Current Practices Within Investigator-Initiated Sponsored Research: 2015 ACRP Survey Results

In 2015, the ACRP Investigator Research Interest Group conducted a survey to gain insights into how investigator-initiated sponsored research (IISR) is conducted, and to provide a valuable benchmark for how researchers and industry manage IISR studies. Through this survey, we hope to provide a way for both sites and industry to improve their communication about the research their efforts create.

Background

IISR is a common tool used throughout the life sciences industry to generate evidence supporting therapies and associated products. IISR studies are independent projects in preclinical, clinical, or observational settings in which the investigator or institution serves as the sponsor. Common sources of support for IISR studies are manufacturers within the life sciences industry, cooperative groups, nonprofit research organizations, and healthcare institutions. Support can come in the form of funding, provision of product, and/or other aid with study conduct. There are five phases of the IISR lifecycle:

  1. Sponsor-investigator submits an independent study proposal to potential supporters
  2. A supporter’s independent, cross-functional review committee reviews the scientific merit and feasibility of new proposals at regular intervals
  3. Approvals and final documentation are granted and generated to support the trial start
  4. Active study conduct and management is launched and maintained by the sponsor-investigator
  5. The sponsor-investigator is responsible to adequately close out the study and report its results appropriately to regulatory bodies and through scholarly publication (supporters expect to review the results to be disclosed, the proof of study closeout, and the regulatory reporting before final milestone payments are made)

The intent of this survey is to better understand current practices in IISR studies and to identify any differences in their conduct in different situations.

Methods and Results

On February 6, 2015 a survey was posted to the ACRP website and distributed to ACRP’s membership via an e-mail notification. The survey was open until April 30, 2015, and included 54 questions spanning eight categories (General Questions, Collaborations, Reviews, Support, Contracting, Compliance, System, and Metrics).1

The Investigator Initiated Sponsored Research Association (IISRA) conducted similar member surveys in 2007, 2008, and 2010. IISRA, which has since been incorporated into ACRP, has expanded the pool of responders to both industry and sites. This analysis does not compare the most recent survey’s results to those of the previous surveys, although they are available for review on the ACRP website.

At the outset of the survey, there were 103 responses; 89% were from the U.S., 6% from the European Union and Canada, 3% from the Asia- Pacific region, and 1% from Latin America.

Respondents had a variety of roles, but were predominantly IISR program managers or site research coordinators (see Figure 1*). Of the 34 industry respondents, 68% represented pharmaceutical companies, 21% represented medical device manufacturers, and 12% represented other companies such as those within nutrition or diagnostics.

There was a significant drop off of responses when comparing the first 10 (~103 responses) and last 10 questions (~40 responses) of the survey. As a learning point, future surveys should be shorter and more directed in scope to improve data capture quality.

Responses were categorized and classified by organization type to determine response variances. The classifications consisted of Research Site, Industry, and Contract Research Organization (CRO) (see Figure 2*). The limited responses from CROs and from other organizations not fitting into the final classifications were excluded from the analysis to focus on the viewpoints of sites and industry.

Year-over-year budget change is an indicator of the program vitality. Survey results indicate that IISR programs are relatively healthy, with respondents stating either that budgets increased (39%), remained approximately the same (40%), or decreased (20%) over the past two years (see Figure 3*).

Upon further breakdown of the data by budget size (see Figure 4*), programs with budgets smaller than $5 million tended to have neutral to decreasing budgets, and programs with budgets larger than $5 million tended to have neutral to increasing budgets. To these points, the overall health and outlook of IISR programs across the industry is positive.

Collaborations

Within the life science industry, a distinction may be made between IISR studies and collaborative studies. Two survey questions focused on whether respondents made a categorical distinction between these two study types, and under which policies a collaborative study would be evaluated. Nearly two-thirds of industry respondents (63%) made a distinction between IISR studies and collaborations, however very few (22%) reported having a separate policy for this research. Alternatively, only 29% of sites make a similar distinction, with 73% of sites responding that collaborations either have no existing policy or are treated as company-sponsored studies.

Among industry and site respondents, the defining factors for calling out collaborations separately from either IISR studies or company-sponsored studies were:

  • Involvement in the study design, execution, or analysis (78%)
  • Ownership of the data/study results (76%)
  • Intellectual property ownership (62%)
  • Sponsorship (56%)

Further, sites placed a greater weight on intellectual property ownership (70%) and industry placed a greater weight on sponsorship (65%) when defining collaborations.

Review Process

Proposal review varied greatly between sites and industry. With respect to sites, 64% had no review process, while 93% of industry respondents have formal review processes. If studies are global, it is common for industry to conduct local, regional, and/or global reviews.

There was a median of five reviewer types, with representatives from the following functional areas: regulatory/legal (20%), clinical development (16%), biostatistics (15%), IISR management (14%), safety (13%), and medical affairs (13%). A point to note is that in a few industry organizations, marketing is involved in the review process (2%). From a best practice standpoint, it is highly recommended to remove all commercial influence from the IISR review process.

Established research areas of interest are common for industry (90%) and sites (56%). When applications are reviewed, the sponsor’s publication plan followed by budget was common for both industry and sites; further, investigator eligibility and qualifications were important to industry. Reviews predominantly took between 46 and 90 days for both industry and sites.

Approval rates varied greatly, with nearly one-third of site respondents approving between 76% and 95% of proposed IISR studies and nearly one-fourth approving between 51% and 75%; and nearly one-third of industry respondents approving at a lower rate of between 26% and 50% and more than one-fourth at between 51% and 75%.

Upon review decision, communication style differed. Industry (46%) favors personal discussion followed by a formal written communication. Sites (41%) prefer formal or standard written communication only. Both industry and sites agree that system-generated notifications are inappropriate, with only 10% of industry and 9% of sites using this method of communication.

Support Provided

The purpose of IISR programs is to provide access to funding and/or product so that qualified researchers are able to conduct and publish independently generated evidence. Respondents stated that their organizations provide the following types of support for studies:

  • Products with marketing authorization approval (89%)
  • Products with unapproved product indications (61%)
  • Investigational products requiring additional regulatory approval (i.e., through Investigational New Drug or Investigational Device Exemption [IND/IDE] applications) (57%)
  • Observational studies (66%)
  • Outcomes research on patient outcomes only (68%)
  • In vitro and in vivo studies (48%)
  • Outcomes research studies on patient outcomes or pharmacoeconomics (45%)
  • Other (12%)

Meanwhile, there are some differences between the two types of studies in terms of the typical support received and other considerations:

  • Study Support: Industry (77%) predominantly provides product and/or funding, whereas sites (35%) provide protocol development, case report form (CRF) development, statistical analysis, and monitoring support, and this difference is often the source of misunderstanding. Legal and regulatory constraints often limit industry’s involvement with study development and conduct, in order to maintain the integrity of the research and the impartiality of the study sponsor. Interestingly, a small portion of industry respondents to the survey (4%) will provide support for protocol, CRF development, statistical analysis, and monitoring. With respect to best practice,2 it is highly recommended that any “sponsor” activities (i.e., protocol development, data analysis, monitoring) are not conducted by the study supporter.
  • Study Costs: Assuring that study costs are aligned to fair market value (FMV) is a well-recognized and required step for most of the industry (90%), while only some sites (42%) evaluate FMV. Use of commercially available datasets to establish FMV is preferred by industry (50%) to establish impartiality, whereas sites (26%) predominantly use internal data to assess costs.
  • Institutional Overhead: Overhead charges are common and are often included in an IISR study budget. Industry (46%) caps these charges at 21% to 30% for clinical research. Sites (45%) have an expanded overhead range of 21% to 40%. Both industry (33%) and sites (31%) lack established limits for preclinical overhead.

According to survey respondents, upon final approval of the study, the following documents are most commonly collected prior to distribution of any funding:

  • Institutional review board/ethics committee (IRB/EC) approval (84%)
  • Final protocol (74%)
  • Executed agreement (73%)
  • Local regulatory approval (68%)
  • IND/IDE and/or U.S. Food and Drug Administration letter if required (64%)
  • Investigator’s curriculum vitae (63%)
  • Final budget (61%)
  • Certification/qualification statement (27%)

It is possible to note within the slight variances mentioned above that industry is focused on the study’s regulatory and legal requirements, whereas sites focus on IRB/EC, protocol, and budget support.

Contracting

A frequently cited concern related to the initiation of IISR studies is the length of time to negotiate the study agreement. The majority of survey respondents (94%) indicated that agreements typically take one to six months to negotiate, with sites estimating slightly shorter timeframes than industry respondents.

When compared to other timeframes within the survey, these results suggest that contracting does not take significantly longer than other steps. The perception that contracting takes too long may be related to contracts being negotiated late and becoming a rate-limiting factor for the study start. Given this, our recommendation is to draft the agreement as soon as studies have a high likelihood of starting, so that the contract is not a rate-limiting step.

Survey respondents reported that IISR agreements were made with both the institution and the investigator (50%), directly with the institution (42%), or directly with the principal investigator (8%).

Posting of trial information on a publicly accessible website, as defined by International Committee of Medical Journal Editors (ICMJE) guidelines,3 is frequently included in IISR agreements (69%). Site respondents included this in their agreements 50% of the time, while industry respondents were much more likely (76%) to include this within the contract.

Milestones included in the study agreement varied widely across the study respondents. The majority of respondents included milestones related to critical deliverables or process steps (75%), study results (65%), finances (58%), or periodic status updates (52%). Industry respondents were more likely to include financial milestones, while only site respondents stated that they were party to agreements that included upfront payments with no contracted milestones.

The approach to indemnification varied widely across survey respondents when they were given the options of no indemnification clause (33%), explicitly stating that indemnification will not be  provided by the respondent (29%), indemnification provided (21%), or indemnification only provided when required by local law (17%). Industry respondents made up the bulk of the respondents who would not provide indemnification for the research (86%). Interestingly, a significant minority of the site respondents favored not including an indemnification clause in the agreement at all (five of 12, 42%).

Lastly, respondents were asked if specific clauses giving reasons for terminating a study were routinely included in agreements (see Table 1*). While the response of “without cause” was not included in the original survey options, a number of respondents indicated that this was common practice at their organization. We recommend that future surveys explore the situations in which studies may be terminated.

Compliance

The Foreign Corrupt Practices Act (FCPA)4 is a U.S. federal law that is jointly enforced by the Securities and Exchange Commission and the Department of Justice. The FCPA makes it illegal for U.S. companies to influence anyone with personal rewards, or bribes, for business. About half of the survey’s industry respondents (52%) and a third of site respondents (33%) self-reported that their organizations had an established policy for IISR studies in relation to the FCPA. Of those with a policy, the vast majority (88%) indicated that the policy applied to all IISR studies, with a handful carving out exceptions for studies that involved funding below a minimum threshold value.

Further, some governments recently have created transparency reporting laws for the “transfers of value” made from manufacturers to healthcare providers. In the United States, transparency laws have been formalized under the “Open Payments” portion of the Patient Protection and Affordable Care Act,5 while in the United Kingdom they are within the Association of the British Pharmaceutical Industry’s (ABPI’s) Code of Practice for the Pharmaceutical Industry 2015.6 Other guidelines are under way in a number of other countries.

The purpose of these laws is to limit the influence of industry on prescribers. Nearly all of industry and site respondents (91%) from the United States and United Kingdom have an established process by which IISR studies are included in their reporting obligations. Respondents outside the U.S. and U.K. infrequently had established processes, indicating that caution should be used when there are “transfers of value” outside one’s home country.

Meanwhile, one of the key risk areas for IISR compliance is the delineation of roles and responsibilities between the investigator-sponsor and the industry supporter. Industry respondents reported that they had little to limited involvement with the development of the research protocol (see Figure 5*).

In addition to protocol development, industry’s involvement in the writing of publications based on IISR studies is another well-known risk area. Table 2 outlines industry and site responses on existing policies tied to IISR-related publications.

When it comes to safety reporting, the investigator-sponsor is responsible for collecting and reporting all applicable adverse events (AEs) to the relevant regulatory authority within the appropriate timeframe. Additionally, the industry supporter has a vested interest in understanding the safety profile of their product, and may have additional reporting obligations in other countries where the company seeks product approval.

Of industry respondents, 46% required investigator-sponsors to provide only serious AEs within a given timeframe of awareness of the event, 27% required all AEs within a given timeframe, and 27% required all AEs without a timeframe specified. Further surveys are needed to determine the periodicity of AEs that are not collected within a given timeframe of awareness of the event.

Taking a look at compliance enforcement actions, 75% of industry and site survey respondents have not been under a government Corporate Integrity Agreement (CIA), 11% had previously been under one (all industry), and 13% were currently under a CIA (four industry respondents, one site respondent).

As one would expect, enforcement action closely correlates to the overall budget of an IISR program; higher volume means higher scrutiny (see Figure 6*).

Systems, Metrics, Approvals, and Durations

Industry respondents were more likely to utilize a commercial IISR system (65%) either alone or in combination with other systems to track study progress, while site respondents were more likely to record all details in hardcopy format or to store them in a clinical trial management system (CTMS) (50%). Only four respondents from industry and one from a site (15%) strictly utilized an in-house system that had been tailored for IISR tracking.

Respondents felt that IISR personnel were sufficiently trained to set up metrics within their current system and conducted metrics that met (38%) or partially met (35%) their needs for improvement. We also found a strong correlation between the overall IISR budget and satisfaction with metrics; organizations with less than $500,000 annual investment were generally dissatisfied, while organizations with more than $2 million annual investment were satisfied with their current metrics.

As Figure 7 demonstrates, when systems were called out separately, 26% were satisfied, 56% saw a need for greater efficiency, and 18% were dissatisfied with their current systems. Nearly 73% of industry respondents receive IISR submissions via a webportal, with 27% receiving hard-copy submissions.

There was a bell curve distribution of time from submission to decision with a median of nearly three months. Sites responded that the majority of IISR studies were approved, while industry stated that a little less than half were approved. Combining these two elements, organizations with high approval rates normally responded in less than two  months, while organizations who approved 26% to 50% of submissions took between two and four months to reach a decision, substantiating the idea of the “slow no.”

The majority of respondents indicated that the median duration of IISR studies was two to three years (74%). The median time from study closure to receipt of clinical study report was one year, however, a significant minority (26%) reported that the median time to publication was more than two years.

When looking at IISR completion rates, the median response across all survey respondents was 75%, however site respondents generally reported a lower rate than industry respondents. This may reflect a difference in how “completion” was interpreted—as either complete enrollment, the achievement of the primary objective, or the disclosure of study results through a conference presentation or publication in a journal.

Conclusions and Next Steps

Results from the 2015 ACRP Investigator Research Interest Group survey provide insight into how sites and industry handle different aspects of IISR studies. Our recommendation is that future surveys should include both shared and separate questions for site and industry respondents, in order to prevent survey fatigue. In particular, smaller, targeted surveys are recommended to evaluate perceptions of site/industry partners, contracting, safety reporting, metrics assessments, and training needs.

These survey results support the view that sites and industry continue to view investigator-sponsored research very differently. IISR studies are considered important for evidence generation, and programs are growing in spite of increased regulations and legal enforcement actions.

Where IISR studies are concerned, industry aims to comply with regulations, support new research, and maintain its budgetary commitments; sites are focused on the development and dissemination of evidence. Investigators can more effectively target study support opportunities by understanding the needs of industry and communicating their own needs, thereby improving the chance that their research requests will be approved and will positively impact the community as a whole.

Legal Disclaimer

The views and opinions expressed are those of the authors, and should not be attributed to any organizations with which the authors are employed or affiliated, or to the organizations’ directors, officers, or employees.

PEER REVIEWED

References

  1. Bench Mark Surveys. 2010 IISR Survey – Fair Market Value & Metrics at www.acrpnet.org/resources/IISR/2010_IISRA_Survey_ FMV_Metrics.pdf; 2008 Survey at www.acrpnet.org/resources/IISR/2008_IISRA_Survey.pdf; 2007 Survey at www.acrpnet.org/resources/IISR/2007_IISRA_Survey.pdf
  2. IISR Guidance Documents, Best Practice Guideline – May 2010. www.acrpnet.org/resources/IISR/may2010.pdf
  3. ICMJE Recommendations. www.icmje.org/recommendations/
  4. Foreign Corrupt Practices Act. www.justice.gov/criminal-fraud/foreign-corrupt-practices-act
  5. Affordable Care Act. www.dol.gov/ebsa/healthreform/
  6. ABPI Code of Practice for the Pharmaceutical Industry 2015. www.pmcpa.org.uk/thecode/interactivecode2015/Pages/default.aspx

Ashley N. Wills (awills@tesarobio.com) is senior manager for medical affairs research with TESARO, Inc. in Waltham, Mass.

Scott N. Cunningham, MS, is business lead for Visiontracker™ with the Envision Pharma Group.

[DOI: 10.14524/CR-16-0006]

*To see all figures and/or tables published originally in this article, please visit the full-issue PDF of the August 2016 Clinical Researcher.