As the clinical research industry becomes more centered on technology, perhaps one of its most underused solutions is the electronic consent (eConsent) platform. A valuable tool for both sites and participants, there are many benefits to adopting eConsent. This blog outlines why adopting an eConsent platform is a beneficial and strategic step sites can take right now.

eConsent Gives Sites Flexibility

In each study, requirements, risk levels, and participant situations can vary. Typically, there are factors such as:

  • The participants’ geographic location
  • The general health of the targeted population
  • Whether or not legally authorized representatives (LARs) or witnesses are required

eConsent has the ability to adapt to any situation and meet the participant population where they are at. This typically allows participants to consent from wherever they are; there’s no need for them to come into the clinic. This flexibility alone can significantly improve the participant experience. Potential participants can read the consent form at their own pace, re-read if needed, leverage multimedia materials if needed, and consult with family members about if the study is the best option for them.

eConsent Saves Staff Time

Clinical research staff time is incredibly valuable, and team members are constantly juggling multiple tasks at any given time. They need to keep the protocol moving along, and even the most seemingly insignificant mistakes can derail study timelines and place additional stress on staff.

One example of this is participants making mistakes on the informed consent form (ICF). Sometimes, they will write down the wrong date, or they will miss a spot in the ICF where they should’ve initialed. Situations like these can potentially be a significant regulatory burden for staff. Often, they will have to bring the participant back in to correct their mistake. In the worst cases, they may have to report the mistake to their institutional review board (IRB) or receive a warning letter or notice for an audit finding.

Since research staff time and bandwidth are limited, tending to these types of mistakes can pull their attention away from necessary tasks related to the study. Adopting an eConsent platform can significantly reduce or eliminate errors and allow team members to focus on higher-value tasks. For example, eConsent can ensure all dates are current, all signatures accounted for before submitting the ICF, and all materials have been reviewed, minimizing the staff burden and ensuring the study stays on track.

Participants Prefer eConsent

As much as eConsent benefits staff, participants are also likely to prefer it over the paper consenting process. In a  recent study done by Memorial Sloan Kettering Cancer Center (MSKCC1), they found more than half of participants prefer clinical trial consent visits to occur via telemedicine versus an in-person appointment. Additionally, MSKCC found telemedicine doesn’t add additional stress during a clinical study – 17% of participants reported they were less stressed when they used telemedicine overall.

There are many other benefits for participants when they engage with an eConsent platform. When agreeing to be a part of a study, participants are giving up time to come into the clinic for appointments, almost always taking them away from their jobs. By using an eConsent platform, participants can consent on their own time and fit it into their schedule, rather than rearrange everything to come into a clinic.

Additionally, participants may feel pressure to consent on the spot; with eConsent, participants have more time to comb through the documents to truly understand what they are consenting to. Agreeing to be part of a clinical trial can be a big ask, and eConsent gives participants the time they need to help them really think through the decision and consult family members if needed.

While there are more benefits to using eConsent than the ones listed above, knowing it’s a platform designed to benefit both staff and participants is unique – and can continually benefit sites time and time again.

References:

1: Electronic Research Consents for complex Early Phase I-II Clinical Trials Integrated with Telemedicine Visits Compared with In-Person Encounters, Michael Buckley, 2022 ASCO Annual Meeting

Budget negotiation is an integral part of a clinical trial’s success. Proper clinical trial financing ensures a site’s internal costs are covered, facilitates better negotiation, and leads to more compliant practices. With the per patient cost in clinical trials averaging around $41k, it is critical to begin with an internal budget appropriately capturing the estimated costs. This internal budget can be used as a baseline when working with the sponsor to achieve appropriate funding.

How to Develop an Internal Budget

Before requesting any edits to the sponsor’s budget template, it is recommended for an institution to develop an internal budget. This budget details the estimated costs associated with conducting the clinical trial. The process begins with a thorough review of the coverage analysis completed by the site and study documents provided by the sponsor (i.e., protocol, informed consent, and sponsor budget). The coverage analysis outlines which items and services are billed to insurance and which items are paid for by the study sponsor.

The research items in the analysis then translate into the direct per patient costs within the internal budget. Additional underlying costs include the time and effort from research staff such as the investigator, study coordinator, and data management. Consider other costs, such as:

  • Administrative fees
  • Institutional overhead
  • Unscheduled visits
  • Screen failures
  • Ancillary department fees
  • Drug costs
  • Patient stipends

Once the internal budget is complete and reviewed for accuracy, it’s time to begin the negotiation.

Best Practices for Budget Negotiation

Prior to contacting the sponsor, redline the sponsor’s proposed budget template to better align with site study costs. Don’t forget to also redline the payment terms commonly found in the clinical trial agreement. It’s important to note negotiations could occur with a contract research organization (CRO) rather than a sponsor. Sponsors may hire a CRO to participate in the negotiation for them and serve as a proxy, similar to Advarra’s role with research institutions.

Regardless of the point of contact, stay consistent and aim for a set negotiation timeline goal. It’s likely there will be several rounds of negotiation with edits required at each counter. In these situations, it’s important to effectively and efficiently communicate. Remain firm on non-negotiable items and maintain flexibility on those items allowing for negotiation. Respond in a timely manner and follow up with the sponsor as needed to keep the timeline on track. Finally, make sure to avoid double billing during negotiations. This occurs when two payments are made for an item or procedure. For instance, the sponsor pays for an item that is also billed to Medicare (as otherwise highlighted in the coverage analysis). This is a major compliance concern and should be avoided at all costs. Once the budget is finalized, the process moves onto the contracts team (if needed) and other study team members for signature routing.

Negotiation Strategies

In a perfect world, sponsors would have unlimited funding for all foreseeable site expenses. However, in lieu of the effect dedicated by an institution, sponsors dedicate just as much time (or more) to properly outline the costs of their clinical trial. If rates fall too low or certain fees are not included, be transparent. Provide reasoning or documentation showing the need for any costs in question. This may include current procedural terminology (CPT) codes relating to specific services, a signed PDF acknowledging the extensive review needed to confirm the expense, or the reallocation of other fees to make up for areas of deficit.

Budget negotiation is an arduous and laborious task with the potential to delay anticipated timelines. Be sure to promptly respond to any sponsor inquiries. If the sponsor has slow response times, follow up with them as needed via email or phone. Institutions facing continued sponsor pushback or delayed timelines should utilize an established internal escalation plan. In the same regard, your institution may encourage the sponsor/CRO to escalate required fees for further review. Through it all, remember to maintain a good relationship with the sponsor. A successful negotiation requires mutual benefit.

As the research community continues to seek clinical trial efficiencies designed to bring therapies to patients faster, more governing bodies are pushing for single institutional review board (single IRB) review as one way to streamline efforts.

To better understand what sIRB review requirements mean for sites and sponsors, it’s important to first understand what an single IRB is and how it works. This blog provides a beginner’s overview of single IRB review in the U.S.

Basics of Single IRB Overview

Before getting into specific requirements for sIRB review, it may be helpful to define sIRB. A single IRB is used to review for human subject protections at all clinical trial sites participating in a multisite study.

This centralized review eliminates multiple local IRBs reviewing a single trial, reducing the administrative burden of managing multiple IRBs’ requirements and timelines. When one IRB reviews a multisite study, this also helps keep participant protections consistent throughout the study and across all sites; for example, single IRB review ensures consistency in the information contained in the informed consent form (ICF).

Advantages to sIRB review include:

  • Reduced administrative burden: Working with an sIRB allows for centralized management of initial and continuing reviews, amendments/modifications, and event reporting for sponsors, contract research organizations (CROs), and sites
  • Increased efficiency: A sIRB review process enables faster study activation, quicker and more consistent amendment and modification reviews throughout the study, and frees local resources to manage more pressing local issues
  • Consistent human subject protections: All sites relying on the same IRB helps ensure consistent study information is presented to all participants during the trial
    • Additionally, since only one IRB is receiving event reports, they may be better aware of potential safety issues across the entire study

Policies and Regulations Affecting Single IRB Review

Working with an sIRB remains completely voluntary in many cases. However, several mandates currently in effect require single IRB oversight for most multisite clinical trials.

National Institutes of Health (NIH) Policy

This policy establishes the expectation that as a condition of NIH funding and support, a single IRB of record will be used in the ethical review of nonexempt human subjects research protocols funded by the NIH that are carried out at more than one site in the U.S. This rule was the first sIRB mandate announced in the U.S., with compliance required beginning January 25, 2018. The policy doesn’t apply to foreign sites.

21st Century Cures Act

Established in December 2016, this act included a requirement for the FDA to harmonize with other U.S. Health and Human Services (HHS) regulations as much as practicable, which includes sIRB requirements. It also removed the term “local” from “institutional review board” references in the regulations governing medical device research, making it clear single IRB oversight is permitted for multisite device trials.

Common Rule Single IRB Policy

The Common Rule refers to the Federal Policy for the Protection of Human Subjects outlined at 45 CFR 46 and applies to research overseen by the Department of Health and Human Services (DHHS) Office of Human Research Protections (OHRP) and other agencies.

The Common Rule’s sIRB mandate states organizations engaged in cooperative research must rely upon approval by a single IRB for that portion of the research conducted in the U.S. Cooperative research is defined as projects covered by this policy involving more than one institution. This requirement entered the regulations as part of a broader update in 2017, commonly referred to as the Revised Common Rule.

In order to be subject to the sIRB requirement, a study must be:

  • Governed by the new rule and initially approved by an IRB on or after January 21, 2019
  • Nonexempt human subjects research
  • Meeting the definition of cooperative research
  • Supported or conducted by a Common Rule department or agency

However, there are exceptions to this, including:

  • The sIRB requirement only applies to research conducted in the U.S.
  • Only sites engaged in nonexempt human subjects research activity need to comply
  • Only sites subject to the Common Rule are subject to their sIRB requirements

Exception to the Common Rule Single IRB Mandate

HHS has released two separate exceptions to the Common Rule sIRB Mandate.

  • November 2019: The Common Rule is not in effect for cooperative research conducted or supported by HHS other than NIH if the IRB approved the research before January 20, 2020
  • October 2020: HHS components can issue exceptions to the Common Rule’s sIRB requirement for any research activity conducted or supported by the component taking place during the COVID-19 pandemic

Food and Drug Administration (FDA) Notices of Proposed Rulemaking (NPRM)

The FDA released two NPRMs in September 2022, proposing harmonization with the HHS Common Rule. One proposal, Institutional Review Boards; Cooperative Research, is geared toward cooperative research. This proposal is intended to require all U.S. sites involved in multisite research to use a single IRB, which would harmonize FDA regulations with NIH and HHS requirements.

The comment period for FDA’s NPRMs is open through December 28, 2022, and stakeholders are encouraged to submit their feedback on the proposals.

While FDA does not currently require single IRB oversight for multisite clinical trials, the agency has been a longtime advocate. FDA’s 2006 guidance document Using a Centralized IRB Review Process in Multicenter Clinical Trials underscores the value a single IRB review can provide.

There are many factors to consider when deciding to work with a single IRB. Understanding the mandates will help your organization determine the best course of action for your study and for your research program.

In the past several years, Health and Human Services (HHS) Office of Human Research Protections (OHRP), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) have announced and/or implemented new regulations to address the challenges of conducting clinical trials involving multiple research sites.

Chief among these requirements is the use of a designated single institutional review board (sIRB) for multisite research (also known as a central IRB [cIRB]). Here’s where the regulations currently stand:

NIH Single IRB Policy

The first of the sIRB mandates announced was the NIH Single IRB Policy. This policy requires domestic awardees and domestic sites conducting NIH-funded multisite research to be overseen by a single IRB of record.

This rule was announced on June 21, 2016, with a compliance date of January 25, 2018. This policy was the forerunner of the later HHS decision mandating all federally funded research would, with little exception, use an sIRB of record. This policy change prompted many institutions to seek partnerships with external IRBs.

The 21st Century Cures Act

This bill was passed by Congress on December 13, 2016, and included the requirement for the U.S. government to reduce “duplication of effort” in human subject protections, suggesting centralized IRB review as one way to do so.

This bill also eliminates the term “local” from “institutional review board” references in the regulations governing device studies, aligning device regulations with established regulations for drug studies and explicitly allowing for sIRB review of multisite device studies. Additionally, it requires differences between the HHS and FDA human subject protection regulations be harmonized, or consistent, “to the extent practicable.”

Final Revisions to the Common Rule

The long-discussed revisions to the Federal Policy for the Protection of Human Subjects, also known as the Common Rule, mandates sIRB oversight for cooperative research. Per 45 CFR 46.114, “cooperative research projects are those projects covered by [the Common Rule] that involve more than one institution.”

The sIRB compliance date for cooperative research went into effect on January 20, 2020, and requires single IRB review for virtually all federally funded multisite research. Click here for more information on the HHS compliance requirements.

FDA Initiatives

FDA has long supported sIRB review for multisite research, releasing the guidance document Using a Centralized IRB Review Process in Multicenter Clinical Trials in 2006. This guidance has led many industry sponsors to require sIRB review for their multisite studies.

In September 2022, FDA released two Notices of Proposed Rulemaking (NPRMs) intended to partially harmonize existing FDA regulations with the Common Rule, in keeping with requirements set forth by the 21st Century Cures Act. Specifically, the NPRM titled “Institutional Review Boards; Cooperative Research” recommends any U.S.-located institution conducting cooperative research be required to rely on sIRB oversight for the research being conducted in the U.S. (with certain exceptions).

These changes are currently under review by the public and industry, and no word is yet available regarding if and when the proposals might become final rules.

Other sIRB Initiatives

The IRB reliance networks SMART IRB and IRB Reliance Exchange were developed to help support single IRB review. Enacted through separate NIH grants, these networks and tools establish a master IRB reliance agreement among member IRBs. A document exchange platform is designed to support and streamline the sIRB process for the sIRB and relying institutions alike.

Additionally, therapeutically focused research networks are moving toward requiring sIRB review for the studies conducted by their member sites.

An Age of sIRB

These regulations and policies reflect the continued progression of multisite clinical research towards centralized human subject protection review, with the understanding that sIRB review reduces administrative burden on investigators, sites, and sponsors and provides clearer guidance and oversight of human subject protections.

The research and regulatory environment continues to evolve, and sIRB review is the new standard for multisite research. Now is the time to work with external and fellow institutional IRBs and figure out the best way to implement the sIRB requirements. In this new paradigm, communication and partnership are the keys to success.

Note: This article was originally published February 5, 2020, and has been updated to include new and clarifying information.

The research informed consent form (ICF) is designed to provide prospective participants with the necessary information to make an informed decision about whether to participate in a clinical trial.

Frequently included in the informed consent is an institution’s Health Insurance Portability and Accountability Act (HIPAA) statement, which informs participants of how their protected health information (PHI) may be used or disclosed by covered entities for research purposes.

HIPAA statements are typically provided to participants in one of two ways:

  • Standalone document in addition to the ICF
  • Embedded content within the ICF itself

In this blog, we’ll explore why HIPAA is important to the informed consent process and why a standalone document is often the most beneficial approach, both for informing participants and for simplifying the institutional review board (IRB) review process.

Why HIPAA in Research?

The HIPAA Privacy Rule, or Standards for Privacy of Individually Identifiable Health Information, was issued in 1996 in response to public concern over potential abuses of the privacy of health information.

The Privacy Rule establishes a category of health information, known as protected health information (PHI). This may only be used or disclosed to others in certain circumstances or under certain conditions. PHI is a subset of what is termed “individually identifiable health information.” With certain exceptions, individually identifiable health information becomes PHI when it is created or received by a covered entity.

Covered entities include health plans, health care clearinghouses, and health care providers who transmit health information electronically in connection with certain defined HIPAA transactions, such as claims or eligibility inquiries. Organizations classified as “business associates” of covered entities may also be obligated to follow HIPAA requirements.

Clinical trial protocols often seek to access patients’ personal health information, like medical charts and test results. This helps identify potential participants, confirm whether someone meets the trial’s eligibility requirements, or establish baseline medical information for trial participants.

Informing participants about their HIPAA rights as part of the informed consent process helps ensure they understand how their information will and won’t be used to make an informed decision about participating.

A HIPAA Authorization allows a covered entity to use or disclose the patient’s PHI in a way not otherwise allowed by the HIPAA Privacy Rule. For clinical research, this may include local researchers sharing the information with a third party, or, in the case of a partial waiver of Authorization, reviewing PHI for recruitment purposes. HIPAA Authorizations must contain numerous required elements, including details about who may use the PHI and for what purposes.

HIPAA and IRB Review

For certain clinical trials, it may be beneficial for recruitment purposes for researchers to request a waiver or alteration (sometimes called a partial waiver) of research participants’ HIPAA Authorization for use/disclosure of their information. Or as NIH explains, “[f]or some types of research, it is impracticable for researchers to obtain written Authorization from research participants.”

By waiving some or all of the Authorization requirements, researchers may more easily access information necessary for activities “preparatory to research,” such as preparing a research protocol or developing a research hypothesis, or for identifying prospective participants who would meet the study’s eligibility criteria for enrollment.

The regulations at 45 CFR Part 164.512 indicate a privacy board or an IRB may waive or alter, in whole or in part, Authorization requirements for use and disclosure of PHI connected with a particular research project.

It’s important to note: “IRB” is not synonymous with “privacy board,” as each board has its own unique membership requirements. To put it another way, a privacy board meeting the Privacy Rule’s membership requirements does not necessarily satisfy the IRB membership requirements laid out in HHS and FDA regulations or other federal laws and requirements applicable to research.

Covered entities may reasonably rely upon documentation from an IRB (whose membership satisfies the requirements of HHS or FDA regulations) in order to use or disclose PHI without Authorization, as permitted by the Privacy Rule at 45 CFR 164.512(i)(1)(i). The Privacy Rule permits a covered entity to accept documentation of such an approval from any qualified IRB or privacy board – this permission does not necessarily need to come from the IRB overseeing the institution’s research.

Why Keep HIPAA Separate from the ICF?

Determining whether an organization is a HIPAA “covered entity” must be made at the individual site level. So including HIPAA in a multisite study-wide ICF doesn’t make sense – HIPAA typically includes unique choices made by the site or institution.

Also worth noting is the IRB’s role under the Privacy Rule is “limited to acting on requests for a waiver or an alteration of the Privacy Rule’s Authorization requirement. IRBs are, thus, not required to review and approve Authorizations under the Privacy Rule…[and] are not required to approve standalone Authorizations” (NIH, Institutional Review Boards and the HIPAA Privacy Rule).

However, when HIPAA language is incorporated into the ICF itself, it becomes part of the IRB’s responsibility to review the HIPAA language in the ICF for required consent elements. Covered entities may want to consider whether such review is necessary.

HIPAA can be particularly troublesome for IRBs serving as the single IRB (sIRB) for a given study. When research sites incorporate their HIPAA content into the ICF language specific to their location, it can require a lot more work for the sIRB to keep the ICF up to date.

For example, any time a study-wide amendment requires site-specific revisions, the sIRB must ensure site-specific HIPAA language is properly incorporated into the revised ICF – adding an additional administrative step to a process usually requiring very timely action. Already managing multiple site-specific ICF requirements, an sIRB may find the HIPAA aspect an additional complication potentially impacting the efficiencies inherent in sIRB oversight.

Ultimately, it is better for all stakeholders to keep HIPAA language separate from the research informed consent:

  • Participants are sure to always have the latest HIPAA information from their institution, since the institution controls that documentation
  • External IRBs can review and process changes to research more efficiently, minimizing delays associated with site-specific ICF requirements
  • Research sponsors can rely on individual research sites’ HIPAA documentation and avoid getting tangled in “covered entity” considerations not applicable to sponsors

Since HIPAA considerations are unique to the individual covered entity, it’s important to consult with your Privacy Officer or another responsible official to understand your local policies and requirements.

The field of cell and gene therapies (CGT) is constantly evolving, and there has been significant progress in this area of research. However, despite the promise of these therapies, the regulations governing them lag the science, which in turn hinders the clinical translation of these novel medicines. There have been recent signals indicating the Food and Drug Administration (FDA) plans to provide greater support for CGT, addressing key issues continuing to impede their development.

Recent Problems in Cell and Gene Therapy Development

Dealing with confusing regulatory guidelines is one of the top obstacles researchers face as they develop CGT products1. In the last two years, there haven’t been any CGT product approvals, primarily because of the COVID-19 pandemic. The FDA, already chronically understaffed, reassigned many reviewers to focus on COVID treatments. This made it difficult to get CGT through the review process in a timely manner. But review issues are not the only problems.

Bottlenecks in the manufacturing process, supply chain issues such as accessibility of good manufacturing practice (GMP)-grade reagents, and shortages of qualified scientists and engineers have caused many therapies to fail at critical stages of the clinical development pipeline. Adding to all of this is the financial feasibility of generating small-batch CGT products for ultra-rare diseases with limited patient populations. Many companies are unable to develop these niche therapies because of the associated costs and limited financial return.

Current Regulatory Trends in Cell and Gene Therapy

The current regulatory landscape of CGT is undergoing significant changes out of necessity. The following are major recent developments, including FDA-led initiatives and new draft guidance for specific types of therapies.

Trend One: Expected Growth in Cell and Gene Therapy IND filings

Statistics recently reported by the director of the FDA’s Office of Tissues and Advanced Therapies (OTAT), indicated the number of CGT investigational new drug (IND) filings submitted to the FDA dropped from 350 in 2020 down to 299 in 2021. However, these numbers are expected to increase again in the coming years. OTAT also noted the recent increase in the number of Breakthrough (BT) and Regenerative Medicine Advanced Therapy (RMAT) designation requests, applications which are made alongside IND submission or during an existing IND filing. There has also been an increase in the number of accepted RMAT requests. BT and RMAT designations provide similar benefits to fast-track designation, however, they also require higher levels of evidence to support their status in either of these categories.

Trend Two: The Bespoke Gene Therapy Consortium

The FDA recently announced a new initiative as part of its NIH Accelerating Medicines Partnership Program. The Bespoke Gene Therapy Consortium (BGTC)2 aims to overcome major obstacles and streamline the development process for small-batch gene therapies. The BGTC will act as a traffic light for these therapies, providing information on basic and clinical research, manufacturing, production, and regulatory requirements.

While each ultra-rare genetic disorder may have a very small patient population, when these conditions are grouped together, they make up a significant number. The FDA has indicated financial incentives are also required to encourage companies to create therapies not “commercially viable”.

Trend Three: INTERACT Meetings and a Gene Therapy Pilot Program

A relatively recent initiative by the FDA is CBER’s “INTERACT”3 informal meeting program. This program is an attempt to address the questions and needs experienced by the CGT industry within current clinical frameworks and involves informal meetings between CBER staff and researchers/sponsors who are at the pre-IND stage of development. No Prescription Drug User Fee Act (PDUFA) fee is associated with the INTERACT meetings. They are granted based on CBER’s availability and resources, and they do not replace other formal meetings. Consequently, it is recommended to request a pre-IND meeting prior to submitting an IND to initiate the first-in-human Phase I study. This is particularly important when seeking guidance on toxicology study designs.

Another new initiative called the Gene Therapy Pilot Program involves the FDA providing real-time feedback to sponsors throughout the clinical development process. Newly created regulatory pathways like the Regenerative Medicine Advanced Therapy (RMAT) designation4. It is hoped that the combination of new meeting modalities will expedite the development process and submission review time. Taken together, these initiatives offer more frequent interactions between sponsors and regulators to communicate and discuss technological advances.

Trend Four: New Draft Guidance for Gene Therapies and CAR-T Cell Therapies

In March 2022, the FDA released two new draft guidance documents to help sponsors who are developing CGT products. The first is titled, Human Gene Therapy Products Incorporating Human Genome Editing, and provides recommendations on the information to include in IND filings for these therapies, including study design, safety, and manufacturing.

The second draft guidance is Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products. While the title refers specifically to CAR-T cell therapies, which are used to treat cancer, the FDA remarked these guidelines are also more applicable to other gene-edited cell therapies, such as natural killer (NK) and T cell receptor (TCR) cell therapies. The document includes recommendations on safety, manufacturing, clinical study design, and analytical comparability of CAR-T products.

Trend Five: Regulatory Harmonization and Agreements on Surrogate Endpoints

A major topic of discussion is the significant problems in multi-country clinical trials due to the different requirements of the parties involved. A complicating factor is the definitions of CGT products and their components differ between countries, making it difficult to achieve any consensus on their regulation. Harmonization of CGT requirements and improved inter-country communication are key for the progression of the field throughout Europe.

Lack of agreement on surrogate endpoints in clinical trials was another key theme during the session. The FDA’s accelerated approval program, which allows for earlier approval of new therapies addressing unmet medical needs, is based on surrogate endpoints. These endpoints are markers designed to predict clinical benefit but are not actual measurements of clinical benefit as would be expected from standard trials.

Accelerated approval using surrogate endpoints is necessary to develop gene therapy products for rare disease populations. However, the FDA often does not agree to surrogate endpoints being accurate predictors of the clinical benefit of a therapy before the trial begins. This lack of agreement between the FDA and trial sponsors leads to significant problems at later stages of clinical trials. Marks indicated this issue needs to be addressed for CGT products to have reasonable chances of success.

Improving Communication Between FDA and Sponsors

Communication issues between sponsors and the FDA is an ongoing issue in CGT development. For researchers and sponsors, progressing from pre-clinical research into clinical trials can be an extremely challenging process, not least because of unclear regulatory guidelines. Fortunately, it seems the FDA is now making it a priority to more effectively communicate with those developing CGT products, encouraging a growth trajectory in the coming years.

OTAT recently announced its plans to provide increased guidance for sponsors, facilitating a variety of workshops and webinars. Increased consistency in the review process and timeliness of reviews have also been touted as key priorities, along with broader public messaging surrounding these therapies. Through these initiatives and further engagement with the industry, the FDA hopes to enable the development and, most importantly, success, of more complex CGT products, bringing them to patients sooner.

References

  1. “What is Gene Therapy?” U.S. Food & Drug Administration. Accessed 4/7/20: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy 
  1. https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/bespoke-gene-therapy-consortium 
  1. FDA, CBER, CDER. Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products – Guidance for Industry. (2017). Available online at: https://www.fda.gov/media/109951/download (accessed on January 8, 2022). 
  1. FDA. Regenerative Medicine Advanced Therapy Designation. (2019). Available online at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/regenerative-medicine-advanced-therapy-designation (accessed on January 11, 2022). 

Study startup is a complicated, multi-faceted process – notoriously prone to delays due to the many stakeholders, systems, and decisions involved. One decision that can greatly impact the success and efficiency of your study is determining which sites you will partner with to conduct the study.

Historically, this process has been littered with pain points and inefficiencies for both sponsors, contract research organizations (CROs), and research sites. Overoptimistic investigators, redundant and duplicative site feasibility questionnaires (SFQs), lack of communication across stakeholders, and more leave room for risk of zero or under-accruing trials. By optimizing your approach to site feasibility and selection, you can remove barriers preventing research sites from delivering the best possible experience for trial participants—and the best possible results for your organization.

The Role of Site Feasibility Questionnaires

Currently, site selection is largely informed by feasibility questionnaires, typically in the form of a survey sent to all prospective investigative sites via email with a fillable survey document attachment or hyperlink to a data capture form field. However, without suitable analytical tools, survey responses gathered from sites may fail to provide enough relevant information to make an informed decision on whether the site is truly capable of reliable performance against the trial protocol. After all, simply collecting data isn’t enough. Establishing a method to collect and analyze relevant and actionable data is a must. Advarra API Gold Partner Devana Solutions’ PROPEL software improves workflows around creating and sending questionnaires in addition to automating data collection and reporting.

Many feasibility questionnaires are antiquated and redundant. They often ask the wrong questions and fail to collect the information required to yield the best decisions. A recent survey conducted by Advarra revealed over half of site respondents don’t believe an SFQ accurately represents their sites’ capabilities. A more precise and accurate feasibility process should provide a realistic assessment of current site capabilities – both therapeutic and physical or facilities-related – and be backed up by historic performance data captured during previous clinical trials completed by the site organization. Today, using a digital platform or software is a must in order for site selection and feasibility analysis professionals to quickly distribute feasibility surveys or questionnaires and, similarly, following distribution to the site-based staff to capture, store, analyze, and act upon site responses.

Obviously, some standard qualifying questions and evaluations about site baseline capabilities must always be included as prerequisites, such as a site’s financial viability and available staff and physical resources like the presence of onsite freezers or secure drug storage units and a patient database, but it’s also important to consider many of the following items during site selection and feasibility:

  • Past study performance in terms of startup timelines, enrollment, and outcomes
  • Current staffing numbers and turnover rate
  • Competing studies potentially impacting patient enrollment
  • If the indication is relevant to the site’s local population
  • If the study protocol and framework suit the site and region

Beyond simple questions, feasibility surveys can also provide guidance to the site, particularly around aspects of patient recruitment potentially helping to qualify the site organization’s level of interest in being selected for an upcoming trial. For example, incorporating questions in the survey about best practices undertaken in the past by successful sites on a similar study, indication, or patient population, may help to improve the accuracy of your feasibility survey responses. If a texting campaign for patient recruitment worked well in a similar location before, it may be worth adding a question asking the site organization to detail its breadth of marketing capabilities.

Building a more focused set of questions tailored to your specific study will provide you with more robust and actionable site responses. Including such questions will give you more specific insights for use during site visits or follow-up conversations with site-based staff. Good or bad, these findings can help you target the sites most likely to succeed on a trial while saving time and money by avoiding those that might not be a good fit. Site responses can also help influence potential protocol adjustments since sites maintain and foster a relationship with their patient population and tend to have a good grasp on if procedures may or may not be well tolerated.

Communication is the Key to Success

Whether a site is accepted or rejected for a study opportunity, it’s important to provide feedback and communicate clearly to site staff so they can accurately respond to feasibility survey questions and address any deficiencies before the next trial opportunity. In Advarra’s recent survey, respondents revealed almost one in five sites never receive feedback, and another 34% of sites state they very rarely receive feedback on why they were or were not selected for a study.

Naturally, such communication should go both ways. By providing the opportunity for site staff to provide comments or more open-ended answers to some questions, you may yield more useful insights about the protocol, the local patient population, past recruitment successes, and more. Even when communicating rejection or non-award to a site, it can still help establish trust by clearly stating why the decision was made and freeing up that site’s resources for other studies.

About Devana Solutions

Devana Solutions is an innovative cloud-based clinical trial software company that supports real-time collaboration between central research operations professionals and decentralized clinicians serving patients in diverse communities. Our platform bridges the technology access and data divide by seamlessly and securely connecting decentralized researchers to other mission-critical clinical trial systems.

Devana Solutions is an Advarra API Gold Partner that integrates seamlessly with Advarra’s Clinical Conductor CTMS. Learn more about Clinical Conductor CTMS, Devana Solutions, and other Advarra partners.

According to the Food and Drug Administration (FDA), data should meet certain fundamental elements of quality. Whether they’re recorded on paper or electronically, source data should follow ALCOA-C, an acronym used in clinical research for: 

  • Attributable 
  • Legible 
  • Contemporaneous 
  • Original 
  • Accurate 
  • Complete 

If these best practices for source documentation aren’t followed, there is no valid evidence the test article is safe and effective. 

What does each element of ALCOA-C mean, and how are the principals implemented differently for data originally collected on paper versus first recorded electronically? 

Attributable 

Is it traceable to a person, date, and subject visit? 

When documenting data on paper, every written element needs to be traced back to the authorized individual responsible for recording it. This requires a signature or initials, the date, and an identifier to a subject visit. Similarly, if something needs to be changed on the record, the change must be initialed, dated, and explained.  

Audit trails in an electronic system make it clear who created a record, when it was created, who made a change, when the change was made, and the reason a change was made. A compliant system will automatically track this information and enable electronic signatures. Data is attributable to a unique user with a secure password and role-based permissions, preventing unauthorized users from making changes. 

Legible 

Is it clear enough to read? 

Everything written on paper must be easy to read and recorded in a permanent medium – not in pencil. Handwriting must be clear to reduce the likelihood of transcription errors and allow accurate study re-creation. 

Electronic source records typically solve the illegible handwriting problem, because data and information are presented in a clean and standardized format. Electronic submissions ensure there is no room to second guess what number or letter someone actually means. 

Contemporaneous 

Was it recorded as it happened? 

Data should be recorded, signed, and dated at the time of trial conduct, rather than risk an individual recalling the wrong information from memory. On paper, data needs to be documented in real time and dated with the current date – no pre- or post-dating. 

Automatic date and time stamps support this every time clinical data is entered, edited, or modified in an electronic system with appropriate controls in place to fully support 21 CFR Part 11 compliance. 

Original 

Is it the first place data is recorded? 

The source is the earliest record – the first place data is documented. If corrections or revisions need to be made, changes shouldn’t obscure prior entries. Paper source documents should be preserved and kept in their original form. 

When the first record is electronic, an audit trail can track any and all subsequent queries and changes. 

Accurate 

Are all the details right? 

It’s critical the source completely reflects true observations. This means an honest, accurate, and thorough representation of facts describing the study conduct. There will be times when source documents are incomplete, inconsistent, or wrong. If changes need to be made, modifying a paper record always needs to be done in a compliant manner. 

When the source is electronic, audit trails can provide transparency to prevent altering data in a way that is difficult to detect. Additionally, automatic edit checks can immediately alert when missing data points or out-of-range data are entered. 

Complete 

Is everything correct and up to date? 

Everyone involved in a study, including researchers and investigators, should strive to make sure data is accurate and complete. To ensure this, record data as soon as it happens. This will help prevent audit findings due to incomplete or missing data. Additionally, it will foster communication between all parties, strengthening relationships.  

Each ALCOA-C principle must be applied to both paper and electronic source data, along with the records holding the data. Serving as evidence of the events taking place during a study, source documents need to paint the full picture of what happened. Using ALCOA-C as a guide to collecting quality data in clinical trials can help ensure a test article is safe and effective. 

 

Advarra EDC allows users to build custom forms, set up edit checks, and use forms across multiple protocols to decrease duplicate data entry and error. 

 

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Clinical trial site selection can make or break a trial’s success before it even begins. The average cost to open an investigator site is estimated at $50,0001 – a price point compounding quickly when onboarding multiple sites. When you consider around 11% of sites2 fail to even accrue one participant on a given study, cost savings become a major consideration when evaluating which sites to partner with for a trial.

To ensure you’re maximizing the time, resources, and funds associated for each clinical trial, we’ve outlined essential strategies for identifying the appropriate sites, analyzing historical site performance and feasibility, and implementing better communication and tools across stakeholders.

Analyzing Selection Criteria and Site Performance to Identify Your Sites

To identify clinical research sites for a study or trial opportunities, sponsors, contract research organizations (CROs), and sites leverage different datasets. Each sponsor collects data on the trials they’ve conducted and the performance of sites they’ve engaged in the past. A CRO may have more data across more therapeutic areas than a single sponsor. A site has historical performance data of their trials across a variety of sponsors and CROs, along with experience in specific clinical areas.

Each dataset is powerful because there is a lot to learn from past site and trial performance. In which trials have sites achieved their enrollment targets? What is a particular compliance rate with a specific site, or even a particular investigator across different studies? What selection criteria may be inhibiting your trial’s success? And do you have the resources to support sites with less experience in a particular clinical research area, but a strong relationship with a specific pool of patients?

Data like this can help solidify if a site will be a good fit for your unique trial and minimize the risk in your decision. However, each study stakeholder is limited in their decision-making by the dataset informing them. According to our recent trend report, The Current State of Trial Opportunity and Selection, 83% of the polled sites are looking for new trial opportunities, and over half of sponsor and CRO respondents indicated they utilize new-to-them research sites in at least half of their studies.

Factors Influencing Site Selection

Communication is an essential part of any effective clinical research relationship, and it’s important to always engage with each site thoroughly. Even if a particular clinical research site isn’t a fit for your current trial, they may be an important partner in future studies. Building these relationships will help you down the road, and can increase transparency between stakeholders.

There is a bi-directional need for communication. Sites need to feel comfortable being honest and transparent about how they think they’ll perform on a study. And even though they’re working with a lot of sites, sponsors need to allow some flexibility in getting information for the site to highlight why they’re an appropriate site for the study. This conversation gives sites the ability to communicate where their true strengths and weaknesses are.

An open line of communication can help to improve site management and engagement in the long term. The site evaluation process is a learning opportunity for everyone involved, and processes like study feasibility questionnaires (SFQs) can prove useful for all stakeholders involved. Our trend report found sponsor organizations are generally seeking to learn about four key evaluation items when selecting a site:

  1. Experience with patient population
  2. Clinical research experience
  3. Access to patient population
  4. Historical performance of enrollment

An SFQ introduces the opportunity for sites to answer sponsor’s key questions and provide additional information, but low site response rates have contributed to frustration—only about 65% of SFQs sponsors and CROs distribute are completed and returned.3

On the other hand, sites are also frustrated by the lack of feedback. We found 83% of sites want more study opportunities, but rarely receive feedback from sponsors and CROs on why their site was not chosen. The lack of communication doesn’t help to foster site relationships, and missing insight likely contributes to low SFQ response rates.

Leveraging Technology in Site Selection

Technology is absolutely vital to a study, and you need a reliable way to store and collect data. Successful site and sponsor/CRO relationships are better enabled with tools designed to bring more insight to the conversation, while ensuring data is reproducible and properly communicated.

Oftentimes, relationships between sites and sponsors are very protocol-specific. Sponsors and CROs typically rely on an SFQ to gather site information. However, sites do not feel the SFQ allows them to properly highlight their abilities to conduct research. The sponsors rely on the SFQ and if the site doesn’t meet the criteria, they are not considered any longer. In some cases, this is in error as a follow-up conversation about the sponsor’s findings and probe of the site may find they actually are qualified and well suited to take on the study.

Communicating beyond these rigid questionnaires can allow for negotiation opportunities, potentially resulting in a highly successful site and clinical trial partner for a sponsor/CRO. The right tools can ensure mutual success, such as additional training resources, a financial feasibility analysis, and a centralized institutional review board (IRB).

It’s important to remember there is a time frame between selecting and activating a site, during which these tools can be implemented. A typical academic medical center may take up to six months on average to activate a trial, while an independent site may take 30-45 days before enrolling patients.4

Another essential step before activation is aligning on standard definitions for operational metrics — establishing common terminology when discussing how activation and trial conduct activities are proceeding. This step will optimize the workflow between all of the trial stakeholders, and can ensure the research is measured with the same set of conditions.

How Advarra can help

At Advarra, we work to advance clinical research through innovative solutions designed to leverage our industry expertise, optimizing your trial all the way from initial research to market.

To streamline site identification for your clinical trial, consider leveraging Advarra SiteIQ. The study planning tool was designed to simplify study startup by identifying suitable sites for your clinical trial using Advarra’s comprehensive database.

References:  

  1. Optimizing Clinical Research Operations with Business Analytics, https://support.sas.com/resources/papers/proceedings11/204-2011.pdf 
  2. Coalition for Clinical Trials Awareness, http://cctawareness.org/about-us/ 
  3. Trend Report: The Current State of Trial Opportunity and Selection 
  4. JCO Oncology Practice, https://ascopubs.org/doi/full/10.1200/OP.19.00325

Is the clinical research industry winning or failing at innovation? It probably depends on who you ask and likely full of nuance. In the past decade, trials have evolved to include not just traditional drugs and medical devices, but also innovations like cell and gene therapies, wearables, and more. As exciting as that growth may be, it invites more complexity. Despite the fast pace of medical innovation, the lack of consistency between technology systems managing these advancements ultimately inhibits research progress.  

As the clinical research industry has evolved, so have the many vendors looking to solve point solutions. While some have legitimate use cases and widespread adoption, the sheer volume have created a new bottleneck to achieving innovation in clinical research. In the funnel of transformative solutions, we see too many solutions stuck in pilot mode after a key case study or two, with few solutions trickling into transformative and driving toward faster treatments. 

As sponsors have adopted technology designed to support automation, document management, and data collection, research sites have also continued to grow more sophisticated in their approach to data and operations management. Between the required sponsor platforms and their internal systems, that is a lot of redundancy, duplicative workflows, frustrated staff, and wasted time.  

Site staff are spending between 10-20+ hours per week just on data entry into sponsor-provided systems. They indicate at least half of this is duplicate data that is otherwise already tracked in sites’ own systems. Imagine if we declared every Monday “Duplicate Data Entry Day” for all sites everywhere. Has innovation really succeeded in clinical research if this is the state we’re currently in? I believe our industry needs an intervention. 

While the numbers above don’t inspire confidence, I believe we are on a path to success, allowing for more innovation and site centricity. The good news is people are talking about the gaps in innovation and site centricity now. Sponsors and sites are more aware and have improved collaboration to address these challenges. More notably, discussion is reversing the pendulum from continued release of more technology solutions, to connecting them to do better with less. Here are a couple of shared ideas, their downfall, and a proposed alternative. 

Idea: Commit to single platform solution 

Challenge: If there were a single platform vendor across all stakeholders, admittedly it would be easier to communicate and exchange information across all stakeholders. However, like all monopolies, it would extinguish innovation due to lack of competition. The solution is not to consolidate all sponsor tech to a monolith single company. We need new technology and new companies to push the envelope, drive innovation, and think differently to keep us moving forward as an industry. 

Idea: Use only site technology instead of sponsor technology 

Challenge: Without some sort of standardized data and visibility at the sponsor level, sponsors would not get on board, and it would make their work impossible. The solution is not to completely flip the switch and have sponsors no longer choose any technology and instead log into each site’s technology. By completely pushing to the other end of the spectrum, we add cost and burden to the place where it directly drives up costs for the patient in the end.  

How can we Innovate While Reducing the Burden on Sites and Improving Outcomes for Sponsors? 

Our answer is to centralize, standardize, and integrate. Centralize sponsor/site collaboration into a single portal and integrate as many touchpoints as possible. Create and use standards wherever we can.  

How can we do this? Let me explain. 

We need to recognize there are items that need to be consistent on the sponsor side, as well as on the site side. There are many touch points between sponsors and sites, and everything must work together for a trial to be successful. For example, the sponsor needs clinical data in a format consistent across sites to run statistical analysis and drive to expedient FDA approval.  

However, does this mean if we want source data directly from the electronic health record (EHR) system, the sponsor chooses the site’s EHR? Of course not. This is where standards become the key to bridging the two sides. Sites have their own systems for source data entry (including, but not limited to, the EHR) and sponsors have their own systems for clinical data such as electronic data capture (EDC), a central clinical data warehouse, etc. CDISC has paved the way for this model through ODM, CDASH, and CDISC standards. 

The same process applies, and is more commonly used, for regulatory documents. Sponsors use their own electronic trial master file (eTMF) system across all studies to remain compliant. Sites use their own electronic investigator site file (eISF) system for the same reason. The solution is not for sponsors to require sites to use a sponsor-approved eISF. That is not best practice for the same reason a sponsor wouldn’t use a separate site eTMF for a single part of a study. 

Advarra has made headway on this through recent launch of the Secure Document Exchange, driven by the Advarra Site-Sponsor Consortium. CDISC is now working within the consortium to develop standards much in the same way, so we can enable integrations across the board.  

We are highly orchestrating these two use cases and working very closely with sites, sponsors, CROs, and CDISC to make the connected research ecosystem a reality, continuously forging our way down this highly collaborative path empowered by integrating both sides of the clinical research spectrum. 

When we work collaboratively, there are many more use cases providing opportunities to ease sites burden. Technology integration is key to enable site-centricity at scale. 

Though it may not be well known among many industry colleagues from sponsors and CROs, sites invest in their own technology. It’s true – most sites now leverage a clinical trial management system (CTMS) to manage their research operations. These systems, built specifically for sites, help them across their entire research portfolio, regardless of the sponsor. In the past few years, additional site technology has been more widely adopted, including eReg, eSource, televisit capabilities, eConsent, and more. This is important context for why sites are pushing back on using any sponsor-driven tools duplicating these same capabilities but only for a single trial.  

Our article, It’s Time for Sites to ‘Bring Your Own Technology’ (BYOT) outlines why site technology is so important for sites.  

Now, let’s fast forward a few years (or decades, depending on your level of optimism), and imagine a site has technology they have optimized, trained all of their staff on, and automated across all of their operations. Imagine the site can go to their own technology and see all of the items they need to tackle for all of the studies they are assigned to, watch refresher training videos on protocols and the technologies they use, document protocol or participant progress once and have it automatically sync with sponsor systems, and trigger next steps and downstream billing workflows. Imagine a new innovative technology is developed, and a sponsor wants to use it for new trials. If it’s integrated in with that same site tech platform, the burden is drastically lower on the sites and thus can be rolled out and adopted with key stakeholders (the sites) to maximize the technology’s potential. 

To make this a reality, we need to forge a new path of site-centric integrations, standards spanning stakeholders and centralizers of clinical research. We are working hard to enable site-centric integrations at scale through the Advarra Site-Sponsor Consortium and through our API Partner Program. Both are aimed at leveraging existing site technology, and provide value to both sites and sponsors through integrations. 

I truly believe if we can integrate with site technology and standardize integrations, we can innovate much faster as an industry. Join us in helping create a better-connected future. 

Informed consent is one of the central protections the regulations provide to research subjects. This tip sheet outlines the regulatory requirements for research informed consent forms (ICFs).  The regulatory requirements for informed consent will vary depending upon which regulations apply to the conduct of a particular study.

Note: Individual institutional review boards (IRBs) may have their own specific policies regarding how ICFs should be formatted, how to address certain regulatory criteria, and other considerations. Always check with your IRB of record to confirm you understand its requirements.

Part C of the Belmont Report notes that respect for persons requires subjects be given the opportunity to choose what will or will not happen to them. The informed consent plays a key role in this respect and should adhere to three main elements:

  • Information
    • Provide information to help potential subjects understand the study’s risks and benefits to help them decide whether they wish to participate in the research
  • Comprehension
    • Provide information in a way that is meaningful to potential subjects. Investigators should be able to make certain the potential subject truly understands the presented information
  • Voluntariness
    • Consent to participate in research is valid only if given voluntarily. To facilitate this, avoid coercion (i.e., threat of harm) and undue influence (i.e., excessive, improper, and/or inappropriate reward) when informing potential subjects about the study

Language and Reading Level

Ensure the ICF is written in a way that will make sense to the study’s specific subject population. U.S. regulatory agencies recommend written ICFs contain easy-to-read and understandable information so a lay person can make an informed decision about participating in a study.

Generally, the aim is for a sixth to eighth grade reading level; however, it is recognized that some consent forms require technical language which will make this level unreachable. Before proceeding with a specific approach, make sure it is appropriate for your study. Flesh-Kincaid readability tools can help with grade level assessments.

The consent form cannot include any exculpatory language. Exculpatory language is that which has the general effect of waiving or appearing to waive a subject’s legal rights, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability from negligence. The Food and Drug Administration (FDA) website has guidance titled Exculpatory Language in Informed Consent, which includes examples.

If you are targeting a community that includes a sizable number of non-English speakers: Have translated ICFs available when English is not a potential subject’s first language. Whenever possible, have translated ICFs available ahead of time so you don’t have to wait to have the consent conversation with a potential subject.

Should an unexpected non-English speaking subject arrive before a translated study ICF is available, the regulations permit providing an oral presentation of the informed consent information along with a short form consent document and a written summary of the oral presentation. To access Advarra’s translated short forms in over 20 languages, login to the Advarra CIRBI Platform and select “Reference Materials.”

If your study will enroll children younger than the legal age of majority in your area: Consider whether assent documents are appropriate (in addition to the standard ICF) and/or whether it may be suitable to add an assent signature line to the standard ICF. Most IRBs identify age ranges when assent may be necessary, so check with your IRB regarding their standards.

Advarra’s IRB requires an assent statement (separate signature block in the standard ICF) for subjects who are minors and old enough to understand the ICF as written (approximately 14-17 years old). An assent form is needed when younger subjects (approximately 7-13 years old) need the information presented in age-appropriate language. The IRB doesn’t typically require subjects 6 years old or younger to sign an assent statement or assent form.

Basic Elements of Informed Consent

The regulations are very specific regarding what to include in the ICF and what to exclude. The basic elements of informed consent are mandated by the Common Rule (i.e., Department of Health and Human Services [DHHS] Office of Human Research Protections [OHRP] regulations) and FDA regulations at 45 CFR 46.116 and 21 CFR 50.25 respectively.

To remain compliant with the International Council of Harmonization’s good clinical practice guidelines (ICH-GCP) for studies conducted outside the U.S., also consider the ICH basic elements. Note that many (though not all) ICH elements are well-aligned with U.S. requirements.

Remember that it is only necessary to include the regulatory elements applicable for a given study. For example, an FDA regulated study would not need to comply with the Common Rule unless there is also DHHS funding involved.

FDA and Common Rule Elements of Informed Consent

  • For research regulated by the Common Rule: ICF should begin with a concise and focused presentation of the key information most likely to assist a prospective subject in understanding the reasons why one might/might not want to participate in the research
  • Purpose of Research:
    • A statement that the study involves research
    • An explanation of the purposes of the research
    • The expected duration of the individual’s participation
    • A description of the procedures to be followed
    • Identification of any experimental procedures
  • Risks and Discomforts: A description of any reasonably foreseeable risks or discomforts to the subject
    • Cross-reference ICF language with risks in the protocol document and product information (i.e., Investigator’s Brochure)
  • Benefits: A description of any benefits to the subject (or to others) which may reasonably be expected from the research
  • Alternatives: Disclosure of appropriate alternative procedures or courses of treatment (if any) that might be advantageous to the subject
  • Confidentiality: A statement describing the extent (if any) to which confidentiality of records identifying the subject will be maintained
    • If applicable, this section should also include a statement noting the possibility that the FDA may inspect the records
  • Compensation for Injury: Only required for research involving more than minimal risk: An explanation as to whether any compensation and/or any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained
  • Research Questions: An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject
  • Voluntary Participation: A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled
  • ClinicalTrial.gov information: Applicable for Phase 2 and later studies, must be verbatim as follows: A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.

Additional Elements of Informed Consent

Note: These elements are instance-specific, and their applicability is at the IRB’s discretion. To help streamline the review process, sponsors and sites should communicate with the IRB regarding the circumstances informing the addition or omission of these elements.

  • A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable
  • Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent
  • Any additional costs to the subject that may result from research participation
  • The consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject
  • A statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject
  • The approximate number of subjects involved in the study
  • For all NIH-funded research, and any other research for which a Certificate of Confidentiality (CoC) has been issued, a description of the CoC
  • If genetic testing results will be returned to the site and/or the subject, include information about the Genetic Information Nondiscrimination Act (GINA)
  • If infectious diseases will be tested for (i.e., tuberculosis [TB], HIV, hepatitis [B, C], COVID-19), a statement that results may be required by law to be reported to local health authorities 
  • For research regulated by the Common Rule: For research with identifiable private information or identifiable biospecimens, a statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and the information or biospecimens could then be used for future research studies or distributed to another investigator for future research studies without additional informed consent
    • OR a statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
  • For research regulated by the Common Rule: A statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will/will not share in this commercial profit
  • For research regulated by the Common Rule: A statement regarding whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions
  • For research regulated by the Common Rule: For research involving biospecimens, whether the research will (if known) or might include whole genome sequencing

For more information on informed consent, review: 21 CFR 50.20, 21 CFR 50.25, 45 CFR 46.116, 45 CFR 46.117, ICH Good Clinical Practice (GCP), FDA Information Sheet: Informed Consent, OHRP Informed Consent FAQs, Belmont Report, PlainLanguage.gov, NCCN Informed Consent Language Database

Note: This article was originally published April 14, 2022, and has been updated to include new and clarifying information. 

The Food and Drug Administration (FDA) is the federal entity in the U.S. charged with (among other things) “ensur[ing] that safe and effective drugs are available to improve the health of the people in the United States.”   

Before the FDA permits a pharmaceutical drug product to be lawfully marketed, sponsors are required to submit information about the product’s safety and efficacy so the FDA can determine: 

  • “Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks. 
  • Whether the drug’s proposed labeling (package insert) is appropriate, and what it should contain. 
  • Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.” 

The FDA requires the data for these assessments to generally come from animal studies and clinical investigations1 of the investigational product(s)2.   

In addition to granting new drug approvals, the FDA is also the gatekeeper for whether a sponsor can conduct the clinical investigations necessary to gather the data required for drug approval. In other words, the FDA also regulates whether investigational products may be manufactured, shipped, and administered to human subjects who participate in clinical investigations.   

This blog focuses specifically on the investigational new drug application (IND)3 and when investigational drugs may be manufactured, shipped, and administered in clinical investigations. 

When Does an IND go into Effect? 

An IND may only be used in a clinical investigation after the following steps are completed: 

  1. The sponsor of the investigation submits an IND to the FDA; 
  2. The IND goes into effect; and 
  3. The sponsor has received institutional review board (IRB) review and approval of a clinical investigation in accordance with FDA regulations at 21 CFR parts 50, 56, and 312. (21 CFR 312.40(a)) 

The FDA will send the sponsor an “IND Acknowledgement” letter or email after the sponsor submits an IND. This letter will include the date the FDA received the application. This is the date the sponsor should use to calculate when the IND goes into effect.    

The IND goes into effect:  

  • 30 days after the FDA receives the application, unless the FDA notifies the sponsor the investigations described in the IND are subject to a clinical hold under 21 CFR 312.42; or  
  • On earlier notification by FDA indicating the clinical investigations in the IND may begin (21 CFR 312.40(b)) 

The period between when the FDA receives the IND and when it goes into effect is often referred to as the “30-day hold.” It’s at the end of that period, unless one of the above criteria is met, when an IND automatically goes into effect. 

When can a Sponsor Submit to the IRB? 

Sponsors may submit research to be conducted under an IND to an IRB at any time before or after the IND is in effect. However, the research itself (including study-specific recruitment) may not begin until after the IND is in effect, even if the IRB has approved the research. (At Advarra, the IRB approval notice notes this requirement.) 

When can a Sponsor Ship an Investigational New Drug? 

Once an IND is in effect, a sponsor may ship the investigational product to the investigator(s) named in the IND application. The regulations at 21 CFR parts 50, 56, and 312 do not require IRB approval (in addition to the IND being in effect) before shipping the investigational product. 

When can an Investigational New Drug be Administered? 

A clinical investigation involving an investigational product may not begin until after both IRB review and approval have been obtained and the IND is in effect. This means in general, an IND can only be administered after both the IND is in effect and an IRB has reviewed and approved the research. 

What About Amendments? 

Sponsors are required under the IND regulations (21 CFR 312) to amend the IND as needed “to ensure the clinical investigations are conducted in accordance with protocols included in the application.” There are three types of amendments specified in these regulations:  

  • New protocols 
  • Change in protocol 
  • New investigator 

According to the regulations, sponsors must submit an IND Change in Protocol Amendments for “any change in a Phase I protocol that significantly affects the safety of subjects or any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study.” (21 CFR 312.30(b)(1))     

Examples of protocol changes requiring an IND amendment include, but are not limited to: 

  • Any increase in drug dosage or duration of exposure of individual subjects to the drug beyond the current protocol 
  • Any significant increase in the number of subjects under study 
  • Any significant change in the design of a protocol (such as the addition or dropping of a control group) 
  • The addition of a new test or procedure intended to improve monitoring for, or reduce the risk of, a side effect or adverse event (AE) 
  • The dropping of a test intended to monitor safety  

Any of the categories of IND amendments may be implemented: 

  • After FDA submission 
  • After the IRB of record reviews and approves the IND amendment (i.e., new protocol, change in protocol, and/or new investigator)  

Note a protocol change intended to eliminate an apparent immediate hazard to human subjects may be implemented immediately, provided the sponsor promptly: 

  • Submits an IND Change in Protocol Amendment to the FDA after the change is implemented 
  • Notifies the IRB of record of the change in accordance with the IRB’s policies and procedures 

Can Recruitment Activities Begin During the 30-day IND Hold? 

In general, no study-specific activities may begin before the IND is in effect and an IRB has reviewed and approved the research. This means study-specific activities such as advertising, eligibility screening, and seeking informed consent are prohibited during the 30-day IND hold.  

The IND waiting period can be particularly challenging in Phase I research, where timelines are especially tight. When appropriate, consider speaking with your IRB to understand what recruitment-related activities might be permitted (or precluded) during the 30-day IND hold period.  

It’s important to bear in mind: the 30-day IND hold is an FDA requirement. IRBs do not have the authority to change these legal requirements. It may be helpful to contact FDA for specific information regarding its IND review.  

 

References:

1Clinical Investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice. (21 CFR 312.3(b)) 

2 Investigational new drug means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms “investigational drug” and “investigational new drug” are deemed to be synonymous for purposes of this part. (21 CFR 312.3(b)) 

3 IND means an investigational new drug application. For purposes of this part, “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New Drug.” (21 CFR 312.3(b)) 

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