RE-NAMING OF INDIAN REGULATORY AGENCY (CDSCO)

Central Drugs Standard Control Organization (CDSCO) is the national drug regulatory agency under the Ministry of  Health and Family Welfare, Government of India.

Over the years, the role of CDSCO has expanded to several areas, for the same the Drugs Technical Advisory Board (DTAB) in its 75th meeting recommended renaming of CDSCO.

In view of this, CDSCO has asked for suggestion for re-naming and logo for CDSCO.

Notice

Experts highlight Ebola vaccine progress and suggest next steps

Despite promising advances, important scientific questions remain unanswered in the effort to develop a safe and effective Ebola vaccine, according to members of an international Ebola research consortium. In a Viewpoint published in The Lancet, the experts review the current field of Ebola vaccine candidates and clinical trials and highlight key gaps in knowledge that need to be addressed by future research.

Researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, are among the Viewpoint’s authors. All authors are with the Partnership for Research on Ebola VACcination (PREVAC). In addition to NIAID, the partnership, established in 2017, comprises experts from the French National Institute of Health and Medical Research (Inserm), the London School of Hygiene & Tropical Medicine (LSHTM), the West African Clinical Research Consortium and their collaborators. PREVAC is currently conducting a Phase 2 clinical trial in Guinea, Liberia, Sierra Leone and Mali to evaluate three Ebola vaccination strategies in people one year and older.

20180803-PREVAC-volunteer

Ebola virus disease remains a public health threat — the Democratic Republic of the Congo (DRC) already has experienced two Ebola outbreaks in 2018 —  underscoring the need for continued efforts to develop an effective vaccine. The authors note that 36 trials of Ebola vaccine candidates have been completed and another 14 are active, according to clinicaltrials.gov. The rVSV-ZEBOV experimental vaccine, which has been deployed in the DRC, is the only candidate with some clinical efficacy data, which were obtained in a clinical trial in Guinea conducted during the 2014-2016 Ebola outbreak in Guinea.

After reviewing the status of four additional vaccine candidates under study (Ad26.ZEBOV, MVA-BN-Filo, chAd3-EBO-Z, and the GamEvac-Combi vaccine), the authors highlight areas where more research is required. Specifically, they note the need for more data in pregnant women, children and immunocompromised populations, including people infected with HIV and the elderly. Additionally, they say more research is needed on the durability and rapidity of immune responses generated by various vaccine approaches. The experts also call for studies to identify reliable correlates of protection (the specific and measurable part of an immune response that would indicate a person is protected from Ebola) as well as large-scale trials to fully evaluate the safety and efficacy of experimental vaccines.

The authors conclude by underscoring the value of embedding social science research in clinical trial design to help build trust and engagement with the affected communities. They note that in addition to the need to investigate various vaccines and vaccination strategies to respond more effectively to future outbreaks, improving the global capacity to conduct clinical research and forming collaborative partnerships, such as PREVAC, are crucial for success.

Mid 2018 – Recap of Warning Letters, Import Alerts and Non-Compliances

In our mid-2018 compliance review, we look at inspection challenges faced by companies across the world. In the first half of this year, manufacturing compliance challenges dominated headlines. But we also saw shortcomings at major pharmaceutical companies like Pfizer, Bayer and Akorngenerate news.

While China, India and the US continued to be the top three countries where regulators uncovered compliance issues, this year has also seen the FDA take action against many South Korean companies. The European authorities found concerns in India, Taiwan, Italy and Spain. However, there were no non-compliance reports issued to firms in China until the end of June 2018.

While data-integrity violations and a failure to thoroughly investigate deviations continued to remain a major concern for inspectors, this year the real concern emanated from the supply of product to market (which had the potential to impact product quality or patient safety).

 

Mid-2018-Recap-of-Warning-Letters-Import-Alerts-and-Non-Compliances-1532589468

China: API with a cancerous impurity, vaccine scandal and data-integrity woes

The most recent regulatory non-compliance issue pertains to the European Medicines Agency (EMA) raising concern over the active pharmaceutical ingredient (API) valsartan supplied by China’s Zhejiang Huahai Pharmaceuticals

The concern was the impurity — nitrosodimethylamine (or NDMA) — detected by the company in their valsartan API. NDMA is classified as a probable human carcinogen and its presence was unexpected as it was not detected by routine tests carried out by Zhejiang Huahai.

Zhejiang Huahai sold over US$ 50 million of the API in 2017 and supplies to most major manufacturers producing valsartan medicines available in the EU and United States.

While a review is underway, national authorities across the EU, US and Asia are recalling medicines containing valsartan supplied by Zhejiang Huahai.

Vaccine scandal: A major vaccination scandal has sparked off a huge outcry in China as vaccine maker Changsheng Biotechnology was found to have falsified production data for its rabies vaccine.

Changchun Changsheng Bio-tech Co, in Changchun, reported serious irregularities, including fabricating production records in the manufacture of rabies vaccines for human use, during an inspection by the State Drug Administration, China FDA said in a statement.

Although there has been no evidence of harm from the vaccine, the firm has been ordered to halt production and recall rabies vaccines. And Chinese Premier Li Keqiang has urged severe punishment for the people involved, saying the incident had “crossed a moral line”.

Data-integrity violations: This year, the FDA also posted the warning letter issued to Henan Lihua Pharmaceutical in China, a company that produces steroid APIs like hydrocortisone and prednisone.

The warning letter highlighted data integrity concerns that landed Henan on FDA’s import alert list in March 2018. 

During the inspection, the FDA investigator observed numerous blank batch manufacturing records in an open cabinet in the firm’s manufacturing workshop office.

Among these was multiple blank, product release forms marked with a red quality assurance release stamp stating ‘Permitted to Leave [the] Factory’.

The FDA also posted a warning letter issued to Jilin Shulan Synthetic Pharmaceutical, a manufacturer of caffeine API in China. The letter revealed flagrant data-integrity violations.

Another warning letter was issued by the FDA to API manufacturer Lijiang Yinghua Biochemical and Pharmaceutical, following an October 2017 inspection.

United States: Drug shortages due to Pfizer’s manufacturing problems 

Drug major Pfizer’s production problems continued to make headlines this year. An article in Fortune put the blame on Pfizer’s much-touted US$ 17 billion acquisition of Hospira in 2015 for turning the United States’ chronic drug shortage into a full-blown crisis. 

According to the article, as of May 11 this year, Pfizer — which is the world’s largest maker of sterile injectable drugs — had 370 products that are depleted or in limited supply, 102 of which the company has indicated will not be available until 2019.

“The simple answer to why America currently has so many shortages of generic sterile injectable drugs: America’s leading manufacturer of generic sterile injectable drugs hasn’t been making them,” the article said.

Mylan’s flagship product EpiPen is also likely to face shortages due to problems at Pfizer. Although Mylan owns the rights to the EpiPen, it subcontracts manufacturing of the auto-injector to Meridian Medical Technologies, a division of Pfizer.

While Mylan is putting pressure on Pfizer to do more to tackle shortages of this life-saving medicine, Pfizer has struggled to meet demand for the EpiPen and the FDA had put the medicine on its official shortages list.

In September last year, the FDA had issued a warning letter to Meridian Medical Technologies over serious component and product failures that had been associated with patient deaths. 

Pfizer’s troubles are far from over as an FDA inspection of an ex-Hospira sterile manufacturing facility in India resulted in the issuance of a 32 page Form 483.  The same facility was issued a warning letter  by the FDA in 2013.

Germany: FDA highlights contamination, data-integrity concerns at Bayer facility

In a shocking warning letter issued by the FDA to Bayer Pharma’s finished pharmaceuticals manufacturing facility located in Leverkusen, Germany, investigators found compliance shortcomings ranging from concerns over data-integrity to serious product contamination problems.  

While reviewing a drug product manufacturing operation, FDA investigators found residue on equipment which seemed most likely from a drug product that had been previously processed in the same room.

When Bayer tested the samples of the tablets being produced to “assess the potential of cross-contamination”, the testing confirmed contamination of the previously processed product inside the tablets which resulted in a recall of several lots of drug products.

India: Data-integrity violations, invalidation of OOS results continue

Alkem has ‘no quality control unit’: After eight days of inspecting Alkem Laboratories’ finished formulation facility in India in March 2018, the FDA investigators concluded — “there is no quality control unit”.

Alkem’s head of quality control (QC) and quality assurance (QA) confirmed out-of-specification (OOS) results for the assay for a batch of tablets. However, the company did not recall the product, which was distributed in the US market.

Less than three weeks before the inspection, the “firm’s QC department deleted two-thousand one hundred one (2,101) files” on its computer network. 

Alembic invalidated OOS results: In the seven days that the FDA investigator — Jessica L Pressley — spent at Alembic Pharmaceuticals’ oral solid dosage manufacturing facility in Tajpura, Gujarat, she uncovered that the firm invalidated 131 of the 140 OOS results (an invalidation rate of 94 percent) for products marketed in the US. 

The firm attributed the invalidation to analyst errors. In 2017, the invalidation rate was 91 percent.

The Form 483 shares a concern that the “OOS results that were invalidated by the firm’s QC unit were without rationale and supporting documentation.”

Alchymars falsified lab data: A September 2017 inspection by the USFDA at Alchymars ICM SM Private Limited in India uncovered that the firm “was falsifying laboratory data”. During the inspection, the FDA investigator found that an analyst reported far fewer colony-forming units (CFU) in a water sample than those observed on the plate by the investigator. 

The FDA raised serious concerns as Alchymars uses the water to manufacture APIs intended for use in sterile injectable dosage form drug products. 

Alchymars is part of a group of companies and the factory is controlled by Trifarma in Italy, a company which was cited by the FDA for data-integrity violations in 2014.

South Korea: Teva’s potential blockbuster gets delayed due to problems at Celltrion

As Korea emerges as a force to reckon with in the emerging world of biosimilars, the USFDA’s issuance of a warning letter to Celltrion (a major manufacturer of biosimilars that has also partnered with Pfizer for commercialization in the United States) came as a major setback.  

In an inspection conducted by the FDA from May 22 to June 2, 2017, the investigators raised concerns over multiple poor aseptic practices during the set-up and filling operations.

The warning letter highlights an example where during the aseptic filling of vials, an operator used restricted access barrier system (RABS) to remove a jammed stopper by reaching over exposed sterile stoppers in the stopper bowl. The RABS disrupted the unidirectional airflow over the stopper bowl, creating a risk for microbial contamination.

After the operator removed the jammed stopper, the filling line was restarted, but the affected stoppers were not cleared.

At Celltrion, the FDA raised concern over 140 complaints received between October 2015 to May 2017, which were identified to have occurred because of vial stoppers. 

The deficiencies at Celltrion impacted Teva as the Korean company is the main API supplier for Teva’s migraine drug fremanezumab.

Teva confirmed that the USFDA had extended the goal date of the Biologics License Application (BLA) for fremanezumab. The Prescription Drug User Fee Act (PDUFA) action date for fremanezumab is currently set for September 16, 2018.

The Celltrion warning letter was followed by an announcement by the US-based Evolusthat a USFDA pre-approval inspection of  Daewoong Pharmaceutical’s plant in South Korea, where a botox biosimilar is being produced, resulted in 10 observations.

Back in 2013, Daewoong had inked a contract with Evolus to export DWP-450 (a botulinum neurotoxin candidate), which was expected to be released in the US market around 2017-18.

While Daewoong said it expects “no significant further actions”, Evolus’ SEC filing highlights that “any failure to adequately resolve the FDA’s observations at the Daewoong facility would likely cause FDA approval of DWP-450 to be delayed or denied”. 

In May, the FDA declined to approve Evolus’ Botox rival citing deficiencies related to the chemistry and manufacturing of its potential treatment for frown lines.

New Report: Improving Clinical Site Payment Practices

Paying sites on time is critical to a trial’s success, sponsors agree, and most believe they’re making the grade. So why are sites so frustrated with how they’re paid? Are their expectations unreasonable or are sponsors operating in the dark?

A recent survey by Metrics Champion Consortium (MCC) indicates the latter is true. More than 70 percent of trial sponsors who manage in-house payment procedures said they’re pleased with their processes; ditto 65 percent of CROs. But sites were overwhelmingly dissatisfied, with 70 percent expressing a negative view.

cww2229_20180723_UmCjpJ-5-1024x709

So what’s the deal?

The survey shows sponsors don’t pay attention to the kind of metrics that can help them solve payment woes. They may know they’re not ponying up promptly but they’re looking for answers in all the wrong places – if at all.

There are many details and data points that can help sponsors figure out how well their payment processes are (or aren’t) working, says Linda Sullivan, MCC’s executive director.

MCC discovered that sites aren’t the only ones unhappy. Sponsors that outsource payment to other entities (like CROs) have less control over the process and often have less insight into how it is working on the contractor’s end.

“Those who are running the process – a sponsor [managing payments] in house or a CRO – think the process is going a lot better than those who are outside of the process,” Sullivan says.

One reason CROs like the process may be the fact that they use more metrics – nearly twice as many as sponsors – to evaluate it.

Understanding how well a process is working requires knowing all aspects of its operations. Tracking a simple metric of how many payments were made “on time” provides no information on why the other payments were not.

Fewer than 50 percent of survey respondents said they use the kind of metrics that provide insight into the root cause(s) of payment problems, such as the number of:

  • Invoices submitted by sites with errors;
  • Payments that are correct the first time;
  • Outstanding invoices with queries;
  • Days it takes to reconcile invoice discrepancies; and
  • Site complaints about payment problems.

This kind of information allows payers to pinpoint areas that need improvement. Sponsors that manage their own payment processes should begin using such metrics; those that outsource payments should make sure their CROs do, too, and require them to share the information.

Sullivan says to truly grasp and fix payment problems, sponsors must shift their focus from overall performance to “quality metrics.” For example, a large number of invoices outstanding may signal glitches in the invoice reconciliation phase. Tracking the number and nature of payment complaints from sites paints a picture of the depth of the problem.

The survey recommends replacing outmodled clunky manual payment systems with speedy automated ones to eliminate time-consuming and error-prone procedures.

Another tip: Parties involved need to communicate more effectively to align expectations, improve transparency and develop solutions.

Risk-Based Monitoring: Widespread Implementation is Underway, but Still Messy

The industry has been abuzz about risk-based monitoring (RBM) for much of the last decade, with the FDA indicating that it would like to see more sponsors give it a try.

But in practice, many companies are only just beginning to fully grasp the ramifications of skewing away from having monitors go to sites every six weeks or so to check all data, and moving toward more centralized electronic monitoring of patient data based on triggers that show there may be problems at the site.

That was the thrust of the DIA session The Risk Assessment is Done: Now What? A Guide to Setting Up a Centralized Monitoring Plan.

“Organizations are really trying to grasp: what is this critical data, these critical processes, how are we going to do that?” said Linda Sullivan, executive director of Metrics Champion Consortium (MCC), an industry association that focuses on the adoption of standardized, consensus-based performance metrics.

images

MCC formed work groups around risk-based monitoring in 2015, and this summer will release survey results (about 80 people in key positions responded to questions about the particulars of RBM implementation at their companies) as well as a guidance document amid what is still a sea of confusion and anxiety about RBM — even about its very nature and definition.

“We realized people still define risk-based monitoring in different ways,” said Sullivan.

At the CRO level in particular, there’s much work to do in sorting out the hows of RBM, said those on the panel during the session.

“Though we’ve done close to 600 central monitoring reviews and 200 RBM studies, there are still lots of challenges with implementation; it’s moving and evolving,” said Olgica Klindworth, associate director of data analytics for PPD.

One of the chief roadblocks, said Klindworth, has been terminology. For instance, “key trigger point” is a common term, but does it mean the same to everyone using it? Not necessarily, she said. Some use “key risk indicator” or KRI, and others with something altogether different. In fact, not everyone calls the process “risk-based monitoring.” Some call it “centralized monitoring.” Some call it something else.

For CROs in particular, it’s important to bring standardization to the process as they work with so many different sponsors. If one sponsor is using one set of terms and another sponsor uses a different one, and the CRO uses yet another, that will cause confusion and possible errors, said Klindworth.

Beyond terminology, the industry also needs to decide on the trigger points themselves, said Nurcan Coşkun, global risk-based monitoring and technology solutions program manager at Medtronic.

Though every trial will of course have its own trigger points based on the nature of the protocol, Coşkun said it’s useful to have standards and KRIs in place for each trial. She shared the standard triggers Medtronic has generated:

  • AE/SAE rates (under or over reporting)
  • Enrollment rates (high or low enrollers)
  • Screen failure rates (high rate)
  • Protocol deviation rate (high rate of non-compliance)
  • Overdue query rate (greater than 30 days)
  • eCRF entry cycle time (long delays in data entry)
  • CRA flag — PI oversight (CRA indicates “no” to PI has adequate oversight of study)
  • CRA flag — Met with PI (CRA indicates “no” to “Met with PI during IMV.”)

MCC’s industrywide survey, due out later this summer, showed that 82 percent of respondents are now preparing a central monitoring plan.

When asked whether they now have a set of KRIs they use for each study, 46 percent of respondents said yes, and 41 percent indicated that they add study-specific KRIs based on information from the risk assessment.

Another 32 percent said they are still developing their approach to KRIs.

“Critical thinking” is a concerning area during this protracted birth of RBM, said Keith Dorricott, director at Dorricott Metrics & Process Improvement in the UK, formerly senior director of site start up and regulatory for INC Research, who worked closely with MCC on its survey and guidance document. The worry is that so many tight processes and SOPs will be put into place to make RBM “work,” that those whose hands are on the process each day will cease to think critically about changes that may need to be made midstream.

Said Dorricott, “There is a lot of discussion around critical thinking — the need for people to have the skills to be able to assess the information they are seeing in doing centralized monitoring, and [for them] to be able to dig down further to even know if they should be digging down further, and what actions they should take and what point should they escalate.”

After all, critical thinking is at the very core of RBM, he said.

Checklists seem like an innocuous tool meant only to help, but for those concerned with keeping critical thinking robust in the RBM process, checklists are concerning.

“Checklists have downsides,” said Dorricott. “They can encourage people to just go down the list one by one without really thinking about what they’re doing.”

These issues are discussed in-depth in the guidance document MCC will release later this summer, said Dorricott.

Another area of concern as the industry looks at fully adopting RBM? Duplication of effort. Who does what?

“More often than not, if you have multiple vendors and companies participating in a process, you will end up with some duplication and overlap,” said PPD’s Klindworth.

Despite the vital questions that remain about the very nature of the RBM process, Klindworth said it’s a favorable time to be involved in the shaping of the process that has the potential to streamline the industry, making data cleaner while making trials cheaper to conduct.

“It’s a great time for all of us, especially for CROs to have an opportunity to work with so many flavors of central monitoring so that we can learn and improve what we do and be better prepared,” she said. “The key is for all of us to remain flexible and nimble in this complex landscape.”

Encouraged by Regulators, Sponsors Begin Adopting Real-World Evidence into Clinical Trials

While the FDA is preparing to develop and implement a program evaluating the potential use of real-world evidence (RWE) for regulatory decision making, a panel discussion at this year’s DIA Global annual meeting described how the industry is already using RWE to complement clinical trials.

Tarek Hammad, MD, PhD, head of signal detection and benefit risk assessment, global patient safety innovation at EMD Serono, talked about the role real-world evidence played in the recent approval of avelumab – an anti-PD-L1 monoclonal antibody — to treat metastatic Merkle cell carcinoma (mMCC), a rare aggressive skin cancer.

RWE-FLOW-V2

As explained by Hammad, there is no approved standard of care for treatment of mMCC, so investigators — instead of a using a formal comparator arm — generated data from electronic medical records (EMRs) on observed clinical outcomes in a patient population that received chemotherapy in current clinical practice. This data was then used as a benchmark for chemotherapy efficacy in a real-world setting.

The researchers were able to identify a subset of trial patients who responded to treatment with avelumab and document the benefit gained by contrasting it to the benchmarked data. Last year the FDA granted accelerated approval to avelumab.

Hammad said that several lessons can be learned from the avelumab approval:

  • The use of RWE can be helpful in contextualizing single arm trials for rare diseases, such as mMCC;
  • Early planning may be needed if it’s necessary to review patient records or biopsies;
  • Response assessment in the real-world setting can be more subjective than those in controlled clinical trials;
  • There is always going to be some reporting bias because only patients with complete follow-up information may have been entered into the database, possibly leading to either an under or overestimation of outcome measures;

Tamy Kim, PharmD, associate director of regulatory affairs, Office of Hematology and Oncology Products at the FDA, noted that the use of RWE must be balanced with several concerns: bias and confounding factors such as different patient characteristics and comorbidities, regional variations in standards of care, the quality and completeness of data, the ways in which physicians assess or diagnose patients and how to deal with data that comes from outside the U.S.

Plus, standards of care are rapidly evolving. “So, when new drugs are introduced into a standard of care it’s going to be harder in a real world setting to determine whether the outcome was the effect of particular drug or study or was related to that standard of care, and what new drugs were introduced in that standard of care.”

“With all that said, we are still excited to use real world submissions,” she said, adding that it could help speed up drug development.

She also observed that that one of the drivers spurring the use of RWE is “that the clinical trial paradigm is a paradigm that is used in a relatively pristine setting,” said Kim

This means exclusion criteria often leave out certain groups of patients. For example, she pointed out that elderly patients, or patients with brain metastases or poor performance status are often excluded from oncology clinical trials, even though these patients do take oncology products in the real world.

“How do you know when you approve the drug that it’s going to have the same effect in the real world?” she asked. “We’d like to be able to use these drugs in the real world.”

Nancy Dreyer, PhD, chief scientific officer & senior vice president at IQVIA, who moderated the panel, noted that not only is the FDA promoting the use of RWE in clinical trials, but that the European Medicines Agency (EMA) has stated its intent to take an adaptive pathways approach to drug development — which means more use of real-world data.

When it comes to the use of RWE in clinical trials, “the train has left the station” as far as regulators and payers are concerned, said Dreyer.

 

Research Projects Show Credentialed Principal Investigators and CRCs Perform Better

The research is clear: certified principal investigators (CPIs) and clinical research coordinators (CRCs) do better work compared with their peers who hold no certification. Much better work, in fact.

That was the thrust of the DIA session Assessing the Impact of Credentialing on Clinical Trial Quality and Performance. It was led by Ken Getz, director of sponsored research programs and associate professor at Tufts Center for the Study of Drug Development, and included the Association for Clinical Research Professionals’ (ACRP) Beth Harper and WCG’s Suzanne Caruso.

“Variance is the enemy of good quality,” said Getz. “There are no real standards or competency requirements for becoming a PI or CRC so the potential for variance in performance is high.”

And the pool of PIs is not stable, which further contributes to the quality problem, he said. In addition, the lack of a structured career path for CRCs and high turnover rates compound the site quality problem, which has devastating consequences for trials, he added.

To offer proper training, ACRP created certification for CRCs, and later, PIs, but neither certification is required to work in the industry. There has historically been much better uptake of the certification for CRCs; about half of all CRCs maintain their certification, which requires that they obtain 24 hours of continuing education credits every two years. Among active PIs, though, as of 2017, only two percent of those working in the field had obtained certification.

certified-clinical-research-coordinator-women-s-t-shirt

Credentialing makes a huge difference in the quality of an investigator’s work.

WCG is working on a study on the topic. Though not complete, the data are already strong. According to Caruso, vice president of clinical solutions for WCG, the majority of ACRP-certified researchers have a low number of protocol deviations. In addition, she said, they have higher enrollment rates across currently active U.S. investigators in WCG’s investigator database, which includes 85 percent of all FDA-regulated investigators and across the company’s site performance data.

Others are studying this issue, too. ACRP has teamed up with the FDA to use FDA inspection outcomes to examine the difference in performance between PIs who have certification versus those who don’t. Thus far, it’s clear that ACRP-certified investigators and coordinators have higher randomization rates and lower numbers of protocol deviations, said Harper, ACRP’s workforce innovation officer. Final results of ACRP’s research on the topic are expected later this summer.

WCG and ACRP are building on research already done by J. M. Hausler in 2009 and David Vulcano in 2012. Hausler performed a retrospective analysis of four trials conducted by a specific sponsor (U.S. multi-center trials) that included 1,400 randomized subjects, which showed that the number of protocol deviations was significantly lower if a PI was certified, and if both a both PI and CRC were certified.

Vulcano — like ACRP is doing now — drilled down on whether there was a difference in FDA inspection outcomes between certified PIs (CPIs) and those who were not certified, and found that CPIs receive fewer for-cause audits, that CPIs are more likely to receive the most favorable outcome and that CPIs are less likely to receive the least favorable outcome.

Explained Harper, the CPI exam is a 100-question multiple-choice test focusing on PI essential duties. To be eligible to take the exam, PIs must have a doctoral degree, show proof of employment as a PI for two of the last five years, and perform all of the duties detailed in an ACRP list of typical PI tasks.

Other key data from the session:

  • Fifty-five percent of the $13 billion the biopharma industry spends annually on clinical trials goes to part-time investigators, while 39 percent goes to academic medical centers and large health systems. Just six percent goes to dedicated sites and site networks.
  • Out of 33,920 unique FDA-regulated investigators in 2015 (the most recent year when complete data are available), 64 percent, or 21,570, had only worked on one clinical trial. Turnover rate in this group was 49 percent. A quarter of those investigators had done two to three trials. Turnover in this group was 20 percent. Just seven percent (2,491 PIs) had done four to six trials (turnover in that group was five percent) and four percent of the 33,920 (1,213) had done seven or more trials. Among this group, the turnover rate was one percent.
  • According to recent data from Tufts, the study initiation (identification through start-up) process takes 36.4 weeks for new sites and 26.2 weeks with repeat sites.

“Site performance is highly unpredictable and expected to be more volatile in the future given growing prevalence of rare and stratified diseases combined with a landscape characterized by fragmentation, low volume, inexperience and turnover,” said Getz, adding that meantime, a growing body of data demonstrates that credentialed site staff perform better in terms of both quality and efficiency measures.

Uber Launches Uber Health, Looks To Improve Patient Experience In Clinical Research

San Francisco-based transportation network company, Uber, is looking to expand their outreach to the clinical research community with the launch of Uber Health, a new dashboard the company hopes will remove transportation as a barrier to proper care.

Using Uber Health, doctors and hospitals will be able to arrange rides for their patients even if the patient hasn’t downloaded the Uber app or does not have a smart phone. Uber Health has been used in beta testing by around 100 hospitals and doctors’ offices since July.

Patient transportation has been the focus of the ride-sharing industry for some time with Uber announcing in October 2016 a non-emergency medical transportation pilot program in conjunction with Circulation. Circulation also announced a preferred partnership with Lyft last year.

Uber Health will address a growing need in the clinical research industry, the company believes. Citing a report by SCI Solutions, Uber says missed healthcare appointments in US alone costs the industry $150 billion a year, and the rate of no-shows in 2017 reached 30% nationwide.

CLN_banner-uber-contribution-clinical-research-407x303

Brad Rosenthal, Uber Health’s Head of Business Development, tells Clinical Informatics News that Uber wanted to approach this new service with patient privacy in mind, working with the idea for a service like Uber Health for two years and making sure the system was HIPAA-compliant before moving toward beta testing.

“In the clinical trial space in particular, we have heard over and over again that recruitment and retention are major issues, to the extent where transportation is a burden and ultimately a barrier for trial retention” Rosenthal said. “We hope we can alleviate some of that.”

Currently Uber Health is leveraging all of Uber’s 750,000 US drivers, a choice Rosenthal says helps put focus on the reliability of the service. “We talked about designating specific Uber drivers for Uber Health, but ultimately we felt that would limit the range of exposure to the service.”

Another focus for Uber Health was limiting the amount of effort on the patient’s part to order the rides. All of the steps from ordering to paying for the ride (which can be handled as either part of the patient’s bill or the organization’s budget) are handled by the healthcare organization, says Rosenthal. That includes the overall health and safety of the patient and evaluating the potential risk of ordering an Uber ride for a given patient.

Uber Health is not an ambulance service, Rosenthal says. “The organization ordering the ride should be confident that the patient is healthy enough to be in the back seat, and if they’re not they should really be calling 9-1-1.”

According to Rosenthal, Uber Health is available in two versions. As a standard web-based dashboard, hospitals and clinical trial sites can use Uber Health to arrange transportation for instant pickup or schedule for up to 30 days before their patient’s scheduled appointment. Uber Health also offers API functionality for the service, giving partners and customers the option to take all the capabilities of arranging transportation and building out their current technology to include these capabilities.

“The functionality between our web-based dashboard and our API is very similar,” Rosenthal says. “But our API allows healthcare organizations to build additional features and ultimately tailor it to how they would like.”

One example of Uber Health’s API capability is through their partnership with healthcare technology company Bracket, who offers research patients the ability to request transportation through Bracket’s Patient Engagement app.

“There’s a growing array of parties that are trying to impact and improve the patient experience in one way or another, and they’re all distant from each other,” Jeff Lee, President of mProve Health (a Bracket company), told Clinical Informatics News in a phone interview. “So when a patient joins a study they’re probably seeing technology from a half dozen or more different providers. That’s quickly becoming an incoherent experience for the patient. Our goal is to help make that all a bit cleaner, [providing] a one-stop shop.”

Bracket is looking to use Uber Health’s API as a more on-demand feature, allowing the patient to request a ride for themselves at any given point and at any given location.

“Sometimes you go to your doctor’s appointment and you’re not sure where you’re going after your visit, or you don’t know where you’re going to be prior to your visit,” Lee says. “Being able to have the patient initiate the ride themselves and have the whole ride experience with all of the Uber hallmarks, is a really complementary way to add value for the patient.”

Rosenthal says the new service has been received well in the clinical trial space, and the company is presently working to connect with a growing clientele he says Uber has not historically interacted with: patients without smart phones or mobile phones at all.

“One of the features we’re currently in build-mode on is interacting via landline,” Rosenthal says. “The question becomes, ‘How can we work on automated reminders through a landline that [a patient has] an appointment and that they’ve been matched with a driver with license plate XYZ driving such-and-such car?’ I think the focus now is how do we work on continuously improving the patient experience.”

Lee believes Uber Health is one of many examples where companies are starting to pay attention and devote time and energy toward clinical research.

This is starting to feel like science fiction, Lee says. Between services like Uber Health reaching directly to the patient and the discussions that Amazon could utilize their Echo Dot as a patient-reported outcome instrument, Lee believes we are moving forward into the space of true patient engagement.

“I think patient centricity and patient engagement are these catch-all terms that mean everything and mean nothing at the same time,” says Lee. “We’re really proud that patient engagement means something specific to us. We know how to put it into practice, and we think things like this type of service can make the patient’s life easier using technology. It’s real patient engagement.”

Compensating Participants in Clinical Research: Current thinking

In clinical research studies, it is not uncommon for monetary compensation to be provided to research participants; as reimbursement for study-related expenses, as compensation for time and effort, and even as incentive payments to encourage enrollment. Sponsors, researchers and Institutional Review Boards (IRBs) are often wary about payments in research participation, citing concerns about coercion and undue influence, whether real or perceived,

and have avoided payments that are “too high.” But new research on how people make decisions about research participation, and new approaches to this question, bring a new perspective; are payments to participants actually too low? This paper explores this question, and whether we should, in fact, worry much less about restricting compensation for research participants.

Unknown

Undue influence and Coercion

At the foundation of the concerns about research participant payment are the issues of undue influenceand coercion. These words are not clearly defined in research regulations or guidance, and are often
used interchangeably when talking about participant payment, but they actually have very different meanings.

To coerce means to achieve something by using force or threat. Situations of true coercion are rare in clinical study recruitment situations. An example of coercion might be a physician who is seeing a patient at a free clinic who says, “If you don’t agree to be in my research study, you can’t come here for care anymore.” Payment offers, though, are not force, nor are they threats. Therefore, offers of payment for participation in research can never be coercive.

Influence is a different concept. Influence, in itself, is not a bad thing. Everyone makes decisions about what they do based on factors that influence them, and sometimes those factors are financial. While many of us really enjoy our jobs, if our employer told us that we wouldn’t get paid anymore, we’d probably stop showing up for work. The issue, then, is not influence, but undue influence. In legal terms, undue influence means that someone makes someone else behave in a way that is contrary to their interests. In research, we often describe undue influence in study recruitment as someone agreeing to take risks that were not reasonable, because they were influenced by other considerations (in this situation, by the offer of money).

But as discussed in the excellent recent paper, Paying Research Participants: The Outsized Influence of “Undue Influence” by Emily Largent and Holly Fernandez Lynch1, the possibility of unreasonable risks requires more consideration as well. In order for an IRB to approve a research study, the Board must ensure that the risks of the research are reasonable in relation to the anticipated benefits, for the target study population. If this is the case, for a research protocol that has been IRB-approved and a potential participant who is in the target study population, how can the offer of payment influence them to take risks that are unreasonable, when the risks have already been determined to be reasonable? With this argument, Largent and Lynch explain that the potential problem of undue influence in IRB-approved research is significantly overestimated, although possible in some very specific situations
(for example, when potential participants are likely to deceive the researchers about their eligibility or when they have some unique characteristics outside the IRB’s purview). In an effort to reduce the occurrence of these situations—although they are already rare—we as a research community have erred on the side of caution in preventing payment or encouraging payment to be kept relatively low. However, underpaying for participation results in the possible exploitation of research participants, the overburdening of certain populations who are willing to accept low payments, and the scientific risks of failed studies due to under- enrollment. For minimal risk research, any concern at all about compensation is likely unnecessary, as the risks are so low that it would be very unlikely that any participant could be making a decision to take a risk that is unreasonable.

Types of Payment to Participants

Reimbursement of Study-Related Expenses

Reimbursement of expenses related to participation in research studies, whether provided by the sponsor or by the institution, should never be of ethical concern. While there are rare instances in which ethically- acceptable studies involve requiring participants to pay for study-required procedures or medications— most often in situations where diagnostic testing is being used for both clinical and research purposes— for the most part, research participation should be cost-neutral. Making research cost-neutral helps to ensure the principle of distributive justice, and that the risks and benefits of research participation are fairly distributed. If each research visit involves out-of-pocket expenses for gas, food during a long wait between scheduled blood draws, parking fees, and child care, then only those who can afford those expenses would be able to participate in the research.

Coverage of expenses for airfare, overnight hotel stays, and other long-distance travel for research participation used to prompt additional ethical concerns based on the higher amounts of money involved. Comfort for these practices has grown over the last several years, in part based on studies in rare diseases and more specific patient populations, where the research is conducted at centers of excellence but potential subjects may be coming from other states or even other countries.

A number of different models for covering out-of-pocket expenses are acceptable including collection of receipts and reimbursement in cash or check; vouchers for taxis, parking or meals; pre-funded debit cards; or providing a per-diem amount based on average and expected expenses. Comfort has also grown with using third party vendors such as Uber and Lyft to bring participants to study visits, with direct billing to the sponsor.

Compensation for Time and Effort

Studies which include compensation for the time and effort of research participants should make an effort to consider the actual time spent on the study, including study visits, tasks outside study visits (completing surveys or diaries), and even travel time to clinical sites, keeping in mind that participants may be missing work in order to complete the study requirements. Payment amounts should be high enough so that they do not take advantage of populations with lower income; proposed payment amounts are sometimes based on local minimum wages, which provides a handy benchmark, but basing study payment on a low wage does have the effect that anyone who makes more than that wage will be losing money if they miss work for study commitments.

There are a number of models that have been proposed for the compensation of research participants, including a wage-payment model, and payment based on market forces and supply and demand.

Incentive Payments

Some study plans include, either explicitly or implicitly, the payment to potential participants in a manner
or at a rate that is intended to persuade them to participate in the research study, above what might
be considered compensation for time or effort. For example, one study offered to pay the costs of elective plastic surgery for which the patients were already scheduled—several thousand dollars—if the patients agreed to participate in a 24-hour-long post-operative study comparing a new pain medication to the standard medication. Another study offered access to services (consultation with personal coaches) and gifts up to a value of approximately $6000 for participation in a study that required the completion of a survey every three months for a year. While the initial reaction to the amounts of money involved is usually caution, if we go back to the discussion of undue influence earlier in the paper, is there truly a valid concern? In both cases, an IRB had determined that the risks of the research were reasonable in relation to the potential benefits; in the second example, the risks were minimal. If the sponsor is willing to pay a certain amount of money to ensure that they were able to enroll the study with the necessary number of participants and in a reasonable amount of time, these types of payments should be acceptable.

Conclusion

Efforts to protect research participants from undue influence, and researchers and sponsors from perceptions of trying to use undue influence, have long been a major concern for IRBs. However, the true risk of undue influence is significantly lower than has often been assumed, when considering research that has been IRB-approved and for which the risks are considered to be reasonable. Instead, parties involved in research should consider whether payments to research participants are sometimes too low.

Visit Us On TwitterVisit Us On Google PlusVisit Us On LinkedinVisit Us On Facebook