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Volume 22, Issue 46. © 2018 CenterWatch. All rights reserved.

see Complex Data on page 4 »

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Caution for NIH's single IRB policy for multi-site researchBy Sue Coons, MA

A tions had to comply with the National Institutes of Health’s (NIH’s) Final

NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Researchpolicy established the expectation that a single institutional review board (sIRB) of record would be used in the ethical review of non-exempt human subjects research protocols funded by NIH that are carried out at more than one site in the United States.

It does not apply to career development, research training, or fellowship awards.

However, some institutions continue to be concerned about their ability to adhere to the policy and the cost of doing so. IRB executives say it is wise to be cautious. Some institutions could spend millions of dollars to upgrade their IRB infrastructure, while some IRBs already have many of the policy requirements in place. In addition, one IRB executive worries that past NIH actions

show that the agency could revise its policy

Emerging trends in clinical research: The need for changeBy John W. Mitchell, MS

T by emerging trends in the clinical trial research sector, consider insight from

a business author and a businessman/politi-cian. In his groundbreaking book, Good to Great: Why Some Companies Make the Leap…And Others Don’t,” Jim Collins wrote:

“Good is the enemy of great. And that is one of the key reasons why we have so little that becomes great. We don’t have great schools, principally because we have good schools. We don’t have great government, principally because we have good govern-ment.”

Secretary Donald Rumsfeld noted that one of the biggest threats to security was driven by factors that fell under the category of “we

don’t know what we don’t know.” In recent issues, Research Practitioner has

explored individual key emerging trends in clinical research, including patient centricity, eMobile advances, and precision medicine. As stand-alone trends, these innovations hold great promise and excitement.

But what insight is gained when all emerg-ing trends are considered in totality? What

clinical research? As Rumsfeld alluded, what might we not know that we don’t know? Are current advancements in clinical research, as Collins asserted, relevant enough to power (great) the sector beyond the status quo (good), given the rapidly evolving medical

ligence (AI), and the expectation of patients?

results on the use of electronic-sourced data, Hugo Stephenson, executive chairman of DrugDev and a physician investigator, observed: “I’m surprised and disappointed there hasn’t been much improvement in the entire clinical trial process, including the

© 2018 CenterWatch. Duplication or sharing of this publication is strictly prohibited. Volume 19, Number 3

Learning Objectives/Outcomes:1. Explain the need for change in clinical research.

2. List key drivers of transformation in clinical trials.

3. Describe examples of clinical trial research trends in action.

4. Discuss why the clinical trial sector will make the jump from trends to practice.

Learning Objectives/Outcomes:1. List the details that local IRBs may know about their

study populations as opposed to a single IRB.2. Describe NIH’s reasoning for going to a single IRB

policy for multi-site research.3. Discuss the impact of using a single IRB on a study’s

direct costs.4. Explain the concern about NIH’s history of choosing

the lowest-cost provider.

42 CE program information

43 Issues in research management

52 SMART IRB

55 CE post-test

May–June 2018

see Emerging trends on page 44

see Single IRB on page 49

o understand the opportunity o�ered

In a 2002 Department of Defense brie�ng,

do these opportunities say about the �eld of

reality of interconnectivity, arti�cial intel-

�ese seem to be fair questions. In a Feb-ruary 2017 CenterWatch article about survey

s of Jan. 25, 2018, research institu-

�is

FDAnews and Technical Resources International Present

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November 19, 2018

Industry Briefs…2

Drug & Device Pipeline News…7Thirteen drugs and devices have entered a new trial phase this week.

CenterWatchWeekly

By Bill Myers

The clinical trials industry is just com-ing to grips with a new FDA approach to inspections that uses advanced

computer algorithms to flag trials for risk. The agency has spent the past few years

preparing for centralized trial inspections and issued a draft guidance on them in February but it’s still relatively early in the process, says Cerdi Beltre, senior vice presi-dent for institutional services at the WIRB-Copernicus Group. Until trial professionals get a better sense of how the algorithm works, they should do some self-auditing, she adds.

Some boxes to check, she says: “How are they ensuring all the sites are compliant? What resources are available? What high-

level checklist can they have to prepare for that?”

Beltre’s advice comes on the heels of a presentation by Jean Mulinde, senior policy advisor at CDER’s clinical compliance evalu-ation division, laying out how the FDA’s “decision tree” algorithm helps the agency determine which trials to inspect.

Mulinde has been briefing sites and sponsors every chance she gets in recent months — including at last week’s Metrics Championship Consortium conference — to help them prepare. But Beltre said it was still eye-opening to hear a top regulator acknowledge that inspections are driven in part by a computer code.

The process is complex — and the FDA is

FDA Trials Inspection Algorithm: Be Ready

Complex Data Need Simplified Trials, Expert Argues

CenterWatch Holiday Notification In observance of Thanksgiving in the U.S., CWWeekly will not be published Monday, Nov. 26. The next issue will be published Monday, Dec. 3.

By Bill Myers

C linical trials professionals will have to be laser-focused as emerging technology tempts them into a fool’s

paradise of big data, a top industry analyst tells CenterWatch.

Machine learning, artificial intelligence and even consumer electronic apps are of-fering troves of data that would have been unimaginable even a couple of decades ago, says Ken Getz, an associate professor at the Tufts Center for the Study of Drug Develop-ment.

But if sponsors, sites and investigators aren’t careful, they can lose control of their studies and see knowledge dissolve in information.

“It is a paradox of our age — right at the

time when our complexity has risen so that it’s having a negative impact on our perfor-mance, we’re at the same point where we can collect so much information on every aspect of our trials,” Getz said after present-ing at the inaugural Metrics Champion Consortium conference last week. “It’s very tempting, isn’t it, to just collect more data? We’ll just let the machine do the thinking for us. And that’s also dangerous.”

Data and information technology have already made trials incredibly complex, he says. According to a Tufts analysis, the average trial has seen the total number of endpoints rise 86 percent since the begin-ning of the century. The number of eligibility criteria has risen by 61 percent, the total

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WCG | CWWeekly November 19, 2018 2 of 7

Industry Briefs

FDA Proposes Informed Consent Waivers for Some Clinical TrialsResearchers in low-risk clinical trials could experiment on patients without obtaining informed consent if they meet at least four conditions, the FDA proposed last week in a new rulemaking notice.

The agency will grant waivers if research-ers can prove:

}} A trial “involves no more than minimal risk” to humans; }} The waiver won’t negatively affect pa-

tients’ health or rights; }} A trial can’t “practicably be carried out”

unless a waiver is granted; and }} Patients are given study details and find-

ings after a trial wraps up.

The proposed rules firm up a 2017 guid-ance that laid out the same conditions for informed consent waivers and conform to the Common Rule.

David Borasky, vice president of IRB compliance at the WIRB-Copernicus Group, welcomed the draft guidance, noting the new rules will help sponsors embrace mod-ern technologies for clinical trials. He added that many IRBs are already using waivers under last year’s guidance.

“As the FDA continues to express an interest in having sponsors utilize retro-spective real-world evidence to inform the regulation of drugs and devices, there will be a greater and greater need for mecha-nisms to allow activities like retrospective chart reviews — which can involve human subject research — to go forward under a waiver of informed consent,” Borasky tells CenterWatch.

But he questioned why the FDA pegged its new rules to the old Common Rule. A revised Common Rule is scheduled to take effect early next year and offer another reason for informed consent waivers.

“It is not clear from the proposal why the FDA would harmonize to a rule that will be

out of date within a few months,” Borasky says.

“The FDA has asked for comments on this, and I suspect that they will receive a lot of comments encouraging complete harmonization with the revised rule,” he adds. “Harmonizing to an outdated rule does not make sense in the big picture, even if the regulated community lacks experience implementing the new waiver criterion.”

Read the agency’s rulemaking notice here: https://bit.ly/2OSPGHq.

FDA Considers Endpoints for Rare, Deadly Prostate CancerThe FDA has issued new draft guidance for clinical trials aimed at a rare but aggressive form of prostate cancer.

A very small percentage of men develop nonmestastatic, castration-resistant prostate cancer, defined by rising levels of prostate-specific antigens even after testosterone levels have been reduced. The disease can take years to run its course, which has made it difficult for sponsors to use overall survival rates — a common measure in cancer trials — as an endpoint.

The major concern is that by the time related tumors crop up, the deadly disease progresses rapidly. For years, sponsors, researchers and other experts have urged the FDA to consider metastasis-free survival a primary endpoint for trials aimed at the rare cancer. The agency now says it’s open to doing so but wants to be sure researchers carefully map out their plans.

Toward that end, it recommends sponsors:

}} Define what they mean by “metastasis-free survival” before the trial starts;}} Consider grouping patients by the type of

therapy (radiation, surgery) they had (or didn’t have) before being diagnosed with this cancer;}} Draw up procedures to account for pa-

tients who withdraw from trials because of concerns over rising prostate levels; }} Be clear about the kind of imaging they’ll

use to test for the disease and its progres-sion. For instance, some patients with nonmetastatic, castration-resistant prostate cancer have enlarged pelvic lymph nodes. In that case, sponsors should make clear how large nodes should be for a patient to be included in the trials; and}} Put together procedures “to minimize

missing data.”

The draft guidance, issued last week, also suggests that sponsors avoid interim efficacy analyses — “because it may lead to over- or underestimation” of a treatment’s impact.

Even though overall survival probably won’t count as a primary endpoint, the FDA urges sponsors to conduct a formal interim analysis of overall survival, and “expects con-tinued follow-up for final” overall survival even after a trial concludes.

Read the FDA’s draft guidance here: https://bit.ly/2zbjnyG.

App Gets to Heart of the MatterA smart phone app appears to be just as effective at diagnosing severe heart attacks as traditional electrocardiograms.

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WCG | CWWeekly November 19, 2018 3 of 7

Industry Briefs

Researchers enrolled 204 patients in clini-cal trials at five sites to test the AliveCor app. Patients were connected to AliveCor, which is administered by a smart phone and has two wires, and two traditional, 12-lead ECGs.

“We found the app helped us diagnose heart attacks very effectively—and it didn’t indicate the presence of a heart attack when one wasn’t occurring,” lead researcher J. Brent Muhlestein of the Intermountain Medical Center Heart Institute in Salt Lake City, Utah, said in announcing his team’s findings.

Stanford researchers are currently testing a heart monitor offered by Apple Watch on some 400,000 patients — the largest clinical trial of its kind.

Lab Owner Nabbed in Trial ScamFederal officials have indicted a laboratory owner on charges that he bilked drug spon-sors in an opioid clinical trial.

Sami Anwar, of Richland, Wash., and two of his companies — Mid Columbia Research and Zain Research — face 47 separate felony counts, including wire and mail fraud, fraudulently obtaining controlled sub-stances and lying to federal agents, in what authorities allege was a scheme to pocket fees for a phony clinical trial supposedly try-ing to find non-opioid pain treatments.

Anwar and his staff are accused of enroll-ing ineligible participants in the trial, forging doctors’ signatures and faking records to make it seem like patients were participat-ing in the trial and taking the experimental drug.

The sham trial netted in excess of $250,000 from the unnamed drug sponsor, federal authorities allege in charging docu-ments.

Anwar has denied wrongdoing. He’s fac-ing up to 20 years in prison and $250,000 in fines, federal authorities say.

EMA Issues Guidance on Safety Monitoring for Pediatric DrugsThe European Medicines Agency (EMA) has

released new guidance calling for sponsors of pediatric drugs to step up monitoring of adverse effects.

It’s important to track effects of medicine in pediatric patients because clinical trials are usually limited in their size and duration, and adverse reactions can differ a lot more in kids than in adults, the EMA says. The final guideline — chapter IV of the agency’s good pharmacovigilance practices (GVP) — applies to approved drugs with pediatric indications and drugs used off-label for treating children ages 2 to 11.

The EMA notes that growth and matura-tion factors in pediatric patients — such as immature organ systems, physiological changes in growth and development, and changes in body mass and composition — mean that they respond substantially differ-ently than adults to adverse events. Because of this, considerations for long-term follow up should carefully weigh these factors.

Findings from adult clinical trials should be used to identify potential risks, character-ize the safety profile and determine tools for reducing risk in the pediatric population. But sponsors should also consider the effect of meds on bone and cartilage during active growth; potential adverse reactions from dif-ferent exposure to metabolites compared to adults; and the long-term effect on develop-ing reproductive and neurodevelopmental systems, the guidance says.

The EMA recommends info sponsors should include in adverse reports, too, such as dosage data, indication or intended use, and the patient’s accurate age, weight and height/length at the time of reaction.

Read the full guidance here: https://bit.ly/2zPqH2k.

FDA Panel Weighs In on Trials of Novel Non-OpioidsAn FDA advisory panel nixed clinical trials for opioid substitutes without active com-parators and a looser definition of “opioid-sparing.”

The Anesthetic and Analgesic Drug Prod-ucts Advisory Committee voted 12-1 that trials for novel non-opioids should involve an active comparator design so the FDA can determine if tested drugs provide a significant clinical benefit over currently available meds.

“I would want to see what’s out there in the market,” said patient representative James O’Brien, president and CEO of the National Sco-liosis Foundation, endorsing trials conducted against active comparators.

The sole “yes” vote, Mary Ellen McCann of Harvard Medical School, said she wouldn’t necessarily design a trial without an active comparator but could see such a study glean-ing useful information.

The committee, by an 11-1 margin, also re-jected defining a drug as “opioid-sparing” simply because it leads to a decrease in opioid use.

Members expressed doubt the term was appropriate as a broad claim without context for the drug’s benefit-risk profile or consider-ation for the population, setting and variability in practice — and worried it could confuse consumers. They said seeking the broader opioid-sparing definition might introduce per-verse incentives into clinical trial design such as withholding standard approaches to analgesia.

“I don’t think any line of evidence would support a broad labeling of a drug as opioid-sparing,” said temporary member James Floyd, an assistant professor of medicine and epide-miology at the University of Washington. Abby Shoben, an associate professor in the division of biostatistics at the Ohio State University’s College of Public Health, also voted “no,” saying she would prefer a definition incorporating more meaningful clinical outcomes, such as reduction in the number of pills dispenses.

For the purposes of the advisory committee, the FDA defined opioid-sparing drugs as drugs or combinations of drugs that contain no opioids that, when used with opioid analgesics, reduce opioid analgesic use. Opioid-sparing drugs are distinct from novel non-opioid drugs, which are meds or med combos that can be substituted outright for an opioid analgesic.

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WCG | CWWeekly November 19, 2018 4 of 7

Features

number of procedures performed in a trial by 70 percent and the number of countries involved in a trial has risen 100 percent.

It’s no coincidence, Getz argues, that drug development costs have risen as dramatically as trial complexity. The average price tag for developing a drug was around $1 billion in 2003, according to Tufts data; a decade later, the average tab had nearly tripled.

Perhaps most troubling is that barely a quarter of those costs have been directly tied to development, Getz says, noting that almost a fifth of them stem from time wasted sifting through irrelevant data.

The amount of “non-core” data has risen by 78 percent since the early 2000s, Tufts reports.

“It’s all around optimizing and utilizing the information really wisely and effectively,” Getz says. “In this age where there’s just this explosion of data, how do we use it really intelligently?”

Complex Datacontinued from page 1

“It’s very tempting, isn’t it, to just collect more data?”

—Ken Getz, associate professor, Tufts Center for the Study of Drug Development

Trends in Protocol Design Practices

Typical Phase III Pivotal Trial (means) 2001 - 2005 2011-2015 Change

Total Number of Endpoints 7 13 86%

Total Number of Eligibility Criteria 31 50 61%

Total Number of Distinct Procedures 22 35 59%

Total Number of Procedures Performed 110 187 70%

Total Number of Planned Volunteer Visits 12 15 25%

Proportion of Data ‘Non-Core’ 18% 32% 78%

Number of Investigative Sites 40 65 63%

Number of Countries 5 10 100%

Number of Patients Randomized 729 597 -18%

Direct Cost Per Procedure per Patient per Visit $728 $978 34%

Total Data Points Collected 494,236 929,203 88%

Number of Data Collection Applications Used 2 6 200%

Source: EvaluatePharma; William Blair & Wells Fargo Securities; Tufts CSDD

High Annual and Capitalized Costs

Annual Global Spending on Pharma R&D Capitalized Cost to Develop a Successful Drug}} 26% Direct Costs }} 18% Time-Based }} 56% Cost of Failure

Source: Tufts CSDD

20152010200520001995 20132003

$33.9

$54.6

$94.2

$127.4$142.2

Annual Global Spending on Pharma R&D

$US Billions

Capitalized Cost to Develop a Successfull Drug

$1,044

$2,558$US Millions(2013 dollars)

Clinical Trial Financial ManagementDECEMBER 56, 2018 • WYNDHAM PHILADELPHIA HISTORIC DISTRICT • PHILADELPHIA, PA

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Features

Inspection Algorithmcontinued from page 1 Trials professionals should

do some self-auditing until they get a better sense of how the

algorithm works.

—Cerdi Beltre, senior vice president for insti-tutional service, WIRB-Copernicus Group

keeping some of its inputs close to the vest — but the essence of it is that the agency is assigning weighted values to certain risks, such as a trial having a new investigator on staff (see chart below). It then runs the differ-ent values through a three-part calculation to come up with a risk score. Trials with higher risk scores are more likely to be inspected.

It’ll be interesting to see how, or whether, the automation changes the nature of the agency’s inspections regime, Beltre says.

“How is this different than the old way

of selecting sites for inspection? Does the industry need to prepare or do anything different than before? What changes shall

we anticipate for sponsors, CROs and sites?” she wonders, adding some answers may not come until there’s more data available.

Linda Sullivan, MCC’s co-founder and president, says shedding light on the pro-cess actually reassured trials professionals that the FDA is still focusing on the broader context of trials even though it’s using ad-vanced statistics to inform its inspections.

“There’s been a lot of anxiety around inspections,” Sullivan says. Melinde “calmed a lot of fears. While we may see things in the numbers, we do spend the time to try to understand the context.”

Inputted Data Processed via Decision Tree Algorithm

Source: FDA; Maintaining Quality in Clinical Research – Optimizing Planning and Oversight Activities

Discrete RiskFunction

ProportionalRisk Function

Log RiskFunction

Statistical Fit Function

Subset of entire

risk tree

Attribute 1

Attribute 2

Attribute 3

Attribute 4 o 0 .25 0.5 0.75 1

Attribute Raw Values

1 2 Risk Functions applied to Attribute Values

3 Hierarchical Weighting Schema applied

0 50% 100% min median max

0 10 20 -30 0 +30

30%

20%

75%

25%

50%

50%

4 Final Risk Score for each site abcdefghij

A crash course in what you should and shouldn’t say in a CTAClinical Trial

AgreementsA Guide to Key Words and Phrases

By Eric Babineaux, Lead Legal Counsel, Clintrax Global, Inc.

A CenterWatch/Clintrax Global Report

Clinical Trial AgreementsA Guide to Key Words and PhrasesReduce confusion and speed the negotiation of clinical trials by using clearly understood words and phrases.

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WCG | CWWeekly November 19, 2018 7 of 7

Drug & Device Pipeline News

Company Drug/Device Medical Condition Status Sponsor Contact

Stallergenes Greer Oralair®, an allergy immunotherapy sublingual tablet

Grass pollen-induced allergic rhinitis

Received FDA approval for the extension of the indication to treat patients ages five to nine

stallergenesgreer.com

REGENXBIO RGX-181, a one-time treatment candidate

Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, one of the most common forms of Batten disease

Granted Orphan Drug Designation by the FDA

regenxbio.com

Eli Lilly and Company

Lasmiditan Migraine with or without aura in adults

Submitted a New Drug Application (NDA) to the FDA

lilly.com

Eli Lilly and Company

Emgality Episodic cluster headache Granted Breakthrough Therapy Designation by the FDA

lilly.com

Lumendi DiLumen™ EIP Easier dissection and resection of polyps without the need for surgical intervention

Received 510(k) clearance from the FDA

lumendi.com

Theravance Biopharma, Inc. and Mylan N.V.

YUPELRITM (revefenacin), once-daily, nebulized bronchodilator

COPD Granted approval by the FDA theravance.com mylan.com

Biohaven Pharmaceutical Holding Company Ltd

Rimegepant, oral calcitonin gene-related peptide (CGRP) receptor antagonist

Migraine Enrolled first patient in Phase III clinical trial

biohavenpharma.com

AbbVie Mavyret (glecaprevir/pibrentasvir)

Hepatitis C (HCV) Results from Phase IIIb EXPEDITION-8 trial: patients receiving the drug for 8 weeks with genotype 1, 2, 4, 5 and 6 had a 100-percent sustained virologic response 12 weeks after treatment

abbvie.com

Merck KEYTRUDA® (pembrolizumab)

Advanced or metastatic esophageal or esophagogastric junction carcinoma in patients whose tumors expressed PD-L1

Significantly improved Overall Survival (OS) compared to chemotherapy in Phase III KEYNOTE-181 clinical trial

merck.com

AbbVie Elagolix, in combination with add-back therapy

Heavy menstrual bleeding associated with uterine fibroids

Achieved statistically significant reductionin two replicate pivotal Phase III clinical trials

abbvie.com

Calliditas Therapeutics

NEFIGARD IgA nephropathy (IgAN) First patient enrolled in pivotal Phase III clinical trial

calliditas.com

Palvella Therapeutics, Inc.

PTX-022 (novel, high-strength rapamycin topical formulation

Pachyonychia congenita (PC) Granted Fast Track Designation by the FDA

palvellatx.com

TWi Biotechnology, Inc.

AC-201CR Hemophilic arthropathy Completed patient enrollment in Phase II clinical trial

twipharma.com

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