A ranking of sorts is sent out every week to the chosen ones, but those who find themselves in the top spots don’t feel lucky at all: They are clinical trial investigators whose sites have just been singled out by contract research organizations (CROs) for having the highest number of outstanding queries.
To be fair, it would be hard not to ignore most of these queries. Out of 100, only one may be related to a serious patient-safety event that merits attention from the investigator, leaving 99 irrelevant distractions, said Andrew Wei, MBBS, PhD, an acute myeloid leukemia researcher at Monash University and Alfred Hospital in Melbourne, Australia.
“This makes some sites look bad because they had 120 queries,” he said. “The CROs don’t take into account that these sites also had the most patients.” Still, it’s a risk that researchers don’t want to take, and they are obliged to respond to all queries.
This perceived stranglehold on clinical trial conduct has bred resentment between investigators and CROs, with some researchers doubting the usefulness and intentions of these organizations.
“CROs [release these lists] purely to humiliate and embarrass the principal investigators as a way of bullying sites into addressing the queries quickly,” Dr. Wei told ASH Clinical News. “Our coordinators are being harassed [and] asked to answer really stupid queries clearly generated by people who don’t understand medicine. Some queries are asking us to educate them on what to do.”
Humiliation and harassment of trial investigators is not what pharmaceutical companies intend when they decide to outsource data management and biostatistical analysis to a CRO. And it’s certainly not what CROs sign up for when they agree to take over a sponsor’s clinical trial.
“CROs pursue innovation in clinical trials because a competitive industry demands it, and because it’s what patients awaiting new medicines deserve,” according to the Association of Clinical Research Organizations (ACRO), the trade organization representing CROs. “Research sponsors choose to work with [CROs] because they have confidence [they] will work tirelessly to conduct safe, thorough trials on schedule and within budget.”1
Unfortunately, to meet those demands while adhering to regulatory and protocol guidelines, CROs are compelled and often incentivized to “bully” investigators. CROs are an easy target for researchers’ frustrations, but are CROs victims of the same bureaucracy plaguing investigators and research sites?
Birth of an Aggravation
When the first CROs came onto the scene in the 1980s, their goal was to help industry partners bring new treatments to patients more quickly and efficiently. This same decade, the U.S. Food and Drug Administration (FDA) completely reworked clinical trial design.
The agency stopped approving drugs on a study-by-study basis; each investigational drug submitted for review had its entire body of evidence evaluated. New Drug Application submissions required increasingly detailed information. The agency also deemed surrogate endpoints acceptable for approval in data analyses, giving lovastatin the green light in 1987 based on the surrogate of reduced cholesterol.2
Pharmaceutical companies felt compelled to hire professional help to cope with the change. In 1982, Quintiles arrived on the biostatistics consulting scene, and the National Cancer Institute contracted with Theradex Oncology Experts to monitor its clinical trials.2
Today, Quintiles (now IQVIA, after merging with IMS Health) is a full-service CRO in a field teeming with competitors who offer assistance with everything from selection of investigators and sites to recruiting trial participants.
For readers who have not yet been initiated into the CRO club, the relationship unfolds as follows: The CRO’s monitor meets the study team (nurses, pharmacists, research coordinators, and other physicians) for a site-initiation visit; the representative reviews the trial’s protocol and investigators’ responsibilities and then tours the site. What comes next is usually a revolving door of site monitors, reminders about upcoming visits, updates about prior visits, and requests to complete documentation through the CRO’s website.
Queries are one way that CROs communicate with on-site study coordinators and clinical investigators, with the intent of getting researchers to respond to issues of patient safety, drug efficacy, or the study process. In reality, though, queries may be picky or identify issues that are irrelevant to patient safety or study conduct, and grow in number as the pressure to address them evolves into an entirely different animal, as observed by Dr. Wei.
The View From the Other Side
Despite their reputation as bureaucratic bullies, CROs certainly have their own battles to fight. “It is in everyone’s interest for clinical trials to be more efficient,” said Matt Feldman, director of communications for ACRO. “We work with our members to address challenges faced by CROs, as innovations in technology, for example, change the way that trials are conducted.”
“The challenges [CROs] are facing are not very different from the challenges that institutions are facing, like nursing shortages, finding well-trained workers, creating standards and practices, and reducing the documentation burden on health-care providers,” Michael Brooks, executive vice president of product registration (Americas) of PRA Health Sciences, told ASH Clinical News.
“It is in everyone’s interest for clinical trials to be more efficient.”
—Matt Feldman, Association of Clinical Research Organizations
The demands of the pharmaceutical sponsors who contract with CROs also represent their own challenge. Some sponsors are now moving from longstanding relationships with a single CRO to three- to five-year contracts with multiple CROs. Regular audits by the sponsor keep CROs on their toes; when a CRO wins a contract, it wants to “perform” for the pharmaceutical company so it can keep other competitors at bay.3
Often, monitors come and go, and their considerable responsibilities (coordinating trials and overseeing data collection from multiple sites) are shifted to an assortment of replacements. CRO associates – many of whom have limited technical training – frequently learn on the job and are compensated at lower rates than their peers at pharmaceutical companies. Some are even required to meet a certain query-generation quota.
“The training on topics we have to discuss with the sites is endless. … I don’t have the appropriate knowledge about the disease and the trial protocol,” admitted David Pleiss, a German CRO employee who wrote to ASH Clinical News in a Letter to the Editor.4 “And, because I work on so many trials in different medical fields, I sometimes look stupid at sites when I am telling a highly professional team how they have to work. I am lucky that most sites are sympathetic and don’t blame me – or don’t blame me too much.”
“All CROs can do a better job in training,” Mr. Brooks agreed. At PRA, he said, they have looked to other industries for guidance. For example, to test site monitors’ readiness to go out in the field, PRA developed a virtual training environment, similar to how airlines train pilots. “The simulation walks site monitors through interactions with investigators, then we give them an opportunity to explain their critical thinking and decision-making processes. It helps us root out who is ready for field visits, and who might not ever be ready.”
CROs are also subject to monitoring. The FDA conducts comprehensive Bioresearch Monitoring (BIMO) inspections, which come with little notice and involve staff interviews and data audits. After just a single visit, study data may be accepted or rejected and warning letters issued to clinical investigators.5
BIMO inspectors lump sponsors, monitors, and CROs together and can penalize them for inadequate monitoring, failure to bring investigators into compliance, inadequate accountability for the investigational product, and failure to obtain FDA and/or institutional review board approval prior to study initiation or amendments. In 2016, violations turned up in 35 percent of 112 such inspections.6
If the FDA asks for documentation, the CRO must be prepared to provide everything it has. After all, when it takes over the sponsor role in a clinical investigation, the organization assumes some or all of the sponsor’s responsibilities: costs, protocol development and compliance, drug disposition, qualified monitors, adverse event (AE) reporting, record-keeping, financial reporting, and the selection of clinical investigators.
Like their U.S. counterparts, European CROs also operate under the watchful eye of a regulatory agency, with the European Medicines Agency (EMA) inspecting investigator sites and sponsors to ensure compliance with European regulations.
“European investigators are plagued by the [CRO] parasite,” wrote Steven Le Gouill, MD, PhD, of France’s Nantes Medical University, and Simon Rule, MD, of Plymouth University in the U.K., in a Letter to the Editor that was cosigned by more than 80 European colleagues.7 “It is time to start questioning the necessity of some aspects of the clinical trial data-collection process, particularly those that cause daily hassles before, during, and after a clinical trial – sometimes years after publication.”
The downstream effects of meeting these requirements are greater burdens on research teams, costlier clinical trials, and slower progress in the war on cancer.
A For-Profit Problem
According to researchers who spoke with ASH Clinical News, their major concerns with CRO-coordinated trials stems not from the CROs themselves, but from the motivations behind their use.
Pharmaceutical sponsors, Dr. Wei argued, are driven by financial gain, rather than quality. “It’s cheaper for the sponsor to contract out to the CRO rather than have trained employees do the job internally,” he said. “However, although the financial benefit is there in the short term, pharmaceutical sponsors risk a damaged reputation in the long term.” He urged sponsors to realize that hiring a CRO is not just a money-saving issue, but an extension of the company’s work and engagement with the investigators.
Hagop Kantarjian, MD, chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, called for researchers and sponsors to more closely scrutinize the quality of CROs’ work. Quality control could come in the form of an index – a scorecard of researchers’ own, in a sense.
“It’s cheaper for the sponsor to contract out to the CRO rather than have trained employees do the job internally … pharmaceutical sponsors risk a damaged reputation in the long term.”
—Andrew Wei, MBBS, PhD
In his experience, he added, working with CROs brings a new, memorable experience every day – and not in a good way. Dr. Kantarjian said there should be much less CRO presence in trials, and then perhaps only in pivotal, phase III trials. “[CROs] should not design trials or select investigators,” he said. “These [tasks] should be done by medical experts, not CROs with people training on the job.”
“The potential effects of CRO use on study safety, ethical conduct, and efficiency are understudied,” Kantarjian and co-authors wrote in a commentary in a Cancer review.3 “Concerns raised by study personnel and occasional reports of misconduct suggest that the current CRO model is flawed and that new standards for CRO monitors are needed.”
Drs. Le Gouill and Rule suggested that more can be done. “The pharmaceutical industry needs to engage properly with the regulators and stop interpreting what they believe is expected of them,” they wrote.7 “Those of us who still run academic studies within the same regulatory frameworks know full well that most of what is being asked for in the name of quality and safety is not required.”
Solutions on the Horizon?
“We need to be more realistic about how trials are conducted and which data are important to collect,” said Alok Khorana, MD, who studies gastrointestinal cancers and cancer-associated thrombosis at the Cleveland Clinic in Ohio. “These are not the responsibilities of the CROs, but rather that of the research community as a whole.”
The goal, he said, should be “making trials more patient-friendly and real world–based, so the types of patients who enter and stay on trials reflect the types of patients we see in practice.”
CROs share the same goal, Mr. Feldman noted, but the solution to relieve some of the burden of clinical trials will have to involve all responsible parties, including pharmaceutical sponsors, regulatory agencies, and research sites. “There are many ways for clinical investigators – individually and as a group – to engage in the dialogues around facilitating a research enterprise that is more appealing to patients and less burdensome to investigators,” he said.
In a report reviewing the present and future states of clinical trials, ACRO recommended several policy changes “to ensure that there remains an atmosphere conducive to innovation and medical research and development.”1 These include:
- updating gov (the U.S. National Library of Medicine’s database of trials) to be more user-friendly
- integrating electronic health records with the federal database of clinical trials to assist patient recruitment
- extending research-and-development tax credits
- clarifying regulations identifying which party is responsible for compliance
One of the recommendations emphasizes CROs’ desires to improve working relationships with regulators and sponsors: “[Make] it explicitly clear within the development process that regulators, trial sponsors, and CROs may communicate before and during trials will improve trial outcomes, advance the adoption of adaptive trial designs, and promote a culture of innovation within the FDA itself.”
“For more trials to be successful and for investments in trials to pay off, regulations for clinical trials must be clear and predictable,” the authors noted. “There also must be even more cooperation, collaboration, and communication among regulatory bodies, research sponsors, and CROs.”1
“What has me excited is that the regulators – the FDA, the EMA, the Japanese and Chinese authorities – want to ease the burden on sites, pharma companies, and CROs,” Mr. Brooks said. “They’re collaborating with us, giving us feedback on the issues they’re seeing, giving us feedback on the technology and the methods that we’re exploring, and encouraging us to implement new technologies.”
The biggest opportunities for pharma companies to help alleviate the burden of conducting clinical trials is to embrace recent innovations in the drug development space, he added. This comes in the form of adopting technologies that “automate workflows and minimize paperwork that accompanies the trial, leveraging data and analytic tools to help us detect risks and issues and move away from the traditional monitoring methodology,” Mr. Brooks explained.
The “heaviest” part of the CRO-coordinated trials process is “collecting documents that support a site’s qualification for participating in the trial, but many of these processes can be automated,” he said, “and then we can use the electronic environment to leverage past documents of clinical trials, validate it, and move on.”
Then, once the trial is up and running, he explained, data can be extracted from electronic health records, placed into the electronic data capture environment, and run through automatic analytic tools that identify signals of adverse events or poor compliance.
“Ultimately, we need the senior leaders and executives within biopharma to adopt these innovations,” he said. “To me, it’s ironic because many of these innovations are not really ‘innovative’ at all – they’re tried-and-true methods.”
Mr. Feldman pointed to TransCelerate BioPharma, a non-profit organization formed by pharmaceutical industry members, as a leader in this effort. Since 2012, its mission has been “to identify, prioritize, design and facilitate implementation of solutions designed to drive the efficient, effective and high-quality delivery of new medicines.”8
In 2015, TransCelerate released its first Common Protocol Template (CPT), a guideline for designing “harmonious” clinical trial protocols. “Having a CPT will ease protocol interpretation and review by sites, IRBs, and regulators,” Dalvir Gill, PhD, TransCelerate chief executive officer explained.9 “Protocols have become increasingly complex and difficult to navigate, with sponsors providing protocols in their own structure. Sites spend time deconstructing and interpreting protocols when that time would be better spent with patients.”
The latest update to the TransCelerate CPT, issued in December 2017, aligns with the NIH-FDA Joint Leadership Council’s protocol template, originally designed for NIH-funded studies. “Following a harmonized template will also enable review and even comparisons of studies by regulators,” Dr. Gill added.
Mr. Feldman also noted that “the FDA and the biopharma industry work with academic centers and a wide range of partners (including ACRO members) through the Clinical Trials Transformation Initiative (CTTI), with shared goals of improving the efficiency and quality of clinical research.”
This public-private partnership envisions “a high-quality clinical trial system that is patient-centered and efficient, enabling reliable and timely access to evidence-based therapeutic prevention and treatment options.” The CTTI’s strategic plan involves “transformative and incremental change” in evidence generation, patient recruitment, and protocol development.10
Since its founding in 2008, it has completed more than 25 projects, supported in part by funding from the FDA, that explore new practices that could correct the inefficiencies in the research enterprise. These projects have produced several official recommendations, outlining actions regulators, CROs, and investigators can take to improve the clinical trials enterprise.
The first official recommendations, issued in May 2011, tackled improving AE reporting – one of the most pressing concerns cited by Dr. Wei and other researchers who spoke with ASH Clinical News. Their recommendations include decreasing the volume of uninterpretable and irrelevant safety reports to investigators (through changes to FDA policy) and supplying investigators with meaningful reports that would improve their understanding of a drug’s safety profile.11
Dr. Khorana echoed these sentiments, deeming it important for the monitors “to focus only on AEs that are relevant [to the investigational drug], rather than on every AE a patient experiences.” Because of the pay-by-query incentive models most organizations use, CRO associates also feel compelled to escalate issues to the trial’s principal investigator on a whim.
Abolishing these financial incentives is at the top of Dr. Wei’s CRO wish list, too. He believes any effort to address the concerns of research teams would go a long way toward improving the clinical trials process – and the validity of its results.
Today, CROs are a multibillion-dollar industry. Their market was worth $25.3 billion in 2013, about one-fifth of the $130 billion that pharmaceutical companies spent on clinical research and development that year. Projections estimate that CROs will take over 70 percent of clinical trials by 2020.12
Clearly, CROs are here to stay, and the entire research community needs to figure out how to work with each other, Dr. Wei agreed. “I’m not interested in eradicating or bashing CROs. I’m worried that financial rewards are driving bad behavior,” he said. “I accept that we need CROs, because regulators need to have confidence in the results being produced, but I want to emphasize that we need a balance between quantity and quality of clinical trial data.” —By Nicole Lou
- Association of Clinical Research Organizations. “Clinical Research: A Legacy of Innovation, A Future of Transformed Medicine.” Accessed February 21, 2018, from http://www.acrohealth.org/wp-content/uploads/2014/10/acro-white-paper-tah10.pdf
- U.S. Food and Drug Administration. “FDA and clinical drug trials: a short history.” Accessed January 20, 2018, from https://www.fda.gov/AboutFDA/WhatWeDo/History/ucm304485.htm.
- Roberts DA, Kantarjian HM, Steensma DP. Contract research organizations in oncology clinical research: challenges and opportunities. Cancer. 2016;122:1476-82.
- Pleiss D. “CROs: a universal problem.” ASH Clinical News, January 2018. Accessed January 20, 2018, from https://www.ashclinicalnews.org/perspectives/cros-universal-problem.
- U.S. Food and Drug Administration. “Pediatric clinical investigator training: GCP, BIMO, monitoring tips on preparing for FDA inspection.” Accessed January 15, 2018, from https://www.fda.gov/downloads/NewsEvents/MeetingsConferencesWorkshops/UCM519807.pdf
- U.S. Food and Drug Administration. “Bioresearch monitoring (BIMO) metrics – FY’16.” Accessed January 15, 2018, from https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RunningClinicalTrials/UCM561049.pdf.
- Le Gouill S, Rule S, et al. “Advocating for a return to common sense in clinical research.” ASH Clinical News, July 2017. Accessed January 11, 2018, from https://www.ashclinicalnews.org/perspectives/advocating-return-common-sense-clinical-research.
- TransCelerate BioPharma. “Our Mission.” Accessed February 21, 2018, from http://www.transceleratebiopharmainc.com/our-mission.
- Outsourcing Pharma. “Updated common protocol templates align clinical trial objectives, endpoints.” Accessed February 21, 2018, from https://www.outsourcing-pharma.com/Article/2017/05/08/Common-protocol-templates-align-clinical-trial-objectives-endpoints.
- Clinical Trials Transformation Initiative. “Strategic Plan.” Accessed February 21, 2018, from https://www.ctti-clinicaltrials.org/who-we-are/strategic-plan.
- Clinical Trials Transformation Initiative. “CTTI Recommendations: Improving Reporting of Unexpected Serious Adverse Events (SAEs) to Investigational New Drug (IND) Investigators.” Accessed February 22, 2018, from https://www.ctti-clinicaltrials.org/sites/www.ctti-clinicaltrials.org/files/recommendations/saereporting-recommendations.pdf.
- Vantage Partners. “Sponsor-CRO collaboration study: executive summary.” Accessed January 27, 2018, from http://www.vantagepartners.com/uploadedFiles/Consulting/Research_And_Publications/Smart_Form_Content/Publications/Articles/Sponsor-CRO_Collaboration_Study_Executive_Summary_(2013-11-19).pdf.
In the U.S. and E.U., national regulatory agencies keep a close watch on site investigators. In areas outside of the FDA and EMA’s purview, particularly in lower- and middle-income countries, though, the limited oversight of clinical research leaves patients vulnerable to exploitation. Some patients are even enrolled in trials without their knowledge because of illiteracy and other barriers to informed consent.
Theoretically, CROs could fill the need for safety monitoring in these areas; however, recent experiences raised the question of whether CROs can be trusted to conduct these types of outsourced trials.
Investigations published in 2017 found that the Eastern European arms of the CRO-coordinated TRUE-AHF (Trial of Ularitide Efficacy and Safety in Acute Heart Failure) and TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trials enrolled ineligible patients from Russia and Georgia. Many patients assigned to the intervention groups did not even receive the study drugs.1,2 This could explain why the drugs seemed to work so well in North and South America, but not in Eastern Europe.
In 2016, an FDA inspection of Semler Research Center’s facilities (a CRO based in India) unearthed “significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples.”3 The agency alerted drug makers that marketing applications containing data prepared by Semler would not be accepted due to concerns about the integrity of the data.
The World Health Organization came to similar conclusions when it examined Semler’s computer servers and found a file containing detailed instructions for manipulating drug samples that were used in its clients’ clinical trials.4 Last year, the E.U. suspended hundreds of drugs that were authorized for use based on what regulators called “flawed” studies conducted by GVK Biosciences, another Indian CRO.12
While the FDA said it did not identify reports that raise serious safety concerns with the medications evaluated in these trials, the actions of these “bad apples” are harming the reputation of the CRO industry – and of the larger clinical trial enterprise.
- Hawkes N. Shortcomings in heart failure drug trial open “can of worms.” BMJ. 2017;357:j2218.
- de Denus S, O’Meara E, Desai AS, et al. Spironolactone metabolites in TOPCAT – new insights into regional variation. New Engl J Med 2017;376:1690-2.
- U.S. Food and Drug Administration. “Notification to Pharmaceutical Companies: Clinical and Bioanalytical Studies Conducted by Semler Research Are Unacceptable,” April 20, 2016. Accessed February 20, 2018, from https://www.fda.gov/Drugs/DrugSafety/ucm495778.htm.
- STAT News. “FDA and WHO warn about clinical trials run by an Indian company.” April 25, 2016. Accessed February 21, 2018, from https://www.statnews.com/pharmalot/2016/04/25/fda-warn-clinical-trials-run-indian-company.