp;top_left_y=876&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6804
  <li>Guldance for Industy Phamacogenomic Data Submissions. FDA. March 2005. (Accessed at<br>
6805
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=25&amp;width=708&amp;top_left_y=953&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6806
  <li>Phammacogenomic Data Submissions - Companion Guldance. FDA Draft Guldance. August 2007 - (Accessed at:<br>
6807
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=29&amp;width=708&amp;top_left_y=1026&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6808
  <li>Reflection Paper on Pnamacogenomics in Oncology. EMEA. 2008. (Accessed at<br>
6809
  www.emea. europa eu/pdfs/human/phamacogenetics/12843506endrat.pat')</li>
6810
  <li>Position paper on Terminology In Pharmacogenetics. EMEA. 2002. (Accessed at wwwemea.europa eu/pdfs/human/press/pp/307001en.pdr)</li>
@@ -6814,7 +6803,7 @@ www.emea.europa eupds/human/phamacogenetics/5327009en.pdr)</li>
6814
  www.emea europa eu/pdts/human/phamacogenetics/20191406en.pdt)</li>
6815
  <li>IshiguroA. Toyoshima S, Uyama Y. Current Japanese regulatory stuations of pharmacogenomics in drug administration. Expert Revew of Clinical Pharmacology, 2006,1: 505-514. (Accessed at <a href="http://www.ingentaconnect.com/" target="_blank" rel="noopener" style="display: inline-block">www.ingentaconnect.com/</a> contentintsecp/2008/00000001/00000004/art00007)</li>
6816
  <li>Amur S, Frueh FW, Lesko LJ, et al. Integraton and use of<br>
6817
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=579&amp;width=197&amp;top_left_y=309&amp;top_left_x=2167" alt="" data-align="center"></figure><br>
6818
  blomarkers in drug development, regulation and cilical practice: A US regulatory practice. Blomarkers Med. 2003; 2, 306-311. (Accessed at: <a href="http://www.Ingentaconnect.com/content/tm/bmm/2008/00000002/00000003" target="_blank" rel="noopener" style="word-break: break-all">www.Ingentaconnect.com/content/tm/bmm/2008/00000002/00000003</a>) ang00010?crawer-(rue)</li>
6819
  <li>Mendrick DL, Brazell C. Mansteld EA, et al. Pharmacogenomics and regulatory decision making: an international perspective. The Pharmacogenomics Journal. 2006; 6(3), 154-157. (Accessed at<br>
6820
  www.nature com/q/poumaliv6/n3/abs/6500364a.htm)</li>
@@ -6835,11 +6824,11 @@ http./Johsr.od.nin.gow/guldelines/helsinkl.html)</li>
6835
  <li>Article 29 Data Protection Working Party. (Accessed at: www.ec.eurcpa.eufustice_home/ts/privacy/workinggroup/ndex_en.htm)</li>
6836
  <li>Human Tissue Act 2004 (UK) (Accessed at: www.opsl.gow.ukfacts/acts2004/en/ukpgaen_20040030_en_1)</li>
6837
  <li>Genetic Information Nondiscrimination Act. (Accessed at:<br>
6838
- <img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-128.jpg?height=24&amp;width=710&amp;top_left_y=395&amp;top_left_x=1443" alt=""> 38. Gudance for Sponsors, Cinical Investgators, and IRBs Data Retention When Subjects Withdraw from FDA-Regulated Cinical Thials. FDA October 2008 www.fda.gowOHRMS/DOCKETS/96t/FDA-2008-D-0576-gdlipdr</li>
6839
  <li>Anderson C. Gomez-Mancilla B, Spear BB, Bames DM, Cheeseman K, Shaw P, Friedman J, Mocarthy A, Brazel C, Ray SC, Mohale D, Hashimoto L. Sandbrink R, Watson ML. Salemo RA, on behalf of The Pharmacogenetks Working Group. Elements of Informed Consent for Pharmacogenetic Research; Perspective of the Phamacogenetics Working Group. Phamacogenomics Journal 2002;2:284-92. (Accessed at: <a href="http://www.nature.com/py/youmal/v2/n5/abs/6600131a.htmi" target="_blank" rel="noopener" style="word-break: break-all">www.nature.com/py/youmal/v2/n5/abs/6600131a.htmi</a>)</li>
6840
  </ol>
6841
  <div>9<br>
6842
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-129.jpg?height=1305&amp;width=1980&amp;top_left_y=305&amp;top_left_x=384" alt="" data-align="center"></figure></div>
6843
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="12.4-list-of-abbreviations">
6844
  12.4 List of Abbreviations</h3>
6845
  <div class="table_tabular" style="text-align: center">
 
2
  <html lang="en-US">
3
  <head>
4
  <meta charset="UTF-8">
5
+ <title>c065aab7-7839-4fa8-afab-f2de6e68017f</title>
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  <meta name="viewport" content="width=device-width, initial-scale=1">
7
  <link rel="stylesheet" href="https://cdn.mathpix.com/fonts/cmu.css"/>
8
  <style>html,body {
 
1509
  2.2 Trial Diagram</h3>
1510
  <div>The trial design is depicted in Figure 1.</div>
1511
  <div class="table" number="1">
1512
+ <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-019.jpg?height=929&width=1522&top_left_y=784&top_left_x=330" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 1 Study Schema</div></div>
1513
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.0-objective(s)-%5C%26-hypothesis(es)">
1514
  3.0 OBJECTIVE(S) &amp; HYPOTHESIS(ES)</h3>
1515
  <div>Pembrolizumab in combination with chemotherapy will be compared with saline placebo in combination with chemotherapy in subjects with advanced or metastatic nonsquamous, nonsmall cell lung cancer (NSCLC) who have not previously received systemic therapy based on the following primary, secondary, and exploratory objectives:</div>
 
2880
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.023ex" height="1.532ex" role="img" focusable="false" viewBox="0 -677 1778 677"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></svg></mjx-container></span> days</td>
2881
  </tr>
2882
  <tr style="border-top: none !important; border-bottom: none !important;">
2883
+ <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="14">Administrative Procedures</td>
 
 
 
 
 
 
 
 
 
 
 
 
2884
  </tr>
2885
  <tr style="border-top: none !important; border-bottom: none !important;">
2886
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Informed Consent</td>
 
3033
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
3034
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
3035
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
3036
+ <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="11"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-052.jpg?height=38&amp;width=1225&amp;top_left_y=1426&amp;top_left_x=1084" alt="" data-align="center"></figure></td>
3037
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
3038
  </tr>
3039
  <tr style="border-top: none !important; border-bottom: none !important;">
 
3787
  <tr style="border-top: none !important; border-bottom: none !important;">
3788
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
3789
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
3790
+ <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="9"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-055.jpg?height=38&amp;width=1220&amp;top_left_y=1004&amp;top_left_x=1136" alt="" data-align="center"></figure></td>
3791
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
3792
  </tr>
3793
  <tr style="border-top: none !important; border-bottom: none !important;">
 
4701
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">±</td>
4702
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
4703
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
4704
+ <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-block ">
4705
+ <mjx-container class="MathJax" jax="SVG" display="true"><svg style="vertical-align: -2.036ex;" xmlns="http://www.w3.org/2000/svg" width="1.76ex" height="5.204ex" role="img" focusable="false" viewBox="0 -1400 778 2300"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mtable"><g data-mml-node="mtr" transform="translate(0,650)"><g data-mml-node="mtd"></g><g data-mml-node="mtd"><g data-mml-node="mi"></g><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g></g></g><g data-mml-node="mtr" transform="translate(0,-650)"><g data-mml-node="mtd"></g><g data-mml-node="mtd"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></g></svg></mjx-container></span></td>
4706
+ <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-059.jpg?height=60&amp;width=27&amp;top_left_y=605&amp;top_left_x=1388" alt="" data-align="center"></figure></td>
4707
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
4708
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
4709
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
 
6049
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="1.448ex" height="1.025ex" role="img" focusable="false" viewBox="0 -442 640 453"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D6FC" d="M34 156Q34 270 120 356T309 442Q379 442 421 402T478 304Q484 275 485 237V208Q534 282 560 374Q564 388 566 390T582 393Q603 393 603 385Q603 376 594 346T558 261T497 161L486 147L487 123Q489 67 495 47T514 26Q528 28 540 37T557 60Q559 67 562 68T577 70Q597 70 597 62Q597 56 591 43Q579 19 556 5T512 -10H505Q438 -10 414 62L411 69L400 61Q390 53 370 41T325 18T267 -2T203 -11Q124 -11 79 39T34 156ZM208 26Q257 26 306 47T379 90L403 112Q401 255 396 290Q382 405 304 405Q235 405 183 332Q156 292 139 224T121 120Q121 71 146 49T208 26Z"></path></g></g></g></svg></mjx-container></span>-allocation for each hypothesis in the ellipse representing the hypothesis. The weights for reallocation from each hypothesis to the others are represented in the boxes on the lines connecting hypotheses. This is further explained below.</div>
6050
  <div>See Figure 2 for the type I error reallocation strategy for endpoints PFS, OS, and ORR.</div>
6051
  <div class="table" number="2">
6052
+ <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-097.jpg?height=624&width=751&top_left_y=1072&top_left_x=719" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 2 Type I Error Reallocation Strategy</div></div>
6053
  <h2 type="section" data-unnumbered="true" class="section-title" id="pfs">
6054
  PFS</h2>
6055
  <div>PFS hypothesis will be tested at <span class="math-inline ">
 
6640
  <h2 type="section" data-unnumbered="true" class="section-title" id="understanding-the-intent%2C-scope-and-public-health-benefits-of-exploratory-biomarker-research">
6641
  Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research</h2>
6642
  <div class="table" number="3">
6643
+ <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-119.jpg?height=388&width=1614&top_left_y=859&top_left_x=670" alt="" style="max-width: 100%;"/></div><div class="caption_figure">A Guide for IRBs/IECs and Investigational Site Staff</div></div>
6644
  <div>This informational brochure is intended for IRBs/IECs and Investigational Site Staff. The brochure addresses issues relevant to specimen collection for biomarker research in the context of pharmaceutical drug and vaccine development.</div>
6645
  <blockquote>
6646
  <div>Developed by<br>
 
6651
  1. What is a Biomarker and What is Biomarker Research?</h2>
6652
  <div>A biomarker is a &quot;characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention&quot;. '</div>
6653
  <div>Biomarker research, including research on pharmacogenomic biomarkers, is a tool used to improve the development of pharmaceuticals and understanding of disease. It involves the analysis of biomolecules (such as DNA. RNA, proteins, and lipids), or other measurements (such as blood pressure or brain images) in relation to clinical endpoints of interest. Biomarker research can be influential across all phases of drug development, from drug discovery and preclinical evaluations to clinical development and post-marketing studies. This brochure focuses on biomarker research involving analysis of biomolecules from biological samples collected in clinical trials. Please refer to I-PWG Pharmacogenomic Informational Brochure <span class="math-inline " data-overflow="visible">
6654
+ <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> and 1 CH Guidance E15 <span class="math-inline " data-overflow="visible">
6655
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.885ex" role="img" focusable="false" viewBox="0 -833.2 436.6 833.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></svg></mjx-container></span> for additional information specific to pharmacogenomic biomarkers.</div>
6656
  <h2 type="section" data-unnumbered="true" class="section-title" id="2.-why-is-biomarker-research-important%3F">
6657
  2. Why is Biomarker Research Important?</h2>
 
6723
  <div>The duration of storage - The permissible duration of storage may vary according to the nature and uses of the samples and may also vary on national, state, and local levels. The intended duration of storage, including indefinite storage, should be specified.</div>
6724
  <h2 type="section" data-unnumbered="true" class="section-title" id="biomarker-research-in-clinical-trials">
6725
  Biomarker Research in Clinical Trials</h2>
6726
+ <div><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-124.jpg?height=996&amp;width=1709&amp;top_left_y=502&amp;top_left_x=418" alt="" data-align="center"></figure></div>
6727
  <h2 type="section" data-unnumbered="true" class="section-title" id="8.-biomarker-sample-collection-in-different-countries">
6728
  8. Biomarker Sample Collection in Different Countries</h2>
6729
  <div>Collection of biological samples for biomarker research is straightforward in most jurisdictions. Some countries have specific laws and regulations regarding collection, labeling, storage, export, and/or use of exploratory samples. In addition, some regulations distinguish between DNA and non-DNA samples or between samples used for diagnostic purposes and samples collected for scientific research. Processes for the collection, labeling, storage. export, and/or use of biomarker samples should always adhere to the laws and regulations of the country/region in which those samples are collected.</div>
 
6789
  <li>Frueh FW, Goodsald F, Rudman A, et al. The need for equcation in phamacogenomics: a regulatory perspectve. The Pharmacogenomics Journal, 2005; 5: 218-220. (Accessed at: www.nature comitpHoumaivsina/ abs/6500316a.ntnl)</li>
6790
  <li>Genomic Blomarkers Related to Drug Response: Context, Structure and Format of Quaification Submissions. ICH E16 Step 3 draft. (Accessed at: <a href="http://www.emea.europa.eu/pdis/humanildh38063609endrat.pdr" target="_blank" rel="noopener" style="word-break: break-all">www.emea.europa.eu/pdis/humanildh38063609endrat.pdr</a>)</li>
6791
  <li>Guiding principles Processing Jolnt FDA EMEA Voluntary Genomic Data Submissions (VGDSs) within the framework of the Conndentialty Arrangement. May 19, 2006. (Accessed at:<br>
6792
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-127.jpg?height=25&amp;width=708&amp;top_left_y=876&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6793
  <li>Guldance for Industy Phamacogenomic Data Submissions. FDA. March 2005. (Accessed at<br>
6794
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-127.jpg?height=25&amp;width=708&amp;top_left_y=953&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6795
  <li>Phammacogenomic Data Submissions - Companion Guldance. FDA Draft Guldance. August 2007 - (Accessed at:<br>
6796
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-127.jpg?height=29&amp;width=708&amp;top_left_y=1026&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6797
  <li>Reflection Paper on Pnamacogenomics in Oncology. EMEA. 2008. (Accessed at<br>
6798
  www.emea. europa eu/pdfs/human/phamacogenetics/12843506endrat.pat')</li>
6799
  <li>Position paper on Terminology In Pharmacogenetics. EMEA. 2002. (Accessed at wwwemea.europa eu/pdfs/human/press/pp/307001en.pdr)</li>
 
6803
  www.emea europa eu/pdts/human/phamacogenetics/20191406en.pdt)</li>
6804
  <li>IshiguroA. Toyoshima S, Uyama Y. Current Japanese regulatory stuations of pharmacogenomics in drug administration. Expert Revew of Clinical Pharmacology, 2006,1: 505-514. (Accessed at <a href="http://www.ingentaconnect.com/" target="_blank" rel="noopener" style="display: inline-block">www.ingentaconnect.com/</a> contentintsecp/2008/00000001/00000004/art00007)</li>
6805
  <li>Amur S, Frueh FW, Lesko LJ, et al. Integraton and use of<br>
6806
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-127.jpg?height=579&amp;width=197&amp;top_left_y=309&amp;top_left_x=2167" alt="" data-align="center"></figure><br>
6807
  blomarkers in drug development, regulation and cilical practice: A US regulatory practice. Blomarkers Med. 2003; 2, 306-311. (Accessed at: <a href="http://www.Ingentaconnect.com/content/tm/bmm/2008/00000002/00000003" target="_blank" rel="noopener" style="word-break: break-all">www.Ingentaconnect.com/content/tm/bmm/2008/00000002/00000003</a>) ang00010?crawer-(rue)</li>
6808
  <li>Mendrick DL, Brazell C. Mansteld EA, et al. Pharmacogenomics and regulatory decision making: an international perspective. The Pharmacogenomics Journal. 2006; 6(3), 154-157. (Accessed at<br>
6809
  www.nature com/q/poumaliv6/n3/abs/6500364a.htm)</li>
 
6824
  <li>Article 29 Data Protection Working Party. (Accessed at: www.ec.eurcpa.eufustice_home/ts/privacy/workinggroup/ndex_en.htm)</li>
6825
  <li>Human Tissue Act 2004 (UK) (Accessed at: www.opsl.gow.ukfacts/acts2004/en/ukpgaen_20040030_en_1)</li>
6826
  <li>Genetic Information Nondiscrimination Act. (Accessed at:<br>
6827
+ <img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-128.jpg?height=24&amp;width=710&amp;top_left_y=395&amp;top_left_x=1443" alt=""> 38. Gudance for Sponsors, Cinical Investgators, and IRBs Data Retention When Subjects Withdraw from FDA-Regulated Cinical Thials. FDA October 2008 www.fda.gowOHRMS/DOCKETS/96t/FDA-2008-D-0576-gdlipdr</li>
6828
  <li>Anderson C. Gomez-Mancilla B, Spear BB, Bames DM, Cheeseman K, Shaw P, Friedman J, Mocarthy A, Brazel C, Ray SC, Mohale D, Hashimoto L. Sandbrink R, Watson ML. Salemo RA, on behalf of The Pharmacogenetks Working Group. Elements of Informed Consent for Pharmacogenetic Research; Perspective of the Phamacogenetics Working Group. Phamacogenomics Journal 2002;2:284-92. (Accessed at: <a href="http://www.nature.com/py/youmal/v2/n5/abs/6600131a.htmi" target="_blank" rel="noopener" style="word-break: break-all">www.nature.com/py/youmal/v2/n5/abs/6600131a.htmi</a>)</li>
6829
  </ol>
6830
  <div>9<br>
6831
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-129.jpg?height=1305&amp;width=1980&amp;top_left_y=305&amp;top_left_x=384" alt="" data-align="center"></figure></div>
6832
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="12.4-list-of-abbreviations">
6833
  12.4 List of Abbreviations</h3>
6834
  <div class="table_tabular" style="text-align: center">
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@@ -1509,7 +1509,7 @@ combination arm at the pre-specified FA, an updated analysis may be conducted wi
1509
  2.2 Trial Diagram</h3>
1510
  <div>The trial design is depicted in Figure 1.</div>
1511
  <div class="table" number="1">
1512
- <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-019.jpg?height=929&width=1522&top_left_y=784&top_left_x=330" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 1 Study Schema</div></div>
1513
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.0-objective(s)-%5C%26-hypothesis(es)">
1514
  3.0 OBJECTIVE(S) &amp; HYPOTHESIS(ES)</h3>
1515
  <div>Pembrolizumab in combination with chemotherapy will be compared with saline placebo in combination with chemotherapy in subjects with advanced or metastatic nonsquamous, nonsmall cell lung cancer (NSCLC) who have not previously received systemic therapy based on the following primary, secondary, and exploratory objectives:</div>
@@ -2880,19 +2880,7 @@ if the subject started new antineoplastic treatment (serious adverse events will
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  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.023ex" height="1.532ex" role="img" focusable="false" viewBox="0 -677 1778 677"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></svg></mjx-container></span> days</td>
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  </tr>
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2884
- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
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  </tr>
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  <tr style="border-top: none !important; border-bottom: none !important;">
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  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Informed Consent</td>
@@ -3045,7 +3033,7 @@ if the subject started new antineoplastic treatment (serious adverse events will
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  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
3046
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
3047
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
3048
- <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="11"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-052.jpg?height=38&amp;width=1225&amp;top_left_y=1426&amp;top_left_x=1084" alt="" data-align="center"></figure></td>
3049
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
3050
  </tr>
3051
  <tr style="border-top: none !important; border-bottom: none !important;">
@@ -3799,7 +3787,7 @@ if the subject started new antineoplastic treatment (serious adverse events will
3799
  <tr style="border-top: none !important; border-bottom: none !important;">
3800
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
3801
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
3802
- <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="9"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-055.jpg?height=38&amp;width=1220&amp;top_left_y=1004&amp;top_left_x=1136" alt="" data-align="center"></figure></td>
3803
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
3804
  </tr>
3805
  <tr style="border-top: none !important; border-bottom: none !important;">
@@ -4713,8 +4701,9 @@ if the subject started new antineoplastic treatment (serious adverse events will
4713
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">±</td>
4714
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
4715
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
4716
- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">±</td>
4717
- <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-059.jpg?height=60&amp;width=27&amp;top_left_y=605&amp;top_left_x=1388" alt="" data-align="center"></figure></td>
 
4718
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
4719
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
4720
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
@@ -6060,7 +6049,7 @@ The analyses planned, endpoints evaluated and drivers of the timing are summariz
6060
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="1.448ex" height="1.025ex" role="img" focusable="false" viewBox="0 -442 640 453"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D6FC" d="M34 156Q34 270 120 356T309 442Q379 442 421 402T478 304Q484 275 485 237V208Q534 282 560 374Q564 388 566 390T582 393Q603 393 603 385Q603 376 594 346T558 261T497 161L486 147L487 123Q489 67 495 47T514 26Q528 28 540 37T557 60Q559 67 562 68T577 70Q597 70 597 62Q597 56 591 43Q579 19 556 5T512 -10H505Q438 -10 414 62L411 69L400 61Q390 53 370 41T325 18T267 -2T203 -11Q124 -11 79 39T34 156ZM208 26Q257 26 306 47T379 90L403 112Q401 255 396 290Q382 405 304 405Q235 405 183 332Q156 292 139 224T121 120Q121 71 146 49T208 26Z"></path></g></g></g></svg></mjx-container></span>-allocation for each hypothesis in the ellipse representing the hypothesis. The weights for reallocation from each hypothesis to the others are represented in the boxes on the lines connecting hypotheses. This is further explained below.</div>
6061
  <div>See Figure 2 for the type I error reallocation strategy for endpoints PFS, OS, and ORR.</div>
6062
  <div class="table" number="2">
6063
- <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-097.jpg?height=624&width=751&top_left_y=1072&top_left_x=719" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 2 Type I Error Reallocation Strategy</div></div>
6064
  <h2 type="section" data-unnumbered="true" class="section-title" id="pfs">
6065
  PFS</h2>
6066
  <div>PFS hypothesis will be tested at <span class="math-inline ">
@@ -6651,7 +6640,7 @@ through appropriate mechanisms (e.g., scientific publications and/or presentatio
6651
  <h2 type="section" data-unnumbered="true" class="section-title" id="understanding-the-intent%2C-scope-and-public-health-benefits-of-exploratory-biomarker-research">
6652
  Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research</h2>
6653
  <div class="table" number="3">
6654
- <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-119.jpg?height=388&width=1614&top_left_y=859&top_left_x=670" alt="" style="max-width: 100%;"/></div><div class="caption_figure">A Guide for IRBs/IECs and Investigational Site Staff</div></div>
6655
  <div>This informational brochure is intended for IRBs/IECs and Investigational Site Staff. The brochure addresses issues relevant to specimen collection for biomarker research in the context of pharmaceutical drug and vaccine development.</div>
6656
  <blockquote>
6657
  <div>Developed by<br>
@@ -6662,7 +6651,7 @@ The Industry Pharmacogenomics Working Group (I-PWG)<br>
6662
  1. What is a Biomarker and What is Biomarker Research?</h2>
6663
  <div>A biomarker is a &quot;characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention&quot;. '</div>
6664
  <div>Biomarker research, including research on pharmacogenomic biomarkers, is a tool used to improve the development of pharmaceuticals and understanding of disease. It involves the analysis of biomolecules (such as DNA. RNA, proteins, and lipids), or other measurements (such as blood pressure or brain images) in relation to clinical endpoints of interest. Biomarker research can be influential across all phases of drug development, from drug discovery and preclinical evaluations to clinical development and post-marketing studies. This brochure focuses on biomarker research involving analysis of biomolecules from biological samples collected in clinical trials. Please refer to I-PWG Pharmacogenomic Informational Brochure <span class="math-inline " data-overflow="visible">
6665
- <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> and ICH Guidance E15 <span class="math-inline " data-overflow="visible">
6666
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.885ex" role="img" focusable="false" viewBox="0 -833.2 436.6 833.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></svg></mjx-container></span> for additional information specific to pharmacogenomic biomarkers.</div>
6667
  <h2 type="section" data-unnumbered="true" class="section-title" id="2.-why-is-biomarker-research-important%3F">
6668
  2. Why is Biomarker Research Important?</h2>
@@ -6734,7 +6723,7 @@ While it can be a chailenge to specify the details of the research that will be
6734
  <div>The duration of storage - The permissible duration of storage may vary according to the nature and uses of the samples and may also vary on national, state, and local levels. The intended duration of storage, including indefinite storage, should be specified.</div>
6735
  <h2 type="section" data-unnumbered="true" class="section-title" id="biomarker-research-in-clinical-trials">
6736
  Biomarker Research in Clinical Trials</h2>
6737
- <div><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-124.jpg?height=996&amp;width=1709&amp;top_left_y=502&amp;top_left_x=418" alt="" data-align="center"></figure></div>
6738
  <h2 type="section" data-unnumbered="true" class="section-title" id="8.-biomarker-sample-collection-in-different-countries">
6739
  8. Biomarker Sample Collection in Different Countries</h2>
6740
  <div>Collection of biological samples for biomarker research is straightforward in most jurisdictions. Some countries have specific laws and regulations regarding collection, labeling, storage, export, and/or use of exploratory samples. In addition, some regulations distinguish between DNA and non-DNA samples or between samples used for diagnostic purposes and samples collected for scientific research. Processes for the collection, labeling, storage. export, and/or use of biomarker samples should always adhere to the laws and regulations of the country/region in which those samples are collected.</div>
@@ -6800,11 +6789,11 @@ ities and policy groups to ensure alignment. More information about the I-PWG is
6800
  <li>Frueh FW, Goodsald F, Rudman A, et al. The need for equcation in phamacogenomics: a regulatory perspectve. The Pharmacogenomics Journal, 2005; 5: 218-220. (Accessed at: www.nature comitpHoumaivsina/ abs/6500316a.ntnl)</li>
6801
  <li>Genomic Blomarkers Related to Drug Response: Context, Structure and Format of Quaification Submissions. ICH E16 Step 3 draft. (Accessed at: <a href="http://www.emea.europa.eu/pdis/humanildh38063609endrat.pdr" target="_blank" rel="noopener" style="word-break: break-all">www.emea.europa.eu/pdis/humanildh38063609endrat.pdr</a>)</li>
6802
  <li>Guiding principles Processing Jolnt FDA EMEA Voluntary Genomic Data Submissions (VGDSs) within the framework of the Conndentialty Arrangement. May 19, 2006. (Accessed at:<br>
6803
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=25&amp;width=708&amp;top_left_y=876&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6804
  <li>Guldance for Industy Phamacogenomic Data Submissions. FDA. March 2005. (Accessed at<br>
6805
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=25&amp;width=708&amp;top_left_y=953&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6806
  <li>Phammacogenomic Data Submissions - Companion Guldance. FDA Draft Guldance. August 2007 - (Accessed at:<br>
6807
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=29&amp;width=708&amp;top_left_y=1026&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6808
  <li>Reflection Paper on Pnamacogenomics in Oncology. EMEA. 2008. (Accessed at<br>
6809
  www.emea. europa eu/pdfs/human/phamacogenetics/12843506endrat.pat')</li>
6810
  <li>Position paper on Terminology In Pharmacogenetics. EMEA. 2002. (Accessed at wwwemea.europa eu/pdfs/human/press/pp/307001en.pdr)</li>
@@ -6814,7 +6803,7 @@ www.emea.europa eupds/human/phamacogenetics/5327009en.pdr)</li>
6814
  www.emea europa eu/pdts/human/phamacogenetics/20191406en.pdt)</li>
6815
  <li>IshiguroA. Toyoshima S, Uyama Y. Current Japanese regulatory stuations of pharmacogenomics in drug administration. Expert Revew of Clinical Pharmacology, 2006,1: 505-514. (Accessed at <a href="http://www.ingentaconnect.com/" target="_blank" rel="noopener" style="display: inline-block">www.ingentaconnect.com/</a> contentintsecp/2008/00000001/00000004/art00007)</li>
6816
  <li>Amur S, Frueh FW, Lesko LJ, et al. Integraton and use of<br>
6817
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-127.jpg?height=579&amp;width=197&amp;top_left_y=309&amp;top_left_x=2167" alt="" data-align="center"></figure><br>
6818
  blomarkers in drug development, regulation and cilical practice: A US regulatory practice. Blomarkers Med. 2003; 2, 306-311. (Accessed at: <a href="http://www.Ingentaconnect.com/content/tm/bmm/2008/00000002/00000003" target="_blank" rel="noopener" style="word-break: break-all">www.Ingentaconnect.com/content/tm/bmm/2008/00000002/00000003</a>) ang00010?crawer-(rue)</li>
6819
  <li>Mendrick DL, Brazell C. Mansteld EA, et al. Pharmacogenomics and regulatory decision making: an international perspective. The Pharmacogenomics Journal. 2006; 6(3), 154-157. (Accessed at<br>
6820
  www.nature com/q/poumaliv6/n3/abs/6500364a.htm)</li>
@@ -6835,11 +6824,11 @@ http./Johsr.od.nin.gow/guldelines/helsinkl.html)</li>
6835
  <li>Article 29 Data Protection Working Party. (Accessed at: www.ec.eurcpa.eufustice_home/ts/privacy/workinggroup/ndex_en.htm)</li>
6836
  <li>Human Tissue Act 2004 (UK) (Accessed at: www.opsl.gow.ukfacts/acts2004/en/ukpgaen_20040030_en_1)</li>
6837
  <li>Genetic Information Nondiscrimination Act. (Accessed at:<br>
6838
- <img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-128.jpg?height=24&amp;width=710&amp;top_left_y=395&amp;top_left_x=1443" alt=""> 38. Gudance for Sponsors, Cinical Investgators, and IRBs Data Retention When Subjects Withdraw from FDA-Regulated Cinical Thials. FDA October 2008 www.fda.gowOHRMS/DOCKETS/96t/FDA-2008-D-0576-gdlipdr</li>
6839
  <li>Anderson C. Gomez-Mancilla B, Spear BB, Bames DM, Cheeseman K, Shaw P, Friedman J, Mocarthy A, Brazel C, Ray SC, Mohale D, Hashimoto L. Sandbrink R, Watson ML. Salemo RA, on behalf of The Pharmacogenetks Working Group. Elements of Informed Consent for Pharmacogenetic Research; Perspective of the Phamacogenetics Working Group. Phamacogenomics Journal 2002;2:284-92. (Accessed at: <a href="http://www.nature.com/py/youmal/v2/n5/abs/6600131a.htmi" target="_blank" rel="noopener" style="word-break: break-all">www.nature.com/py/youmal/v2/n5/abs/6600131a.htmi</a>)</li>
6840
  </ol>
6841
  <div>9<br>
6842
- <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/f2508539-9c16-467e-81eb-f7cdab2e8511-129.jpg?height=1305&amp;width=1980&amp;top_left_y=305&amp;top_left_x=384" alt="" data-align="center"></figure></div>
6843
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="12.4-list-of-abbreviations">
6844
  12.4 List of Abbreviations</h3>
6845
  <div class="table_tabular" style="text-align: center">
 
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  <html lang="en-US">
3
  <head>
4
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+ <title>c065aab7-7839-4fa8-afab-f2de6e68017f</title>
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  <meta name="viewport" content="width=device-width, initial-scale=1">
7
  <link rel="stylesheet" href="https://cdn.mathpix.com/fonts/cmu.css"/>
8
  <style>html,body {
 
1509
  2.2 Trial Diagram</h3>
1510
  <div>The trial design is depicted in Figure 1.</div>
1511
  <div class="table" number="1">
1512
+ <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-019.jpg?height=929&width=1522&top_left_y=784&top_left_x=330" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 1 Study Schema</div></div>
1513
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="3.0-objective(s)-%5C%26-hypothesis(es)">
1514
  3.0 OBJECTIVE(S) &amp; HYPOTHESIS(ES)</h3>
1515
  <div>Pembrolizumab in combination with chemotherapy will be compared with saline placebo in combination with chemotherapy in subjects with advanced or metastatic nonsquamous, nonsmall cell lung cancer (NSCLC) who have not previously received systemic therapy based on the following primary, secondary, and exploratory objectives:</div>
 
2880
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="4.023ex" height="1.532ex" role="img" focusable="false" viewBox="0 -677 1778 677"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g><g data-mml-node="mn" transform="translate(1278,0)"><path data-c="34" d="M462 0Q444 3 333 3Q217 3 199 0H190V46H221Q241 46 248 46T265 48T279 53T286 61Q287 63 287 115V165H28V211L179 442Q332 674 334 675Q336 677 355 677H373L379 671V211H471V165H379V114Q379 73 379 66T385 54Q393 47 442 46H471V0H462ZM293 211V545L74 212L183 211H293Z"></path></g></g></g></svg></mjx-container></span> days</td>
2881
  </tr>
2882
  <tr style="border-top: none !important; border-bottom: none !important;">
2883
+ <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="14">Administrative Procedures</td>
 
 
 
 
 
 
 
 
 
 
 
 
2884
  </tr>
2885
  <tr style="border-top: none !important; border-bottom: none !important;">
2886
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Informed Consent</td>
 
3033
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
3034
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
3035
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; " class="_empty"></td>
3036
+ <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="11"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-052.jpg?height=38&amp;width=1225&amp;top_left_y=1426&amp;top_left_x=1084" alt="" data-align="center"></figure></td>
3037
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
3038
  </tr>
3039
  <tr style="border-top: none !important; border-bottom: none !important;">
 
3787
  <tr style="border-top: none !important; border-bottom: none !important;">
3788
  <td style="text-align: left; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">Survival Status <span class="math-inline " data-overflow="visible">
3789
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="31" d="M213 578L200 573Q186 568 160 563T102 556H83V602H102Q149 604 189 617T245 641T273 663Q275 666 285 666Q294 666 302 660V361L303 61Q310 54 315 52T339 48T401 46H427V0H416Q395 3 257 3Q121 3 100 0H88V46H114Q136 46 152 46T177 47T193 50T201 52T207 57T213 61V578Z"></path></g></g></g></g></g></svg></mjx-container></span></td>
3790
+ <td style="text-align: center; border-left-style: solid !important; border-left-width: 1px !important; border-right-style: solid !important; border-right-width: 1px !important; border-bottom: none !important; border-top: none !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; " colspan="9"><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-055.jpg?height=38&amp;width=1220&amp;top_left_y=1004&amp;top_left_x=1136" alt="" data-align="center"></figure></td>
3791
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">X</td>
3792
  </tr>
3793
  <tr style="border-top: none !important; border-bottom: none !important;">
 
4701
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; ">±</td>
4702
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
4703
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
4704
+ <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-block ">
4705
+ <mjx-container class="MathJax" jax="SVG" display="true"><svg style="vertical-align: -2.036ex;" xmlns="http://www.w3.org/2000/svg" width="1.76ex" height="5.204ex" role="img" focusable="false" viewBox="0 -1400 778 2300"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mtable"><g data-mml-node="mtr" transform="translate(0,650)"><g data-mml-node="mtd"></g><g data-mml-node="mtd"><g data-mml-node="mi"></g><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g></g></g><g data-mml-node="mtr" transform="translate(0,-650)"><g data-mml-node="mtd"></g><g data-mml-node="mtd"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></g></svg></mjx-container></span></td>
4706
+ <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-059.jpg?height=60&amp;width=27&amp;top_left_y=605&amp;top_left_x=1388" alt="" data-align="center"></figure></td>
4707
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
4708
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.05ex;" xmlns="http://www.w3.org/2000/svg" width="2.891ex" height="1.557ex" role="img" focusable="false" viewBox="0 -666 1278 688"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mo"><path data-c="B1" d="M56 320T56 333T70 353H369V502Q369 651 371 655Q376 666 388 666Q402 666 405 654T409 596V500V353H707Q722 345 722 333Q722 320 707 313H409V40H707Q722 32 722 20T707 0H70Q56 7 56 20T70 40H369V313H70Q56 320 56 333Z"></path></g><g data-mml-node="mn" transform="translate(778,0)"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></svg></mjx-container></span></td>
4709
  <td style="text-align: left; border-right-style: solid !important; border-right-width: 1px !important; border-bottom-style: solid !important; border-bottom-width: 1px !important; border-top: none !important; width: auto; vertical-align: middle; "><span class="math-inline ">
 
6049
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: -0.025ex;" xmlns="http://www.w3.org/2000/svg" width="1.448ex" height="1.025ex" role="img" focusable="false" viewBox="0 -442 640 453"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="mi"><path data-c="1D6FC" d="M34 156Q34 270 120 356T309 442Q379 442 421 402T478 304Q484 275 485 237V208Q534 282 560 374Q564 388 566 390T582 393Q603 393 603 385Q603 376 594 346T558 261T497 161L486 147L487 123Q489 67 495 47T514 26Q528 28 540 37T557 60Q559 67 562 68T577 70Q597 70 597 62Q597 56 591 43Q579 19 556 5T512 -10H505Q438 -10 414 62L411 69L400 61Q390 53 370 41T325 18T267 -2T203 -11Q124 -11 79 39T34 156ZM208 26Q257 26 306 47T379 90L403 112Q401 255 396 290Q382 405 304 405Q235 405 183 332Q156 292 139 224T121 120Q121 71 146 49T208 26Z"></path></g></g></g></svg></mjx-container></span>-allocation for each hypothesis in the ellipse representing the hypothesis. The weights for reallocation from each hypothesis to the others are represented in the boxes on the lines connecting hypotheses. This is further explained below.</div>
6050
  <div>See Figure 2 for the type I error reallocation strategy for endpoints PFS, OS, and ORR.</div>
6051
  <div class="table" number="2">
6052
+ <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-097.jpg?height=624&width=751&top_left_y=1072&top_left_x=719" alt="" style="max-width: 100%;"/></div><div class="caption_figure">Figure 2 Type I Error Reallocation Strategy</div></div>
6053
  <h2 type="section" data-unnumbered="true" class="section-title" id="pfs">
6054
  PFS</h2>
6055
  <div>PFS hypothesis will be tested at <span class="math-inline ">
 
6640
  <h2 type="section" data-unnumbered="true" class="section-title" id="understanding-the-intent%2C-scope-and-public-health-benefits-of-exploratory-biomarker-research">
6641
  Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research</h2>
6642
  <div class="table" number="3">
6643
+ <div class="figure_img" style="text-align: center;"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-119.jpg?height=388&width=1614&top_left_y=859&top_left_x=670" alt="" style="max-width: 100%;"/></div><div class="caption_figure">A Guide for IRBs/IECs and Investigational Site Staff</div></div>
6644
  <div>This informational brochure is intended for IRBs/IECs and Investigational Site Staff. The brochure addresses issues relevant to specimen collection for biomarker research in the context of pharmaceutical drug and vaccine development.</div>
6645
  <blockquote>
6646
  <div>Developed by<br>
 
6651
  1. What is a Biomarker and What is Biomarker Research?</h2>
6652
  <div>A biomarker is a &quot;characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention&quot;. '</div>
6653
  <div>Biomarker research, including research on pharmacogenomic biomarkers, is a tool used to improve the development of pharmaceuticals and understanding of disease. It involves the analysis of biomolecules (such as DNA. RNA, proteins, and lipids), or other measurements (such as blood pressure or brain images) in relation to clinical endpoints of interest. Biomarker research can be influential across all phases of drug development, from drug discovery and preclinical evaluations to clinical development and post-marketing studies. This brochure focuses on biomarker research involving analysis of biomolecules from biological samples collected in clinical trials. Please refer to I-PWG Pharmacogenomic Informational Brochure <span class="math-inline " data-overflow="visible">
6654
+ <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.887ex" role="img" focusable="false" viewBox="0 -833.9 436.6 833.9"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="32" d="M109 429Q82 429 66 447T50 491Q50 562 103 614T235 666Q326 666 387 610T449 465Q449 422 429 383T381 315T301 241Q265 210 201 149L142 93L218 92Q375 92 385 97Q392 99 409 186V189H449V186Q448 183 436 95T421 3V0H50V19V31Q50 38 56 46T86 81Q115 113 136 137Q145 147 170 174T204 211T233 244T261 278T284 308T305 340T320 369T333 401T340 431T343 464Q343 527 309 573T212 619Q179 619 154 602T119 569T109 550Q109 549 114 549Q132 549 151 535T170 489Q170 464 154 447T109 429Z"></path></g></g></g></g></g></svg></mjx-container></span> and 1 CH Guidance E15 <span class="math-inline " data-overflow="visible">
6655
  <mjx-container class="MathJax" jax="SVG"><svg style="vertical-align: 0;" xmlns="http://www.w3.org/2000/svg" width="0.988ex" height="1.885ex" role="img" focusable="false" viewBox="0 -833.2 436.6 833.2"><g stroke="currentColor" fill="currentColor" stroke-width="0" transform="scale(1,-1)"><g data-mml-node="math"><g data-mml-node="msup"><g data-mml-node="TeXAtom" data-mjx-texclass="ORD"></g><g data-mml-node="TeXAtom" transform="translate(33,363) scale(0.707)" data-mjx-texclass="ORD"><g data-mml-node="mn"><path data-c="33" d="M127 463Q100 463 85 480T69 524Q69 579 117 622T233 665Q268 665 277 664Q351 652 390 611T430 522Q430 470 396 421T302 350L299 348Q299 347 308 345T337 336T375 315Q457 262 457 175Q457 96 395 37T238 -22Q158 -22 100 21T42 130Q42 158 60 175T105 193Q133 193 151 175T169 130Q169 119 166 110T159 94T148 82T136 74T126 70T118 67L114 66Q165 21 238 21Q293 21 321 74Q338 107 338 175V195Q338 290 274 322Q259 328 213 329L171 330L168 332Q166 335 166 348Q166 366 174 366Q202 366 232 371Q266 376 294 413T322 525V533Q322 590 287 612Q265 626 240 626Q208 626 181 615T143 592T132 580H135Q138 579 143 578T153 573T165 566T175 555T183 540T186 520Q186 498 172 481T127 463Z"></path></g></g></g></g></g></svg></mjx-container></span> for additional information specific to pharmacogenomic biomarkers.</div>
6656
  <h2 type="section" data-unnumbered="true" class="section-title" id="2.-why-is-biomarker-research-important%3F">
6657
  2. Why is Biomarker Research Important?</h2>
 
6723
  <div>The duration of storage - The permissible duration of storage may vary according to the nature and uses of the samples and may also vary on national, state, and local levels. The intended duration of storage, including indefinite storage, should be specified.</div>
6724
  <h2 type="section" data-unnumbered="true" class="section-title" id="biomarker-research-in-clinical-trials">
6725
  Biomarker Research in Clinical Trials</h2>
6726
+ <div><figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-124.jpg?height=996&amp;width=1709&amp;top_left_y=502&amp;top_left_x=418" alt="" data-align="center"></figure></div>
6727
  <h2 type="section" data-unnumbered="true" class="section-title" id="8.-biomarker-sample-collection-in-different-countries">
6728
  8. Biomarker Sample Collection in Different Countries</h2>
6729
  <div>Collection of biological samples for biomarker research is straightforward in most jurisdictions. Some countries have specific laws and regulations regarding collection, labeling, storage, export, and/or use of exploratory samples. In addition, some regulations distinguish between DNA and non-DNA samples or between samples used for diagnostic purposes and samples collected for scientific research. Processes for the collection, labeling, storage. export, and/or use of biomarker samples should always adhere to the laws and regulations of the country/region in which those samples are collected.</div>
 
6789
  <li>Frueh FW, Goodsald F, Rudman A, et al. The need for equcation in phamacogenomics: a regulatory perspectve. The Pharmacogenomics Journal, 2005; 5: 218-220. (Accessed at: www.nature comitpHoumaivsina/ abs/6500316a.ntnl)</li>
6790
  <li>Genomic Blomarkers Related to Drug Response: Context, Structure and Format of Quaification Submissions. ICH E16 Step 3 draft. (Accessed at: <a href="http://www.emea.europa.eu/pdis/humanildh38063609endrat.pdr" target="_blank" rel="noopener" style="word-break: break-all">www.emea.europa.eu/pdis/humanildh38063609endrat.pdr</a>)</li>
6791
  <li>Guiding principles Processing Jolnt FDA EMEA Voluntary Genomic Data Submissions (VGDSs) within the framework of the Conndentialty Arrangement. May 19, 2006. (Accessed at:<br>
6792
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-127.jpg?height=25&amp;width=708&amp;top_left_y=876&amp;top_left_x=1443" alt="" data-align="center"></figure></li>
6793
  <li>Guldance for Industy Phamacogenomic Data Submissions. FDA. March 2005. (Accessed at<br>
6794
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+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-127.jpg?height=579&amp;width=197&amp;top_left_y=309&amp;top_left_x=2167" alt="" data-align="center"></figure><br>
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6829
  </ol>
6830
  <div>9<br>
6831
+ <figure style="text-align: center"><img src="https://cdn.mathpix.com/cropped/c065aab7-7839-4fa8-afab-f2de6e68017f-129.jpg?height=1305&amp;width=1980&amp;top_left_y=305&amp;top_left_x=384" alt="" data-align="center"></figure></div>
6832
  <h3 type="subsection" data-unnumbered="true" class="sub_section-title" id="12.4-list-of-abbreviations">
6833
  12.4 List of Abbreviations</h3>
6834
  <div class="table_tabular" style="text-align: center">